Special considerations with psychotropic treatment

Concordance, adherence and compliance with psychotropics

The nature of the clinician-patient relationship is evolving. In recent years, patients have been more willing to
have an active role in the management of their illness, have had a desire to be better informed and, often,
have had a wish to be an equal partner in a shared decision-making process. This is referred to as a
collaborative process between a client and a practitioner, both of whom recognise each other as experts and
work together to exchange information and clarify values to arrive at health care decisions. Consequently, the
terms compliance and adherence, associated with the more traditional clinician-patient alliance, have come
to be viewed as possibly condescending and inappropriate. Compliance is defined as the consistency and
accuracy with which someone follows a prescribed regimen, while adherence refers to the extent to which a
patient continues an agreed mode of treatment without close supervision. Both terms are seen as emphasising
an unequal partnership and diminishing the importance of self-care and autonomy. The term concordance is
now preferred as it indicates a more equal alliance, involving a negotiated shared agreement between a
clinician and a patient concerning treatment regimen(s), outcomes and behaviours.

Forgetting to take or deliberately not taking medications as prescribed is a common occurrence with all
chronic conditions. Psychiatric illness is no exception to this with treatment nonconcordance rates of up to
69% reported. For most chronic conditions, regardless of whether it is a physical or mental illness, failure to
take medications as prescribed has a serious impact on long-term outcomes. It increases the likelihood of
illness relapse, possibly leading to rehospitalisation, and risks greater disability and poorer quality of life with
likely devastating consequences on family and others. It is critical to explore patient attitudes towards taking
their medications, allaying fears and clarifying misconceptions. There are many possible reasons why
patients do not take their medications as prescribed and unless these issues are dealt with treatment will
invariably fail.

Treatment is more likely to be effective if clinicians and patients have a good working relationship and they
take joint responsibility in agreeing to treatment regimens. For this to occur, the patient must be actively
involved in the negotiation and feel ownership of the decision-making process. The partnership agreement
should include issues such as patient concordance with evidence-based treatment plans, and an understanding
by both the patient and the clinician of the advantages of taking their medication and the disadvantages of
prematurely reducing or ceasing medication.

Some measures to improve medication concordance are described below.

Educate the patient:

Determine the patient's understanding of, and attitude to, their illness and its treatment. Encourage
them to express any fears or concerns they have, and talk about these. Discuss the goals of treatment,
how they will be achieved, and the advantages and disadvantages of particular approaches to treatment.
Encourage the patient to actively participate in the treatment and personalise it in terms the patient can
understand and respond to.
Tell the patient the approved/generic and brand/trade names of the medication, when to take it and what
it is expected to do. Explain the reasons for the advice and check that the patient has understood the
information.
Warn patients about potential adverse effects of the medication and explain what to do if they occur.
Provide and discuss personalised instructions, as well as standard written information such as consumer
medicine information (CMI) leaflets. CMIs are available from pharmacies and some clinical software
packages. Patients can access CMIs directly via the National Prescribing Service website [URL].
Provision of reliable accurate information is important as patients may access information about their
medication from a range of sources (eg the internet).
Include others involved in the patient's care, such as partners, family members and psychologists, when
appropriate. Confidentiality must always be maintained and the patient's consent obtained. Keep in
mind that family members and others can often influence the patient's attitude towards their
medication.
Involve the pharmacist, who can then reinforce the message to the patient and, if applicable, their carer.

Simplify treatment regimens:

Prescribe the least complex regimen that is acceptable to the patient. For example, if the properties of
 the drug enable once-daily dosing, patients are more likely to take the drug than with a three-times-a-
day regimen.
Aim for continuity of care and treatment.

Use prompts/behavioural methods to help medication concordance:

Use daily routines as prompts to remind patients to take their medication, such as with breakfast or
after brushing teeth at night.
Use cues, dose administration aids (eg blister packs), calendars or other self-monitoring tools.
Involve family or friends where appropriate.
Develop practical individualised strategies for improving treatment concordance.
Positively acknowledge treatment concordance.

Monitor medication use:

Involve a local mental health team to actively monitor and encourage concordance. Outreach services
are now provided by many private psychiatric hospitals.
Check medication use by tablet counts or by noting the regularity of prescriptions.
If symptoms fail to respond to the treatment regimen, consider the possibility of nonconcordance and
raise the issue in a nonconfrontational manner.
Ensure the patient has access to financial resources to afford the proposed medications.
Actively ask about medication adverse effects, including potentially embarrassing subjects such as
sexual adverse effects. Manage these with dose reduction, adjuvant medication or a change in
medication. Some adverse effects may be minimised by night-time dosing. Often patients attribute
symptoms, such as agitation or chest tightness, to a particular medication, when they may be due to
anxiety.

Specific concordance-enhancing interventions have been developed but are not widely available. In some
circumstances it may be appropriate to consider depot medication for treatment of nonconcordant patients
(see Schizophrenia and related psychoses: depot antipsychotics).

Informed consent in mental illness

Anyone providing mental health care must balance a duty of care to their patients against implications for the
wider society if mental illness goes untreated. When recommending a treatment to a patient, health
professionals should weigh up its potential benefits and potential adverse effects; however, clinical judgment
will be influenced by the same variety of conscious and unconscious factors that influence societal thinking.

The imbalance of knowledge between the clinician and the patient means that the patient may have little
understanding of what a particular treatment implies. However, patients often have knowledge and attitudes
about their medical condition from other sources of information, such as the internet or advice from friends or
family or other clinicians. This may influence their decision-making.

When patients with a mental illness are not a risk to themselves or others, and are competent to appreciate the
consequences of refusing or agreeing to a treatment regimen, they have the right to decide what medications
they do or do not take. They also have a right to assume that any treatment will be undertaken only with their
permission. The act of consulting a clinician does not necessarily imply such permission has been given. The
acceptability of a proposed treatment should therefore be a matter for negotiation between the clinician and
the patient. The clinician is obliged to provide the patient with the information that is necessary for the
patient to make an informed choice. There are no absolute standards about how much information needs to be
provided. The degree of disclosure relates to the condition being treated, the patient's state of mind and the
likely consequences of the proposed treatments. However, some useful questions to consider are:

Are the patient's mental processes sufficiently robust to allow the patient to make a reasonable
assessment of the relevant issues?
If you believe the answer to that is ‘no’, then do you and your patient need the protection that the
mental health legislation in your state or region offers?
If the answer is ‘yes’, is there any information about the treatments you are suggesting that you would
like to hold back because that information would decrease the patient's enthusiasm for the proposed
line of care? If so, that is the very information you must be sure to provide to the patient, along with the
other information about the diagnosis, as well as the positive and negative effects of the treatments you
are suggesting. Otherwise, the patient is not making an informed choice.
How should you document your negotiation?
In many institutions, the outcomes of negotiations over treatments are documented using specific
consent forms. However, signing of a consent form may not be adequate and ensuring that the
discussion about treatment is fully documented in the patient's notes is always a wise precaution.
Dependence, tolerance and the discontinuation syndrome
It is not uncommon for patients to need higher doses of their psychotropic drugs over time. This may be due
to the changing nature of their illness, that is, it is becoming more treatment resistant, or this may be due to
the development of tolerance to the drugs. Tolerance is a physical state whereby, after repeated
administration, a given dose of drug produces a decreased effect due to adaptive changes to the target organ
system. Increasingly larger doses must be taken to obtain the effects observed with the original dose. For
instance, patients may respond to a standard dose of an antidepressant but after a number of months or even
years, their symptoms of depression recur. Increasing the dose of the antidepressant may once again result in
a remission of symptoms. The same effect has been observed, but less commonly, with antipsychotic drugs.

Some psychotropic drugs, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and
noradrenaline reuptake inhibitors (SNRIs), are associated with a discontinuation (withdrawal) syndrome.
This occurs due to the development of a physiological dependence on the drug, and is distinct from drug
dependence as defined below. The discontinuation syndrome is usually not severe, but antidepressants that
have a short half-life can be difficult to stop (eg paroxetine, venlafaxine). Discontinuation symptoms include
an influenza-like syndrome with agitation, headache, fatigue and dysphoria. Therefore a very gradual tapering
of these drugs is advised if possible (see Antidepressant discontinuation).

All drugs that cause dependence act to increase the tone of the mesolimbic dopaminergic (‘reward’)
pathway. Drug dependence is a maladaptive pattern of drug use, leading to clinically significant impairment
or distress, and is characterised by tolerance, discontinuation symptoms, salience, cravings and continued use
despite an awareness of adverse consequences. Patients behave as if the effects of the drug are needed for
continued wellbeing. The term addiction is best used synonymously with dependence. The term drug abuse is
applied when serious social and interpersonal consequences occur, such as drink-driving and crime. Most
psychotropic drugs do not cause dependence and are usually not abused unless the individual is predisposed.
Certain psychotropic drugs are at greater risk for abuse and dependence, including benzodiazepines,
psychostimulants and certain hypnotics such as zolpidem. A careful history, including from a significant
other, can be helpful in identifying patients with drug dependence, and a urine drug screen when assessing
patients.

Benzodiazepines are associated with tolerance, discontinuation symptoms and dependence. The short-acting
benzodiazepines (eg alprazolam) are most likely to cause dependence. Be alert for patients who appear to
need larger doses to get the same effect, and be aware that sudden withdrawal of benzodiazepines may be
associated with a discontinuation syndrome, which can be severe and include seizures. For management of
benzodiazepine withdrawal, see Benzodiazepines, zolpidem and zopiclone: problem use. Patients with a
current drug use disorder, especially involving alcohol or opioid use, or a history of such a disorder, are at
particular risk of developing benzodiazepine dependence. Clear communication is required between the
general practitioner and other clinicians who may occasionally care for these patients, such as practice
partners, locums and emergency department staff.

If a drug use problem is identified it is important to investigate the use of other substances because multiple
drug use problems are very common (see Alcohol and other drug problems). Many patients with psychiatric
disorders use drugs such as alcohol, cannabis and amphetamines. Psychiatric disorders also occur with
greater frequency among patients with problem drug use. The most commonly associated are depression,
anxiety disorders (particularly social phobias) and personality disorders.

Further reading

Cami J, Farre M. Drug addiction. N Engl J Med 2003;349(10):975–86. [URL]

Psychotropic treatment in older people

Psychotropic drugs should be used with caution in older people because their use is often complicated by the
physiological changes that occur with ageing, multiple coexisting pathologies, and other drugs the older
patient is likely to take. Drug regimens should be kept as simple as possible to aid concordance and avoid or
minimise drug interactions. The starting dose of a drug in older patients should usually be at the lower end of,
or below, recommended ranges, and dose increases should be gradual and reviewed regularly (ie start low, go
slow and monitor frequently). However, it must always be remembered that each older patient is an
individual and therapeutic decisions should not be overly influenced by chronological age alone.

Older patients are often taking multiple drugs from a variety of clinicians and communication between
clinicians should occur. It is important that the patient's complete medication regimen is reviewed
periodically to minimise the risk of drug interactions and the unnecessary continuation of medication. The
patient's general practitioner is well placed to do this or the patient may be eligible for a Home Medicines
Review [Note 1]. Education of patients about their treatment is essential.

Clearance of drugs in older people may be reduced by kidney or liver impairment and decreased cardiac
output. This may lead to increased steady-state drug concentrations. See also Kidney disease and Liver
disease in ‘Psychotropic treatment in patients with concurrent diseases’. The half-life of lipid-soluble drugs is
increased because of a relative increase in the ratio of adipose tissue to lean body mass in older people.

Older people are more vulnerable to adverse effects and toxicity from many psychotropic drugs. In particular,
any drug or combination of drugs with anticholinergic properties (eg tricyclic antidepressants [TCAs],
antiparkinsonian drugs, sedating antihistamines, some antipsychotics) can precipitate a central anticholinergic
syndrome characterised by confusion, hallucinations and central excitation (see Delirium).

Psychotropic drugs with alpha-adrenergic blocking activity (eg TCAs) can cause orthostatic hypotension,
which is particularly significant in older people. It increases the risk of falls and fractures. Older people are
especially vulnerable to ataxia, falls and injury, memory loss and cognitive impairment from
benzodiazepines.

Confusion, lethargy or worsening of psychosis or dementia may be manifestations of hyponatraemia, which

can be caused by most psychotropic drugs. The most commonly implicated are antipsychotics,
carbamazepine, selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake
inhibitors (SNRIs).

There are studies that suggest there may be a small increased risk of stroke in older people who are treated
with antipsychotics. The risk is slightly greater in patients treated with second-generation antipsychotics
compared with first-generation antipsychotics and in patients with dementia compared with patients without
dementia.

See also Insomnia: management for older people.

Note 1: For information on Home Medicines Reviews, see the Pharmacy Guild of Australia website.

Psychotropic treatment in patients with cardiovascular disease

Patients with psychiatric illness have an increased risk of death from cardiovascular disease. It is therefore
important that their general medical health is well managed. This includes attention to cardiovascular risk
factors such as diet, exercise and smoking.

When prescribing for people with cardiovascular disease and mental illness, it is important to consider not
only the risks of the drugs, but also the risk profile of the patient. A baseline electrocardiogram (ECG) may
therefore be prudent in a variety of circumstances.

Psychotropic drugs may contribute to increased cardiovascular morbidity and mortality. This may be through
indirect effects (eg hypotension or metabolic disturbances secondary to antipsychotics) or through a direct
effect on the heart (eg tricyclic antidepressants [TCAs] can be cardiotoxic). TCAs are particularly dangerous
if taken in overdose or if there is underlying cardiovascular disease. In these situations they can cause serious
arrhythmias and be fatal. Clozapine has been linked with acute myocarditis early in treatment and
cardiomyopathy, which may occur after long-term treatment. For discussion of clozapine monitoring
requirements, see Treatment-resistant schizophrenia: clozapine.

Many antipsychotics and TCAs can prolong the QTc interval. This can lead to life-threatening arrhythmias
(see Management of antipsychotic adverse effects: QTc interval prolongation). Lithium can also cause ECG
changes and arrhythmias (sick sinus syndrome).

Benzodiazepine discontinuation can cause palpitations. Initiation of selective serotonin reuptake inhibitors
(SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) may temporarily increase anxiety and
cause palpitations.

Orthostatic hypotension is an adverse effect of many antipsychotic drugs (see Table 8.21) and TCAs.
Monoamine oxidase inhibitors (MAOIs) lower blood pressure and cause postural symptoms. When tyramine-
containing foods are consumed by patients who are prescribed an irreversible nonselective MAOI, a sudden
rise in blood pressure may result. This may lead to severe headache, stroke and can be fatal. For information
on foods to avoid in patients taking irreversible nonselective MAOIs, see Appendix 8.3. Antidepressants that
have a noradrenergic effect, such as the SNRIs and reboxetine, can also mildly elevate blood pressure.
The interactions of psychotropic drugs may also have adverse effects on the management of cardiovascular
disease. For example, drugs that inhibit cytochrome P450 (CYP) 1A2 (eg fluvoxamine) or induce CYP3A4
(eg carbamazepine) may alter the anticoagulant effects of warfarin. Similarly, cardiovascular drugs may
interact adversely with psychotropic drugs. For example, diuretics, angiotensin II receptor blockers and
angiotensin converting enzyme inhibitors reduce the clearance of lithium.

Psychotropic treatment in patients with epilepsy

Patients with epilepsy often develop psychiatric symptoms and may require treatment with psychotropic
drugs. Adequate doses of antiepileptic drugs must be maintained in all patients and serum concentrations
should be monitored.

Care is needed when prescribing antipsychotic drugs to patients with epilepsy as many lower the seizure
threshold. Clozapine has the greatest potential for inducing seizures, especially at doses more than 600 mg
daily. All antipsychotics may alter the electroencephalogram (EEG).

Most antidepressants lower the seizure threshold and in overdose all can produce seizures. In therapeutic
doses in patients with epilepsy, particular risks are evident with the TCAs and mianserin. However, there are
animal and human data suggesting SSRIs may reduce the risk of seizures, an area under investigation at
present.

At usual therapeutic serum concentration, lithium is unlikely to induce seizures but they may occur with
overdose.

Where benzodiazepines (eg diazepam, clobazam, clonazepam) are used in the management of epilepsy,
further use of benzodiazepines for the management of anxiety or insomnia should generally be with the same
drug used for epilepsy, modifying the dose or time of administration if necessary.

As some antiepileptic drugs interfere with the metabolism of psychotropic drugs, and vice versa, be aware of
interactions and the need to increase or decrease the dose according to patient response.

For a discussion of the use of antiepileptic drugs in patients receiving electroconvulsive therapy (ECT), see
ECT and psychotropic drugs.

See also Epilepsy in the Neurology guidelines.

Psychotropic treatment in patients with kidney disease

Lithium is almost entirely dependent on excretion by the kidneys for its elimination and the serum
concentration of lithium will rise when there is significant kidney impairment. In fact a rise in serum lithium
concentration may be an early sign of kidney impairment and may occur before a change in the estimated
glomerular filtration rate (eGFR). A carefully collected 24-hour creatinine clearance is a much more accurate
test of kidney function and should be considered whenever kidney impairment is suspected. Referral to a
renal physician may also be appropriate.

Lithium can quite often be continued in patients with mild or moderate kidney impairment, but dose
adjustment is required. It is advisable that the lithium serum concentration is maintained at the minimum
therapeutic concentration to minimise the risk of lithium toxicity. In general, lithium should be avoided or the
dose should be modified in patients with severe kidney impairment. However, the risk of recurrence of
bipolar I disorder can be high after lithium cessation in a patient who has been well on lithium for many
years. The harms and benefits of treatment with lithium must be carefully weighed and discussed with the
patient and their significant others. Close liaison with a renal physician is recommended. If lithium is
continued, lithium serum concentration should be monitored more frequently and kidney function should be
reviewed regularly (see Prophylaxis of bipolar disorder: lithium). Excessive dosing may cause lithium
toxicity and impair kidney function further.

Dehydration and drugs that may reduce the clearance of lithium (nonsteroidal anti-inflammatory drugs
[NSAIDs], angiotensin II receptor blockers, angiotensin converting enzyme inhibitors and diuretics) must be
avoided in patients with kidney disease. The concurrent use of other potentially nephrotoxic drugs should be
undertaken cautiously.

Amisulpride, paliperidone and the hydroxylated metabolites of TCAs are also excreted by the kidneys and
dose reductions are appropriate in patients with kidney impairment, especially those with advanced kidney
disease. In severe kidney impairment, there is an increased sensitivity to the central nervous system effects of
benzodiazepines, so use a lower initial dose and increase slowly.
Further reading

Adam WR. Utility, or not, of estimates of glomerular filtration rate in modifying drug dosage, with particular
reference to enoxaparin. Intern Med J 2012;42(4):463–6. [URL]

Faull R, Lee L. Prescribing in renal disease. Aust Prescr 2007;30(1):17–20. [URL]

Psychotropic treatment in patients with liver disease

The liver is the major site of drug metabolism and the elimination of many drugs is impaired in patients with
acute or chronic liver dysfunction. Routine measurement of liver biochemistry is a poor guide to the capacity
of the liver to metabolise drugs and it is not possible to predict the extent of impairment of drug metabolism
in the individual patient.

Care should be taken when prescribing drugs to patients with significant liver disease. If the drug is known to
be metabolised by the liver, the dose should be reduced or the dosing interval lengthened. Repeated
assessment of patients with significant liver disease should be undertaken when they are on psychotropic
drugs, looking particularly for adverse effects.

Psychotropic treatment in patients with diabetes

Weight gain induced by some psychotropic drugs can increase the risk of diabetes. Depressed patients may
put on weight as they recover, but this gain may also be an effect of antidepressants, especially mirtazapine
and TCAs. Some patients gain weight while taking SSRIs. Lithium and sodium valproate are also associated
with increased weight. Both first- and second-generation antipsychotics, especially chlorpromazine,
clozapine, olanzapine and quetiapine, can induce weight gain. They can also cause hyperglycaemia. Some
psychiatric conditions, such as schizophrenia and bipolar disorder, are associated with an increased incidence
of diabetes independent of the effects of drugs.

Regular monitoring of patients at risk of diabetes is required, especially if they are being treated with an
antipsychotic drug (see Weight gain and other cardiometabolic effects for monitoring requirements). SSRIs
are possibly the least likely of the antidepressants to interfere with diabetic control.

Further reading

Keks NA, Hope J. Long-term management of people with psychotic disorders in the community. Aust Prescr
2007;30:44–6. [URL]

Psychotropic treatment in patients with other diseases

In patients with obstructive airways disease, sedatives should be used cautiously as they compromise the
respiratory drive. Benzodiazepines should be avoided in sleep apnoea as they may relax the airway further
and exacerbate already obstructed airflow.

Larger doses of drugs with marked anticholinergic properties (eg chlorpromazine, clozapine, olanzapine,
TCAs) may precipitate narrow angle glaucoma or urinary retention. They may also decrease bronchial
secretions and exacerbate pulmonary disorders.

Psychotropic treatment in people who smoke

Tobacco smoking in patients with a mental illness is common and occurs at a higher rate than in the general
Australian population. Smoking cessation should be particularly encouraged in patients with a mental illness
as smoking increases their risk of developing cardiovascular and other smoking-related diseases and may
impact their illness and its treatment.

Tobacco smoke contains polycyclic aromatic hydrocarbons that induce some hepatic enzymes (eg
cytochrome P450 [CYP] 1A2). This can significantly reduce the plasma concentration of some hepatically
metabolised psychotropic drugs such that higher doses are required than in nonsmokers. When patients stop
smoking, it can take over a week for enzyme activity to return to normal and for the plasma concentrations of
affected drugs to rise, necessitating a decrease in dose. The actual effect of smoking on drug plasma
concentrations varies between individual patients and is unpredictable so it is essential to monitor patients
closely for clinical progress and adverse effects, and adjust drug doses as needed. Patient smoking may be
intermittent as patients often require repeated attempts to stop smoking. This further complicates the effect of
smoking on drug concentrations and also requires close patient monitoring. The use of nicotine replacement
therapy (NRT) does not affect this interaction because it is due to components of tobacco smoke, rather than
nicotine.

Psychotropic drugs that may be affected by the patient's smoking status are benzodiazepines, carbamazepine,
chlorpromazine, clozapine, duloxetine, fluphenazine [Note 2], fluvoxamine, haloperidol, mirtazapine,
olanzapine, tricyclic antidepressants (TCAs) and zuclopenthixol. The interaction with smoking is particularly
important for drugs with significant adverse effects (eg clozapine) or a narrow therapeutic index, or where
drug concentration is correlated to illness control (eg antipsychotics). For some drugs, plasma concentrations
may vary by up to 50% in an individual as a result of starting or stopping smoking.

All patients should be offered assistance with smoking cessation, including discussion of the likely harms and
benefits of any smoking cessation strategy, advice on nonpharmacological interventions and ongoing support.
If pharmacotherapy is considered, NRT and bupropion are the usual first-line interventions to aid smoking
cessation. Bupropion has the potential to cause mood dysregulation in some patients. Varenicline should only
be used in patients with a psychotic disorder if a trial of NRT has failed and the patient's mental state is
carefully monitored. Varenicline has been implicated in serious neuropsychiatric events (eg change in
behaviour, hostility, agitation, depressed mood), cardiovascular events and suicidal thoughts or actions. For
further discussion on interventions for smoking cessation, see Smoking cessation.

Further reading

Zwar N, Richmond R, Borland R, Peters M, Litt J, Bell J, et al. Supporting smoking cessation: a guide for
health professionals. Melbourne: The Royal Australian College of General Practitioners; 2011. [URL]

Note 2: Fluphenazine was discontinued in Australia in 2017.

Key references
Concordance, adherence and compliance with psychotropic treatment

Buckley P, Foster A, Patel N, Wermert A. Adherence to mental health treatment. Oxford; New York: Oxford
University Press; 2009.

Psychotropic treatment in older people

Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ.
2008;337a1227. [ ]

Psychotropic treatment in patients with concurrent diseases

Adam WR, Sshweitzer I, Walker RW. The trade-off between the benefits of lithium and the risk of chronic kidney
disease. Nephrology. 2012;17(8):776–9. [ ]

Hoppe C, Elger CE. Depression in epilepsy: a critical review from a clinical perspective. Nat Rev Neurol.
2011;7(8):462–72. [ ]

Kanner AM. The use of psychotropic drugs in epilepsy: what every neurologist should know. Semin Neurol
2008;28(3):379–88. [ ]

Kripalani M, Shawcross J, Reilly J, Main J. Lithium and chronic kidney disease. BMJ 2009;339:b2452. [
]

Psychotropic treatment in people who smoke

Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917–21. [ ]

Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann
Pharmacother. 2010;44(4):727–32. [ ]

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell;
2012.

Published March 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Nonpharmacological therapies for psychiatric
illness
Psychological interventions for psychiatric illness: introduction
Psychological interventions alone provide effective treatment for anxiety disorders, mild to moderate
depression and a variety of other psychiatric conditions. Evidence of efficacy is strongest for cognitive
behavioural therapy and interpersonal psychotherapy. However, the value of other psychological therapies,
such as supportive psychotherapy and various psychoanalytically oriented therapies, should not be
underestimated.

Patients and their family or carers can benefit substantially from supportive psychotherapy in the context of
an empathic relationship with a health professional. The components of supportive psychotherapy include
empathic listening, education, assistance with problem-solving techniques, encouragement and, when
appropriate, reassurance. This can be enhanced by use of appropriate eTherapy or other resources.

For a specific discussion of psychological and psychosocial therapies in schizophrenia, see Psychological and
psychosocial therapies. Patients with bipolar disorder or severe continuing depression may also benefit from
some of the psychological therapies used in schizophrenia.

Cognitive behavioural therapy

Cognitive behavioural therapy (CBT) is an empirical psychological treatment. It is based on two key
principles: cognitions may control feelings and behaviour; and behaviours affect thought patterns and
emotions. CBT aims to identify, challenge and modify maladaptive, automatic or core thoughts, beliefs,
perceptions and behaviours. This occurs over a series of clinical interviews, and cognitive and behavioural
tasks. Acute treatment typically involves between 12 and 20 weekly sessions. Follow-up booster sessions
after 3 or 6 months are often useful. CBT may be effective alone, or it may aid pharmacotherapy in acute
treatment and reduce relapse risk after drugs are discontinued. Benzodiazepines can interfere with the
effectiveness of CBT.

Elements of CBT, such as activity scheduling and identifying and challenging dysfunctional thoughts, can be
used as a brief form of psychological intervention in patients with a variety of diagnoses, particularly in
primary care settings.

Newer forms of CBT include acceptance and commitment therapy (ACT), dialectical behaviour therapy
(DBT) and mindfulness-based cognitive therapy. There is a growing evidence base for these therapies, which
all teach mindfulness techniques. ACT encourages individuals to initially notice, recognise and then accept
their cognitions and emotions, rather than trying to control them. Other core principles include allowing
thoughts to come and go without struggling with them, becoming more aware of the here and now, observing
self and setting realistic goals. DBT has been most effective as a treatment for individuals with impaired
emotional regulation, such as borderline personality disorder.

Interpersonal psychotherapy
Interpersonal psychotherapy (IPT) was developed for the treatment of depression. IPT uses the connection
between onset of depressive symptoms and current interpersonal problems as the treatment focus. Treatment
typically occurs over 12 to 16 weekly sessions. A maintenance form of therapy for prevention of relapse has
also been developed.

Interpersonal counselling, derived from IPT, is a brief form of therapy (up to 6 sessions) that is suited to use
in primary care settings.

Family therapy for psychiatric illness

Family therapy is a form of psychotherapy that emphasises family relationships as an important factor in
psychological health. There are many different forms but most include psychoeducation and a systems
approach, emphasising interactions between family members. Family therapies have been found to be helpful
in schizophrenia, bipolar disorder, anorexia nervosa, alcohol dependency, and childhood- and adolescent-
onset psychiatric disorders.

eTherapy for psychiatric illness

A number of self-help programmes for management of psychiatric illness are available through interactive
websites. These generally provide a CBT-based treatment approach (eg The MoodGYM Training Program
[URL]). There is growing evidence of their effectiveness in patients who complete the programmes, although
dropout rates tend to be high. Incorporation of eTherapy into the primary care management plan has been
shown to be particularly effective in improving completion rates, as pioneered by the Clinical Research Unit
for Anxiety and Depression (CRUfAD) (see THIS WAY UP Clinic [URL]). The Beacon portal ([URL])
categorises, reviews and rates self-help websites based on the evidence to support their effectiveness.

Self-help books for psychiatric illness

A range of self-help books are available on treatment of depression and anxiety, for use either alone or as part
of an overall management plan (guided self-help). While self-help books are recommended as part of a
stepped-care approach to depression and anxiety by the National Institute for Health and Clinical Excellence
(NICE) and have good face validity, there is only limited evidence for their effectiveness. See Further reading
for a list of some self-help books on depression and anxiety.

Further reading
Addis ME, Martell CR. Overcoming depression one step at a time: the new behavioral activation approach to
getting your life back. Oakland, CA: New Harbinger Pub; 2004.

Burns DD. Feeling good: the new mood therapy. Revised ed. New York: Avon; 1999.

Kennerley H. Overcoming anxiety: a self-help guide using cognitive behavioral techniques. London:
Robinson; 2009.

Williams CD. Overcoming depression and low mood: a five areas approach. 3rd ed. London: Hodder
Education; 2009.

Electroconvulsive therapy
Introduction
Electroconvulsive therapy (ECT) involves the delivery of an electric current to induce a seizure for a
therapeutic purpose. Notwithstanding its use as a valued treatment in psychiatry for over 60 years, ECT has
attracted considerable criticism, most of which is historical and ill-informed.

ECT is indicated for the treatment of severe depression if any of the following are present:

psychotic depression (ECT is more effective than antidepressants combined with antipsychotics)
melancholic depression unresponsive to antidepressants
depressive stupor, severe psychomotor disturbance leading to severe self-neglect, or life-threatening
refusal to accept fluid and food intake
severe postnatal depression and psychosis
strong suicidal ideation
previous good response to ECT
ECT is the patient's preferred method of treatment.

ECT can be helpful in treatment-resistant mania (see Acute mania: failure to respond to treatment) and
bipolar depression (see Bipolar depression: failure to respond to treatment). It may also be effective for
schizoaffective psychoses in the acute phase and treatment-resistant acute schizophrenia (see Treatment-
resistant schizophrenia: electroconvulsive therapy).

Treatment approaches
Modern ECT involves individually determined stimulus dosing based on monitoring the postictal
electroencephalogram (EEG) and clinical response. This individually tailored approach provides a greater
likelihood of response and fewer adverse effects.

Treatments are typically given three times a week and reduced to twice weekly if severe cognitive
impairment emerges. Before the procedure, the patient is anaesthetised and given a short-acting muscle
relaxant. A course of ECT is typically 6 to 14 treatments, but can be up to 24 treatments for some individuals.
Relapse rates after ECT are high and recovery should be maintained with appropriate pharmacotherapy that
has not previously been ineffective. Occasionally, maintenance ECT may be considered for those
unresponsive to any maintenance pharmacotherapy.

Adverse effects
The most common adverse effects are muscle aches and pains from the muscle relaxant used in the ECT
procedure, headaches and usually transient confusion for an hour or so after treatment.

There may be some memory loss, particularly of autobiographical memories (memories of personal
experiences), for the period of treatment and to a lesser degree for antecedent events. Memory impairment is
minimal or not apparent for most patients, but more severe, extensive and persistent for some. It is greater for
those with a poorer response to ECT. Some patients complain of enduring memory problems, even though
new learning appears unaffected after ECT and is often improved after recovery from depression. A small
proportion of patients report extensive and persistent memory problems from long before ECT to long
afterwards. Cognitive adverse effects are greater with bilateral than right unilateral treatment. Bifrontal ECT
may have fewer cognitive adverse effects than bitemporal treatment, but this has not been well studied. There
have recently been promising results with right unilateral ultrabrief pulse-width ECT, which appears to cause
fewer cognitive adverse effects.

ECT and psychotropic drugs

Where possible, it is usually desirable to cease psychotropic drugs when administering ECT, although in
some instances concurrent psychotropic drugs can help.

Benzodiazepines should be tapered and ceased as they raise the seizure threshold and may impair the efficacy
of ECT.

There is little to be gained from continuing failed antidepressants during acute ECT and there is some
evidence it may increase adverse effects. As a general rule it is best to taper and discontinue all
antidepressants before ECT.

Lithium does not impair the effectiveness of ECT but may occasionally result in severe postictal confusion
even at a low serum concentration. In such cases lithium should be ceased.

Continuation of an antiepileptic during ECT is likely to reduce the efficacy of ECT, prolong the course of
therapy and increase cognitive adverse effects. Antiepileptics may be used either for the treatment of epilepsy
or in the management of bipolar disorder. In patients with epilepsy, antiepileptics are not usually withdrawn
for ECT due to the high risk of spontaneous seizures. In patients taking antiepileptics for the management of
bipolar disorder, antiepileptics are preferably withdrawn before or early in the course of ECT. They can be
quickly reinstated at the conclusion of the course of therapy if necessary, with the exception of lamotrigine,
which requires the usual slow dose titration to reduce the risk of skin rash.

For acute psychoses, antipsychotics may be continued unless clearly ineffective or interacting adversely with
ECT (eg prolonged seizures with clozapine). Limited evidence suggests that outcomes with antipsychotics
and ECT are better than for either treatment alone.

Legislation
Most Australian states and territories have specific legislation regarding who can perform ECT, where it can
be done, the minimum facilities required, consent and withdrawal of consent. In some jurisdictions, enduring
power of medical attorney does not apply and notwithstanding a patient's previous wish, if they are
incompetent they have to be treated under the provisions for involuntary patients, not as voluntary patients
treated under enduring power of attorney. The consent of the nominated relative or friend is not acceptable as
consent for ECT under present legislation in most Australian states and territories.

Further reading
Tiller JWG, Lyndon RW, editors. Electroconvulsive therapy: a guide. 2nd ed. Melbourne: Health Education
Australia Limited; 2013.
Transcranial magnetic stimulation
Transcranial magnetic stimulation (TMS) is a noninvasive treatment that uses a rapidly changing magnetic
field to induce weak electric currents in the cerebral cortex; it can increase or decrease cortical excitability in
discrete cortical regions and neural circuits. TMS is usually reserved for patients with depression who have
not responded to or have only partially responded to antidepressants. Clinically it is applied in trains of
repeated pulses (repetitive TMS [rTMS]) and is usually given as a course of daily treatments over 2 to 4
weeks. Daily left prefrontal rTMS has been shown in several large trials to have significant antidepressant
properties when compared to sham. TMS is less effective than ECT for the more severe cases of depression
and relapse rates are high.

TMS should be administered in accordance with guidelines produced by The Royal Australian and New
Zealand College of Psychiatrists [Note 1]. rTMS does not require anaesthesia and can be administered in an
outpatient setting. It is relatively safe and well tolerated; induction of a seizure is an extremely rare adverse
effect. Depending on stimulus parameters, patients may experience some local scalp discomfort and
headache.

Note 1: The Royal Australian and New Zealand College of Psychiatrists (RANZCP). Repetitive
transcranial magnetic stimulation (Position statement 79). Melbourne: RANZCP; 2013. [URL]

Key references
Psychological interventions for psychiatric illness

Andrews G, Cuijpers P, Craske MG, McEvoy P, Titov N. Computer therapy for the anxiety and depressive
disorders is effective, acceptable and practical health care: a meta-analysis. PLoS One. 2010;5(10):e13196. [
]

Coull G, Morris PG. The clinical effectiveness of CBT-based guided self-help interventions for anxiety and
depressive disorders: a systematic review. Psychol Med. 2011;41(11):2239–52. [ ]

Johnston L, Titov N, Andrews G, Spence J, Dear BF. A RCT of a transdiagnostic internet-delivered treatment for
three anxiety disorders: examination of support roles and disorder-specific outcomes. PLoS One.
2011;6(11):e28079. [ ]

Kahl KG, Winter L, Schweiger U. The third wave of cognitive behavioural therapies: what is new and what is
effective? Curr Opin Psychiatry. 2012;25(6):522–8. [ ]

Williams C, Garland A. A cognitive-behavioural therapy assessment model for use in everyday clinical practice.
Adv Psychiatr Treat. 2002;8(3):172–9. [URL]

Physical therapies for psychiatric illness

Fitzgerald PB. Transcranial magnetic stimulation-based methods in the treatment of depression. Aust Prescr.
2012;35(2):59–61. [URL]

Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral
prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2009;39(1):65–75. [
]

The Royal Australian and New Zealand College of Psychiatrists (RANZCP). Transcranial magnetic stimulation
(Clinical Memorandum 18). Melbourne: RANZCP; 2008. [URL]

Tiller JWG, Lyndon RW, editors. Electroconvulsive therapy: an Australasian guide. Melbourne: Australian
Postgraduate Medicine; 2003.

Published March 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Depression in adults
Prevalence of depression
The 12-month prevalence of major depression in the Australian community is 4.1%. However, despite its high prevalence,
major depression has been underdiagnosed and undertreated. It should be distinguished from normal sadness (eg in
bereavement) (see Grief). Identifying the subtype of depression is important to guide treatment (see Subtypes of depression).
For information on bipolar depression, see Bipolar depression.

Treatment of depression in childhood and adolescence differs; see Major depression in childhood and adolescence. For
management of depression in patients receiving palliative care, see Depression in the Palliative Care guidelines.

Grief
Grief is a normal response after a significant loss (eg death of a spouse, loss of employment), severe illness or personal injury. It
may be accompanied by a wide variety of symptoms, including insomnia and sadness, some of which may mimic depression or
another mental disorder. Uncomplicated grief is not accompanied by feelings of worthlessness or strong suicidal thoughts, and
improves with time.

Conventional supports (eg family, social, religion) are usually sufficient to help someone who is grieving. Support from a
general practitioner or other clinician can be helpful, but there is normally little place for pharmacotherapy. Anxiolytics or
hypnotics may be helpful for a brief period in acute grief to control excessive anxiety or assist with sleep for a few nights
(usually for fewer than 7 nights), but there is a risk that ‘brief’ use can become long-term.

Pathological states may arise in the setting of grief. In about one-quarter of those who have recently lost a spouse, grief is
complicated by the emergence of major depression.

For a discussion of grief in the palliative care setting, see Loss, grief and bereavement.

Subtypes of depression
Major depression
In depressive episodes, the individual suffers from depressed mood and/or loss of interest and enjoyment, and a number of
other psychological and somatic symptoms. These include reduced energy, concentration/attention and self-esteem; ideas of
guilt/unworthiness; bleak or pessimistic views of the future; ideas or acts of self-harm/suicide; and disturbed sleep and appetite.
The lowered mood varies little from day-to-day and is often unresponsive to circumstances. It interferes with functioning and
must last for at least 2 weeks to meet the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International
Classification of Diseases (ICD) diagnostic criteria.

Depressive episodes can be classified as mild, moderate or severe.

Mild depression—the individual is usually distressed by symptoms and has some difficulty carrying out usual activities.

Moderate depression—several symptoms may be present to a marked degree and the individual usually has considerable
difficulty continuing with usual activities.

Severe depression—the individual usually shows either considerable distress or agitation, or retardation, and is unlikely to be
able to continue usual activities beyond a minimal extent. Somatic symptoms are prominent and suicide is a particular risk.
Major depression with melancholia is a form of severe depression characterised by psychomotor retardation or agitation, loss of
pleasure in all or almost all activities, marked weight loss and a lack of reactivity of mood. Psychotic symptoms can occur in
severe depression. In primary care or community (outpatient) practice, severe major depression is uncommon (less than 5% of
those presenting with depression) and psychotic depression is rare.

In primary care severe major depression is uncommon and psychotic depression is rare.

Dysthymic disorder
Dysthymic disorder is characterised by enduring, often fluctuating, low mood (of at least 2 years duration), but with insufficient
symptoms to meet the criteria for major depression. Underlying personality vulnerabilities are common, and antidepressants are
less predictably effective than in major depression.

Adjustment disorder with depressed and/or anxious mood

Adjustment disorder with depressed and/or anxious mood is a period of distress and emotional disturbance (usually interfering
with social functioning) following a significant stressful life event. However, the duration and severity of symptoms do not
meet the criteria for another depressive or anxiety disorder. Some degree of personal vulnerability may be present, but the
disorder would not be expected without the life event. Such symptoms may resolve spontaneously, or benefit from short-term
counselling or supportive psychotherapy. There is no evidence that antidepressants are helpful. For discussion of adjustment
disorder with anxious mood, see Adjustment disorder with anxious mood.

Assessing patients with depression

General information
Thorough assessment of patients with depression (including assessment of suicide risk) and establishment of an effective
therapeutic relationship between the patient and clinician are central to effective treatment. Some factors to consider when
assessing a patient with depression are shown in Box 8.15 and Box 8.16.

Early consultation or referral to a psychiatrist is indicated if there is significant risk of suicide; in complex clinical situations; or
when there is uncertainty about diagnosis, management or safety.

Assessing patients with depression (Box 8.15)

When assessing a patient with depression consider the following factors:

Risk—assess the risk of suicide, self-harm and harm/neglect to others (especially in perinatal depression) (see
Assessing suicide risk).
Psychosocial aspects—ask about stressful situations/events (eg relational, occupational, financial or legal problems;
domestic violence; gambling problems).
Premorbid personality—assess the patient's usual coping styles.
Medication—check for recent change in medication or dose (eg corticosteroids, beta blockers, oral contraceptives,
levodopa, interferon, isotretinoin); consider withdrawal/substitution or a reduction in the dose of the suspected
causative drug.
Bipolar disorder—check for previous manic or hypomanic episode, bipolar disorder, or family history of bipolar
disorder, and assess and treat accordingly (see Bipolar disorder).
Comorbid anxiety—if onset with depression, anxiety is likely to resolve with effective antidepressant treatment. If
longstanding or predating the onset of depression, treat anxiety concurrently with the depression (see Anxiety and
associated disorders).
Comorbid substance abuse—integrate the management of both problems, preferably by a team (see Alcohol and other
drug problems: general information). Alcohol is powerfully depressogenic; drinking alcohol decreases the efficacy of
antidepressants.
Other physical conditions—assess and treat accordingly (eg cerebrovascular disease, hypothyroidism).

Assessing suicide risk

Assessment of suicide risk is crucial, but can be difficult. Key clinical questions to assess suicide risk are listed in Box 8.16 and
some risk factors for suicide are shown in Box 8.17.

For a discussion of suicidal ideation and behaviour in adolescents, see Major depression in childhood and adolescence. For
assessment of suicide in patients receiving palliative care, see Suicidal ideation in the Palliative Care guidelines.

Early consultation or referral to a psychiatrist is indicated if there is a significant risk of suicide.

Key clinical questions in assessing suicide risk (Box 8.16)

Assessment of suicide risk

When people feel like you are/have been feeling, they sometimes think that life is not worth living—have you been
thinking like that or have you ever thought like that?
Have you been thinking of harming yourself?
Are you thinking of suicide?
If yes, how often are you having these thoughts?
Have you thought about how you would act on these (is there a plan)? (Does this plan seem feasible? Are the methods
available? Is it likely to be lethal?)
Have you thought about when you might act on this plan?
Are there any things/reasons that stop you from acting on these thoughts?
Have you tried to harm yourself in the past?
If yes, how many times?
When was the most recent time?
Do you know anyone who has recently tried to harm themselves?
Do you feel safe at the moment?

If a suicide attempt has been made

What did you hope would happen as a result of your attempt? (Did they want to die, or end their pain?)
Do you regret that you did not succeed?
Do you still have access to the method used?
Did you use alcohol or drugs before the attempt? What did you use?
Do you have easy access to a weapon?

Assessment of risk of harm to others

Have you thought of hurting anyone else?

If yes, have you acted on these thoughts?
Have you been involved in any fights recently?
If yes, were you using drugs or alcohol at the time?

Risk factors for suicide (Box 8.17)

Risk factors for suicide include:

psychiatric disorder—especially major depression, bipolar disorder, schizophrenia, schizoaffective disorder, substance
use disorder, personality disorder
current psychosis
family history of suicide
ready access to means of suicide with high potential lethality (eg drugs, firearms, ropes, hosepipes)
definite plan for suicide attempt
history of dangerous behaviour on impulse
low likelihood of suicide attempt being detected
ambivalence towards survival of a suicide attempt
social isolation/absence of social supports
chronic medical illness, especially if painful
recent major loss (includes ‘loss of face’ in some cultures)
feeling of hopelessness.

Principles for the treatment of depression

Good clinical management of depression should include discussion with the patient and/or family about relevant acute or
chronic stressors, the nature of the depression, its course, treatment options, and likelihood of response to treatment and adverse
effects of treatment. Reassurance of the probable effectiveness of treatment and the commitment of the clinician to supporting
the patient through the episode is important in combating feelings of hopelessness and in maintaining treatment concordance
[Note 1]. Education and support for family and friends who are in a caring role is beneficial for both them and the patient with
depression.

In mild depression, psychological therapies are generally more effective than antidepressants. In moderate depression,
psychological therapies and antidepressants are equally effective, and the initial choice of therapy should be based largely on
patient preference. Antidepressants are more effective than psychological therapies for moderate to severe depression, although
concurrent psychological therapies may often be helpful if the patient can concentrate enough to participate in these. If
psychotic symptoms are present, antipsychotics should be added to treatment and urgent specialist review should be sought.
Electroconvulsive therapy (ECT) should be considered in psychotic depression and some other forms of severe depression (eg
melancholic depression) (see Nonpharmacological therapies for psychiatric illness: electroconvulsive therapy). It is important
to consider the acceptability of this treatment to the patient.

Most depression is managed successfully in primary care or community (outpatient) settings, predominantly by general
practitioners. Inpatient treatment is recommended if the patient is experiencing depression with psychosis (ie with delusions or
hallucinations); is at significant risk of suicide, or homicide (eg ‘altruistic homicide’ by a woman suffering severe perinatal
depression); is inadequately supported at home; or is seriously physically unwell. Inpatient treatment may also be useful to
allow more intensive assessment and treatment of complicated and treatment-resistant depression. In some services, extensive
home- or community-based support is available as an alternative to inpatient care. When the patient's depression puts
themselves or others at significant risk and the patient is not competent to agree to treatment, involuntary hospitalisation under
the relevant mental health legislation must be considered (see Informed consent in mental illness).

Depressed patients may act on their suicidal ideas in the early stages of response to treatment since apathy may remit before
depressive mood. Education and guidance for family and friends about this can be useful. However, rates of suicide attempts in
the month after starting treatment are still lower than in the month before treatment. For information on assessing suicide risk,
see Assessing suicide risk.

Note 1: For the definition of concordance, see Concordance, adherence and compliance with psychotropic treatment.

Psychological treatment of depression

Some simple psychological techniques, such as structured problem-solving or stress management, may be undertaken in the
primary care setting. A number of self-help techniques may also be of assistance to the patient and their family, particularly for
mild to moderate depression (see Appendix 8.1 for patient resources and support organisations).

More formal psychotherapies, such as cognitive behavioural therapy (CBT), interpersonal psychotherapy (IPT) and short-term
dynamic therapy, have been demonstrated to be effective in moderate depression (see Nonpharmacological therapies for
psychiatric illness: psychological interventions). Referral is usually necessary. Although web-based CBT may be a useful
adjunct, it does not replace the supportive nature of the clinician-patient relationship. Patients with severe continuing
depression may also benefit from some of the psychological therapies recommended for schizophrenia (see Schizophrenia and
related psychoses: psychological and psychosocial therapies).

For some patients, concurrent use of specific psychological treatments and antidepressants is the most effective management. In
many situations, although not for severe depression, psychological treatments alone may be most appropriate. However,
addressing specific stressors, encouraging effective coping styles and utilising potential supports should always be part of the
management plan.

Pharmacological treatment of depression

General considerations

Older evidence suggests that all antidepressants are of similar efficacy in treating major depression. While one prominent meta-
analysis [Note 2] suggested differences in efficacy between antidepressants, a subsequent meta-analysis did not replicate this
finding [Note 3]. These guidelines consider that, on balance, all antidepressants registered for clinical use in Australia are of
substantially similar efficacy in treating major depression, with some possible exceptions. Reboxetine was significantly less
efficacious than other antidepressants in the earlier meta-analysis, and was not included in the later meta-analysis.
Moclobemide and agomelatine were not included in either of the meta-analyses. Many clinicians view moclobemide and
reboxetine as less efficacious than other antidepressants. Agomelatine is a new antidepressant and, at the time of writing,
clinical experience with its use is limited.

Individual patient responses differ between drugs and, currently, there is no way of predicting which drug will be effective in an
individual patient. There is insufficient evidence to support the role of cytochrome P450 genotyping in selecting or modifying
antidepressant therapy.

Combinations of antidepressants are not recommended for first-line treatment of major depression. There is only limited
evidence for combining antidepressants in treatment-resistant depression. There are also significant concerns regarding the
potential for serious drug interactions when combining antidepressants.

Individual drugs differ in their adverse effect profiles (see Table 8.14), potential for drug interactions and safety in overdose.
Tricyclic antidepressants (TCAs) and irreversible nonselective monoamine oxidase inhibitors (MAOIs) are less well tolerated
and have a narrower safety margin than other classes of antidepressants. Rarely, mianserin can cause agranulocytosis. These
drugs are therefore generally reserved for use if there is failure to respond to better tolerated antidepressants (see Failure to
respond to initial pharmacological therapy).

As there are usually concerns about suicidality when treating depression, the potential lethality of an antidepressant should be
considered in community settings. Antidepressants that are relatively safer in overdose, such as the selective serotonin reuptake
inhibitors (SSRIs), are usually preferred. However, the SSRIs citalopram and escitalopram have been associated with
prolongation of the QTc interval, which is more pronounced in overdose. In 2011, citalopram was involved in two-thirds of all
deaths from SSRI overdoses in the UK. For TCAs, ingestion of more than 10 mg/kg (ie less than a week's prescription at
standard doses) can produce potentially life-threatening cardiotoxicity. When TCAs are prescribed, serious consideration
should be given to dispensing them in small and safer quantities (eg in a weekly Webster-pak) and, if need be, to supervision of
administration by a significant other. Pharmacists can dispense small quantities of drug when requested by prescribers. For
venlafaxine, the risk of seizures increases with the dose ingested (seizures are likely with ingestions of more than 5 g;
cardiotoxicity is rare except with ingestions of more than 8 g). The toxic dose of desvenlafaxine is not known, but the
therapeutic dose of desvenlafaxine is two-thirds of the therapeutic dose of venlafaxine (50 mg desvenlafaxine versus 75 mg
venlafaxine). Deaths have been reported following overdoses of duloxetine over 1000 mg. For information on management of
overdose with antidepressants, see Mirtazapine, Selective serotonin reuptake inhibitors, Serotonin and noradrenaline reuptake
inhibitors, or Tricyclic antidepressants in the Toxicology and Wilderness guidelines.
In summary, the choice of antidepressant is determined by the following:

antidepressant adverse effect profile

patient response or lack of response to previous treatments
adverse effects of previous treatments
family history of response to treatments
risk of drug interaction with concurrently administered drugs
antidepressant safety in overdose
patient comorbidities (see Psychotropic treatment in special patient groups).

A delay in onset of response of at least 1 to 2 weeks usually occurs with all antidepressants, and full benefit may not occur for
up to 4 to 6 weeks or even longer in some cases. In those who do respond, full recovery may take 6 weeks or longer. If there is
a favourable response, antidepressants should be continued for at least 6 months, and preferably up to 12 months, after a single
episode of major depression as there is a high risk of relapse during this period. If there is a history of recurrence, longer-term
prophylactic treatment is recommended (see Recurrent depression).

Referral to a psychiatrist is recommended when patients do not respond to an adequate trial of these drugs (see Failure to
respond to adequate antidepressant therapy).

Note 2: Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and
acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373(9665):746-58.
[URL]

Note 3: Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, et al. Comparative benefits and harms of
second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med
2011;155(11):772-85. [URL]

Initial pharmacological therapy

Antidepressants recommended first-line in the initial treatment of major depression in the community are the selective serotonin
reuptake inhibitors (SSRIs), the serotonin and noradrenaline reuptake inhibitors (SNRIs) and mirtazapine. These drugs are
generally considered to be of similar efficacy and to have a wide safety margin, but they differ in their adverse effect profiles
(see Table 8.14) and in their potential for interaction with concurrently administered drugs. There is no good comparative meta-
analytic evidence to support the inclusion of moclobemide, reboxetine and agomelatine as first-line treatments so these drugs
are recommended as second-line treatments (see Pharmacological treatment of depression: general considerations for further
discussion).

If an antidepressant is indicated and preferred by the patient, the following approach is recommended:

Use any first-line antidepressant (see Table 8.13 for dosing regimens). About 50% of patients with major depression
respond to treatment with an initial antidepressant.
Assess response to antidepressant after 2 to 4 weeks of treatment:
–
Continue at the usual initial treatment dose if the patient responds well.
–
If there is no initial response, increase the dose. If there is still no response after 2 to 4 weeks of treatment at the
higher dose, switch to a different drug. If there is only a partial response after 2 to 4 weeks of treatment at the
higher dose, increase the dose further if possible within the recommended dose range. If a further dose increase is
not possible, switch to a different drug.
–
If there is a partial initial response, increase the dose. If there is no additional response after 2 to 4 weeks of
treatment at the higher dose, switch to a different drug. If there is an additional response after 2 to 4 weeks of
treatment at the higher dose but the effect is still inadequate, increase the dose further if possible within the
recommended dose range. If a further dose increase is not possible, switch to a different drug.
–
The relatively flat dose-response curve of SSRIs limits the advantages of increasing the dose; however, due to
individual patient variability, some patients will respond to increased doses of SSRIs. There is more evidence to
support a dose-response relationship with venlafaxine.
–
If an alternative antidepressant is indicated, the new drug may be from the same or a different class. There is
currently little evidence to guide the choice of an alternative treatment. In particular, if the initial treatment was
with an SSRI, there is little evidence that changing to another class of antidepressant is superior to using another
SSRI. See also Failure to respond to initial pharmacological therapy.
If there are severe or unacceptable adverse effects, switch to an antidepressant with a lower propensity to cause those
adverse effects. See also Management of antidepressant adverse effects.

Considerations when changing from one antidepressant to another are discussed in Changing from one antidepressant to
another and summarised in Table 8.15.

Initial treatment options for major depression (Table 8.13)

First-line treatment options

Drug Usual initial treatment dose [NB1] Maximum daily dose [NB2]
Selective serotonin reuptake inhibitors (SSRIs)
 less than 65 years of age: 20 mg orally, in the
morning less than 65 years of age: 40 mg [NB3]
citalopram
more than 65 years of age: 10 mg orally, in the more than 65 years of age: 20 mg [NB3]
morning
escitalopram 10 mg orally, in the morning 20 mg
fluoxetine 20 mg orally, in the morning 80 mg
starting dose 50 mg orally, at night. Generally
fluvoxamine increase to 100 mg at night in 5 to 7 days as 300 mg [NB4]
tolerated
paroxetine 20 mg orally, in the morning 50 mg (increase dose in increments of 10 mg)
starting dose 50 mg orally, in the morning.
sertraline Generally increase to 100 mg in the morning in 5 200 mg
to 7 days as tolerated
Serotonin and noradrenaline reuptake inhibitors (SNRIs)
desvenlafaxine
50 mg orally, in the morning 200 mg
(controlled-release)
duloxetine 60 mg orally, in the morning 120 mg
venlafaxine (controlled-
75 mg orally, in the morning 375 mg [NB5]
release)
Other
60 mg (increase dose in increments of 15 to 30
mirtazapine [NB6] 15 to 30 mg orally, at night
mg)
Second-line treatment options
Drug Usual initial treatment dose [NB1] Maximum daily dose [NB2]
agomelatine [NB7] 25 mg orally, at night 50 mg
600 mg in 2 divided doses or as a single dose
moclobemide [NB8] 300 mg or more commonly 450 mg orally, daily
(increase dose in increments of 150 mg)
reboxetine [NB9] 2 to 4 mg orally, twice daily 10 mg (increase dose in increments of 2 mg)
NB1: The usual initial treatment dose is effective for most patients.
NB2: Dose may be increased to maximum daily dose in increments at 2- to 4-week intervals.
NB3: The recommended maximum daily dose of citalopram was reduced from 60 mg in November 2011 following safety concerns, see [URL].
NB4: Doses of fluvoxamine more than 150 mg daily may be given in 2 divided doses for better tolerability.
NB5: The maximum daily dose of venlafaxine in the Australian approved product information is 225 mg; however, daily doses of up to 375 mg are approved in other
countries.
NB6: Mirtazapine blocks presynaptic alpha2-adrenoreceptors, increasing adrenergic transmission, and indirectly enhancing serotonergic transmission.
NB7: Agomelatine is an agonist at melatonin MT1 and MT2 receptors, and an antagonist at serotonin 5-HT2C receptors.
NB8: Moclobemide is a reversible inhibitor of monoamine oxidase type A (MAO-A); however, when used at higher than recommended doses, it also inhibits monoamine
oxidase type B (MAO-B) and dietary restrictions are warranted (see Appendix 8.3).
NB9: Reboxetine is a selective noradrenaline reuptake inhibitor.

Failure to respond to initial antidepressant therapy

Due to their less favourable adverse effect profiles, tricyclic antidepressants, mianserin and irreversible nonselective
monoamine oxidase inhibitors would generally only be used after unsuccessful trials of at least two first-line treatments (either
drug [see initial pharmacological therapy] or psychological). These antidepressants should, however, be considered first-line for
those who responded well to them previously. Some patients respond only to these therapies. Referral to a psychiatrist is
advisable.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) include amitriptyline, clomipramine, dothiepin, doxepin, imipramine, nortriptyline and
trimipramine [Note 4]. TCAs have a role in the management of patients with severe or melancholic depression. However, some
people are unable to tolerate their adverse effects. These include anticholinergic effects (eg dry mouth, blurred vision,
constipation, urinary retention), orthostatic hypotension, sexual dysfunction, weight gain and sedation. Nortriptyline has a
lower incidence of anticholinergic effects, orthostatic hypotension and sedation than the other TCAs. TCAs are potentially
lethal in overdose (see Pharmacological treatment of depression: general considerations).

Surveys of TCA use consistently show use of an inadequate dose in 50% of patients treated for major depression. Measurement
of serum concentration may be helpful in determining the appropriate therapeutic dose for some TCAs (eg nortriptyline,
imipramine).

If TCAs are indicated, an appropriate regimen is:

a TCA 25 to 75 mg orally, at night, increasing by 25 to 50 mg every 2 to 3 days (depending on

adverse effects) to 75 to 150 mg at night by the 7th day. The maximum daily dose is 150 mg for
nortriptyline and 200 to 300 mg for all other TCAs [Note 5].

Lower doses of TCAs are likely to be required in older persons, and in patients with reduced ability to metabolise drugs (eg
impaired liver function) or with increased vulnerability to adverse effects.

Widening of the QRS complex occurs with TCA toxicity. QTc interval prolongation and arrhythmias may also occur. TCAs
should be avoided in patients with underlying cardiovascular disease. Before commencing a TCA, a baseline electrocardiogram
(ECG) should be performed and repeated periodically, particularly following dose increases. Avoid concurrent use of other
drugs that can prolong the QTc interval (see Table 17.2 for drugs highly associated with QT prolongation and torsades de
pointes).

TCAs should not be combined with other antidepressants. Interactions with monoamine oxidase inhibitors may be fatal (see
Management of antidepressant adverse effects: serotonin toxicity).

Note 4: Trimipramine was discontinued in Australia in December 2013.

Note 5: The maximum daily dose of nortriptyline in accepted usage is greater than the maximum suggested in the Australian
approved product information (100 mg).

Mianserin
Mianserin has fewer cardiovascular and anticholinergic adverse effects than the TCAs and has a wider margin of safety in
overdose. Marked sedation is a common adverse effect; weight gain occurs infrequently. Orthostatic hypotension and
conversely hypertension may occur. Mianserin can rarely induce neutropenia and deaths have occurred from agranulocytosis. A
full blood count is required before initiation of treatment and should be repeated at 4 to 6 weeks or if there are any clinical
features suggestive of neutropenia (eg infection, sore throat).

An appropriate regimen is:

mianserin 30 to 60 mg orally, at night initially, increasing to 60 to 120 mg at night by the 7th day.

Irreversible nonselective monoamine oxidase inhibitors

Irreversible nonselective monoamine oxidase inhibitors (MAOIs) include phenelzine and tranylcypromine. Treatment with
these antidepressants should only be initiated by a psychiatrist familiar with their use. Common adverse effects include
orthostatic hypotension, dry mouth, blurring of vision, constipation, sexual dysfunction, weight gain, insomnia and arousal.
Paradoxically, some patients experience sedation and fatigue.

For phenelzine, the usual dose range is 45 to 60 mg orally, daily in 2 or 3 divided doses, up to a maximum of 45 mg twice daily.
For tranylcypromine, the usual dose range is 15 to 20 mg orally, twice daily, up to a maximum of 30 mg twice daily [Note 6].
For both drugs, the starting dose should be increased every 3 to 4 days (depending on adverse effects) to reach the usual dose
range by the 7th day. The last dose each day should be given no later than early afternoon to minimise the risk of insomnia.

Irreversible nonselective MAOIs may cause significant hypertension when combined with certain foods (see Table 8.22).

MAOIs interact with many drugs. Always check for drug interactions before prescribing.

Avoid administration of MAOIs with other serotonergic drugs as there is an increased risk of serotonin toxicity (see Table 17.4
for drugs that have been associated with serotonin toxicity). The combination of an irreversible nonselective or a reversible
selective MAOI and an SSRI or an SNRI is absolutely contraindicated. The combination of an irreversible nonselective MAOI
and pethidine or tramadol is also contraindicated.

MAOIs may cause significant hypertension when combined with indirectly acting sympathomimetic amines (eg phenylephrine,
pseudoephedrine, phentermine, methylphenidate, amphetamines) or certain foods (see Appendix 8.3 for dietary guidelines), and
concurrent administration should be avoided. As directly acting sympathomimetic amines (eg adrenaline, dopamine,
isoprenaline, noradrenaline) are inactivated primarily by catechol-O-methyltransferase, not monoamine oxidase, they can be
used cautiously while monitoring blood pressure. For treatment of hypertensive crisis, see Urgent reduction of blood pressure.

For a detailed listing of drug interactions with MAOIs, see the product information for individual drugs or an appropriate
reference (eg Australian Medicines Handbook). Always check for drug interactions before prescribing.

Note 6: The maximum daily dose of tranylcypromine in accepted usage is greater than the maximum suggested in the Australian approved product information (30
mg).

Failure to respond to adequate antidepressant therapy

If there has been failure to respond to antidepressant therapy, reassess diagnosis and management by considering the points
listed in Box 8.18. Referral to a psychiatrist is recommended.

Although only a third of patients experience full remission after 6 weeks of treatment with an initial antidepressant, the
STAR*D trial of up to four antidepressants (administered sequentially) reported overall remission rates of approximately two-
thirds [Note 7].

If there has been failure to respond to adequate antidepressant therapy, depending on the severity of the depression, consider
one of the following therapies:
 electroconvulsive therapy (ECT)—response rate of 50% to 80% (see Nonpharmacological therapies for psychiatric
illness: electroconvulsive therapy)
lithium augmentation of antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) and tricyclic
antidepressants (TCAs)—response rate of up to 50%. At present there is little evidence to support the use of lithium with
other classes of antidepressants, in particular the serotonin and noradrenaline reuptake inhibitors (SNRIs). Commence
lithium under specialist supervision and monitor serum lithium concentration; the target serum concentration for this
indication is 0.4 to 0.6 mmol/L. See Prophylaxis of bipolar disorder: lithium for a discussion of lithium adverse effects
and other monitoring recommendations
liothyronine (T3) augmentation of antidepressant treatment—commence under specialist supervision
second-generation antipsychotic augmentation of antidepressant treatment—the potential benefit of these drugs in
nonpsychotic unipolar depression is becoming clearer. Quetiapine and aripiprazole have the best evidence to support their
use in depression, but at present only quetiapine is indicated for the adjunctive treatment of major depression in
Australia. There is some evidence from meta-analyses for the use of risperidone and olanzapine as augmenting agents.
For discussion of adverse effects and monitoring requirements of antipsychotic drugs, see Management of antipsychotic
adverse effects.

Many other drugs have been used for augmentation of antidepressant treatment but the evidence to support their use is limited,
as they have not been studied in randomised controlled trials, the studies have had insufficient numbers to be conclusive or the
trials have failed. The role of other combinations may be considered following specialist consultation, and with the patient's
informed consent to the potential harms and benefits of the particular combination.

Some studies have found omega-3 fatty acids to be beneficial in the treatment of depression; however, meta-analyses of such
trials have shown considerable heterogeneity and publication bias, and there is no robust evidence to support their use.

Key questions in assessing failure to respond to psychotropic drugs (Box 8.18)

For patients who have failed to respond to psychotropic treatment, the following questions should be asked:

Is the diagnosis correct?

Has the patient been taking their medication regularly? See Concordance, adherence and compliance with psychotropic
treatment.
Have possible underlying medical causes been identified and treated?
Is the patient reacting adversely to a current medication?
Have the drug dose and duration of administration been adequate?
Have relevant psychosocial or personality factors been addressed?
Have alcohol or other substance use problems been addressed? See Alcohol and other drug problems
Could an interacting drug be compromising the response? Information on cytochrome P450 drug interactions can be
found at the University of Indiana School of Medicine's drug interaction website [URL].

Note 7: Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one
or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163(11):1905-17. [URL]

Management of antidepressant adverse effects

Introduction
Adverse effects from antidepressants are common, but there is a wide range of individual differences in their occurrence (see
Table 8.14). Starting at low doses and stepping up the dose slowly may reduce their impact. Additive and synergistic effects
may occur when two or more drugs with similar adverse effects are used concurrently.

If adverse effects occur, review the dose, timing of the dose, and potential drug interactions that may be contributing to the
adverse effect burden. Some practical management strategies for common adverse effects of psychotropic drugs are outlined in
Table 8.23. If these strategies are ineffective or if the adverse effects are severe or unacceptable, a change in antidepressant is
indicated (see Changing from one antidepressant to another).

For information on management of overdose with antidepressants, see Mirtazapine, Selective serotonin reuptake inhibitors,
Serotonin and noradrenaline reuptake inhibitors, or Tricyclic antidepressants in the Toxicology and Wilderness guidelines.

Bleeding
Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of bleeding, especially gastrointestinal bleeding, by
blocking the uptake of serotonin into platelets. However, the absolute risk of this is low. The risk is increased by concurrent use
of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulant drugs and antiplatelet drugs. Patients with liver cirrhosis or
liver failure and patients susceptible to gastrointestinal bleeding (eg patients with a history of peptic ulcer disease or
oesophageal varices, or who are undergoing surgery) are also at increased risk. Consider an alternative class of antidepressant
or the addition of a gastroprotective drug (eg a proton pump inhibitor) in patients at increased risk of bleeding. If NSAID use
must be continued, a less gastrotoxic NSAID is recommended (eg ibuprofen, diclofenac).

Hyponatraemia

Hyponatraemia can be induced by tricyclic antidepressants (TCAs), SSRIs, serotonin and noradrenaline reuptake inhibitors
(SNRIs) and monoamine oxidase inhibitors (MAOIs). It is usually either asymptomatic or accompanied by mild symptoms
such as nausea and general malaise. In mild cases, symptoms of hyponatraemia may overlap with the underlying psychiatric
disorder. If severe (serum sodium concentration less than 125 mmol/L) or rapidly developing, hyponatraemia can result in
convulsions, coma and death.

Risk factors for hyponatraemia include:

older age
female gender
low body weight
concurrent drugs (eg diuretics, NSAIDs, carbamazepine, chemotherapy)
impaired renal function
comorbidity (eg hypothyroidism, diabetes, chronic obstructive pulmonary disease, hypertension, stroke, head injury)
hot weather.

Routine monitoring of serum sodium concentration is not indicated, but measurement of serum sodium may be considered in
patients at high risk of hyponatraemia approximately 3 to 4 weeks after initiating treatment. If hyponatraemia occurs,
discontinuation of the causative drug normalises serum sodium concentration within 2 weeks. If the causative drug is an SSRI,
subsequent rechallenge with the same or a different SSRI may be possible without recurrence of hyponatraemia. If the
rechallenge is unsuccessful, consider moclobemide or reboxetine.

For management of hyponatraemia, see Hyponatraemia in the Endocrinology guidelines.

Psychomotor impairment and sedation

Patients should be warned that sedating antidepressants (see Table 8.14) can impair psychomotor skills (eg driving, operating
machinery, cycling, reaction times as a pedestrian), although some tolerance to this develops over a period of days. Sedation
may persist the following day after night-time dosing.

Commencing treatment at a lower dose and increasing the dose slowly as tolerance develops reduces the degree of sedation.
Mirtazapine may be started at a higher dose (30 mg per day or more) as noradrenergic enhancement may counteract some of the
histaminergic blockage that predominates at lower doses and is responsible for causing sedation. Avoid concurrent use of other
central nervous system depressants (eg alcohol, benzodiazepines).

Serotonin toxicity
Serotonin toxicity can develop within hours of commencing the serotonergic agent or interacting drugs and can be a medical
emergency. A list of drugs that have been associated with serotonin toxicity is provided in Table 17.4. Combinations of drugs
with different pharmacological actions listed in the table can produce serotonin toxicity, which has been associated with
fatalities. For further information on serotonin toxicity, including a discussion of management, see Toxidromes: serotonin
toxicity in the Toxicology and Wilderness guidelines.

Approximate relative frequency (not intensity) of common adverse effects of antidepressants (Table 8.14)
[NB1]

This table lists the approximate relative frequency of adverse effects, not the intensity with which they occur.

Orthostatic Sexual Weight

Gastrointestinal
Drug Agitation Insomnia
Hypertension hypotension Sedation dysfunction gain (more
effects [NB2]
/ dizziness [NB3] than 6 kg)
Selective serotonin reuptake inhibitors (SSRIs)
citalopram + ++ ++ – + ++ +++ +
escitalopram – ++ ++ – + + ++ –
fluoxetine + ++ ++ [NB4] ? ++ ++ +++ [NB5] + [NB6]
fluvoxamine + +++ ++ ? + ++ +++ + [NB6]
paroxetine + ++ ++ + ++ ++ +++ [NB5] ++ [NB6]
sertraline + +++ ++ – ++ ++ +++ [NB5] + [NB6]
Serotonin and noradrenaline reuptake inhibitors (SNRIs)
desvenlafaxine + +++ ++ + ++ ++ + ?
duloxetine
+ ++ ++ – ++ ++ +++ +
[NB7]
venlafaxine + +++ ++ [NB4] + ++ ++ +++ [NB5] + [NB6]
Others
agomelatine
– + + ? + – – –
[NB8]
mirtazapine ? + + ? + +++ [NB9] + +++
moclobemide ? ++ ++ [NB4] – ++ + + –
reboxetine + + +++ + + – + –
Approximate frequencies of adverse effects: ? = little or no information reported; – = negligible or absent; + = infrequent; ++ = moderately frequent; +++ = frequent
NB1: The information in this table is based on a combination of reported adverse effect data and expert opinion; it is intended only as a guide and should be interpreted in
the context of the patient's particular situation (eg concurrent drugs, drug history, physical health, the considerable interindividual variation in elimination half-lives) and
the doses of the drugs. See Tricyclic antidepressants, Irreversible nonselective monoamine oxidase inhibitors and Mianserin for their adverse effects.
NB2: Gastrointestinal adverse effects may include nausea, anorexia, diarrhoea and abdominal discomfort.
NB3: Sexual dysfunction may include decreased libido, anorgasmia and ejaculatory disturbance.
NB4: Insomnia is more likely if the antidepressant is dosed in the evening.
NB5: Priapism has been reported.
NB6: Weight loss reported initially.
NB7: Avoid duloxetine in patients with liver impairment.
NB8: Increase in serum transaminases has been reported with agomelatine and, rarely, hepatitis can occur so avoid agomelatine in patients with liver impairment. Liver
biochemistry should be performed in all patients at baseline; then 3, 6, 12 and 24 weeks after starting treatment with agomelatine; then as clinically indicated. Stop
treatment if the increase in serum transaminases exceeds 3 times the upper limit of normal.
NB9: Sedation is decreased at higher doses of mirtazapine (more than 15 mg daily).

Interactions between antidepressants and alcohol

In general, alcohol should be avoided in all patients with depression as alcohol is powerfully depressogenic and can affect
treatment concordance. Patients should be warned that the effects of alcohol and other central nervous system depressant drugs,
including illicit drugs, can be potentiated if they are taken in conjunction with sedating antidepressants (see Table 8.14). Ideally,
alcohol should be avoided during treatment with these drugs.

There is no specific interaction between alcohol and the less-sedating antidepressants, such as reboxetine, selective serotonin
reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and agomelatine. However, duloxetine
and agomelatine may interact with alcohol to cause liver injury so these antidepressants should be avoided in patients with
substantial alcohol use. Patients taking phenelzine or tranylcypromine should be advised to avoid certain alcoholic drinks due
to their tyramine content (see Table 8.22). In particular, home-brewed alcoholic drinks should be avoided as they have a highly
variable tyramine concentration.

If the patient experiences drug-induced sedation, alcohol should be avoided at least until this adverse effect disappears.

Anxiolytic or hypnotic co-prescription with antidepressants

Although many depressed patients are anxious and suffer insomnia, co-prescription of an anxiolytic or hypnotic with an
antidepressant is generally not necessary, as these symptoms will resolve with effective treatment of the depression and
antidepressants also have anxiolytic activity. SSRI- and SNRI-induced insomnia and anxiety during the initial stages of therapy
often settle within a week, but may necessitate dose manipulation or changing to another antidepressant (see Changing from
one antidepressant to another). Any prescription of an anxiolytic or hypnotic should be short term.

St John's wort in depression

Extracts of St John's wort (Hypericum perforatum) are widely used, often as self-medication, for the treatment of depression of
varying severity. Unless specifically asked about, patients may not volunteer that they are taking such complementary
medicines.

Short-term studies have indicated that extracts of St John's wort are more effective than placebo for the treatment of mild to
moderate depression. A 2008 Cochrane review indicates that St John's wort may have equivalent efficacy to standard
antidepressants in major depression, although this conclusion is complicated by the more positive findings arising
predominantly from German-speaking countries [Note 8]. The mode of action of St John's wort is unknown but may involve
increasing synaptic availability of neurotransmitters such as serotonin.

There are reports of serotonin toxicity with concurrent administration of St John's wort and antidepressants with serotonergic
action, so avoid this combination.

St John's wort appears to be well tolerated but gastrointestinal symptoms, allergic reactions, photosensitivity, fatigue and
restlessness have been reported. St John's wort induces cytochrome P450 (CYP) 3A4 and may therefore reduce the plasma
concentration of drugs metabolised by this isoenzyme.

Note 8: Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev 2008;(4):CD000448. [URL]

Changing from one antidepressant to another

An appropriate antidepressant-free interval is recommended when changing from one antidepressant to another to reduce the
risk of drug interactions. General recommendations are given in Table 8.15, based on the pharmacokinetics of the drug to be
ceased and, where appropriate, its active metabolites. These recommendations should be interpreted mindful of the patient's
particular situation (eg concurrent drugs, drug history, physical health, the considerable interindividual variation in elimination
half-lives) and the doses of the drugs.

Higher doses of antidepressant should be tapered before commencing a change of drug to avoid a discontinuation syndrome
(see Antidepressant discontinuation). The new drug should be started at a low dose. The risk of adverse effects from drug
interaction needs to be weighed against the risk of undue delay in response to treatment. Monitor closely to detect adverse
effects, particularly serotonin toxicity. If significant adverse effects emerge during the changeover period, consider a longer
elimination half-life of the antidepressant being ceased as a possible cause and adjust the duration of changeover accordingly.

Antidepressant-free intervals recommended when changing from one antidepressant to another (Table
8.15) [NB1] [NB2]

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Individualise the suggested approach for each patient.

short- irreversible
CHANGING acting SNRIs TCAs nonselective agomelatine
fluoxetine mianserin mirtazapine moclobemide reboxetine
TO ▸ SSRIs [NB4] [NB5] MAOIs [NB7]
[NB3] [NB6]
CHANGING
FROM ▾
2 to 4
short-acting 2 to 4 2 to 4 days 2 to 4
nil nil 2 to 4 days 2 to 4 days days 1 week 2 to 4 days
SSRIs [NB3] days [NB8] days
[NB9]
2
fluoxetine
1 week – 1 week 1 week 1 week 1 week 1 week weeks 5 weeks 1 week
[NB10]
[NB9]
2 to 4 2 to 4 2 to 4 2 to 4
mianserin – 2 to 4 days 2 to 4 days 2 to 4 days 1 week 2 to 4 days
days days days days
2 to 4 2 to 4 2 to 4 2 to 4 2 to 4
mirtazapine – 2 to 4 days 2 to 4 days 1 week 2 to 4 days
days days days days days
1 to 2 1 to 2 1 to 2 1 to 2 1 to 2
1 to 2 days 1 to 2 days 1 to 2 days
moclobemide days days days – days days nil [NB11]
[NB11] [NB11] [NB11]
[NB11] [NB11] [NB11] [NB11] [NB11]
1 to 2 1 to 2 1 to 2 1 to 2 1 to 2
reboxetine 1 to 2 days 1 to 2 days – 1 week 1 to 2 days
days days days days days
1 to 2 1 to 2 1 to 2 nil 1 to 2
SNRIs [NB4] 1 to 2 days 1 to 2 days 1 to 2 days 1 week 1 to 2 days
days days days [NB12] days
2 to 4 2 to 4 2 to 4 2 to 4 days 2 to 4
TCAs [NB5] 2 to 4 days 2 to 4 days nil 1 week 2 to 4 days
days days days [NB13] days
irreversible
nonselective 2 2 2
2 weeks 2 weeks 2 weeks nil [NB14] 2 weeks 2 weeks 2 weeks
MAOIs weeks weeks weeks
[NB6]
agomelatine
nil nil nil nil nil nil nil nil 1 to 2 days –
[NB7]
nil = start the new antidepressant the next day; MAOIs = monoamine oxidase inhibitors; SSRIs = selective serotonin reuptake inhibitors; SNRIs = serotonin and
noradrenaline reuptake inhibitors; TCAs = tricyclic antidepressants
NB1: Recommendations in this table should be interpreted in the context of the patient's particular situation (eg concurrent drugs, drug history, physical health, the
considerable interindividual variation in elimination half-lives) and the doses of the drugs. Higher doses of antidepressant should be tapered before commencing a change
of drug. The new drug should be started at a low dose.
NB2: If quetiapine, a second-generation antipsychotic, is used for treatment of major depression then an antidepressant-free interval is not required when changing from
an antidepressant to quetiapine or vice versa, and the new drug can be started the next day.
NB3: The short-acting SSRIs are citalopram, escitalopram, fluvoxamine, paroxetine and sertraline.
NB4: The SNRIs are desvenlafaxine, duloxetine and venlafaxine.
NB5: The TCAs are amitriptyline, clomipramine, dothiepin, doxepin, imipramine, nortriptyline and trimipramine.
NB6: The irreversible nonselective MAOIs are phenelzine and tranylcypromine. They should be commenced with caution after all other antidepressants because of the
risk of severe hypertension, stroke and serotonin toxicity. Allowance should be made for a washout period of 5 half-lives and individual patient differences in
pharmacokinetics.
NB7: Data on antidepressant-free intervals when changing to and from agomelatine are limited.
NB8: If changing from low or moderate doses of short-acting SSRIs, the dose of moclobemide should be held at 300 mg/day for the first week. The dose of moclobemide
may be subsequently increased if necessary.
NB9: The TCA concentration may be elevated for at least several weeks due to persisting SSRI-induced cytochrome P450 inhibition.
NB10: Care is required when changing from fluoxetine to another antidepressant as it has a longer half-life than other SSRIs, leading to meaningful concentrations of
fluoxetine or its active metabolite being present for about 5 weeks after cessation.
NB11: This recommendation applies if moderate or low doses of both drugs are involved.
NB12: If changing from venlafaxine or desvenlafaxine to duloxetine, start duloxetine at 30 mg/day and increase the dose slowly.
NB13: Changing from clomipramine requires a 1-week antidepressant-free interval. If changing from low or moderate doses of TCAs (eg up to 150 mg imipramine), the
dose of moclobemide should be held at 300 mg/day for the first week. The dose of moclobemide may be subsequently increased if necessary.
NB14: This recommendation applies if moderate or low doses of both drugs are involved. However, irreversible nonselective MAOI dietary guidelines (see Table 8.22)
should still be continued for 2 weeks.

Antidepressant discontinuation
When ceasing an antidepressant, either at the end of a course of therapy or when changing to another drug, consideration must
be given to the possibility of a discontinuation (withdrawal) syndrome (see Dependence, tolerance and the discontinuation
syndrome with psychotropic drugs). Discontinuation symptoms may also arise when a patient discontinues a drug abruptly.
Some patients experience discontinuation effects after missing one or two doses, especially when taking drugs with short half-
lives. Discontinuation symptoms may include insomnia, nausea, postural imbalance, sensory disturbances, hyperarousal and
flu-like symptoms. Usually, these symptoms are mild, last 1 to 2 weeks, and are rapidly extinguished with reinstitution of the
antidepressant. Exceptionally, delirium may occur. A discontinuation syndrome does not necessarily indicate that drug
dependence has occurred.
Discontinuation symptoms from a drug that has been ceased may be misattributed to adverse effects of a substituted drug,
leading to the latter being inappropriately reduced in dose or ceased. If clinical circumstances permit, it is useful to stop the first
drug, allow time for any discontinuation effect to manifest, and then introduce the new drug.

In general, antidepressants should be tapered slowly, rather than stopped abruptly, to reduce the risk of discontinuation
syndrome. Antidepressant discontinuation syndrome is more likely to occur with a higher dose, a longer duration of treatment
and a shorter half-life drug so the rate of tapering may need to be adjusted depending on these factors. As a general rule, the
dose should be halved every week until the daily dose is half of the lowest unit strength available, in which case the
antidepressant can be stopped after 1 week on this dose. If antidepressant therapy is being ceased completely, tapering may
need to be undertaken more slowly to prevent relapse.

Taper antidepressant dose slowly, rather than stopping abruptly.

Paroxetine, venlafaxine, desvenlafaxine and duloxetine have short half-lives and their doses should be tapered slowly when
ceasing. The Therapeutic Goods Administration (TGA) has received many reports of antidepressant discontinuation reactions
particularly relating to paroxetine and venlafaxine. Despite its short half-life, there is currently no evidence of a discontinuation
syndrome occurring with agomelatine, but data are limited. Due to the long half-lives of fluoxetine and its active metabolite,
norfluoxetine, tapering is not usually required when stopping fluoxetine as discontinuation symptoms rarely occur; however,
care is required when changing to another antidepressant (see Table 8.15 for antidepressant-free intervals recommended when
changing from one antidepressant to another).

Rapid withdrawal of the more potently anticholinergic tricyclic antidepressants (TCAs) (eg amitriptyline) can precipitate
cholinergic rebound (agitation, headache, sweating, gastrointestinal symptoms), parkinsonism and problems with balance.

Perinatal depression
Perinatal depression affects around 10% to 20% of mothers. It is particularly important to identify and treat early because of its
potentially detrimental and enduring effect on the mother–infant relationship. See further information in Depression in
pregnancy and the postpartum. Treatment of perinatal depression is generally the same as for treatment of depression in other
adults (see Treatment of depression). However, see Psychotropic drug use during pregnancy: antidepressants and Psychotropic
drug use while breastfeeding: antidepressants regarding the safety of drugs used in these circumstances.

Recurrent depression
Many patients with depression will experience one or more recurrences in their lifetime. It is important to reduce the risk of
relapse by attention to vulnerability factors (eg continuing relationship or employment difficulties) during remission, and to
assist the patient to identify early warning signs of relapse and develop a plan for early intervention.

While a continuation phase of treatment (after full resolution of symptoms) of up to 6 to 12 months is recommended following
a single episode of major depression, longer-term prophylactic treatment is recommended when there have been recurrences. A
common indication for longer-term prophylactic treatment is two or more depressive episodes within 5 years or three previous
episodes, although a single severe episode of psychotic depression or a serious suicide attempt may also warrant this. Longer-
term treatment should probably be continued for at least 3 to 5 years (including continuing work on vulnerability factors), and
then the need for further management should be explicitly reviewed. Some patients may require lifelong antidepressant therapy.

Antidepressants (of all classes) and lithium have been proven to be effective in reducing the risk of recurrence of major
depression. Antidepressants tend to be the first choice for prophylaxis, although lithium should be considered for patients who
continue to suffer recurrence on antidepressants. There is some evidence to support combining an antidepressant and lithium for
long-term prophylaxis if an antidepressant alone is inadequate.

Continuing the antidepressant at the same dose necessary for recovery from the acute episode provides greater protection from
recurrence than the ineffective practice of using a reduced prophylactic dose.

Psychological therapies, such as cognitive behavioural therapy (CBT), either alone or in conjunction with antidepressants, have
also been demonstrated to reduce the likelihood of future depressive relapse. Significant benefit has been demonstrated for
quarterly ‘booster’ sessions during the first year of recovery.

There is a limited place for maintenance electroconvulsive therapy (ECT) in the specialist treatment of severe recurrent
treatment-resistant depression.

Key references
Prevalence of depression

Australian Bureau of Statistics (ABS). National survey of mental health and wellbeing: summary of results, 2007. Canberra: ABS;
2007. [URL]

Pharmacological treatment of depression: general considerations

Deaths related to drug poisoning in England and Wales, 2011. London: Office for National Statistics; 2012. [URL]

Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-
generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–58. [ ]
 Eyding D, Lelgemann M, Grouven U, Harter M, Kromp M, Kaiser T, et al. Reboxetine for acute treatment of major depression:
systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled
trials. BMJ 2010;341:c4737. [ ]

Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, et al. Comparative benefits and harms of second-generation
antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med. 2011;155(11):772–85. [
]

Depression: initial pharmacological therapy

Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-
generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–58. [ ]

Eyding D, Lelgemann M, Grouven U, Harter M, Kromp M, Kaiser T, et al. Reboxetine for acute treatment of major depression:
systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled
trials. BMJ 2010;341:c4737. [ ]

Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M, et al. Comparative benefits and harms of second-generation
antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med. 2011;155(11):772–85. [
]

Posternak MA, Baer L, Nierenberg AA, Fava M. Response rates to fluoxetine in subjects who initially show no improvement. J Clin
Psychiatry. 2011;72(7):949–54. [ ]

Depression: failure to respond to adequate antidepressant therapy

Baumann P, Nil R, Souche A, Montaldi S, Baettig D, Lambert S, et al. A double-blind, placebo-controlled study of citalopram with
and without lithium in the treatment of therapy-resistant depressive patients: a clinical, pharmacokinetic, and pharmacogenetic
investigation. J Clin Psychopharmacol. 1996;16(4):307–14. [ ]

Chan HN, Mitchell PB, Loo CKA, Harvey SB. Pharmacological treatment approaches to difficult-to-treat depression. Med J Aust
Open. 2012;1(Suppl 4):44–7. [URL]

Katona CL, Abou-Saleh MT, Harrison DA, Nairac BA, Edwards DR, Lock T, et al. Placebo-controlled trial of lithium augmentation of
fluoxetine and lofepramine. Br J Psychiatry. 1995;166(1):80–6. [ ]

Mischoulon D, Nierenberg AA, Kizilbash L, Rosenbaum JF, Fava M. Strategies for managing depression refractory to selective
serotonin reuptake inhibitor treatment: a survey of clinicians. Can J Psychiatry. 2000;45(5):476–81. [ ]

Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61 Suppl 213–9. [ ]

Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled
randomized trials. Am J Psychiatry. 2009;166(9):980–91. [ ]

Posternak MA, Baer L, Nierenberg AA, Fava M. Response rates to fluoxetine in subjects who initially show no improvement. J Clin
Psychiatry. 2011;72(7):949–54. [ ]

Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed
outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–17. [ ]

Sackeim HA, Roose SP, Burt T. Optimal length of antidepressant trials in late-life depression. J Clin Psychopharmacol. 2005;25(4
Suppl 1):S34-7. [ ]

Management of antidepressant adverse effects

de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications
for use in elderly patients. Drugs Aging. 2011;28(5):345–67. [ ]

Dodd S, Malhi GS, Tiller J, Schweitzer I, Hickie I, Khoo JP, et al. A consensus statement for safety monitoring guidelines of
treatments for major depressive disorder. Aust N Z J Psychiatry. 2011;45(9):712–25. [ ]

Virani A, Bezchlibnyk-Butler KZ, Jeffries JJ, Procyshyn RM, editors. Clinical handbook of psychotropic drugs. 19th rev. ed. Ashland,
OH: Hogrefe Publishing; 2012.

Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or
paroxetine in elderly people. Br J Clin Pharmacol. 1999;47(2):211–7. [ ]

St John's wort in depression

Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. [ ]
Changing from one antidepressant to another

McAllister-Williams RH, Baldwin DS, Haddad PM, Bazire S. The use of antidepressants in clinical practice: focus on agomelatine.
Hum Psychopharmacol. 2010;25(2):95–102. [ ]

Antidepressant discontinuation

McAllister-Williams RH, Baldwin DS, Haddad PM, Bazire S. The use of antidepressants in clinical practice: focus on agomelatine.
Hum Psychopharmacol. 2010;25(2):95–102. [ ]

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Published June 2013. Amended February 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and
distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Bipolar disorder
Overview of bipolar disorder
Bipolar disorder occurs in 0.9% of the Australian population over 12 months and 1.2% over a lifetime.
Characterised by distinct episodes of mania and depression, the impact of the illness is severe, impinging on
relationships, career, self-esteem and longevity. Some episodes manifest with both manic and depressive
symptoms—these ‘mixed episodes’ are usually a variant of mania (see Mixed episodes [dysphoric mania] and
rapid cycling bipolar disorder). Most patients with bipolar disorder also experience periods of low-grade
depression between the major mood episodes. Comorbid anxiety disorders occur in about 60% of patients, and
concurrent alcohol or other substance abuse or dependence is present in 25% to 32% of patients.

The clinical features of mania are elevated, expansive or irritable mood, accelerated speech, racing thoughts with
flight of ideas, increased activity and reduced sleep. Patients may develop grandiose ideas, act recklessly
(including increasing spending), and show increased sexual drive and activity. Symptoms often appear abruptly.
With recurrent mania, there may be subtle early warning signs, which alert the patient or their family to incipient
relapse. For symptoms that are less severe and of shorter duration, the term hypomania is used.

If patients have had at least one manic episode at any stage of their life, the condition is termed bipolar I disorder.
If patients have had only hypomanic and depressive episodes, this is called bipolar II disorder. At present, there
are varying definitions of bipolar II disorder. The Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, text revision (DSM-IV-TR) diagnostic system defines bipolar II disorder based on episodes of hypomania
lasting a minimum of 4 days.

Peak onset of illness is usually in early adult life (late adolescence to late 20s) and there is a strong genetic basis.
Mania occurring for the first time in later life (particularly after 40 years of age) may be secondary to drugs (eg
antiparkinsonian drugs, corticosteroids) or medical illness (eg hyperthyroidism, cerebrovascular disease, brain
tumour), and should be investigated appropriately.

The diagnosis of juvenile (paediatric) bipolar disorder in childhood or early adolescence is controversial when
made in the absence of elevated mood, and largely premised on chronic irritability. There is little evidence to guide
treatment of this presentation, with the symptoms frequently overlapping with attention deficit hyperactivity
disorder (ADHD) and disruptive behaviour disorders. For the more classic euphoric form of the illness, which can
occur (albeit uncommonly) in early to mid-adolescence, treatment is based on recommendations for adults (see
Juvenile bipolar disorder).

Patients, and their family and friends, need education and support to understand bipolar disorder and its treatment.
Information on bipolar disorder is available through a number of Australian and overseas websites. Support
organisations can play an important role (see Appendix 8.1).

In the management of bipolar disorder, the term mood stabiliser is widely used to describe a drug that:

is effective for the acute treatment of mania and/or bipolar depression; or

is effective in preventing episodes of mania and/or bipolar depression; or
possesses both of the above clinical profiles.

Due to variability in the use of the term mood stabiliser, these guidelines refer to drugs used either for acute
treatment of mania or bipolar depression, or for prophylaxis of bipolar disorder.

While efficacy in both the acute treatment and prophylaxis of bipolar disorder has been reported in at least one trial
for lithium, olanzapine and quetiapine, currently no drug has convincing replicated data demonstrating both of
these clinical profiles.

At present, there is minimal evidence from controlled trials for the treatment of bipolar II disorder, with the vast
majority of studies only including patients with bipolar I disorder. The treatment recommendations in this topic
can be most confidently applied to bipolar I disorder; however, in practice, these guidelines are often extrapolated
to bipolar II disorder.

Management of bipolar disorder in pregnancy can be challenging and preconception planning is important (see
discussion in Bipolar disorder in pregnancy and the postpartum). For information on drug use in pregnancy and
breastfeeding, see Psychotropic drug use during pregnancy: drugs used in treatment of bipolar disorder and
Psychotropic drug use while breastfeeding: drugs used in treatment of bipolar disorder.
Acute mania
Principles of treatment
An episode of acute mania is a medical emergency. Patients have the capacity to destroy their reputations,
relationships and finances within hours or days. Insight and judgment are usually impaired early, even in the
absence of delusions. The initial aim of acute treatment is to contain behavioural disturbances, such as aggression,
violence, agitation, overactivity and disinhibition. Many patients with acute mania require hospitalisation for their
protection. Insight is usually lacking and involuntary admission under the relevant mental health legislation may
be required. Hospitalisation can protect the patient and their family from damage that may result from impaired
judgment associated with the illness; however, primary care or community (outpatient) treatment is preferred if
possible.

Manic relapses in established bipolar disorder are often due to poor treatment concordance so serum drug
concentrations should be checked where relevant [Note 1]. Other common causes of relapse include substance
abuse, use of antidepressants and stressful life events.

A recent meta-analysis indicates that antipsychotics are the most efficacious drugs in acutely controlling symptoms
of mania, with olanzapine, risperidone and haloperidol identified as being particularly effective [Note 2].

Manic episodes can develop into a behavioural emergency, or present as such. For management of behavioural
emergencies, see Acute psychiatric settings.

For treatment of acute mania, use:

1 olanzapine (see Table 8.16 for dosing regimen)

OR

1 risperidone (see Table 8.16 for dosing regimen)

OR

2 haloperidol 1.5 mg orally, at night initially, increasing in stages up to a maximum of 10

mg at night. Higher doses are approved for use, but are not recommended because of the
risk of extrapyramidal adverse effects (see Acute mania: haloperidol for further
information)

OR

2 aripiprazole (see Table 8.16 for dosing regimen)

OR

2 asenapine (see Table 8.16 for dosing regimen)

OR

2 paliperidone (see Table 8.16 for dosing regimen)

OR

2 quetiapine (see Table 8.16 for dosing regimen)

OR

2 ziprasidone (see Table 8.16 for dosing regimen)

OR

2 lithium carbonate 750 to 1000 mg orally, daily, in 2 or 3 divided doses or as a single dose
 at night. Lithium serum concentration should be determined after 5 to 7 days of steady-
dose treatment. The daily dose may be increased in increments of 250 to 500 mg
depending on the serum concentration. The daily dose required to achieve therapeutic
concentrations may range from 1000 to 2500 mg (see Acute mania: lithium for further
information)

OR

2 sodium valproate 200 to 400 mg orally, twice daily. The dose should be increased every 2
to 3 days in increments of 200 to 500 mg per day and the serum concentration determined
after 3 days of steady-dose treatment. Alternatively, a loading dose strategy may be used,
giving an initial oral dose of 20 mg/kg per day. Most patients require a regular daily dose
of 1000 to 2000 mg, though some may need 3000 mg or higher (see Acute mania: sodium
valproate for further information)

OR

2 carbamazepine 100 to 200 mg orally, twice daily. The dose should be increased every 2 to
3 days in increments of 100 to 200 mg per day and the serum concentration determined 5
to 7 days after achieving a dose of 400 to 800 mg daily. Some patients may need a daily
dose of 1000 mg (see Acute mania: carbamazepine for further information).

Combination therapy with any of the antipsychotics recommended for acute mania plus either lithium or sodium
valproate is commonly used in practice, particularly for patients with more severe episodes of acute mania or if
there is failure to respond to monotherapy (see Acute mania: failure to respond to treatment). The same doses are
recommended in combination therapy as for monotherapy.

Following remission of a first episode of mania, it is critical to continue treatment for at least 12 months to prevent
relapse. If an antipsychotic is used in combination with lithium or sodium valproate for acute treatment, the
antipsychotic should be withdrawn within a few months after remission. Some patients may require long-term
prophylactic treatment (see Prophylaxis of bipolar disorder).

Note 1: For the definition of concordance, see Concordance, adherence and compliance with psychotropic
treatment.

Note 2: Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, et al. Comparative efficacy and
acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet
2011;378(9799):1306-15. [URL]

Considerations with drugs used in the treatment of acute mania

Second-generation antipsychotics

Most of the second-generation antipsychotics have been demonstrated to be more effective than placebo in the
treatment of acute mania, irrespective of the presence of psychotic symptoms. The strongest evidence is for
olanzapine and risperidone. See Table 8.16 for dosing regimens of second-generation antipsychotics indicated in
acute mania.

For discussion of adverse effects and monitoring requirements of antipsychotic drugs, see Management of
antipsychotic adverse effects.

Dosing regimens of second-generation antipsychotics indicated in acute mania (Table 8.16)

Drug Initial treatment dose Maximum daily dose

First-line treatment options
5 mg orally, at night initially, increasing to 10 mg
olanzapine 30 mg [NB1]
at night
0.5 to 1 mg orally, at night initially, increasing to 2
risperidone 6 mg
mg at night
Second-line treatment options
10 mg orally, once daily initially, increasing to 15
aripiprazole mg once daily (this is usually an effective dose) 30 mg
[NB2]
5 mg sublingually, twice daily initially, increasing
asenapine 20 mg
to 10 mg twice daily [NB3]
paliperidone 3 mg orally, at night initially, increasing to 6 mg at
(controlled-release) 12 mg
night [NB5]
[NB4]
quetiapine 50 mg orally, twice daily on day 1, then
100 mg twice daily on day 2, then increasing to
quetiapine 200 mg twice daily (response is frequently not 800 mg
seen until higher doses of up to 400 mg twice
daily are achieved) [NB6]
40 mg orally, twice daily initially, increasing to 80
ziprasidone 160 mg
mg twice daily [NB7]
NB1: The maximum daily oral dose of olanzapine in accepted usage is greater than the maximum suggested in the Australian approved product
information (20 mg).
NB2: As aripiprazole can be activating, it is best taken in the morning initially.
NB3: Asenapine wafers should not be swallowed and food and drink should not be consumed for 10 minutes after dosing.
NB4: At the time of writing, paliperidone is not approved by the Australian Therapeutic Goods Administration (TGA) for treatment of acute mania. See
the TGA website for current information [URL].
NB5: Dose adjustment of paliperidone is required in patients with kidney impairment.
NB6: A controlled-release formulation of quetiapine is available that allows for once daily night-time dosing.
NB7: Ziprasidone should be taken with food.

Haloperidol

Although evidence indicates haloperidol, a first-generation antipsychotic, is highly effective in the treatment of
acute mania, it is not recommended as a first-line drug due to its potential significant short-term and long-term
adverse effects. In particular, there is a risk of tardive dyskinesia with long-term use. If haloperidol is used for the
treatment of acute mania, it is recommended for short-term use only and should be withdrawn as soon as remission
of acute symptoms is achieved. If ongoing therapy is necessary, the patient should be commenced on lithium or
sodium valproate (see Acute mania: principles of treatment for dosing regimens).

For discussion of adverse effects and monitoring requirements of antipsychotic drugs, see Management of
antipsychotic adverse effects.

Lithium

Educate patients and family or carers to recognise symptoms of early lithium toxicity (see Prophylaxis of bipolar disorder:
lithium toxicity).

When monitored, the serum lithium concentration should be measured 8 to 12 hours after the last dose. The serum
lithium concentration required in acute mania is higher than for prophylactic therapy, and ranges from 0.8 to 1.2
mmol/L with twice or thrice daily dosing. The 12-hour concentration is 10% to 25% higher after a single night-
time dose, so a correspondingly higher serum concentration than that required for more frequent daily dosing
should be aimed for (eg 0.9 to 1.4 mmol/L). The usual serum concentration may not be tolerated by older patients.

The margin separating therapeutic and toxic concentrations of lithium is narrow, and frequent regular serum
lithium concentration monitoring is required. Patients in their 60s or 70s may require only one-third to one-half of
the dose required in young or middle-aged adults to achieve therapeutic serum concentrations. Lithium is excreted
by the kidneys, and impaired kidney function decreases lithium elimination. A reduced dose and more intensive
monitoring are required in patients with kidney impairment.

Educate patients and family or carers to recognise symptoms of early lithium toxicity. For discussion of adverse
effects, toxicity and monitoring requirements of lithium, see Prophylaxis of bipolar disorder: lithium.

Sodium valproate

There is strong evidence to support a linear relationship between serum drug concentration and therapeutic
response in acute mania for sodium valproate. Particular benefit has been demonstrated for concentrations above
660 micromol/L (94 mg/L). Toxicity is likely at concentrations of 875 micromol/L (125 mg/L) or higher.

For discussion of adverse effects and monitoring requirements of sodium valproate, see Prophylaxis of bipolar
disorder: antiepileptic drugs.

Carbamazepine

A therapeutic serum concentration range for carbamazepine has not been established for acute mania or
prophylaxis of bipolar disorder. In practice, therapeutic concentrations established for epilepsy, 20 to 50
micromol/L (5 to 12 mg/L), are used as a general guide.
Due to liver microsomal enzyme induction by carbamazepine (autoinduction), serum concentrations may fall in the
early stages of treatment. After dose adjustment, further autoinduction does not occur. It should be emphasised,
however, that where clinical response is not evident and there is no evidence of major adverse effects, further
increases in dose may be required to achieve antimanic effect.

For discussion of adverse effects and monitoring requirements of carbamazepine, see Prophylaxis of bipolar
disorder: antiepileptic drugs.

Failure to respond to treatment

For patients with acute mania who do not respond to the above drugs, the following options should be considered:

ensure that maximum tolerable drug concentration has been achieved. For example, some patients on lithium
only respond to serum concentrations of 1.0 to 1.2 mmol/L
switch to a different drug (eg from a second-generation antipsychotic to lithium)
combine drugs (eg a second-generation antipsychotic plus lithium)
electroconvulsive therapy (ECT)—this is a proven treatment for mania and may be extremely effective even
when patients fail to respond to one or more antimanic drugs (for further information, see
Nonpharmacological therapies for psychiatric illness: electroconvulsive therapy).

Reassess diagnosis and management by considering the points listed in Box 8.18.

Bipolar depression
Principles of treatment
There is continuing controversy internationally concerning the role of antidepressants in bipolar depression. There
is conflicting evidence regarding both their efficacy and propensity to induce a switch into mania or rapid cycling.
These guidelines consider that there is a valid role for antidepressants in bipolar depression, as long as they are
used in conjunction with appropriate prophylactic pharmacological therapy. Factors to consider when choosing an
antidepressant are, in general, similar to those outlined for major depression (see Pharmacological treatment of
depression: general considerations).

Do not use antidepressants alone in the treatment of bipolar depression.

Antidepressants must be used with caution in bipolar disorder and patients must be warned of the risks and
monitored closely. When used in bipolar depression, antidepressants may induce manic episodes in the acute
situation, or provoke a rapid cycling pattern (4 or more episodes per year) if continued long term (see Mixed
episodes [dysphoric mania] and rapid cycling bipolar disorder). However, the likelihood of this occurring is not as
high as previously suggested, particularly for the selective serotonin reuptake inhibitors (SSRIs). There are also
concerns that antidepressants may induce irritability, dysphoria and agitation. Antidepressants that have
noradrenergic activity, such as the tricyclic antidepressants (TCAs), serotonin and noradrenaline reuptake
inhibitors (SNRIs) and irreversible nonselective monoamine oxidase inhibitors (MAOIs), are more likely to induce
switching than the SSRIs.

It is recommended that all antidepressants are withdrawn as soon as feasible, preferably within 1 or 2 months of
successful resolution of bipolar depression. However, relapse of depression may occur and discontinuation of the
antidepressant is therefore not always possible. Some patients with frequent episodes of bipolar depression are best
controlled with the long-term combination of a prophylactic drug plus an antidepressant. For information on
prophylactic therapy, see Prophylaxis of bipolar disorder.

There is good evidence from randomised placebo-controlled trials to support the efficacy of quetiapine
monotherapy in bipolar depression.

For treatment of bipolar depression, use:

1 an antidepressant (see Table 8.13 for dosing regimens)

PLUS
a drug recommended for prophylaxis of bipolar disorder

OR

1 quetiapine 50 mg orally, twice daily on day 1, then 100 mg twice daily on day 2, then
increasing to 150 to 300 mg, twice daily [Note 3].
Ensure optimal serum drug concentrations where relevant.

There is limited evidence for the following regimens in the treatment of bipolar depression: olanzapine
monotherapy, olanzapine plus fluoxetine, lithium monotherapy and lamotrigine monotherapy.

Note 3: A controlled-release formulation of quetiapine is available that allows for once daily night-time dosing.

Failure to respond to treatment

For patients with bipolar depression who do not respond to the above therapy, the following options should be
considered:

if using an antidepressant in combination with a prophylactic drug, change to a different antidepressant or a

different prophylactic drug (eg lamotrigine or olanzapine)
augment pharmacotherapy with psychological treatment. Psychotherapies, such as cognitive behavioural
therapy and psychoeducation techniques, have been shown to be effective in bipolar depression (see
Prophylaxis of bipolar disorder: psychological treatment)
electroconvulsive therapy (ECT)—this is an effective treatment for bipolar depression and should be
considered especially if the patient is psychotically depressed or displays significant psychomotor
retardation or agitation (for further information, see Nonpharmacological therapies for psychiatric illness:
electroconvulsive therapy).

Reassess diagnosis and management by considering the points listed in Box 8.18.

Prophylaxis of bipolar disorder

Key interventions

Over 90% of patients with mania will have multiple recurrences. Most patients also experience recurrent episodes
of depression. Some key interventions to prevent recurrence, which should commence during recovery from the
first and/or subsequent episodes, are listed in this section.

Continue pharmacological treatment for an adequate duration

Following the first episode, continue pharmacological treatment for at least 12 months.
Most patients have multiple episodes and require long-term treatment (see Prophylaxis of bipolar disorder:
pharmacological treatment).
Actively ask about and monitor for adverse drug effects, and respond by lowering the dose or switching to
another drug with a lower propensity for adverse effects as appropriate.

Use a broadly based treatment program

Foster a therapeutic alliance using supportive psychotherapeutic strategies (eg active listening, empathic
responsiveness, explanation, reassurance). Provide the patient with a working explanatory model of their
disorder.
Most patients with bipolar disorder require treatment under specialist psychiatric care, especially those with
poorly controlled illness. However, liaison with a general practitioner for both maintenance of the patient's
general physical health (see below) and for the treatment of bipolar disorder is strongly recommended.
Shared-care programs can be used to help improve a range of health outcomes for people with bipolar
disorder.
Access the following as necessary: case management services, assertive community treatment, cognitive
behavioural therapies (eg medication compliance therapy, motivational interviewing for substance abuse,
coping strategies enhancement, symptom control interventions), cognitive remediation for cognitive deficits,
social skills programs, supported employment programs, accommodation and disability support options,
education and training assistance, and social interventions to combat isolation (see Prophylaxis of bipolar
disorder: psychological treatment). See Appendix 8.1 for patient resources and support organisations.

Manage comorbidity

Actively monitor substance use. Inform all patients about the risks of comorbid substance dependence or
abuse; for example, increased risk of relapse, increased symptoms, increased risk of self-harm. Management
through an integrated treatment program that provides simultaneous treatment for substance use disorders
and mental illness appears to provide the best outcome (see Alcohol and other drug problems).
Assess for and treat comorbid anxiety and/or panic disorder (see Anxiety and associated disorders).

Maintain physical health

Target cardiometabolic adverse effects, by:

 –
encouraging physical fitness with daily exercise, healthy eating and smoking cessation. Smoking
cessation may increase the plasma concentrations of some antipsychotics (eg clozapine, olanzapine)
necessitating a dose reduction. See also Psychotropic treatment in people who smoke
–
monitoring blood pressure, weight, body mass index (BMI), waist circumference, serum lipids and
blood glucose.
Many antipsychotics can cause cardiometabolic problems—for prevention and management, see
Management of antipsychotic adverse effects: weight gain and other cardiometabolic effects.

Work with family/carers

Engage the patient and their family in a psychoeducation program. This should include identification of the
patient's ‘relapse signature’, namely, the characteristic early symptoms and signs that precede the manic or
depressive episodes.
If available, family therapy using problem-solving techniques or focusing on communication has been
shown to be useful in preventing relapse or rehospitalisation.
Carer assistance programs can help to support and educate family members, and to provide respite care. For
further information, see Appendix 8.1.

Pharmacological treatment

Principles of treatment

Prophylactic (maintenance) treatment following treatment of an acute episode should be considered if a patient has
had two or more previous episodes of either mania or depression, or if the first episode was particularly severe.
The frequency and severity of the acute episodes, the patient's age, concurrent medical conditions and treatment
concordance should be taken into account. Prophylactic treatment may be time-limited (3 to 5 years) or indefinite,
depending on illness history, response to treatment, and the patient's age and tolerability of the treatment.

In general, the choice of drug for prophylaxis is the same as for acute treatment. Lithium has the most extensive
evidence for prophylactic benefits in bipolar disorder. Most of the second-generation antipsychotics (aripiprazole,
asenapine, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone) have at least one randomised
controlled trial to support their use in prophylaxis. Only the depot formulation of risperidone has been shown to be
effective in prophylaxis of bipolar disorder, with studies of the oral formulation having negative findings. There
are a small number of studies reporting that olanzapine and quetiapine are effective for prophylaxis of both manic
and depressive episodes, while lithium and the other recommended second-generation antipsychotics are more
effective in preventing manic rather than depressive episodes. There is strong evidence that lamotrigine is effective
for prophylaxis of depressive, but not manic, episodes. Although carbamazepine and sodium valproate are widely
used for prophylaxis of bipolar disorder, there is no or minimal evidence from randomised controlled trials
supporting their use.

For prophylaxis of bipolar disorder, use:

1 lithium carbonate 125 to 500 mg orally, twice daily for 2 weeks. The dose should then be
adjusted according to the serum concentration determined after 5 to 7 days of steady-dose
treatment (see Prophylaxis of bipolar disorder: lithium for further information)

OR

1 aripiprazole (see Table 8.17 for dosing regimen)

OR

1 asenapine (see Table 8.17 for dosing regimen)

OR

1 olanzapine (see Table 8.17 for dosing regimen)

OR

1 paliperidone (see Table 8.17 for dosing regimen)

 OR

1 quetiapine (see Table 8.17 for dosing regimen)

OR

1 risperidone depot (see Table 8.17 for dosing regimen)

OR

1 ziprasidone (see Table 8.17 for dosing regimen)

OR (if depression is prominent)

1 lamotrigine 25 mg orally, at night for 2 weeks, then 50 mg at night for 2 weeks, then 100
mg at night for 1 week, then 200 mg at night. To reduce the risk of serious skin reactions
in patients also taking sodium valproate, the dose of lamotrigine should be half of the
above at each step, aiming for a final maximum dose of 100 mg at night (see Prophylaxis
of bipolar disorder: antiepileptic drugs for further information) [Note 4]

OR

2 carbamazepine 100 to 200 mg orally, twice daily. The dose should be increased weekly in
increments of 100 to 200 mg per day and the serum concentration determined after 5 to 7
days of steady-dose treatment. Most patients require a daily dose of 400 to 800 mg to
obtain a therapeutic serum concentration (see Prophylaxis of bipolar disorder:
antiepileptic drugs for further information)

OR

2 sodium valproate 200 to 400 mg orally, twice daily. The dose should be increased weekly
in increments of 200 to 400 mg per day and the serum concentration determined after 3
days of steady-dose treatment. Most patients require a daily dose of 1500 to 3000 mg to
obtain a therapeutic serum concentration (see Prophylaxis of bipolar disorder:
antiepileptic drugs for further information) [Note 5].
Note 4: At the time of writing, lamotrigine is not approved by the Australian Therapeutic Goods Administration
(TGA) for the prophylaxis of bipolar disorder. See the TGA website for current information [URL].

Note 5: At the time of writing, sodium valproate is not approved by the Australian Therapeutic Goods
Administration (TGA) for the prophylaxis of bipolar disorder. See the TGA website for current information
[URL].

Considerations with drugs used in prophylaxis of bipolar disorder

Lithium

General considerations

Educate patients and family or carers to recognise symptoms of early lithium toxicity.

When monitored, the serum lithium concentration should be measured 8 to 12 hours after the last dose. For most
patients the therapeutic serum lithium concentration for prophylaxis of bipolar disorder is 0.6 to 0.8 mmol/L with
twice or thrice daily dosing, but there is considerable interpatient variability. Some patients may need a
concentration of 0.8 to 1.0 mmol/L and some may be maintained satisfactorily at 0.4 to 0.6 mmol/L. The 12-hour
concentration is 10% to 25% higher after a single night-time dose, so a correspondingly higher blood
concentration than that required for more frequent daily dosing should be aimed for (eg 0.7 to 1.0 mmol/L).

Lithium is excreted by the kidneys, and impaired kidney function decreases lithium elimination. A reduced dose
and more intensive monitoring are required in patients with kidney impairment (see also Special considerations
with psychotropic treatment: kidney disease). Intercurrent illness, fluid loss, or the use of diuretics, nonsteroidal
anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers or angiotensin converting enzyme inhibitors
may reduce the renal clearance of lithium and lead to increased tissue concentrations and toxicity.

Before commencing lithium, assess kidney, thyroid and parathyroid functions. Advise patients of the likely adverse
effects of lithium and the need for routine clinical and serum lithium concentration monitoring. Patients should be
warned that symptoms such as confusion, unsteadiness, nausea, diarrhoea or worsening tremor may indicate that
their lithium dose requires adjustment. Measure serum lithium concentration every 3 to 6 months after a stable
therapeutic concentration is achieved. Monitor kidney function, with measurement of serum creatinine and
electrolyte concentrations and assessment of estimated glomerular filtration rate (eGFR), every 3 to 6 months. If
kidney impairment is suspected, consider a carefully collected 24-hour creatinine clearance. Monitor thyroid
function, including measurement of serum thyroid stimulating hormone concentration, every 6 to 12 months in
addition to clinical assessment. To screen for hyperparathyroidism, calcium concentrations should be measured at
least annually. Parathyroid hormone concentrations should be measured if calcium concentrations are raised.

For many patients with bipolar disorder, abrupt cessation of lithium leads to relapse of mania (or, less likely,
depression) within a few months. Therefore, if lithium is to be ceased, it should be withdrawn slowly over at least
2 months.

Adverse effects

Long-term adverse effects of lithium are responsive to dose reduction so monitoring for these is important (see
General considerations). Clinical hypothyroidism is commonly reported, especially in females. It responds well to
thyroxine replacement therapy while treatment with lithium is continued. Consider referral to an endocrinologist.

Lithium can inhibit responsiveness to antidiuretic hormone in the distal nephron, thus decreasing renal
concentrating ability with consequent polyuria and polydipsia.

At therapeutic concentrations lithium can produce a fine tremor and, rarely, muscular weakness and extrapyramidal
features. Occasionally, patients may complain of cognitive difficulties, including memory problems. Some
practical management strategies for common adverse effects of psychotropic drugs are outlined in Table 8.23.

Lithium is available in standard (250 mg) and controlled-release (450 mg) tablets. The latter gives lower peak
serum lithium concentrations after ingestion. Any significant adverse effect that mainly occurs 1 to 2 hours after
taking standard lithium tablets may be potentially improved by changing to the controlled-release formulation.

Toxicity

At toxic concentrations lithium can cause ataxia, vomiting, coarse tremor, neurological signs (including
hemiplegia), disorientation, dysarthria, muscle twitches, impaired consciousness, acute kidney failure and death.
Prolonged toxic concentrations may lead to irreversible brain damage. Toxicity usually occurs at concentrations
more than 1.5 mmol/L, but may develop at lower concentrations, especially in older people. Educate patients and
family or carers to recognise symptoms of early lithium toxicity.

Acute lithium overdose (inadvertent or deliberate) rarely leads to significant toxicity due to rapid elimination of
lithium by the kidneys and slow uptake into the central nervous system. Acute ingestions of less than 25 g are
unlikely to cause major effects unless patients have kidney failure. Acute-on-chronic ingestions are similar to acute
overdose. Most patients with acute poisoning require no specific treatment other than serial measurement of
lithium concentrations to confirm elimination. However, as there have been rare cases of significant complications,
expert toxicological advice should be sought.

Chronic poisoning is associated with significant morbidity and mortality. It has an insidious onset and often
requires treatment with intravenous fluids and occasionally dialysis. Clinical recovery can take days to weeks and
is significantly delayed compared with the decrease in serum lithium concentrations. The most important causes of
lithium toxicity in the context of chronic use are:

interactions with drugs that affect the renal clearance of lithium (eg diuretics, NSAIDs, angiotensin
converting enzyme inhibitors or angiotensin II receptor blockers)
reduced fluid intake
severe reduction in sodium chloride intake (eg changing to a vegetarian diet)
fluid loss from vomiting, diarrhoea or excessive sweating
kidney impairment.

For more detailed information on lithium toxicity, see Toxicology: lithium in the Toxicology and Wilderness
guidelines.

Second-generation antipsychotics

Table 8.17 lists the dosing regimens of second-generation antipsychotics indicated for prophylaxis of bipolar
disorder.
 Consider the harm–benefit ratio with long-term use of second-generation antipsychotics.

As there is an increased risk of hyperlipidaemia and diabetes with long-term use of second-generation
antipsychotics, consider the harm–benefit ratio in the use of these drugs. For discussion of adverse effects and
monitoring requirements of antipsychotic drugs, see Management of antipsychotic adverse effects.

Dosing regimens of second-generation antipsychotics indicated for prophylaxis of bipolar

disorder (Table 8.17)

Drug Prophylactic dose

aripiprazole 10 to 30 mg orally, once daily
asenapine 5 to 10 mg sublingually, twice daily [NB1]
olanzapine 5 to 30 mg orally, at night [NB2]
paliperidone (controlled-release) [NB3] 3 to 12 mg orally, at night [NB4]
quetiapine 50 to 400 mg orally, twice daily [NB5]
risperidone depot [NB6] 25 to 50 mg IM, every 2 weeks [NB7]
ziprasidone [NB3] 40 to 80 mg orally, twice daily [NB8]
NB1: Asenapine wafers should not be swallowed and food and drink should not be consumed for 10 minutes after dosing.
NB2: The maximum daily oral dose of olanzapine in accepted usage is greater than the maximum suggested in the Australian approved product
information (20 mg).
NB3: At the time of writing, this drug is not approved by the Australian Therapeutic Goods Administration (TGA) for the prophylaxis of bipolar
disorder. See the TGA website for current information [URL].
NB4: Dose adjustment of paliperidone is required in patients with kidney impairment.
NB5: A controlled-release formulation of quetiapine is available that allows for once daily night-time dosing.
NB6: The oral formulation of risperidone has not been shown to be effective in prophylaxis of bipolar disorder.
NB7: Risperidone is not released from the microspheres of the depot formulation for the first 3 weeks. Therefore, always provide antipsychotic
supplementation for the first 3 weeks after the initial injection. See also Depot antipsychotics.
NB8: Ziprasidone should be taken with food.

Antiepileptic drugs

The doses of antiepileptic drugs should be adjusted according to clinical response and toxicity. The dose of
lamotrigine should be titrated slowly to reduce the risk of serious rash.

Therapeutic serum concentrations of antiepileptics for prophylaxis of bipolar disorder have yet to be established.
For sodium valproate, the therapeutic serum concentration range for mania can be used as a guide (see
Considerations with drugs used in the treatment of acute mania: sodium valproate). For carbamazepine, the
therapeutic serum concentration range for epilepsy (ie 20 to 50 micromol/L [5 to 12 mg/L]) can be used as a guide
and to help avoid toxic concentrations. There is no apparent relationship between the serum concentration of
lamotrigine and clinical efficacy.

Before starting carbamazepine or sodium valproate, measure full blood count, serum urea and electrolyte
concentrations, and liver biochemistry. Full blood count should be monitored at least every 3 to 6 months after
treatment has commenced. There is no evidence that monitoring liver biochemistry enables prediction of
impending liver toxicity.

Anticonvulsant hypersensitivity syndrome has been reported with carbamazepine and, less commonly, with
lamotrigine. It usually occurs after 1 to 4 weeks of therapy and is characterised by fever, rash and systemic organ
involvement (lymphadenopathy, hepatitis, myositis, myocarditis, pneumonitis). The skin rash may range from an
exanthematous eruption to Stevens-Johnson syndrome and toxic epidermal necrolysis. If anticonvulsant
hypersensitivity syndrome occurs, discontinuation of the offending drug is essential. Sodium valproate is
structurally different to carbamazepine and lamotrigine, and has not been associated with anticonvulsant
hypersensitivity syndrome. It may therefore be considered as an alternative after any acute hepatitis has resolved.

For further discussion of adverse effects of antiepileptic drugs, see the Neurology guidelines. Some practical
management strategies for common adverse effects of psychotropic drugs are outlined in Table 8.23.

Controlled-release carbamazepine gives a lower maximal serum concentration than an equivalent dose of the
immediate-release formulation, which lessens the incidence of dose-related adverse effects. When switching
between immediate- and controlled-release carbamazepine, the same daily dose may be used initially. The
controlled-release tablets may be broken in half without affecting absorption, but should not be crushed.

Seizures may occur with rapid discontinuation of antiepileptics used in the management of bipolar disorder.

Psychological treatment
For many patients, augmentation of pharmacotherapy with psychological treatment focused on the bipolar disorder
is effective and is the preferred management approach. Psychotherapies, such as cognitive behavioural therapy,
social rhythms therapy and psychoeducation techniques, have been shown to be effective in preventing relapse in
bipolar disorder, with particular benefit for preventing depressive relapse. For further discussion, see
Nonpharmacological therapies for psychiatric illness: psychological interventions. Patients with bipolar disorder
may also benefit from some of the psychological therapies recommended for schizophrenia (see Schizophrenia and
related psychoses: psychological and psychosocial therapies).

Failure to respond to treatment

For patients with bipolar disorder who experience recurrences despite apparently adequate pharmacological
monotherapy, the following options should be considered:

ensure optimal serum concentrations where relevant. For example, lower recurrence rates have been shown
at lithium concentrations of 0.8 mmol/L or more than at concentrations of 0.6 mmol/L or less
check for treatment concordance
check for substance abuse (eg cannabis)
implement adequate psychological management of any comorbid anxiety disorder
combine prophylactic treatments (eg lithium plus sodium valproate, lithium plus lamotrigine, or lithium plus
olanzapine).

Reassess diagnosis and management by considering the points listed in Box 8.18.

Mixed episodes (dysphoric mania) and rapid cycling bipolar disorder

During manic episodes, some patients also experience depressive symptoms, a presentation known as a mixed
episode or dysphoric mania. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text
revision (DSM-IV-TR) diagnostic system only uses the term mixed episodes for patients concurrently fulfilling the
criteria for mania and a major depressive episode. However, other authorities use this term for patients with fewer
symptoms of depression. There is some limited evidence that mixed episodes may respond better to sodium
valproate, carbamazepine or a second-generation antipsychotic, than to lithium.

Similarly, there is some limited evidence that rapid cycling bipolar disorder (4 or more episodes of depression,
manic or mixed episodes in a 12-month period) may respond better to sodium valproate or carbamazepine. It
should be emphasised, however, that no treatment has been shown to be more effective than placebo in the rapid
cycling form of bipolar disorder in randomised controlled trials with adequate sample sizes. In other words, this is
the most difficult to treat of all presentations of bipolar disorder. Sometimes rapid cycling may be due to
concurrent antidepressants or subclinical hypothyroidism, so these issues should be addressed early in treatment.

Key references
Bipolar disorder: introduction

Mitchell PB, Johnston AK, Frankland A, Slade T, Green MJ, Roberts G, et al. Bipolar disorder in a national survey
using the World Mental Health Version of the Composite International Diagnostic Interview: the impact of differing
diagnostic algorithms. Acta Psychiatr Scand. 2012;[Epub ahead of print]. [ ]

Acute mania

Allen MH, Hirschfeld RM, Wozniak PJ, Baker JD, Bowden CL. Linear relationship of valproate serum concentration to
response and optimal serum levels for acute mania. Am J Psychiatry. 2006;163(2):272–5. [ ]

Berwaerts J, Xu H, Nuamah I, Lim P, Hough D. Evaluation of the efficacy and safety of paliperidone extended-release
in the treatment of acute mania: a randomized, double-blind, dose-response study. J Affect Disord. 2012;136(1-2):e51–
60. [ ]

Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability
of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746–58. [
]

Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, et al. A randomized, placebo- and active-controlled
study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder.
Bipolar Disord. 2010;12(3):230–43. [ ]

Bipolar depression
Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis
and meta-regression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194(1):4–9. [ ]

Prophylaxis of bipolar disorder: pharmacological treatment

Berwaerts J, Melkote R, Nuamah I, Lim P. A randomized, placebo- and active-controlled study of paliperidone
extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. J
Affect Disord. 2012;138(3):247–58. [ ]

Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care.
Pharmacotherapy. 2007;27(10):1425–39. [ ]

Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, et al. Lithium plus valproate combination
therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial.
Lancet. 2010;375(9712):385–95. [ ]

Schweitzer I. Anticonvulsant hypersensitivity syndrome: a rare and serious complication. Med J Aust.
2011;194(11):609–10. [ ]

Published March 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Schizophrenia and related psychoses
Overview of schizophrenia
Schizophrenia is a severe psychiatric illness, which is likely to affect seven in every thousand people during their lifetime. Schizophrenia is
the most common psychotic illness in Australia, accounting for 47% of people with psychoses. It is more common in men than in women,
making up 56% of psychotic illness in men and 33% of such illness in women. It contributes a disproportionately large amount to the total
disease burden attributable to mental illnesses.

Schizophrenia is characterised by disturbances in speech, perception, cognition, volition and emotion. Signs and symptoms of
schizophrenia are shown in Table 8.18. In Australia, two-thirds of people with a psychotic illness experienced their first episode before the
age of 25 years. For a little under one-third of sufferers, the onset is gradual, taking between 1 and 6 months to develop. However, for
almost half of sufferers, the onset is insidious, taking more than 6 months to develop and often associated with a marked social and
functional decline. Schizophrenia is associated with morphological and neuropathological changes that suggest subtle disruptions in brain
development and maturation. Changes in cognitive, motor and language abilities, and social or behavioural anomalies have frequently been
noted many years before the onset of the positive symptoms of the illness.

Present aetiological models propose that the disorder is caused by an interaction of genetic, epigenetic and environmental factors. Family,
twin and adoption studies have consistently demonstrated the role of genetic factors in the aetiology of schizophrenia. A number of
potential candidate genes have been identified; however, these findings have not been unambiguously replicated. It is likely that the
disorder is polygenetic in origin and no one gene is either necessary or sufficient in and of itself to cause the disorder. There is also
considerable genetic overlap with other psychiatric disorders (eg bipolar disorder). In addition, risk factors such as migration, season of
birth, prenatal viral infection, pregnancy and birth complications, and urban birth clearly point to the importance of other forces in the
genesis of the disorder. Cannabis use, particularly before the age of 18 years, plays a significant role in the onset and aetiology of
schizophrenia.

Many patients with schizophrenia have physical and psychiatric comorbid conditions, which also require specific treatment. Depression is
particularly common, with approximately 5% of people with schizophrenia committing suicide. Anxiety syndromes occur in up to 40% of
patients with schizophrenia, with 60% reporting symptoms of anxiety in the past year. In Australia, 58% of men and 39% of women with a
psychotic illness have a lifetime history of alcohol abuse or dependence, and 63% of men and 42% of women have a lifetime history of
cannabis or other illicit substance abuse or dependence. Rates of tobacco smoking are 2 to 3 times community rates, with two-thirds of
people with a psychotic illness currently smoking. These substance use disorders lead to increased rates of hospital admissions, reduced
responsiveness to medication, and more self-harm, arrests and accommodation problems.

Physical disease is common in patients with schizophrenia, including respiratory and cardiovascular disorders and diabetes. These can
occur as a consequence of the type of antipsychotic prescribed as well as secondary to lifestyle factors such as smoking, obesity, lack of
exercise and socioeconomic disadvantage. People with schizophrenia are more likely to die early from physical diseases (especially
cardiovascular disease) than the general community, due to receiving both less and later care in the course of their physical illness.

For information on schizophrenia in childhood and adolescence, see Schizophrenia and other childhood psychoses.

Maternal schizophrenia has been associated with adverse obstetric outcomes and increased risk of neonatal mortality (see Schizophrenia in
pregnancy and the postpartum). For information on drug use in pregnancy and breastfeeding, see Psychotropic drug use during pregnancy:
antipsychotics and Psychotropic drug use while breastfeeding: antipsychotics.

Signs and symptoms of schizophrenia (Table 8.18)

Positive Negative Cognitive Excitement Mood

hallucinations (eg hearing
lack of motivation
voices)
impaired planning
delusions (eg persecutory, poor self-care disorganised behaviour
reduced mental flexibility depression
bizarre, grandiose)
blunted affect aggression
impaired memory anxiety
impaired insight reduced speech output hostility
impaired social cognition
disorganised thinking and social withdrawal
speech

Psychoses other than schizophrenia

Brief psychotic disorder is an illness of less than 2 weeks' duration in which symptoms of hallucinations, delusion and thought disorder
predominate. Very rapid and full resolution of symptoms suggest that a briefer course of treatment is possible, otherwise treat as for First
psychotic episode.

Schizophreniform disorder denotes a psychotic illness with many of the features of schizophrenia, but with a shorter duration of
symptoms (less than 6 months). Again, rapid and full resolution of symptoms is associated with a better prognosis; however, this disorder
may develop into schizophrenia. Treatment of schizophreniform disorder is as for First psychotic episode.

Delusional disorder (paranoid disorder) usually presents in middle or late adult life. It is characterised by delusions (eg grandiose,
persecutory, erotomanic, somatic). Auditory or visual hallucinations, if present, are not prominent. Patients have less general impairment
than those with schizophrenia; however, they may have isolated areas of dysfunction related to their delusional ideas. The course of
delusional disorder is variable, with most patients having either persistent symptoms or a pattern of remission and relapse. Drug treatment
is the same as for schizophrenia (see First psychotic episode). Cognitive behavioural therapy targeting specific delusional beliefs can be
beneficial.

Schizoaffective disorder has prominent mood symptoms in addition to the core symptoms of schizophrenia. Patients may have episodes
of elevated mood, and/or episodes of depression. Management usually involves the combination of an antipsychotic with an antidepressant
(when depressed), and/or lithium or sodium valproate (when manic). Drugs used for prophylaxis of bipolar disorder can also be used for
prophylaxis of the mood component of schizoaffective disorder. Doses of these drugs are in line with those prescribed for bipolar disorder
(see Bipolar disorder); however, care must be taken, as the burden of adverse effects tends to increase with this polypharmacy.

Principles of schizophrenia treatment

The therapeutic relationship: The cornerstone of effective treatment of schizophrenia over the long term is engagement of the patient in a
therapeutic relationship with the clinician. Such engagement is essential in the treatment of any psychiatric disorder to instil realistic
optimism, build an effective working partnership between the patient and the clinician, and ensure continuity of care. However, there is
greater emphasis on engagement of patients with schizophrenia because of the effect of the disorder on insight, motivation and cognition,
and the need for long-term treatment that is often only partially effective and/or associated with adverse effects. The clinician must take the
initiative in actively engaging the patient by listening attentively to their worries and concerns, and responding effectively, as well as
responding empathically to emotional cues.

Early identification and intervention: There appears to be a long-term advantage for the early identification and treatment of psychosis.
Reducing the often surprisingly long period during which a person suffers from an undiagnosed psychotic illness improves outcome.
However, the most difficult part in this is the identification of young people experiencing psychotic symptoms. Health and community
agencies (eg general practitioners and teachers) have an important role in the prompt identification of psychosis and early referral. See also
‘At-risk’ or prodromal stage.

Diagnosis: Psychosis needs early identification and treatment; however, it is good clinical practice to delay definitive diagnosis at the first
presentation of a psychotic episode, as bipolar disorder and schizophrenia may be indistinguishable initially. Relevant investigations for
possible organic aetiologies are required and specific attention should be paid to possible comorbid conditions (eg substance abuse,
depression). The longitudinal course of illness will help clarify the diagnosis.

Tailored treatment: In all cases, treatment should be carefully tailored to the unique needs of the individual, taking into consideration the
patient's age, gender, ethnicity, psychosocial maturity, stage of illness, style of recovery, personality, coping style, cognitive abilities,
natural aptitudes, living situation, medical risk factors (including family history) and socio-cultural environment. Because of difficulties
with insight and poor motivation, care may sometimes need to be assertively provided with the assistance of a community mental health
team.

The role of the general practitioner: General practitioners have an important role in:

detecting and intervening in the early stages of a first or recurrent psychotic episode
monitoring treatment and clinical progress, discussing relapse prevention strategies, referring to other agencies and services,
counselling and family support
maintaining good physical health, and identifying physical illness early and providing optimal treatment.

The role of the family: Families have a central role in the treatment of young people with schizophrenia through the provision of social
and emotional support, financial assistance and a stable, secure living environment. The tremendous pressures of caring for a family
member with a psychotic illness can cause considerable dysfunction even in highly functional families. Families will need assistance from
mental health services, carer support groups and general practitioners to help them provide support.

Psychosocial interventions: Pharmacological treatment is only one part of a comprehensive management approach that also includes a
range of psychosocial interventions (see Psychological and psychosocial therapies). Intensive multimodal interventions with assertive
follow-up should be pursued for 3 to 5 years from the onset of the first psychotic episode. This gives the patient the best opportunity
possible to achieve stable remission and maximise their levels of functioning in the community. Longer-term psychosocial interventions
will be required for most people with a chronic psychotic illness.

Pharmacological treatment:

Antipsychotics are the cornerstone of the management of schizophrenia (see Treatment with antipsychotic drugs).
Overactivity and aggression should be treated with appropriate and safe containment. Antipsychotics or benzodiazepines can be of
use (see Behavioural emergencies: acute psychiatric settings). Ongoing treatment of the psychotic illness should be considered
separately to the treatment of the behavioural emergency.
The prevention of relapse by maintaining antipsychotic therapy is a crucial element in caring for people with schizophrenia.
Repeated relapses are not only associated with poorer immediate clinical outcomes, but also with a poorer long-term prognosis (see
Recovery, and relapse prevention).
Concordance with antipsychotic therapy is perhaps the biggest challenge in treatment, with nonconcordance being the largest single
cause of relapse, especially in young people with recent-onset disease [Note 1].

Comorbid disorders:

Depression and anxiety require specific enquiry as they are frequently missed. They may settle with the treatment of acute psychotic
symptoms; however, if they persist or emerge in the post-psychotic period they require appropriate treatment (see Depression and
Anxiety and associated disorders). Psychological therapies for depression also have a valuable place in treatment. The depressed
patient should be monitored closely for risk of self-harm (see Assessing suicide risk).
People with schizophrenia often have problems associated with comorbid abuse of alcohol, nicotine and/or illicit drugs. This requires
careful clinical assessment and a therapeutic approach that incorporates the treatment of both substance use and schizophrenia
concurrently (see Alcohol and other drug problems). Such treatment is probably best delivered by an integrated mental health and
substance abuse program, with staff trained in the combined approach.

Note 1: For the definition of concordance, see Concordance, adherence and compliance with psychotropic treatment.

Introduction to antipsychotics for schizophrenia

In patients with schizophrenia or related psychoses, antipsychotic drugs diminish positive symptoms such as hallucinations, delusions and
thought disorder. They also decrease symptoms of excitement, including hostility. They have limited impact on cognitive impairment,
negative symptoms and mood disturbance, all of which require additional treatment. Antipsychotics are also important for preventing
relapse. The clinician should, at the earliest suitable opportunity, explain to the patient and their family the need for medication, its
purposes, limitations, adverse effects and its place in the multimodal treatment approach. The aim is to enlist the collaboration of the
patient as an active and responsible participant in their own treatment (see Principles of treatment).

A number of different terms are used to classify antipsychotic drugs. Throughout these guidelines, amisulpride, aripiprazole, asenapine,
clozapine, olanzapine, paliperidone, quetiapine, risperidone, sertindole [Note 2] and ziprasidone are referred to as second-generation
antipsychotics (SGAs), and chlorpromazine, flupenthixol, fluphenazine[Note 3] , haloperidol, pericyazine, trifluoperazine [Note 4] and
zuclopenthixol are referred to as first-generation antipsychotics (FGAs). This distinction originally related to the propensity of SGAs to
cause fewer extrapyramidal adverse effects and other movement disorders than FGAs. However, this differentiation is now less important
as the SGAs also have significant adverse effects (eg cardiometabolic effects), and neither group acts as a single class of drugs. Therefore
the terminology now reflects, if anything, the length of time the drugs have been available.

The relative benefits and harms of SGAs compared with FGAs remains contentious. A limited range of FGAs was used in the comparative
trials and the high doses of haloperidol used in many of these studies may have exaggerated differences in rates of adverse effects. At least
one meta-analysis has found that amisulpride, clozapine, olanzapine and risperidone have an overall efficacy advantage over the FGAs for
acute symptoms [Note 5]. The other SGAs were found to be as effective as the FGAs in the acute treatment of schizophrenia. However,
another meta-analysis concluded that the benefits of SGAs versus FGAs remain uncertain [Note 6]. There is more consistent evidence that
clozapine may have an overall efficacy advantage and an advantage against positive symptoms compared to the other antipsychotics.

Given the inconsistency in comparative meta-analytic findings, these guidelines are unable to identify antipsychotics of superior efficacy.
In addition, there is a lack of experimental data and clinical experience with the newest antipsychotic, asenapine. In general, the SGAs are
recommended in preference to the FGAs due to their more favourable adverse effect profile. Due to the risk of cardiac arrhythmias,
sertindole is reserved for use in patients who are unable to tolerate at least one other antipsychotic [Note 2]. Due to the risk of
agranulocytosis, clozapine should be reserved for treatment-resistant patients and other specific patient groups (see Treatment-resistant
schizophrenia: clozapine).

For a discussion of antipsychotic adverse effects, see Management of antipsychotic adverse effects.

Most antipsychotic drugs are absorbed rapidly from the gut and are highly lipid soluble. For a first psychotic episode, oral treatment is
preferred; however, rarely, parenteral treatment may be required. It is good clinical practice to use only one antipsychotic drug at a time.
Combinations of antipsychotics seldom lead to additional clinical improvement and frequently cause adverse effects. In the longer term,
polypharmacy has been associated with increased morbidity and mortality.

Antipsychotic drugs should be used for their antipsychotic properties, rather than for any sedating effects they may have. Sedation often
occurs in the first few days of treatment, but persistent sedation may indicate that therapeutic doses have been exceeded. If sedation is
required in the short term, it is preferable to add a benzodiazepine.

Note 2: Sertindole was discontinued in Australia in January 2014.

Note 3: Fluphenazine was discontinued in Australia in 2017.

Note 4: Trifluoperazine was discontinued in Australia in 2018.

Note 5: Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for
schizophrenia: a meta-analysis. Lancet 2009;373(9657):31-41. [URL]

Note 6: Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS. Antipsychotics in adults with schizophrenia:
comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Ann Intern
Med 2012;157(7):498-511. [URL]

Management of the prodromal stage

The ‘at risk’ or prodromal stage of a psychotic illness is indicated by:

signs of deterioration in the level of functioning in the context of a positive family history of the disease
brief instances of positive symptoms (lasting less than one week) that spontaneously remit
attenuated psychotic symptoms, such as unusual perceptual experiences, occurring frequently for periods of more than a week
presence of the basic symptoms of schizophrenia in the context of individual distress or dysfunction.

Individuals identified using these strategies have an increased risk of developing a psychotic disorder, with 22% of those identified
transitioning to a psychotic disorder after 1 year and 36% after 3 years. In 73% of cases the illness that develops is a schizophrenia-
spectrum disorder.

Treatment options for this period include close monitoring, specific cognitive behavioural therapy (CBT) (see Psychological and
psychosocial therapies), selective serotonin reuptake inhibitors (SSRIs), omega-3 fatty acids and ultra-low-dose antipsychotic treatment. If
available, referral to a specialist service is recommended. Caution is required if considering commencing antipsychotic treatment at this
stage as the evidence base is incomplete and the balance of harms against benefits is unclear.

Management of the first psychotic episode in schizophrenia

Assessment

A thorough psychiatric history, mental status examination and physical examination, with particular attention to neurological assessment,
should always be conducted at first presentation. Investigations recommended at an appropriate stage include full blood count; serum
electrolytes, calcium, creatinine and urea concentrations; liver biochemistry; fasting blood glucose and serum lipid concentrations; thyroid
function tests; prolactin concentration; urine toxicology; and computerised tomography (CT) / magnetic resonance imaging (MRI) of the
brain. If indicated, also perform an immunological screen, electroencephalogram (EEG) and electrocardiogram (ECG). Blood tests should
be conducted before commencing antipsychotic treatment if possible. If available, neurocognitive testing should also be conducted as this
may reveal deficits that are important to take into consideration when planning and conducting psychosocial treatments and rehabilitation.
Neurocognitive testing is best performed after the acute symptoms of psychosis have settled. Disorders involving brain autoantibodies (eg
anti-NMDA receptor encephalitis) have been recently identified as a cause of psychosis, and can be detected through an immunological
screen—seek expert advice.

It is critical to assess the patient's ability to accept treatment and their immediate risk of self-harm or danger to others. The need for
hospitalisation should be evaluated in light of the clinical condition of the patient, and the availability of both community mental health
resources and family or other social supports. With any episode of psychosis, there is a particular need to be mindful of drug-induced or
drug-withdrawal states accompanied by psychotic symptoms and to manage these accordingly (see Alcohol and other drug problems).

Oral treatment

In clinical practice, treatment of first-episode psychosis is generally commenced with an oral second-generation antipsychotic (SGA) other
than sertindole or clozapine (see Treatment with antipsychotic drugs) [Note 7]. Sertindole is reserved for patients with difficulties tolerating
at least one other antipsychotic and clozapine is reserved for treatment-resistant patients and other specific patient groups (see Treatment-
resistant schizophrenia: clozapine). Asenapine is ranked second-line as it has the least comparative evidence and clinical experience with
its use, and requires twice-daily sublingual administration. The choice of SGA is based on the patient's presentation, clinician experience,
and the properties of the drug, including its adverse effect profile and anticipated tolerability.

Start with a low dose of antipsychotic, rising to the initial target dose detailed below. Increase the dose if there is no response within the
next 1 to 2 weeks, or in the next 3 to 4 weeks if response is inadequate. The size of the dose increase depends on tolerability, but usually 2
to 3 steps (holding the new dose steady for 1 to 3 weeks) are made to reach the top of the range. This process may be accelerated if the
patient is acutely unwell and very distressed.

There is considerable interindividual variability in the dose of an antipsychotic drug required to achieve optimum symptom remission with
minimal adverse effects. Gender and ethnic differences in drug sensitivity and metabolism need to be kept in mind. Doses at the lower end
of the recommended therapeutic range may be adequate for those in the early phases of their illness and for very young or old patients. In
particular, patients with a first psychotic episode tend to be very sensitive to antipsychotic drugs and may respond to lower-than-usual
doses. For those with a long history of exposure to antipsychotic drugs, doses at the upper end of the recommended therapeutic range will
often be necessary. In rare cases the recommended dose range may need to be exceeded, but the harm–benefit balance for the individual
patient needs to be considered. Evidence shows that substantially higher-than-recommended doses of antipsychotic drugs are associated
with increased adverse effects but no greater reduction in symptoms. High doses of SGAs risk losing the benefits of low rates of movement
disorders. Other adverse effects, such as cardiometabolic problems, tend to increase with high doses.

Patients with a first psychotic episode may respond to lower-than-usual antipsychotic doses.

Treatment options include:

1 amisulpride 100 mg orally, at night initially, increasing to 200 mg twice daily. Maximum daily dose is 1200
mg. Dose adjustment is required in patients with kidney impairment

OR

1 aripiprazole 10 mg orally, once daily initially, increasing to 15 mg once daily. Maximum daily dose is 30 mg.
As this medication can be activating, it is best taken in the morning initially

OR

1 olanzapine 5 mg orally, at night initially, increasing to 10 mg at night. Maximum daily dose is 30 mg [Note 8]

OR

1 paliperidone controlled-release 3 mg orally, at night initially, increasing to 6 mg at night. Maximum daily

dose is 12 mg. Dose adjustment is required in patients with kidney impairment

OR

1 quetiapine 50 mg orally, twice daily on day 1, then 100 mg twice daily on day 2, then increasing to 200 mg
twice daily. Response is frequently not seen until higher doses of up to 400 mg twice daily are achieved.
Maximum daily dose is 800 mg [Note 9]

OR

1 risperidone 0.5 to 1 mg orally, at night initially, increasing to 2 mg at night. Maximum daily dose is 6 mg

OR

1 ziprasidone 40 mg orally, twice daily. Maximum dose is 80 mg twice daily. Ziprasidone should be taken with
food

OR

2 asenapine 5 mg sublingually, twice daily. Maximum dose is 10 mg twice daily. Asenapine wafers should not
be swallowed and food and drink should not be consumed for 10 minutes after dosing

OR

3 sertindole 4 mg orally, once daily initially, increasing by 4 mg every 4 to 5 days until a stable dose of 12 to 20
mg once daily is achieved. Maximum daily dose is 20 mg [Note 7].

For acutely ill patients, agitation usually settles within days. Positive symptoms may require several weeks to respond fully, but some
treatment response can be expected early (ie within 1 to 2 weeks of starting an antipsychotic). The negative symptoms of schizophrenia are
responsive to antipsychotics, but less so than positive symptoms (see Treatment of negative symptoms). Once a patient has responded to a
drug it is usually possible to use once-daily dosing, which improves treatment concordance.

Particularly for the less-sedating antipsychotics, treat anxiety, agitation, insomnia or the activation syndrome (agitation/pacing, irritability,
insomnia, nausea and vomiting) with short-term benzodiazepine therapy. Use:

diazepam 5 to 10 mg orally, repeated as required, up to a maximum of 40 mg per day.

If there is unacceptable partial response after 6 to 12 weeks of treatment at adequate doses, with good treatment concordance and an
absence of complicating factors (eg substance abuse), switch to an antipsychotic with different properties from the first drug used. No
response after 4 weeks would prompt an earlier change. Use:

1 an alternative second-generation antipsychotic as recommended above

OR

2 chlorpromazine 200 mg orally, at night initially, increasing in stages up to a maximum of 800 mg at night

OR

2 haloperidol 1.5 mg orally, at night initially, increasing in stages up to a maximum of 10 mg at night. Higher
doses are approved for use, but are not recommended because of the risk of extrapyramidal adverse effects

OR

2 pericyazine 10 mg orally, at night initially, increasing in stages up to a maximum of 75 mg daily in divided

doses

OR

2 trifluoperazine 2 mg orally, twice daily initially, increasing in stages up to a maximum of 20 mg at night.

Higher doses are approved for use, but are not recommended because of the risk of extrapyramidal adverse
effects [Note 10].

For considerations when switching between antipsychotics, see Changing from one antipsychotic to another.

For patients with treatment-resistant schizophrenia, see Treatment-resistant schizophrenia.

It is essential to monitor closely for adverse effects of antipsychotic drugs. Adverse effects are commonly encountered, such as movement
disorders (eg extrapyramidal effects, akathisia), increased appetite and rapid weight gain, undue sedation, hyperprolactinaemia causing
breast enlargement and/or galactorrhoea, sexual dysfunction (this does not appear immediately), and orthostatic hypotension. If possible,
adverse effects such as weight gain should be anticipated and lifestyle interventions (eg dietary measures, exercise) should be instituted
early. For management of adverse effects, see Management of antipsychotic adverse effects.

For discussion of duration of therapy, see Recovery, and relapse prevention.

Note 7: Sertindole was discontinued in Australia in January 2014.

Note 8: The maximum daily oral dose of olanzapine in accepted usage is greater than the maximum suggested in the Australian
approved product information (20 mg).

Note 9: A controlled-release formulation of quetiapine is available that allows for once daily night-time dosing.

Note 10: Trifluoperazine was discontinued in Australia in 2018.

Parenteral treatment

Parenteral treatment should be avoided if at all possible in the acute care of patients with schizophrenia. However, if the patient's illness is
so severe or the patient poses a risk to themselves or others such that they require detention under the relevant mental health legislation,
then treatment may need to be enforced despite the patient's refusal to take oral treatment. In that cas​e, until they can be convinced to take
oral medication, parenteral medication may be required. For recommendations and monitoring requirements for parenteral treatment, see
Behavioural emergencies: acute psychiatric settings.

Recovery and relapse prevention in schizophrenia

Introduction
Return to a productive life is possible for the vast majority of people with schizophrenia, but this requires the coordination of families and
mental health services, working with schools, colleges and vocational specialists.

There is clear evidence for antipsychotics in the prevention of relapse; however, no antipsychotic has been shown to have a superior effect
in this regard. The second-generation antipsychotics (SGAs) may have a small advantage over the first-generation antipsychotics (FGAs)
[Note 11]. Maintenance on the best-tolerated antipsychotic is the most effective way of reducing relapse rates. Maintenance medication
needs to be continuous and, if possible, at the lower end of the dose range. Intermittent treatment (ie a ‘drug holiday’) is not recommended.
The need for adequate symptom control and cognitive function must be balanced against the risk of movement disorders, sedation,
hyperprolactinaemia, weight gain and other cardiometabolic adverse effects, and sexual dysfunction. There is also a risk of persistent
movement disorders (eg tardive dyskinesia) with long-term treatment, the risk of which appears to be less with SGAs than with FGAs.

Note 11: Kishimoto T, Agarwal V, Kishi T, Leucht S, Kane JM, Correll CU. Relapse prevention in schizophrenia: a systematic review
and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry 2013;18(1):53-66. [URL]

Key interventions
Some key interventions in this maintenance phase, which should commence during recovery from the first and/or subsequent episodes, are
listed in this section.

Continue pharmacological treatment for an adequate duration

Following a first psychotic episode, continue antipsychotic treatment beyond the acute stage and maintain for 2 years if possible,
depending on the duration and severity of the episode and the degree of remission achieved. At the end of this period, if there has
been full remission, the antipsychotic can be cautiously tapered and discontinued over a period of at least 3 months. The patient must
be carefully monitored for early warning signs of relapse during this process and for a further 12 months after drug cessation. If a
definitive diagnosis of schizophrenia has been made, the antipsychotic should be continued for a minimum of 2 years before making
a critical appraisal of the need to continue or withdraw the drug.
If relapse occurs after cessation of maintenance therapy, longer-term treatment (ie at least 5 years) is required. Indefinite continuation
of maintenance therapy is required for the majority of people with schizophrenia.
Actively ask about and monitor for adverse drug effects, including extrapyramidal adverse effects and other movement disorders. If
adverse effects are present, respond by lowering the dose or switching to another drug with a lower propensity to cause adverse
effects (see Management of antipsychotic adverse effects). Unless specifically asked about, adverse effects such as sexual
dysfunction will rarely be volunteered.
Depot antipsychotics may be superior to oral antipsychotics for the prevention of relapse. Consider the use of depot antipsychotics if
psychosocial therapies fail to achieve adequate treatment concordance. In some cases more coercive measures are required, such as
community treatment orders.

Use a broadly based treatment program

Foster a therapeutic alliance using supportive psychotherapeutic strategies (eg active listening, empathic responsiveness, explanation,
reassurance). Provide the patient with a working explanatory model of their disorder.
Involvement of the patient's general practitioner for both the patient's general physical health and the treatment of schizophrenia is
strongly recommended. Shared-care programs can be used to help improve a range of health outcomes for people with
schizophrenia.
Access the following as necessary: case management services, assertive community treatment, cognitive behavioural therapies (eg
medication compliance therapy, motivational interviewing for substance abuse, coping strategies enhancement, symptom control
interventions), cognitive remediation for cognitive deficits, social skills programs, supported employment programs, accommodation
and disability support options, education and training assistance, and social interventions to combat isolation (see Psychological and
psychosocial therapies). See Appendix 8.1 for patient resources and support organisations.

Manage comorbidity

Actively monitor substance use. Inform all patients about the risks of comorbid substance abuse; for example increased risk of
relapse, increased symptoms, increased risk of self-harm. Management by an integrated treatment program that provides
simultaneous treatment for substance use and mental illness appears to have the best outcome (see Alcohol and other drug problems).
Assess for and treat comorbid depression, suicidality and anxiety disorder (see Depression and Anxiety and associated disorders).

Maintain physical health

Target cardiovascular risk factors, by:

–
encouraging physical fitness with daily exercise, healthy eating and smoking cessation. Smoking cessation may increase the
plasma concentrations of some antipsychotics (eg clozapine, olanzapine) necessitating a dose reduction. See also Psychotropic
treatment in people who smoke
–
monitoring blood pressure, weight, body mass index (BMI), waist circumference, serum lipids and blood glucose.
Many antipsychotics can cause cardiometabolic problems—for prevention and management, see Weight gain and other
cardiometabolic effects.
Involve the patient in other appropriate preventive health programs (eg bowel cancer screens, pap smears).

Work with family/carers

Engage the patient and their family in a psychoeducation program (see Psychological and psychosocial therapies). This should
include information about their illness, their characteristic early symptoms and signs of relapse, their medication, the adverse effects
of the medication, and their physical health needs.
If available, family therapy using problem-solving techniques or focusing on communication has been shown to be useful in
preventing relapse or rehospitalisation.
Carer assistance programs can help to support and educate family members and to provide respite care. For further information, see
Appendix 8.1.

Depot antipsychotics
Poor treatment concordance is often a cause of relapse of illness. Contributing factors to nonconcordance can include persistent adverse
effects, impaired insight, disorganisation or cognitive impairment, lack of community support, inadequate community treatment and lack of
patient or caregiver education. If persistent nonconcordance does not respond to psychosocial interventions, a trial of a depot antipsychotic
is indicated. If the patient does not consent to depot antipsychotics, the relevant mental health legislation may need to be considered (eg
community treatment orders). Depot formulations are also an option if the patient is unable to take oral medication or if they are preferred
by the patient.

There is no strong evidence to suggest that one depot antipsychotic has efficacy advantages over another. The adverse effect profiles of
depot antipsychotics are comparable to that of their oral forms.
Apart from risperidone depot, antipsychotic depot formulations are decanoate, palmitate or pamoate esters dissolved or suspended in an
oily or aqueous base. When injected deeply into muscle, the ester slowly diffuses into the circulation. The time course of onset of action is
variable. Risperidone depot uses risperidone molecules in a synthetic and absorbable polymer microsphere base suspended in water. After a
single injection of risperidone microspheres, there is a small initial release of drug (less than 1%) followed by a lag time of 3 weeks during
which no drug is released.

It is preferable for the patient to be stabilised on the oral formulation of the antipsychotic before switching to the depot formulation as dose
titration is far easier and more accurate with oral medication. For approximate comparative oral and intramuscular depot maintenance
doses for some antipsychotics, see Table 8.19.

For most depot formulations, it may take several months for drug concentrations to reach steady-state so oral antipsychotic
supplementation may be required initially and then reduced and ceased after the first few weeks. Preferably the oral form of the depot
antipsychotic should be used. As very little risperidone is released from the microspheres of the depot formulation for the first 3 weeks,
oral supplementation should always be provided for the first 3 weeks after the initial injection of risperidone depot. A loading dose of the
depot formulation is recommended for olanzapine and paliperidone depots so initial oral supplementation may not be required with these
drugs. For all depot formulations, dose adjustment before steady-state is reached should be undertaken carefully and infrequently. The dose
of risperidone depot should not be adjusted in the first 3 weeks of dosing.

Depot antipsychotics may take 2 to 4 months to achieve steady-state plasma concentrations so adjust dose carefully and infrequently.

In the case of haloperidol, olanzapine, paliperidone and risperidone depots, an initial test dose of the oral medication should precede the
depot injection. For other depot formulations, where an oral formulation is not available, a small initial test dose of the depot drug is
recommended, especially if the patient has not been exposed to that class of antipsychotic previously.

If a depot formulation is required, use one of the following:

1 flupenthixol decanoate 10 mg IM, initially, then dose titrated to between 20 and 40 mg and the frequency
titrated to between 2- and 4-weekly

OR

1 fluphenazine decanoate 12.5 mg IM, initially, then dose titrated to between 12.5 and 50 mg and the frequency
titrated to between 2- and 4-weekly [Note 12]

OR

1 haloperidol decanoate 50 mg IM, initially, then dose titrated to between 50 and 200 mg every 4 weeks

OR

1 paliperidone palmitate 150 mg IM, then 1 week later 100 mg IM as a loading dose; thereafter 75 mg every 4
weeks (the dose may be titrated to between 50 and 150 mg every 4 weeks). Dose adjustment is required in
patients with kidney impairment

OR

1 risperidone 25 mg IM, initially, then dose titrated to between 25 and 50 mg every 2 weeks. Risperidone is not
released from the microspheres of the depot formulation for the first 3 weeks. Therefore, always provide
antipsychotic supplementation for the first 3 weeks after the initial injection

OR

1 zuclopenthixol decanoate 100 mg IM, initially, then dose titrated to between 200 and 400 mg and the
frequency titrated to between 2- and 4-weekly. Patients switched from zuclopenthixol acetate do not require a
test dose of zuclopenthixol decanoate

OR

2 olanzapine pamoate monohydrate 210 mg IM, every 2 weeks or 405 mg IM, every 4 weeks as a loading dose
for 2 months, then 150 mg every 2 weeks or 300 mg every 4 weeks. The maximum dose is 300 mg every 2
weeks.
Monitor patients every 30 minutes for the first 3 hours after every injection of olanzapine depot.

Olanzapine depot can cause a post-injection syndrome of profound sedation with dizziness, weakness, altered speech, hypertension and
seizures, coma or delirium. The reported rate of occurrence is 0.07% of injections. Patients should be monitored every 30 minutes for the
first 3 hours after every injection of olanzapine depot.

Most depot formulations are given by deep intramuscular injection with a 21-gauge needle in the upper and outer quadrant of the buttock.
Subsequent injections are alternated between left and right buttock sites. Risperidone, paliperidone and olanzapine depots have specific
administration packs. The Z-track technique is used to break the needle path and aims to reduce seepage of drug and discomfort at the
injection site. Using the nondominant hand, the skin and subcutaneous tissue is pulled away from the injection site. Maintaining traction,
the injection is given slowly, waiting 10 seconds before removing the needle, then immediately releasing traction.

Doses of depot antipsychotics should not be raised or lowered for minor reasons over short periods as this may augment adverse effects
and/or compromise symptom control.

Approximate comparative oral and IM depot maintenance doses for some antipsychotics (Table 8.19)
 Drug Approximate comparative oral and IM depot maintenance doses [NB1]
Oral IM depot
5 mg daily 100 mg every 4 weeks
haloperidol 7.5 mg daily 150 mg every 4 weeks
10 mg daily 200 mg every 4 weeks
10 mg daily 150 mg every 2 weeks
olanzapine 15 mg daily 210 mg every 2 weeks
20 mg daily 300 mg every 2 weeks
3 mg daily 50 mg every 4 weeks
paliperidone 6 mg daily 75 mg every 4 weeks
9 mg daily 100 mg every 4 weeks
2 mg daily 25 mg every 2 weeks
risperidone 3 mg daily 37.5 mg every 2 weeks
4 mg daily 50 mg every 2 weeks
IM = intramuscular injection
NB1: Formulation strengths were taken into consideration when determining comparative doses. For comparative oral doses of different antipsychotics, see Table 8.20.

Note 12: Fluphenazine was discontinued in Australia in 2017.

Treatment of relapse in schizophrenia

For treatment of behavioural emergencies, see Behavioural emergencies.

Relapse is very common in schizophrenia, occurring in 80% of patients who recover from the first episode. Relapse is usually associated
with drug discontinuation either due to poor concordance or planned discontinuation. Educating the patient and their family about
schizophrenia, the early warning signs of relapse and strategies for early intervention has been shown to reduce the risk of relapse. Relapse
represents a personal and family crisis. Repeated relapse is often associated with treatment resistance and poor long-term outcome.

Risk factors for relapse include poor insight into the purpose of medication, psychosocial stressors, substance use, and premature lowering
of the dose or discontinuation of antipsychotic treatment. A thorough review of the history and current stressors, including consideration of
substance use, may reveal these and other risk factors, which should become the focus of an intensified relapse prevention strategy.

If relapse occurs, an assessment should be undertaken of the risk of harm to self and to others, and of the competency of decision-making,
level of insight and degree of disorganisation of the patient. If, in addition to these factors, treatment concordance has been poor despite
intervention, consider commencing a depot antipsychotic (see Depot antipsychotics) and/or initiation of proceedings for involuntary
community treatment.

If relapse is associated with obvious affective symptoms (especially if manic-like) consider adding lithium, carbamazepine or sodium
valproate to maintenance antipsychotic drugs.

The drugs listed in First psychotic episode and their corresponding dose ranges are suitable for routine use in the treatment of relapse.
Patients who have had two or more psychotic episodes, particularly if they have a long history of treatment, will generally be less sensitive
to antipsychotic drugs and will often require doses at the upper end of the recommended range.

Treatment-resistant schizophrenia
Introduction

Even when clinically stable and in apparent remission, up to 40% of patients with schizophrenia continue to experience residual symptoms
of varying severity. Severe treatment resistance refers to the continuation or recurrence of relatively severe positive, negative and/or
cognitive symptoms, often accompanied by emotional distress and/or severe disability, in spite of what appears to be adequate treatment.
Management of treatment-resistant schizophrenia requires specialist review.

The first step in management is to identify any reasons for treatment resistance. A diagnostic review should be undertaken and treatment
concordance should be assessed. Family and social factors that may be undermining treatment need to be sought and evaluated. The abuse
of alcohol and other drugs (eg cannabis, amphetamines) also needs to be assessed, as such problems are known to interfere with treatment
response (see Alcohol and other drug problems). Urine drug screening may be indicated, but this only identifies recent use and does not
constitute a diagnosis of drug abuse or dependence, which requires a thorough clinical assessment for diagnosis. See also Box 8.18 for key
questions in assessing failure to respond to psychotropic drugs. If any of these factors are identified, the treatment approach should be
modified accordingly.

If none of the preceding factors are thought to be occurring and the symptoms have not settled substantially after assured concordance with
an adequate drug trial of 6 to 12 weeks' duration on optimal doses of at least two different antipsychotics (see Oral treatment), then
treatment resistance should be diagnosed. The trial of a course of depot antipsychotic treatment may be the only way of confirming
treatment concordance and this trial may take longer than 12 weeks because of the need to achieve and maintain an adequate steady-state
antipsychotic concentration.

For management of patients with persistent negative symptoms, see Treatment of negative symptoms.

There is no evidence that substantially higher-than-recommended doses of any antipsychotic drug are of benefit in treatment-resistant illness.

Clozapine

There is strong evidence demonstrating the efficacy of clozapine for treatment-resistant schizophrenia. A trial of clozapine should be
offered to all patients who have not responded to an adequate trial of two or more alternative antipsychotic drugs (see Treatment-resistant
schizophrenia: introduction). This includes patients with a first-episode psychosis whose illness has failed to show adequate remission in
spite of adequate pharmacological treatment. At least a third of patients show at least moderate improvement after a 6- to 12-month trial of
clozapine. The principal factors limiting clozapine use are the need for the patient to be willing to take oral medication and clozapine's
unique adverse effect profile.

In addition to severe and persistent positive and/or negative symptoms, clozapine is also indicated for patients with schizophrenia who
have:

persistent or frequently recurrent suicidal ideation and/or behaviours

severe and persistent extrapyramidal adverse effects (eg tardive dyskinesia)
marked aggressive behaviour
severe comorbid substance abuse.

If indicated, clozapine should be commenced at a very low dose, increasing as tolerated and according to patient response. The usual
effective daily dose is 200 to 600 mg.

Clozapine has been reported to cause neutropenia in 2% to 3% of patients and agranulocytosis in 1% of patients. Hence it requires strict
monitoring and its distribution is limited to registered centres. There have been reports of myocarditis in the early weeks of clozapine
treatment and, later on, cardiomyopathy. Patients must be closely supervised when treatment is started. For comprehensive monitoring
recommendations, refer to protocols available from the manufacturers of clozapine or relevant government authorities. In general,
clozapine monitoring should include systematic evaluation of the following parameters:

white blood cell and neutrophil counts for at least the first 18 weeks
cardiac parameters, including regular measurement of body temperature, pulse rate, blood pressure and respiratory rate. Troponins
and C-reactive protein should be measured weekly for the first 4 weeks. Further investigations, including electrocardiogram (ECG)
and echocardiogram, are recommended at baseline and should be repeated on the basis of the other observations and results
metabolic parameters, including weight, body mass index (BMI), waist circumference, blood glucose concentration and lipid profile
(see Weight gain and other cardiometabolic effects).

Avoid concurrent use of drugs that can cause blood dyscrasias, such as carbamazepine or chemotherapeutic agents. Clozapine is
metabolised by cytochrome P450 (CYP) 1A2. Drugs that inhibit or induce CYP1A2 may increase or decrease plasma clozapine
concentration. Plasma clozapine concentration can increase significantly in patients who stop smoking (see Psychotropic treatment in
people who smoke).

Patients should also be monitored for adverse effects such as gastrointestinal hypomotility (ranging from constipation to bowel perforation
and death), urinary retention, urinary incontinence, hypersalivation (with risk of aspiration pneumonia), sedation, orthostatic hypotension,
myoclonus and seizures.

Clozapine can be monitored by plasma concentration. The threshold for therapeutic effect has been variously reported from 200 to 550
micrograms/L, although failure to respond at or above this concentration does not preclude increasing the dose. Rapid dose increase, doses
more than 600 mg per day and plasma concentrations above 1000 micrograms/L are associated with a higher incidence of seizures. An
upper limit of 900 mg per day is recommended, though rarely needed. The indications for measuring plasma clozapine concentration
include failure to respond, the presence of significant adverse effects in a responder, complicating physical disease (especially liver
disease), concurrent administration of other drugs, advanced age and suspicion of poor treatment concordance. Blood should only be taken
for clozapine concentration measurement after the patient has achieved a steady-state concentration on a stable dose for at least one week.
An early morning trough blood sample is required.

Other pharmacological treatments

Between 30% and 70% of treatment-resistant patients will not respond to a trial of clozapine. Further treatment is recommended for this
group. A small number of augmenting strategies with clozapine have received limited support including:

amisulpride up to 400 to 800 mg orally, per day

haloperidol up to 2 to 3 mg orally, per day
lamotrigine up to 300 mg orally, per day (dose should be titrated slowly)
omega-3 fatty acids (in particular formulations high in eicosapentaenoic acid) 2 to 3 g orally, per day.

The addition of an antiepileptic drug, including sodium valproate or lamotrigine (at doses used in epilepsy), or lithium has been useful in
augmenting medication for schizoaffective disorder.

Polypharmacy with multiple antipsychotic drugs has been deployed in numerous trials but seldom with consistent success.

Electroconvulsive therapy

Although there is a lack of consensus regarding the role of electroconvulsive therapy (ECT) in the management of schizophrenia, it has
been found to be a relatively safe and tolerable treatment for patients with otherwise resistant positive symptoms of psychosis, catatonia or
an associated severe depression. However, the relapse rate is high after ceasing an acute course of ECT. Therefore, maintenance
antipsychotic drug treatment is essential. A trial of adjunctive ECT should be considered in patients who fail to respond to clozapine.

Maintenance ECT for schizophrenia has a limited evidence base and is not usually practised.

See also Nonpharmacological therapies for psychiatric illness: electroconvulsive therapy.

Treatment of negative symptoms of schizophrenia

Negative symptoms are a significant cause of long-term disability in schizophrenia. Although negative symptoms respond partially to
antipsychotic drugs, they frequently remain at high levels despite adequate pharmacotherapy. Assessment of the patient at this stage should
include a review of their level of engagement with their family and the community; a detailed cognitive assessment; and investigation for
secondary causes of negative symptoms such as extrapyramidal adverse effects, depression, marked anxiety causing social avoidance or
agoraphobia, or excessive antipsychotic doses. Excessive doses of antipsychotic drugs can augment negative symptoms and cause
additional dysphoria.

Management of negative symptoms requires psychosocial interventions that aim to motivate and cognitively engage the patient in addition
to antipsychotic treatment. One meta-analysis has suggested that a small number of second-generation antipsychotics (amisulpride,
clozapine, olanzapine and risperidone) are superior to first-generation antipsychotics in the treatment of negative symptoms [Note 13].
Successful augmentation strategies that have been examined include the use of antidepressants, particularly fluoxetine, and the use of
lamotrigine combined with clozapine. A small number of trials suggest that low-dose amisulpride has benefits for negative symptoms;
however, low-dose antipsychotics generally may be beneficial.

If negative symptoms are prominent and have not improved with first-line therapy, consider changing to:

1 amisulpride 100 to 300 mg orally, daily

OR

1 clozapine (see Clozapine for information on dosing and monitoring)

OR

1 a second-generation antipsychotic other than clozapine (see First psychotic episode: oral treatment for dosing
regimens)

PLUS
an antidepressant (fluoxetine preferred) (see Table 8.13 for dosing regimens)

OR

2 clozapine (see Clozapine for information on dosing and monitoring)

PLUS
an antidepressant (fluoxetine preferred) (see Table 8.13 for dosing regimens)

OR

2 clozapine (see Clozapine for information on dosing and monitoring)

PLUS
lamotrigine 25 mg orally, daily (on alternate days if combined with sodium valproate) for 2 weeks,
then increase the daily dose by 25 mg every 2 weeks to 100 mg twice daily (50 mg twice daily if
combined with sodium valproate). If necessary, increase up to 300 mg twice daily (150 mg twice
daily if combined with sodium valproate).

The dose of lamotrigine should be titrated slowly to reduce the risk of serious rash. If the patient is also on sodium valproate, lower
lamotrigine doses are needed and the rate of introduction should be slower.

Note 13: Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for
schizophrenia: a meta-analysis. Lancet 2009;373(9657):31-41. [URL]

Changing from one antipsychotic to another in schizophrenia

Changing between antipsychotic drugs is frequently done in the treatment of schizophrenia due to poor treatment response or adverse
effects, or on patient request. Before changing it is prudent to check if previous treatment failure has been due to poor concordance and if
so, why, as this may be the proper focus of treatment and/or guide the selection of the next antipsychotic. If good control of symptoms is
present, but adverse effects are a concern, lowering the dose of the present antipsychotic may avoid the need to change to another drug.

When the decision has been made to change antipsychotics, it is important to:

educate the patient about the risks (relapse, temporary adverse effect exacerbations) and potential benefits (improved symptom
control, eventual reduction in adverse effects)
plan the changeover.

The target dose for the new drug should be therapeutically comparable to the dose of the antipsychotic being ceased to avoid relapse due to
inadequate dosing. The speed of the changeover affects the likelihood of adverse effects with the new antipsychotic.

When switching between oral antipsychotics in the nonacute patient, a crossover phase of at least 1 to 2 weeks is recommended, during
which the dose of the drug being ceased is reduced and the dose of the new drug is gradually increased (see Table 8.20 for considerations
when switching between oral antipsychotics).

When switching a patient from a depot to an oral formulation, the depot formulation should be ceased and the dose of the oral formulation
gradually increased. Concentrations of the depot antipsychotic may remain clinically relevant for weeks to months and upwards titration of
the oral antipsychotic may need to be slowed. Initial extrapyramidal adverse effects may be due to the depot medication that is slowly
washing out, rather than the oral antipsychotic being commenced. A return of psychotic symptoms 2 to 5 months after changing treatment
may indicate inadequate dosing or treatment failure with the newer drug. For information about switching a patient from an oral to a depot
formulation, see Depot antipsychotics.

Changing between drugs may cause particular problems relating to the pharmacokinetic and pharmacodynamic properties of the drugs.
These include:

emergent movement disorders due to a change in the level of dopaminergic blockade. Movement disorders frequently settle
quickly, but rarely can be chronic and require either a prolonged period to settle or consideration of a change to treatment with
clozapine
increased risk of pregnancy due to loss of the contraceptive effect of hyperprolactinaemia secondary to stopping some
antipsychotics (eg amisulpride, paliperidone, risperidone, all first-generation antipsychotics). This requires warning and starting
 contraception
cholinergic rebound syndrome (causing a flu-like syndrome [ie malaise, myalgia, rhinorrhoea], nausea, vomiting and agitation)
when changing to an antipsychotic with less anticholinergic properties (eg amisulpride, aripiprazole, haloperidol, paliperidone,
risperidone, ziprasidone). Short-term treatment with an anticholinergic such as benztropine 1 to 2 mg orally, daily may be required
an activation syndrome of restless overactivity, insomnia, nausea and vomiting has been described when starting less-sedating
antipsychotics, such as amisulpride or aripiprazole. This is probably distinct to akathisia and can be treated with a short course of
benzodiazepines, such as diazepam 2 to 10 mg orally, twice daily
changes in QTc interval.

During the crossover, clinicians, carers and patients should look out for early signs of breakthrough psychosis. Some patients have a
consistent symptom pattern that heralds relapse (the ‘relapse signature’). It is also helpful to set predetermined treatment goals to decide
whether to continue or stop the trial (eg reduction in symptoms, improved adverse effect profile).

Rapid cessation of an antipsychotic, particularly clozapine, has been associated with a supersensitivity psychosis, which is a psychotic
syndrome with rapid onset of symptoms often marked by high levels of positive symptoms, agitation and relative resistance to treatment. If
possible, patients should be slowly withdrawn from clozapine to avoid this.

A small number of antipsychotics have significant drug interactions and these should be considered whenever a new antipsychotic is
commenced. For a detailed listing of drug interactions, see the product information for individual drugs or an appropriate reference (eg
Australian Medicines Handbook).

Considerations when switching between oral antipsychotics (Table 8.20) [NB1]

Therapeutically comparable daily

doses of oral antipsychotics [NB2] Problems seen starting this Problems seen stopping this
Antipsychotic
Low dose Medium High dose drug drug
(mg) dose (mg) (mg)
Second-generation antipsychotics
risk of unplanned
increased prolactin pregnancy due to decrease
amisulpride 400 600 800
in prolactin

aripiprazole 10 20 30 initial agitation

oral hypoaesthesia
asenapine 10 15 20
sedation
insomnia, decreased
rapid weight gain and other
olanzapine 5 20 30 [NB3] sedation
cardiometabolic effects

initial orthostatic risk of unplanned

paliperidone 6 9 12 hypotension pregnancy due to decrease
increased prolactin in prolactin

sedation
weight gain and other decreased sedation
quetiapine 300 600 800
cardiometabolic effects

initial orthostatic risk of unplanned

hypotension pregnancy due to decrease
risperidone 2 4 6
increased prolactin in prolactin

QTc interval prolongation

sertindole [NB4] 12 16 20 multiple drug interactions

QTc interval prolongation

ziprasidone 80 120 160 nausea

First-generation antipsychotics
sedation decreased sedation
anticholinergic effects risk of unplanned
movement disorders pregnancy due to decrease
orthostatic hypotension in prolactin
chlorpromazine 200 400 800
weight gain and other dyskinesias
cardiometabolic effects cholinergic rebound
increased prolactin syndrome

risk of unplanned
QTc interval prolongation
pregnancy due to decrease
movement disorders
haloperidol 2 10 20 in prolactin
increased prolactin
dyskinesias

decreased sedation
risk of unplanned
sedation
pregnancy due to decrease
anticholinergic effects
pericyazine 20 40 75 in prolactin
increased prolactin
cholinergic rebound
syndrome

risk of unplanned
movement disorders pregnancy due to decrease
trifluoperazine [NB5] 5 to 10 15 to 20 30 increased prolactin in prolactin
dyskinesias

NB1: Clozapine has not been included in this table; if switching to or from clozapine, seek specialist advice.
NB2: Start the new antipsychotic at a very low dose and gradually increase the dose aiming for a dose therapeutically comparable to the dose of the most recently used antipsychotic.
Most switches can be done as a cross-taper. Be aware of possible interactions (eg prolonged QTc interval or emergent movement disorders).
NB3: The maximum daily oral dose of olanzapine in accepted usage is greater than the maximum suggested in the Australian approved product information (20 mg).
NB4: Sertindole was discontinued in Australia in January 2014.
NB5: Trifluoperazine was discontinued in Australia in 2018.

Management of antipsychotic adverse effects

Introduction
Adverse effects due to antipsychotics are common, but there is a wide range of individual differences in their occurrence (see Table 8.21).
Starting at low doses and stepping up the dose slowly can reduce the impact of adverse effects. Additive and synergistic effects may occur
when two or more drugs with similar adverse effects are used concurrently.

If adverse effects occur, review the dose, timing of the dose, and potential drug interactions that may be contributing to the adverse effect
burden. Some practical management strategies for common adverse effects of psychotropic drugs are outlined in Table 8.23. If these
strategies are ineffective or if the adverse effects are severe or unacceptable, a change in antipsychotic may be required (see Changing from
one antipsychotic to another). Be aware there are particular problems that may arise when changing from a first- to a second-generation
antipsychotic.

Particular problems may arise when changing from a first- to a second-generation antipsychotic.

For a specific discussion of clozapine adverse effects, see Treatment-resistant schizophrenia: clozapine.

For information on management of overdose of antipsychotics, see Toxicology: antipsychotics.

Approximate relative frequency (not intensity) of common adverse effects of antipsychotics (Table 8.21) [NB1]

This table lists the approximate relative frequency of adverse effects, not the intensity with which they occur.

Anticholinergic Extrapyramidal Orthostatic Weight

Drug Dyslipidaemia Hyperglycaemia Hyperprolactinaemia Sedation
effects effects hypotension gain
Second-generation antipsychotics
amisulpride – ? + – +++ – + +
+
aripiprazole + – + – – + –
[NB2]
asenapine
+ ++ + ++ + + + +
[NB3]
clozapine +++ [NB4] +++ – +++ +/– +++ [NB5] +++ +++
olanzapine ++ +++ +/– +++ + + ++ +++
paliperidone + ++ + + +++ ++ [NB5] + ++
quetiapine + ++ + +++ + ++ ++ ++
risperidone + ++ + ++ +++ ++ [NB5] + [NB5] ++
sertindole
– – – – + + [NB6] – +
[NB12]
ziprasidone + – + + ++ + + +
First-generation antipsychotics
chlorpromazine +++ +++ ++ +++ +++ +++ [NB7] +++ +++
flupenthixol ++ ? ++ ++ +++ + + ++
fluphenazine
+ ? +++ ++ +++ + + +++
[NB9]
haloperidol + + +++ [NB8] ++ +++ + + [NB7] ++
pericyazine +++ ? + + [NB10] +++ ++ +++ ++
trifluoperazine
+ ? +++ + +++ ++ + ++
[NB11]
zuclopenthixol ++ [NB4] ? ++ + [NB10] +++ + +++ ++
Approximate frequencies of adverse effects: ? = little or no information reported; – = negligible or absent; + = infrequent; ++ = moderately frequent; +++ = frequent
NB1: The information in this table is based on a combination of reported adverse effect data and expert opinion; it is intended only as a guide and should be interpreted in the context of
the patient's particular situation (eg concurrent drugs, drug history, physical health, the considerable interindividual variation in elimination half-lives) and the doses of the drugs.
NB2: Weight loss reported.
NB3: Data on asenapine adverse effect frequencies are limited.
NB4: Hypersalivation reported.
NB5: Frequency may be higher at the start of therapy or with rapid dose increase.
NB6: Frequency may be higher with rapid dose increase, but data are conflicting.
NB7: More frequent with rapid dose increase.
NB8: Lower incidence with depot formulation.
NB9: Fluphenazine was discontinued in Australia in 2017.
NB10: Reported to occur but no definitive data published as to the incidence.
NB11: Trifluoperazine was discontinued in Australia in 2018.
NB12: Sertindole was discontinued in Australia in January 2014.
Weight gain and other cardiometabolic effects
Antipsychotic drugs differ in their potential to cause cardiometabolic adverse effects such as weight gain, dyslipidaemia, hyperglycaemia
and hypertension (see Table 8.21). Among the second-generation antipsychotics, clozapine and olanzapine have the highest risk of
cardiometabolic adverse effects, followed by quetiapine. Amisulpride, aripiprazole and ziprasidone are thought to have a lower risk of
cardiometabolic problems. Of the first-generation antipsychotics, chlorpromazine has the highest risk of cardiometabolic adverse effects,
while haloperidol and trifluoperazine [Note 15] are considered to have a lower risk.

Just under 50% of people with psychosis in Australia fulfil the criteria for the metabolic syndrome, which is defined by an increased waist
circumference and the presence of any two of the following factors [Note 14]:

raised triglyceride levels

reduced high-density lipoprotein cholesterol (HDL-C) levels
hypertension
hyperglycaemia.

The metabolic syndrome increases the risk of developing diabetes and cardiovascular disease and a range of other conditions including
nonalcoholic fatty liver disease and gout. The metabolic syndrome and its consequences contribute substantially to the increased risk of
morbidity and mortality observed in patients with psychotic illness. Being aware of metabolic syndrome criteria may help identify patients
at particularly high risk, but each cardiometabolic abnormality should be screened for and managed in its own right. Additional
cardiovascular risks, especially cigarette smoking, need to be concurrently managed.

The following strategies should be actively pursued in the prevention of cardiometabolic adverse effects associated with antipsychotics:

Assess the propensity for cardiometabolic problems at the time of prescribing and factor this into the choice of antipsychotic. Drug
selection is particularly important in patients who are overweight, already at increased risk of cardiovascular disease or have a
positive family history for relevant conditions such as diabetes or hypertension.
Cease any drug that is causing rapid weight gain, if possible.
Provide dietary and other lifestyle advice (including advice on smoking cessation) before or soon after starting an antipsychotic.
Repeat this advice and monitor uptake of the suggestions, especially when commencing high-risk drugs such as clozapine or
olanzapine. Stopping smoking may increase the plasma concentrations of some antipsychotics (eg clozapine, olanzapine)
necessitating a dose reduction (see Psychotropic treatment in people who smoke).
Monitor all patients on an antipsychotic drugs clinically and biochemically for cardiometabolic abnormalities. Monitoring
parameters should consist of:
–
weight, body mass index (BMI) and waist circumference
–
blood pressure
–
fasting blood glucose concentrations
–
full lipid profile (triglycerides, total cholesterol, HDL-C, low-density lipoprotein cholesterol [LDL-C]).

Monitoring should be done at baseline, 3-monthly for the first year and then 6-monthly for the duration of therapy. It is essential to identify
the clinician responsible for ensuring that monitoring occurs (usually the patient's general practitioner or psychiatrist).

If present, cardiometabolic abnormalities may need further investigation (eg oral glucose tolerance test, ambulatory or home blood pressure
monitoring) and treatment. Effective management requires cooperation and communication between the psychiatrist, the general
practitioner, other specialists, the mental health team, and the patient and their supports. Management strategies include:

ongoing lifestyle interventions

–
education on healthy eating and weight reduction programs (eg physical activity) (see Management of overweight and obesity)
–
smoking cessation
review of concurrent drugs that may be contributing to the weight gain (eg mirtazapine, sodium valproate)
pharmacotherapy
–
for management of impaired glucose tolerance or impaired fasting glucose, and type 2 diabetes, see Diabetes
–
for management of dyslipidaemia, see Dyslipidaemia
–
for management of hypertension, see Elevated blood pressure
–
for management of overweight and obesity, see Overweight and obesity
–
there is some emerging evidence supporting the use of metformin in both the prevention and treatment of weight gain, and to
ameliorate other cardiometabolic abnormalities associated with antipsychotics
switching to an antipsychotic with a lower propensity to cause cardiometabolic adverse effects. For considerations when switching
between antipsychotics, see Changing from one antipsychotic to another
specialist referral (eg to an endocrinologist).

Note 14: For specific values, see the 2006 International Diabetes Federation (IDF) consensus worldwide definition of the metabolic
syndrome [URL].

Note 15: Trifluoperazine was discontinued in Australia in 2018.

Hyperprolactinaemia
Raised prolactin may lead to gynaecomastia, galactorrhoea, menstrual cycle disturbance, anovulation, impaired spermatogenesis, decreased
libido, impaired sexual arousal, impotence and anorgasmia. Sexual dysfunction can also be produced by the anticholinergic activity and
alpha1-receptor inhibition of antipsychotic drugs. Hyperprolactinaemia secondary to antipsychotics may cause a reduction in bone mineral
density, which is of concern in young people who have not yet reached their peak bone mass and in patients with osteoporosis. Possible
links between hyperprolactinaemia and breast cancer remain a concern, but are not yet conclusively ruled in or out.

Effects due to hyperprolactinaemia are dose-dependent and associated to varying degrees with all antipsychotic drugs, with the possible
exceptions of aripiprazole and clozapine. Hyperprolactinaemia is more likely to occur with amisulpride, paliperidone, risperidone and first-
generation antipsychotics (see Table 8.21).

Effects of hyperprolactinaemia are frequently unacceptable to patients. They may be reluctant to report these adverse effects and instead
simply stop treatment. It is therefore important for the clinician to routinely ask about menstrual irregularities and sexual function. If
reducing the dose is impractical or ineffective, switch to an antipsychotic with a low risk of hyperprolactinaemia. For considerations when
switching between antipsychotics, see Changing from one antipsychotic to another. If switching the antipsychotic is not advisable, adding a
small dose of aripiprazole (5 mg daily) has been reported to decrease prolactin concentrations.

It is unclear how best to balance the risks and benefits of antipsychotic treatment in the context of asymptomatic hyperprolactinaemia, but
it is likely that adverse effects will arise if prolactin concentrations remain high. All patients prescribed an antipsychotic should have their
prolactin concentration monitored. If the concentrations are raised, consider reducing the dose or changing the drug, and actively ask about
symptoms of hyperprolactinaemia.

QTc interval prolongation

Many antipsychotics can prolong the QTc interval, which could lead to life-threatening arrhythmias (torsades de pointes). This has been
noted as a particular problem with sertindole [Note 16]. People already treated with a drug that prolongs the QTc interval, or who have
hypokalaemia, hypomagnesaemia, hypocalcaemia, kidney failure, heart failure or a congenital disposition, are more prone to prolongation
of the QTc interval secondary to antipsychotic treatment. Female gender is an additional risk factor. For further information on drugs that
can prolong the QTc interval, see Table 17.2 and the Arizona CERT website [URL].

If a patient's history or family history suggests susceptibility to QTc interval prolongation, an electrocardiogram (ECG) should be done
before and after starting treatment. ECG monitoring must be performed during treatment with sertindole. A QTc interval of 430
milliseconds (ms) for men and 450 ms for women are accepted as the upper limits of normal. If the ECG shows prolongation of the QTc
interval, drugs that could lengthen it should be used with caution.

Note 16: Sertindole was discontinued in Australia in January 2014.

Sedation
Sedation is associated with all antipsychotics if they are given in sufficiently high doses. However, antipsychotics can cause sedation
within, and even in some cases below, the optimal therapeutic range. Sedation may be beneficial initially in agitated patients; however, in
the medium to long term, sedation interferes substantially with the ability of the patient to engage with their recovery and should be
avoided.

Sedation tends to be most pronounced on starting therapy or with upward dose titration. Starting at low doses and stepping up the dose
slowly can reduce the impact. Since these effects are often temporary, the initial response is usually to reassure the patient that the degree
of sedation is likely to decline over 1 to 2 weeks. If this does not occur and the degree of sedation is unacceptable to the patient, or
incompatible with patient safety and wellbeing, the only alternatives are to reduce the dose if therapeutic benefit can be maintained at a
lower dose, or change to a less-sedating antipsychotic (see Table 8.21). For considerations when switching between antipsychotics, see
Changing from one antipsychotic to another.

Patients should be warned to expect sedation in the early stages of treatment, and that this may affect their ability to drive and operate
machinery safely.

Orthostatic hypotension
Many antipsychotic drugs cause orthostatic hypotension (see Table 8.21). In particular, orthostatic hypotension can occur initially with
risperidone or paliperidone, both of which should be initiated at a low dose. It usually subsides within the first few days of initiating
treatment, but can be a particular problem in older patients where it may lead to falls. If the degree of blood pressure drop is severe and
persists for more than a few days, the drug should be ceased and replaced by one with little effect on blood pressure. For considerations
when switching between antipsychotics, see Changing from one antipsychotic to another.

Anticholinergic effects
All antipsychotic drugs possess some degree of anticholinergic activity; however, clinical difficulties are more likely with clozapine,
chlorpromazine and pericyazine (see Table 8.21). Anticholinergic effects include dry mouth, blurred vision, increased intraocular pressure,
constipation and urinary hesitancy. At very high doses (eg with deliberate or unintentional overdose) an anticholinergic delirium may occur
with enlarged pupils, hot, dry and flushed skin, and tachycardia. Older people are more susceptible to central anticholinergic effects, such
as delirium. Milder anticholinergic effects may be tolerable to the patient, but if not, reduce the dose if therapeutic benefit can be
maintained at a lower dose, or change to an antipsychotic with less anticholinergic effect. For considerations when switching between
antipsychotics, see Changing from one antipsychotic to another.

Movement disorders

Introduction

First-generation antipsychotics (FGAs) have been associated with a range of movement disorders such as acute dystonia, akathisia,
parkinsonism and tardive dyskinesia. These adverse effects are less frequent with second-generation antipsychotics (SGAs) (see Table
8.21).

Extrapyramidal effects

Acute dystonias

Dystonias are a sustained or brief muscle contraction resulting in twisting movements or abnormal postures. Dystonia can be focal,
multifocal, segmental (affecting more than one contiguous region) or generalised. Acute dystonias are more likely to develop after the use
of FGAs, especially the parenteral administration of haloperidol. They generally develop within minutes to days and affect the face, neck
and trunk. Oculogyric crisis, laryngeal spasm and opisthotonus can occur. Young males are more susceptible.

For the treatment of acute dystonias, use:

benztropine 1 to 2 mg IV or IM, as a single dose.

Following immediate relief of acute signs, switch to oral benztropine in the lowest effective dose. Benztropine should be discontinued
within several weeks at the most.

Consider if a reduction in the dose of antipsychotic is possible or if change to an antipsychotic with a lower propensity to cause dystonia is
required (see Table 8.21). For considerations when switching between antipsychotics, see Changing from one antipsychotic to another.

Parkinsonism

Parkinsonism is more typically seen in the early weeks of treatment with FGAs (see Table 8.21). The antipsychotic dose should be reduced
or the patient should be switched to an SGA. For considerations when switching between antipsychotics, see Changing from one
antipsychotic to another.

For the treatment of parkinsonism, use an anticholinergic drug:

1 benztropine 0.5 to 2 mg orally, daily

OR

2 benzhexol 2 mg orally, daily up to a maximum of 10 mg per day in up to 3 or 4 divided doses.

After several weeks the anticholinergic drug should be ceased.

Tardive dyskinesia

Tardive dyskinesia is a chronic movement disorder characterised by repetitive involuntary choreiform movements particularly of the
tongue, lips and mouth, but may include a wide range of abnormal movements of any part of the body. This adverse effect is most
commonly seen with FGAs, but can occur with SGAs (see Table 8.21). Tardive dyskinesia is best prevented by use of the lowest effective
dose of antipsychotic and the use of SGAs that have a lower propensity to cause the disorder.

If tardive dyskinesia occurs, switch to another antipsychotic. Changing from an FGA to an SGA, or specifically to clozapine, is the best
substantiated approach. For considerations when switching between antipsychotics, see Changing from one antipsychotic to another.
Specific treatment of tardive dyskinesia, if required, would include review by a specialist in movement disorders.

Akathisia

Akathisia is an abnormal, uncomfortable sensation of restlessness combined with an urge to move about. On movement, the patient
experiences some degree of relief. If akathisia occurs, the antipsychotic dose should be reduced until the akathisia disappears, or an
alternative antipsychotic (usually an SGA) should be trialled. For considerations when switching between antipsychotics, see Changing
from one antipsychotic to another.

As a short-term measure, consider:

1 propranolol 20 to 40 mg orally, 3 or 4 times a day

OR

2 diazepam 2 to 5 mg orally, 3 times a day.

Propranolol should be avoided in patients with asthma or severe peripheral vascular disease and some patients with heart failure. It should
be used cautiously in patients with diabetes. A number of other drugs, including anticholinergic drugs, cyproheptadine, mirtazapine and
clonidine, have been used with mixed results. Only a small proportion of patients respond favourably to any of the above drugs and dose
reduction or change of antipsychotic are better options.

Neuroleptic malignant syndrome

Neuroleptic (antipsychotic) malignant syndrome is a potentially lethal adverse effect from treatment with a drug that affects dopaminergic
transmission. Antipsychotic drugs are a leading cause of this syndrome, but it may occur with antiemetic drugs, antidepressants and
lithium, or after the cessation of dopamine agonist drugs. It is characterised by severe muscle rigidity, increased temperature, autonomic
instability, delirium and raised creatine kinase. There is a diagnostic overlap with malignant (or lethal) catatonia.

Treatment depends on the severity of the symptoms. In all cases, specialist care is required. Discontinue the antipsychotic drug, monitor
vital signs and ensure adequate hydration using intravenous fluids. Cool the patient and give deep vein thrombosis prophylaxis. Consider
giving a benzodiazepine (lorazepam is most commonly used). For mild cases conservative management may be sufficient. In a life-
threatening situation, treatment in an intensive care unit is indicated (see Toxidromes: neuroleptic malignant syndrome in the Toxicology
and Wilderness guidelines).

In patients with suspected or documented neuroleptic malignant syndrome, the continuing need for antipsychotics should be reviewed by a
psychiatrist. Thirty per cent of these patients develop the syndrome again on rechallenge.

For those patients who cannot be managed off drugs, the following steps are recommended:
 wait at least 5 days before the antipsychotic rechallenge
use an alternative antipsychotic (for considerations when switching between antipsychotics, see Changing from one antipsychotic to
another)
commence on low doses and increase slowly, monitoring closely for signs of re-emergence of the syndrome.

Psychological and psychosocial therapies for schizophrenia

There is good evidence for a number of psychological and psychosocial treatments that are essential to the satisfactory care of a patient
with schizophrenia and their family. These treatments require the involvement of a range of health professionals in the management plan.
Not all patients with schizophrenia will require all of the psychosocial treatments discussed below, but most will be applicable at some
stage of their illness. Most patients with schizophrenia or other chronic psychotic illnesses do not receive an adequate range of
psychosocial treatments.

Psychosocial treatments are often underutilised in patients with schizophrenia.

While these treatments should be seen as an essential part of the treatment of schizophrenia, antipsychotic drugs remain the cornerstone of
the management plan. It would be unusual for a patient with schizophrenia to be treated with psychological and psychosocial treatments
alone.

Assertive community treatment is the collaborative care of an individual with a severe mental illness in the community by a team of
mental health professionals who provide a broad range of psychosocial treatments. These may include, but are not limited to, assistance
with medication concordance, social skills training, welfare support, financial planning, health promotion, housing and counselling. The
model assumes a low staff-to-patient ratio (less than 1:10), no time limit to the delivery of services, and a flexible and assertive provision
of services in settings that are convenient to the patient on a 24-hour basis.

Psychoeducation is the provision of basic information about mental illness (the symptoms, the aetiology and treatment), the mental health
care system (roles of mental health professionals and the relevant mental health legislation) and the principles of caring for oneself. It is
provided to the patient and their family or carers over a number of sessions, frequently in a group format, but also on a one-to-one basis.

Cognitive behavioural therapy (CBT) is a targeted psychological treatment that can be used to control residual positive symptoms and/or
assist the patient to cope more effectively with them. The treatment asks patients to examine the evidence for a psychotic belief, and use
reasoning, coping and problem-solving skills to challenge and decrease the salience and threat of their beliefs. The approach has been used
for a number of psychotic symptoms (including lack of insight, hallucinations and delusions) and treatment nonconcordance with varying
degrees of success. CBT for comorbid anxiety or depression can also be used in patients with schizophrenia. See also Nonpharmacological
therapies for psychiatric illness: cognitive behavioural therapy.

Behavioural therapy aims to alter dysfunctional habits or behaviours by changing the consequences of those behaviours. This is done by
carefully defining the problem behaviours, measuring them and then manipulating aspects of the positive and negative reinforcements that
help maladaptive behaviours persist. These strategies are especially usefully in structuring the day of a person with significant negative
symptoms to increase their level of activity and self-care.

Substance abuse or dependence is a common comorbidity in patients with schizophrenia or a related psychosis. Motivational interviewing
and cognitive behavioural therapy aimed specifically at the treatment of the substance use disorder has improved relapse rates of
schizophrenia, functioning within the community and treatment attendance. These benefits, though not found in all studies, may be more
likely if treatment of the drug use problem is integrated with the treatment of schizophrenia and administered by a multidisciplinary team
including the therapist providing the psychotherapeutic intervention.

Caring for a family member with schizophrenia is a significant challenge that can disrupt normal family functioning. Increased levels of
hostility and conflict within the family have been noted to increase the risk of relapse. Family therapy aims to assist families in
understanding and coping with their relative's illness, decrease the degree of expressed emotion, and develop better ways of dealing with
the effects of the illness on the family and the person with the disorder. This can be achieved by altering the habitual mode of
communication within the family or by developing better problem-solving skills.

Social skills training aims to improve the poor level of psychosocial functioning frequently found in people with schizophrenia. These
approaches have used a variety of strategies (eg goal setting, increased structure or routine in the day, rehearsal of activities, role
modelling, feedback and positive reinforcement) to teach new skills to improve self-care, activities of daily living and interpersonal
function.

People with schizophrenia have very high levels of unemployment and welfare dependency. Supported employment, sometimes known
as individual placement and support, involves a vocational specialist working with an individual with schizophrenia to identify and place
the person in a preferred employment or educational setting. The vocational specialist provides as much support as is necessary, or is
allowed by that individual, to keep them in that setting. The model is most effective if the vocational specialist is placed within the mental
health team providing care to the individual with schizophrenia.

Neurocognition (attention, concentration, memory, planning and executive skills) and social cognition (emotion recognition, theory of
mind, understanding of social rules) are eroded before the onset of a psychotic disorder, and remain impaired despite adequate
pharmacotherapy. These deficits contribute disproportionately to the level of functional impairment in patients with schizophrenia. A
number of specific treatments, such as cognitive remediation therapy and social cognitive remediation therapy, have been developed to
address these deficits. They utilise a variety of web-based, computer-assisted, face-to-face and group treatment modalities to practise and
improve identified cognitive deficits. Both have been demonstrated to significantly improve underlying cognitive deficits; however, the
generalisation of these improvements to daily function is less clear and remains contested by some authors.

Further reading
Weinberger DR, Harrison PJ, editors. Schizophrenia. 3rd ed. Oxford: Wiley-Blackwell; 2011.

Castle DJ, editor. Pharmacological and psychosocial treatments in schizophrenia. 3rd ed. London: Informa Healthcare; 2012.

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Virani A, Bezchlibnyk-Butler KZ, Jeffries JJ, Procyshyn RM, editors. Clinical handbook of psychotropic drugs. 19th rev. ed. Ashland, OH:
Hogrefe Publishing; 2012.

Management of antipsychotic adverse effects: weight gain and other cardiometabolic effects

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

The IDF consensus worldwide definition of the metabolic syndrome. Brussells: International Diabetes Federation; 2006. [URL]

Morgan VA, Waterreus A, Jablensky A, Mackinnon A, McGrath JJ, Carr V, et al. People living with psychotic illness 2010: report on the second
Australian national survey. Canberra: Australian Department of Health and Ageing; 2011. [URL]

Newall H, Myles N, Ward PB, Samaras K, Shiers D, Curtis J. Efficacy of metformin for prevention of weight gain in psychiatric populations: a
review. Int Clin Psychopharmacol. 2012;27(2):69–75. [ ]

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Waterreus AJ, Laugharne JD. Screening for the metabolic syndrome in patients receiving antipsychotic treatment: a proposed algorithm. Med J
Aust. 2009;190(4):185–9. [ ]

Management of antipsychotic adverse effects: hyperprolactinaemia

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

Byerly M, Suppes T, Tran QV, Baker RA. Clinical implications of antipsychotic-induced hyperprolactinemia in patients with schizophrenia
spectrum or bipolar spectrum disorders: recent developments and current perspectives. J Clin Psychopharmacol. 2007;27(6):639–61. [
]

Molitch ME. Medication-induced hyperprolactinemia. Mayo Clin Proc. 2005;80(8):1050–7. [ ]

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: QTc interval prolongation

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: sedation

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: orthostatic hypotension

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: anticholinergic effects

Australian medicines handbook (online). Adelaide: Australian Medicines Handbook; July 2012.

Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: movement disorders

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Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Management of antipsychotic adverse effects: neuroleptic malignant syndrome

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Taylor D, Paton C, Kapur S. The Maudsley prescribing guidelines in psychiatry. 11th ed. Oxford: Wiley-Blackwell; 2012.

Published March 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and distilled by
Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Behavioural emergencies
Introduction to behavioural emergencies
Behavioural emergencies refer to situations where patients show behaviour that potentially places themselves or
others at risk of physical harm and that require immediate targeted intervention. The criteria for defining
behavioural emergencies are vague. A reasonable working definition is any patient who is threatening or assaultive
and/or displays a range of behaviours that includes refusal to cooperate, intense staring, motor restlessness,
purposeless movements, affective lability, loud speech, irritability, intimidating behaviour, aggression to property,
signs of imminent intentional or unintentional self-harm, and demeaning or hostile verbal behaviour. There is a
continuum of severity of behavioural emergencies, varying from the equivalent of ‘quietly simmering’ to ‘boiling
over’, but there is no generally agreed method for defining or dividing up this continuum, nor for systematically
matching interventions to different levels on the continuum.

The three main aetiological groups implicated in behavioural emergencies are:

medical disorders, usually associated with delirium

substance intoxication or withdrawal, with or without delirium
psychiatric disorders.

Psychiatric disorders associated with behavioural emergencies may include schizophrenia, mania, psychotic
depression, personality disorders and posttraumatic stress disorder. Dementia and acquired brain injury may also
be contributing causes. Often two or more aetiological factors may be present simultaneously (eg psychiatric
disorder and substance intoxication, medical disorder and substance withdrawal). Some people may exhibit
aggressive or apparently disturbed behaviour when it is unlikely that there is a medical or psychiatric cause. Under
such conditions, police intervention without medical involvement is appropriate.

While determining the aetiology of a behavioural emergency can help direct acute management, this may be
difficult when the patient is unsettled. In most cases, the diagnosis may be unknown or provisional at best, and
there is a need for immediate intervention despite limited information. Once control has been established, it is
important to investigate and address the underlying cause(s) of the behavioural disturbance.

The evidence base of effective interventions for behavioural emergencies is limited and comprehensive evidence-
based guidelines are lacking. In their absence, the clinician must rely on expert consensus, as well as their clinical
experience and best judgment at the time.

Legal and professional obligations for behavioural emergencies

When asked to respond to acutely disturbed people, medical personnel should first determine whether the problem
is suitable for medical or psychiatric intervention. This involves establishing whether the disturbance is likely to be
related to one or more of the three main aetiological factors implicated in behavioural emergencies (medical
disorders associated with delirium, substance intoxication or withdrawal, or psychiatric disorders), and whether the
disturbance can safely be addressed by medical personnel. Where these aetiological factors are thought unlikely to
be involved, or where the situation is too dangerous for medical personnel to intervene (eg when weapons are
involved or there is a high likelihood of extreme violence), security staff and/or police will be required to disarm
and restrain the patient.

If the situation is too dangerous for medical personnel to intervene, security staff and/or police are required to disarm and
restrain the patient.

If the police have brought someone to a health care facility in restraints (ie handcuffs), the police officers and the
handcuffs should remain in place for the initial assessment until decisions have been made regarding management.
The handcuffs can be removed once the individual has been assessed and it has been determined that it is safe to
do so. The patient may need to be given medication for their own protection and/or the protection of staff before
the handcuffs are removed.

Treatment without consent may be regarded as assault unless conducted under the auspices of the relevant mental
health act or other legislative provisions. Those treating an acutely disturbed person in such an emergency should
be aware of the provisions of the relevant legislation and be satisfied that the person meets the criteria for
involuntary treatment (see information in Informed consent in mental illness). In addition, under the common law,
clinicians may use the principle of ‘duty of care’ as a basis for supporting an intervention, but must ensure they are
acting in accordance with professional guidelines and with due regard for good clinical judgment. If in doubt, the
clinician should consider the likely consequences of no intervention versus treatment, and consult a senior
colleague whenever possible. Whatever their course of action, clinicians should clearly document their
management and its rationale, and that the patient lacked decision-making capacity.

Given the availability of community treatment teams, some acutely disturbed patients can be treated in their home,
providing appropriate supports exist. Under these circumstances the patient must agree to accept the treatment and
the clinician must be assured that the patient has given informed consent to the treatment. Family and friends who
are providing the care should also be given information and support, and their safety should be taken into
consideration.

Initial steps in management of behavioural emergencies

Box 8.19 gives a summary of steps in the management of acute behavioural disturbance.

The setting in which a behavioural emergency occurs significantly influences the management approach. Protocols
for intervention in behavioural emergencies should be developed that are suitable for the setting in which such
emergencies will be managed (eg location, design, staffing, resources). General practitioners should not attempt to
manage a behavioural emergency in the community, such as in the patient's home, unless they have sufficient
assistance from a mental health team, ambulance service and/or police, all of whom are able to intervene in
accordance with their own protocols. Health care professionals who expect to encounter behavioural emergencies
should have appropriate training in the management of aggressive behaviour.

In approaching the patient, ensure the safety of self, staff and others present (eg other patients, family members),
and of the patient. Privacy needs to be ensured while still maintaining a safe environment for assessment and
intervention. Measures that can reduce the risk of harm include: a room with two exits and furniture that cannot be
thrown, adequate backup from staff (including security staff and/or police) who are nearby but unobtrusive, a
duress alarm, removal of any personal belongings that could be used as a weapon, and maintaining a safe distance
between the patient and an exit. A calm, confident, empathic but business-like approach to the patient is
recommended, avoiding sudden movements, intrusion on the patient's personal space, prolonged eye contact and
confronting or intimidating behaviours. Keep the patient within your field of vision at all times, be aware of
possible hidden weapons and spend the minimum time necessary to gather an outline of the history.

Assess the patient's mental state (including cognitive function if possible) and attempt to reduce the tension of the
situation (eg offering water to drink). If a physical examination is possible, the minimum requirements include
visual inspection of the patient and assessment of vital signs. If investigations are possible, consider measurement
of oxygen saturation and blood glucose concentrations. Perform a toxicology risk assessment. Reassure family and
friends present and organise debriefing for them where relevant.

Patients with a behavioural emergency generally require an increased level of observation because of the risk they
potentially pose to themselves and others. The specific level of observation depends on individual circumstances.
The Department of Health mental health triage tool provides a guide for staff [URL].

Steps in the management of acute behavioural disturbance (Box 8.19)

If an acute behavioural disturbance occurs:

Recognise warning signs before escalation occurs.

Attend to such patients as a priority, as delay exacerbates the situation.
Ensure safety of self, staff and others present (eg other patients, family members), and of the patient.
Summon support (eg security staff) early if the situation is deteriorating.
Use the least invasive method necessary to gain control:
verbal de-escalation and early negotiation (including the offer of oral medication)
‘show of force’
physical restraint by a trained team
chemical restraint (see Behavioural emergencies: pharmacological treatment)—intravenous (IV)
access is preferred if this can be safely achieved; drugs recommended for IV use include diazepam,
midazolam, droperidol and olanzapine.
If medication has been administered, undertake post-medication monitoring and management.

De-escalation of behavioural emergencies

Verbal de-escalation and early negotiation
A calm, solicitous verbal approach, offering the patient time to state their concerns in a nonjudgmental atmosphere
and explaining your wish to help the patient, may encourage the patient to settle into a calmer discussion of their
current concerns. Explain your role and use both your own name and the patient's name to personalise the
interaction. Identify, if possible, the trigger for the current agitation. This may be unmet expectations, pain or
communication failures that can be dealt with.

Support can be offered verbally; in the form of food, cool drinks or other assistance (eg providing access to a
telephone or attending to the patient's physical needs); or in the form of oral medication (see below). These
strategies help to assess the patient's responsiveness to verbal de-escalation, the immediacy of self-harm or harm to
others, and the likelihood of psychotic symptoms. These strategies also provide the basis for negotiating a
cooperative approach to clinical intervention if it is deemed necessary (eg pharmacological treatment).

Should the patient be prepared to accept oral medication, use:

1 diazepam 10 to 20 mg orally, repeated after 60 minutes if required

OR

2 olanzapine 10 to 20 mg orally, as a single dose.

Both options are acceptable in most situations; however, diazepam may be preferred in behavioural emergencies
due to drug withdrawal or stimulant intoxication, while olanzapine may be preferred in acute psychosis. If
available, use liquid or orally disintegrating formulations (eg wafers) in preference to tablets when giving oral
medication to ensure that the dose has been consumed.

‘Show of force’

If verbal de-escalation is impossible to implement or is ineffective in eliciting cooperation, the next step is a ‘show
of force’, which involves having a sufficient number of staff visibly backing up the clinician who is attempting to
negotiate with the patient. This strategy may be effective in obtaining the patient's cooperation with the chosen
clinical intervention (eg pharmacological treatment), but if not it will be necessary to use physical restraint.

Physical restraint

Physical restraint is human action taken to immobilise the patient. Immobilisation of the limbs, through the
application of pressure on the main joints of the limbs, and control of the head is the safest means of restricting
movement while medication is administered. Physical restraint should only be used if there is persistent or
recurrent evidence of a behavioural emergency. It should be instituted rapidly if aggression or distress is escalating
and violence appears imminent, and there are sufficient trained staff present to deal safely with the patient.
Physical restraint should be maintained until the desired level of sedation or tranquillisation is achieved (see
pharmacological treatment).

The aim of physical restraint is to minimise the ability of the patient to move and injure themselves or others,
while ensuring that the patient has a patent airway and circulation is not obstructed. This requires a practised, well-
trained and coordinated team following a set protocol. An appropriate number of team members is six, one for
each limb, one for the head, and one to deliver an injection of drug. The team should proceed with an agreed plan
with each member knowing what is expected of them. The team must be well rehearsed in the restraint procedure;
ad hoc groups of people without proper training in aggression minimisation and control should not be used as they
are less effective and injury may result.

Mechanical restraint (eg four-point restraints, use of sheets) should be used only in extreme circumstances on the
order of the treating clinician.

Pharmacological treatment of behavioural emergencies

Introduction

Differences in the settings in which behavioural emergencies present must be taken into consideration. Broadly
speaking, behavioural emergencies may present in acute medical settings (such as emergency departments or acute
medical admission wards) or acute psychiatric settings (such as psychiatric assessment areas or inpatient units).
The resources available, risks and, consequently, treatment objectives and recommendations differ between the two
settings.

Tranquillisation is defined here as a state of calmness (ie not showing anxiety, anger or other emotions) and
sedation is defined here as a state of rousable drowsiness. The drugs used in behavioural emergencies have
tranquillising effects and, at higher doses, sedating effects.
In acute medical settings the cause of acute agitation is frequently unknown and may be a combination of mental
illness, intoxication and medical illness. The immediate objective is to achieve rapid tranquillisation, if necessary
to the point of sedation, and hence secure the safety of all concerned and enable any necessary tests or procedures
to be undertaken. Once safety is accomplished, the next priorities are medical examination and investigation to
reach a diagnosis and institute appropriate medical management. Acute medical settings are considered to be
settings in which cardiorespiratory resuscitation resources are immediately available and staff are highly trained
and experienced in their use. Therefore, any adverse cardiorespiratory consequences of drugs can be readily
managed.

In contrast, behavioural emergencies in acute psychiatric settings vary widely in their nature and severity, and
encompass a broad spectrum of psychiatric diagnoses, typically psychotic illnesses. In these settings the immediate
objective is to achieve tranquillisation, and hence secure the safety of all concerned and increase the patient's level
of cooperation with staff. The patient is likely to be known to staff as is the probability of success with different
strategies. Once safety is accomplished, the next priorities are psychiatric examination and investigation to reach a
diagnosis and institute appropriate psychiatric management, while ruling out significant medical contributing
factors. In acute psychiatric settings, while cardiorespiratory resuscitation resources must be available and staff
appropriately trained in their use, generally psychiatric staff are not as experienced or expert in using these
resources as staff in acute medical settings who regularly exercise these skills.

In all settings, sedation is an appropriate immediate objective for very severe behavioural disturbances. However,
the lower levels of resuscitation skills among psychiatric staff and the less immediate access to cardiorespiratory
resuscitation resources may mean that the risk of excessive sedation is unacceptably high in acute psychiatric
settings.

Highly agitated patients presenting in other settings (eg general practices or medical wards that do not meet the
criteria for acute medical settings) may need initial pharmacological treatment before being transported to an
appropriate acute setting for further management. Consideration must be given to the availability of resuscitative
equipment and skilled staff (both at the initial setting and in transport), the options for drug delivery and the
availability of medications. A single dose of a drug with sedative properties given intramuscularly, such as
droperidol or olanzapine, is preferred. Diazepam should not be given intramuscularly as absorption is poor and
erratic. Intravenous medication should not be administered without appropriate cardiorespiratory resuscitation
resources available, both in terms of staffing and equipment. If an appropriate sedative drug is not available, urgent
transfer by security staff or police without pharmacological intervention may be required. For specific
considerations during transport, see Transportation of patients.

In all settings, appropriate post-medication monitoring and management should be undertaken, and the eventual
goals of treatment are to:

reduce the risk of people harming themselves or others

allow diagnostic assessment and clinical management to proceed
allow transport to an appropriate treatment setting.

Although management of behavioural emergencies can be very complex, patient safety must be given high priority
irrespective of the setting and interventions required.

Acute medical settings

General considerations

Acute medical settings are considered to be settings in which cardiorespiratory resuscitation resources are
immediately available and staff are highly trained and experienced in their use.

The intravenous route is preferred for achieving rapid tranquilisation, if necessary to the point of sedation, because
it allows titration of the dose and provides a more immediate effect. If a patient cannot be physically restrained to
the point where an intravenous line can be established without risk of harm to staff members, then initial
intramuscular medication is appropriate. In all cases, undertake post-medication monitoring and management.

Dosing of drugs used in behavioural emergencies is complex. Where ranges are provided within dose
recommendations, factors such as level of agitation, response to treatment, body size, age, medical history,
medication history and previous response to sedative drugs should be taken into account when selecting a suitable
dose and dosing interval.

Intravenous medication

If intravenous medication is considered appropriate (see Acute medical settings: general considerations), use:

1 diazepam 5 mg IV, repeated every 3 to 4 minutes, titrated to clinical response, up to a

maximum of 30 mg. If adequate control is not achieved after 30 mg has been given, seek
 specialist advice as the patient may be unable to be sedated with benzodiazepines. It may
be necessary to give diazepam in larger boluses (10 to 20 mg) under specialist advice

OR

1 midazolam 2.5 to 5 mg IV, repeated every 3 to 4 minutes, titrated to clinical response, up

to a maximum of 30 mg. If adequate control is not achieved after 30 mg has been given,
seek specialist advice as the patient may be unable to be sedated with benzodiazepines. It
may be necessary to give midazolam in larger boluses (10 to 20 mg) under specialist
advice.

Both midazolam and diazepam have a rapid onset of action; however, diazepam is a little slower acting and so
more dependent on a rapid limb/brain circulation time. To decrease the risk of oversedation, the recommended
maximum dose of diazepam allows for fewer incremental doses to be administered.

Droperidol or olanzapine can be used in combination with diazepam or midazolam, or as a single drug in patients
who are tolerant of benzodiazepines or if there is a failure of benzodiazepines. Patients who appear very resistant
to the sedative effect of benzodiazepines may only need a small dose of droperidol or olanzapine to be effectively
sedated. Use:

1 droperidol 2.5 to 5 mg IV, repeated every 3 to 4 minutes, titrated to clinical response, up

to a maximum of 20 mg. If adequate control is not achieved after 20 mg has been given,
seek specialist advice (see also droperidol warnings, Box 8.21) [Note 1]

OR

2 olanzapine 5 mg IV, repeated every 5 minutes, titrated to clinical response, up to a

maximum of 20 mg. If adequate control is not achieved after 20 mg has been given, seek
specialist advice.

While intravenous benzodiazepines have a faster onset of action compared with droperidol, by 10 minutes the
proportion of patients adequately sedated will be the same when benzodiazepines or droperidol are used as
monotherapy. When droperidol or olanzapine is used in combination with a benzodiazepine, the effect is
synergistic. If combination therapy is considered appropriate, each drug should be administered separately (ie do
not combine drugs in the same syringe).

Olanzapine is not currently approved for intravenous use in Australia, but research supports its use by this route
[Note 2]. The intramuscular formulation of olanzapine can be used for intravenous administration. Intravenous
olanzapine has the same onset of action as droperidol, but it is longer acting so there may be less need for re-
sedation. Olanzapine is more readily available in some countries than droperidol and is more likely to be used
orally or intramuscularly in the post–acute care setting.

If significant extrapyramidal adverse effects (particularly acute dystonia) emerge due to antipsychotic drugs, they
may be relieved by the administration of an anticholinergic drug. See Post-medication monitoring and
management for anticholinergic drug recommendations.

Note 1: If droperidol is unavailable, haloperidol may be substituted using the same dose as for droperidol, but
haloperidol is less effective than the recommended drugs.

Note 2: Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or
olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind,
placebo-controlled clinical trial. Ann Emerg Med 2013;61(1):72-81. [URL]

Intramuscular medication

If intramuscular medication is considered appropriate (see Acute medical settings: general considerations), use:

midazolam 5 to 10 mg IM.

Diazepam is not recommended for intramuscular injection as absorption is poor and erratic.

Droperidol or olanzapine should be considered in patients who are tolerant of benzodiazepines or if there is a
failure of midazolam. Use:

1 droperidol 5 to 10 mg IM (see droperidol warnings, Box 8.21) [Note 3]

 OR

1 olanzapine 10 mg IM.

Physical restraint should be continued until clinical response is apparent. Intravenous access may then be
established. Apparent failure to respond after intramuscular administration should be determined cautiously before
giving additional doses. It is preferable to titrate sedative drugs intravenously.

If significant extrapyramidal adverse effects (particularly acute dystonia) emerge due to antipsychotic drugs, they
may be relieved by the administration of an anticholinergic drug. See Post-medication monitoring and
management for anticholinergic drug recommendations.

Note 3: If droperidol is unavailable, haloperidol may be substituted using the same dose as for droperidol, but
haloperidol is less effective than the recommended drugs.

Acute psychiatric settings

General considerations

In acute psychiatric settings, medication should generally be administered to achieve tranquillisation and any
degree of sedation arising as an adverse effect should not exceed the point of rousable drowsiness;
unconsciousness is an adverse outcome in all settings. Administration of medication in behavioural emergencies
can be safely carried out only in locations where there is access to resuscitation equipment. Speed of onset and
reliability of delivery are the most important factors in choosing a route of drug administration, followed by patient
preference.

The oral route is preferred for drug administration as it encourages engagement between the patient and staff,
allows the patient to feel more in control, aids future treatment concordance [Note 4] and reduces the risk of
adverse effects. Often a calm, persistent approach by the clinician over time (eg 30 minutes) will allow the patient
to ventilate distress and accept oral medication. If this is not possible, parenteral medication may be given.
Intramuscular injections are preferred in acute psychiatric settings as they are quicker and easier to administer, and
safer than intravenous injections. However, onset of effect is less immediate and titration to effect is more difficult
with intramuscular administration, and repeated dosing may lead to oversedation. This is particularly problematic
when using benzodiazepines. Due to the increased risk of excessive sedation and cardiorespiratory complications
with parenteral medication, this should only be administered if monitoring of vital signs is possible, personnel are
trained in cardiorespiratory resuscitation techniques, and appropriate monitoring and resuscitation equipment is
immediately available. Minimum equipment requirements include an oxygen supply, suction, a blood pressure
monitor, and a fully equipped resuscitation trolley with electrocardiogram (ECG) monitor and pulse oximetry.

There is an increasing range of choices for tranquillisation in behavioural emergencies, but they carry certain risks.
It is important for clinicians to be aware of these risks and ensure that tranquillisation is conducted in a manner and
in a location that is compatible with the highest possible standards of safety. Benzodiazepines have fewer adverse
effects and most agitated patients prefer treatment with them rather than an antipsychotic.

Benzodiazepines are generally preferred over antipsychotics for tranquillisation.

There are few data to support frequent administration of ‘as needed’ (prn) antipsychotic drugs. ‘As needed’
antipsychotics should be considered if the patient is already taking an antipsychotic, or if any of the following are
present:

psychotic symptoms
intense agitation, including subjective turmoil
a high risk of severe and immediate physical danger
inadequate tranquillisation with a benzodiazepine alone.

If patients repeatedly require ‘as needed’ antipsychotics, their regular treatment regimen should be reassessed.
Definitive treatment of patients with mania, schizophrenia or delirium is a separate issue from that of
tranquillisation (see Acute mania, Schizophrenia and Delirium).

Dosing of drugs used in behavioural emergencies is complex. Where ranges are provided within dose
recommendations, factors such as level of agitation, response to treatment, body size, age, medical history,
medication history and previous response to sedative drugs should be taken into account when selecting a suitable
dose and dosing interval.

In all cases, undertake post-medication monitoring and management.

See Box 8.20 for recommendations for the use of tranquillising medications.

Recommendations for tranquillisation in psychiatric settings (Box 8.20)

Use the oral route of administration whenever possible.

Closely monitor vital signs and mental state during and after administration of medication.

Aim to achieve an appropriate level of calmness by using sufficient medication initially; repeated subtherapeutic
doses may lead to insufficient behavioural control and greater total doses of medication.

If doses outside the guidelines appear to be required, consult a psychiatrist, an emergency physician or an
anaesthetist.

Do not give diazepam by intramuscular injection as absorption is poor and erratic.

Do not give parenteral chlorpromazine as it can cause catastrophic hypotension, abscess formation (IM use) and
sudden death (IV use).

Use benzodiazepines with particular caution in patients with significant respiratory impairment (eg chronic
obstructive pulmonary disease).

Older patients, particularly if frail, may require doses of medications lower than the recommended range. Avoid
benzodiazepines (especially if long-acting) if possible in this group; repeated doses of benzodiazepines are likely
to result in cumulative effects that may prove dangerous to the patient (see Psychotropic treatment in older
people).

The principles of treatment for older children and adolescents are generally the same as for adults.

Administration of parenteral (IM or IV) medication in children should only be undertaken under the supervision
of a specialist child psychiatrist or paediatrician, and only in a psychiatric setting where staff are trained in
resuscitation procedures and have immediate access to resuscitation and monitoring equipment.

When considering restraint procedures and drug selection, take into account the possibility that female patients
may be pregnant and conduct a test for pregnancy as soon as is practicable.

Accurately record details of restraint, medication administered and monitoring procedures. The record should
travel with the patient if they are transferred to another facility.

Frequent administration of ‘as needed’ (prn) medication for more than 24 hours usually indicates an inadequate
regimen of regular medication. There is evidence that frequent ‘as needed’ IM injections of antipsychotic
medication, especially when used over extended periods of time, increase the risk of neuroleptic malignant
syndrome and assaults upon nursing staff.

IM = intramuscular; IV = intravenous

Note 4: For the definition of concordance, see Concordance, adherence and compliance with psychotropic
treatment.

Oral medication

If available, use liquid or orally disintegrating formulations (eg wafers) in preference to tablets when giving oral
medication to ensure that the dose has been consumed.

If oral medication is considered appropriate (see Acute psychiatric settings: general considerations), use:

1 diazepam 5 to 20 mg orally, repeated every 2 to 6 hours, titrated to clinical response, up to

a maximum of 120 mg in 24 hours

OR

1 lorazepam 1 to 2 mg orally, repeated every 2 to 6 hours, titrated to clinical response, up to

a maximum of 10 mg in 24 hours.

If the desired effect is not achievable with diazepam or lorazepam alone, or the other indications for using
antipsychotic drugs apply (see Acute psychiatric settings: general considerations), add:
 1 a suitable dose of the patient's current antipsychotic medication

OR (if the patient is not currently taking antipsychotic medication)

1 olanzapine 5 to 10 mg orally, repeated every 2 to 4 hours, titrated to clinical response, up

to a maximum of 30 mg in 24 hours, or 15 to 20 mg as a single initial loading dose on the
first day [Note 5]

OR

1 risperidone 0.5 to 1 mg orally, repeated every 2 to 4 hours, titrated to clinical response, up

to a maximum of 6 mg in 24 hours. Risperidone may cause orthostatic hypotension and
extrapyramidal adverse effects, particularly if doses exceed 4 to 6 mg

OR

2 chlorpromazine 50 to 200 mg orally, repeated every 2 hours, titrated to clinical response,

up to a maximum of 800 mg in 24 hours. Avoid using chlorpromazine in older patients.
Chlorpromazine may cause orthostatic hypotension

OR

2 haloperidol 0.5 to 2 mg orally, repeated every 2 hours, titrated to clinical response, up to a

maximum of 10 mg in 24 hours. Haloperidol may cause significant extrapyramidal
adverse effects, including acute dystonia, particularly if doses exceed 3 to 4 mg in a
patient who has not previously been exposed to antipsychotic drugs.

For patients not currently taking an antipsychotic, the antipsychotic used to treat the acute disturbance may be
continued as long-term treatment if an underlying psychotic illness is identified.

If significant extrapyramidal adverse effects (particularly acute dystonia) emerge due to antipsychotic drugs, they
may be relieved by the administration of an anticholinergic drug. See Post-medication monitoring and
management for anticholinergic drug recommendations.

Note 5: The maximum 24-hour oral dose of olanzapine in accepted usage is greater than the maximum
suggested in the Australian approved product information (20 mg).

Intramuscular medication

Parenteral medication should only be administered if monitoring of vital signs is possible, personnel are trained in
cardiorespiratory resuscitation techniques, and appropriate monitoring and resuscitation equipment is immediately available.

If respiratory depression occurs, seek urgent expert medical advice.

If intramuscular medication is considered appropriate (see Acute psychiatric settings: general considerations), use:

1 midazolam 2.5 to 10 mg IM, repeated every 20 minutes, titrated to clinical response, up to

a maximum of 20 mg in 24 hours. Patients should be regularly monitored for at least 4
hours after last administration in case of excessive sedation, respiratory depression or
hypotension (see Post-medication monitoring and management)

OR

2 droperidol 2.5 to 10 mg IM, repeated after at least 20 minutes, titrated to clinical

response, up to a maximum of 20 mg in 24 hours (see droperidol warnings, Box 8.21)
[Note 6]

OR

2 olanzapine 5 to 10 mg IM, repeated every 2 to 4 hours, titrated to clinical response, up to

a maximum of 30 mg in 24 hours

OR THE COMBINATION OF (if the desired effect is not achievable with midazolam alone)
 2 midazolam 2.5 to 5 mg IM, repeated every 20 minutes, titrated to clinical response, up to
a maximum of 20 mg in 24 hours. Patients should be regularly monitored for at least 4
hours after last administration in case of excessive sedation, respiratory depression or
hypotension (see Post-medication monitoring and management)

PLUS
droperidol 2.5 to 10 mg IM, repeated after at least 20 minutes, titrated to clinical
response, up to a maximum of 20 mg in 24 hours (see droperidol warnings, Box 8.21)
[Note 6].

If combination therapy is considered appropriate, each drug should be administered separately (ie do not combine
drugs in the same syringe).

Alternatively, if tranquillisation lasting 2 to 3 days is required, zuclopenthixol acetate can be used. Zuclopenthixol
acetate should not be used for first-line treatment of behavioural emergencies. It should only be administered after
specialist psychiatric assessment has confirmed the presence of a primary psychotic disorder or there is clear
evidence of a psychotic illness, and there is a high likelihood of recurrent agitation and aggression. Zuclopenthixol
can cause extrapyramidal adverse effects.

If zuclopenthixol acetate is considered appropriate, use:

zuclopenthixol acetate 50 to 150 mg IM as a single dose, repeated every 2 to 3 days if

necessary (a repeat dose may be needed 24 hours after the first dose), up to a maximum of
400 mg per course given over no more than 4 doses. Treat for a maximum of 2 weeks
before switching to an alternative zuclopenthixol formulation or another antipsychotic
drug.

Zuclopenthixol acetate has an onset of action within 2 hours and the peak effect is achieved approximately 24
hours after injection. Midazolam 2.5 to 5 mg intramuscularly may be administered at the same time as
zuclopenthixol acetate (not in the same syringe) to settle the patient before the effects of zuclopenthixol begin.

If significant extrapyramidal adverse effects (particularly acute dystonia) emerge due to antipsychotic drugs, they
may be relieved by the administration of an anticholinergic drug. See Post-medication monitoring and
management for anticholinergic drug recommendations.

Warnings on the use of droperidol (Box 8.21)

A number of hospitals have withdrawn droperidol from their formularies and the drug has been deleted from
some clinical guidelines following the US Food and Drug Administration (FDA) Black Box warning concerning
potential for cardiac complications. However, there is no convincing evidence for a causal relationship between
therapeutic droperidol administration in the present context and life-threatening cardiac events [NB1].
Droperidol is preferred over haloperidol for behavioural emergencies because it is more sedating, has a quicker
onset of action, a shorter half-life and is less cardiotoxic than haloperidol.

NB1: Kao LW, Kirk MA, Evers SJ, Rosenfeld SH. Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med
2003;41(4):546-58. [URL]

Note 6: If droperidol is unavailable, haloperidol may be substituted using the same dose as for droperidol, but
haloperidol is less effective than the recommended drugs.

Intravenous medication

Parenteral medication should only be administered under conditions in which monitoring of vital signs is possible, personnel are
trained in cardiorespiratory resuscitation techniques, and appropriate monitoring and resuscitation equipment is immediately
available.

If respiratory depression occurs, seek urgent expert medical advice.

Intravenous medication is not usually needed for management of behavioural emergencies in acute psychiatric
settings (see Acute psychiatric settings: general considerations). If intravenous medication is required, see Acute
medical settings: intravenous medication for drug recommendations. Routine use of a pulse oximeter and frequent
monitoring is advised. It is preferable to contain the patient and strictly avoid oversedation.
Post-medication management of behavioural emergencies
The main risks of medication used in the management of behavioural emergencies are:

airway obstruction
respiratory depression
aspiration
profound hypotension
laryngospasm (if antipsychotics have been used).

After sedation or tranquillisation has been achieved, the patient should be supervised and monitored closely at all
times. Develop an appropriate monitoring and management plan with consultation between medical and nursing
staff. Specify intermittent nursing observations and medical reviews in the plan and undertake them accordingly.
Some examples of monitoring schedules are shown in Box 8.22, but each patient is different and the monitoring
plan must be flexible.

Constant visual observation is required until it is clear that the patient is not oversedated and can maintain a patent
airway, and that it is safe to monitor them intermittently. Monitoring by video surveillance alone is completely
inadequate.

Vigilant monitoring, particularly for signs of airway obstruction, respiratory depression and hypotension, during the post-
medication period is essential.

Tailor the nature and frequency of monitoring to the clinical needs of each patient depending on: the type, route,
dose(s) and onset of action of drugs used; level of tranquillisation or sedation; the patient's clinical (both physical
and psychiatric) condition; past exposure and response to antipsychotics and anxiolytics; and the possible
potentiation of effects (particularly sedation) of previously administered drugs or nonprescribed substances.
Undertake observations in a way that minimises unnecessary stimulation of, or irritation to, the patient. However,
balance this with the requirement to detect and intervene if complications arise. A degree of interruption to the
patient's rest is inevitable when carrying out required observations. Calm, supportive speech and presence are
important.

Required observations include:

pulse
respiratory rate (without disturbing the patient)
airway patency
skin colour
blood pressure
oxygen saturation
level of alertness
evidence of ongoing behavioural disturbance or agitation
response to medication.

Routinely use pulse oximetry in heavily sedated patients. Patients should remain monitored in an appropriate
clinical area, with suitable resuscitation equipment available, at least until they:

are able to maintain oxygen saturation greater than 90% on room air
have intact airway reflexes
have a systolic blood pressure greater than 100 mm Hg (in otherwise healthy adults). In physically ill
patients, especially those with cardiovascular disease, and in older people, a higher systolic blood pressure
may be more appropriate (eg 120 mm Hg).

Parenteral drugs should only be administered if monitoring of vital signs is possible, personnel are trained in
cardiorespiratory resuscitation techniques, and appropriate monitoring and resuscitation equipment is immediately
available. Minimum equipment requirements include an oxygen supply, suction, a blood pressure monitor, and a
fully equipped resuscitation trolley with electrocardiogram (ECG) monitor and pulse oximetry.

The most concerning adverse consequence of sedation is unconsciousness and loss of protective airway reflexes.
This should be managed as a medical emergency and expert medical assistance should be sought immediately.

If antipsychotic drugs have been used, monitor for extrapyramidal adverse effects for 48 hours. If significant
extrapyramidal adverse effects (particularly acute dystonia) emerge due to antipsychotic drugs, they may be
relieved by the administration of an anticholinergic drug. Use:

1 benztropine 1 to 2 mg orally, IV or IM
 OR

2 benzhexol 2 mg orally.

Anticholinergic drugs should not be given routinely for prophylaxis, particularly in older patients.

If seclusion is required, do not allow it to compromise patient monitoring. Observe the statutory requirements of
mental health legislation in regard to observation and supervision of someone in seclusion.

If mechanical restraints are used, authorisation, documentation, monitoring and nursing care as required by the
relevant legislation must be carried out (see Legal and professional obligations). Explain the reasons for restraints
and provide opportunity for debriefing once the condition has stabilised.

Examples of post-medication monitoring schedules (Box 8.22)

After oral or intramuscular medication—observations (including respiratory and pulse rate) are carried
out at least every 15 minutes for 1 hour, if the patient's mental state and/or level of alertness permit. The
airway must be checked if the patient is asleep, especially if snoring.
After intravenous medication—observations (including level of consciousness, airway, and respiratory
and pulse rate) are carried out every 10 minutes for 30 minutes and then every 15 minutes for at least
another 30 minutes, depending on the patient's mental state and level of alertness.

Transporting an acutely disturbed person

Transportation of an acutely disturbed person cannot proceed without the patient's consent or compliance with
relevant mental health legislation (see Legal and professional obligations). Consideration needs to be given to the
type of transport available and the duration of the trip and possible delays, and provisions need to be made for
repeated administration of medication and pressure area care if necessary.

If the patient is to travel in an ambulance, organise appropriate means of restraint and supervision during the trip.
Provide instructions regarding repeated administration of medication if the duration of transportation is likely to be
prolonged. Ambulance officers transporting a patient long distances must be qualified to administer medications in
addition to having the capacity to monitor vital signs and implement resuscitation procedures if necessary.
Provision of extra or relief staff should be considered. See Box 8.23 for recommendations relating to
tranquillisation and sedation during transport.

In extreme cases it may be necessary to anaesthetise and transport the patient under the supervision of a specialist
medical retrieval team.

Recommendations for tranquillisation and sedation during transport (Box 8.23)

Observe appropriate legislation (ie ensure that the patient meets criteria for involuntary treatment if refusing
consent, and that the correct legal documents have been completed by someone authorised under relevant mental
health legislation).

The level of tranquillisation or sedation during transport should be at a level consistent with patient and staff
safety. Ensure that there is constant supervision, resuscitation equipment and a capacity to attend to respiratory
depression or obstruction en route.

Ensure regular monitoring of vital signs during transport when medication is used.

If the patient is to be transported by police vehicle then medications should NOT be administered because
medical and nursing supervision as well as resuscitation equipment are not available.

Ensure that close family and friends receive reassurance and support.

Key references
Behavioural emergencies: acute medical settings

Chan EW, Taylor DM, Knott JC, Kong DC. Variation in the management of hypothetical cases of acute agitation in
Australasian emergency departments. Emerg Med Australas. 2011;23(1):23–32. [ ]

Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct
to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial.
Ann Emerg Med. 2013;61(1):72–81. [ ]

Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular
droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med
2010;56(4):392–401. [ ]

Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for
sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47(1):61–7. [ ]

Published March 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Delirium
Risk factors for delirium
Delirium occurs in the vulnerable patient with identifiable risk factors. The most common of these are age more
than 65 years and pre-existing dementia. In some cases, the dementia may not have been recognised and delirium
may be the first indication of a cognitive disorder. The condition has been most studied in the acute hospital
setting, with severe medical and surgical illnesses important precipitants of delirium. In patients with an acute hip
fracture, the median total rate of delirium during hospital admission is 35% (range 29% to 68%). In patients
admitted to general medical or stroke units, median total rates of 25% have been reported. Although there is a high
prevalence rate of delirium among patients in long-term residential care, there is a paucity of research on this
patient group.

Delirium is a risk factor for increased hospital stay and increases the likelihood of admission to an aged care
facility. Three years after an episode of delirium, the likelihood of being diagnosed with dementia is also
increased. Mortality is a significant consequence of delirium, and this effect appears to be independent of time
since the delirious episode.

Diagnosis of delirium
Delirium is a clinical syndrome of disordered attention, presenting as an inability to focus, shift or sustain
attention. It generally occurs acutely (over hours to days), but it can also occur over longer periods of time and the
diagnosis may be missed.

There are various measures to screen for the presence of delirium. The Confusion Assessment Method (CAM) is
one such measure, which may be useful [Note 1]. The ‘short version’ of CAM considers that a diagnosis of
delirium is likely if the following are present:

acute onset and fluctuating course, and

inattention, and
either disorganized thinking or an altered level of consciousness.

While delirium associated with agitated behaviour, hallucinations and delusions may be obvious, hypoactive
delirium is easily missed. Information about changes in the patient's cognition and behaviour should be sought
from a corroborative source, such as a spouse or carer. In a person with pre-existing dementia, this may be the only
way to establish the diagnosis. Similarly, the history may assist in identifying the underlying cause (see below).
Differential diagnoses for apparent delirium include dementia, especially dementia with Lewy bodies.

The episode of acute delirium is often triggered by one or more events or illnesses. While the exact
pathophysiology of this triggering is complex and not well understood, assessment and treatment of these
underlying causes is a key part of the overall management of the delirium.

Well-recognised precipitants include:

infections (especially urosepsis, pneumonia and central nervous system infections)

metabolic disturbance (eg hypoglycaemia, hyperglycaemia, hyponatraemia)
drugs (including prescription and over-the-counter medicines, and alcohol and illicit drugs) (see Box 8.24
for drugs commonly implicated in delirium)
organ failure (especially kidney failure, liver failure, and respiratory failure with hypoxia/hypercapnia)
intracerebral events (eg subdural haematoma, haemorrhage, stroke)
cardiac events (eg myocardial infarction, arrhythmia, congestive heart failure)
seizures and postictal states
withdrawal states (especially from alcohol and benzodiazepines; suspect alcohol withdrawal if tremors,
sweating and visual hallucinations are present—see Acute alcohol withdrawal)
pain and discomfort (eg urinary retention, constipation).

History (taken from a corroborative source such as the spouse or carer) and physical examination may well reveal
a likely precipitant; however, in most patients an investigative work-up is required. At minimum, this should
include:

oxygen saturation with or without blood gas measurement

electrocardiogram (ECG)
blood glucose concentration
 serum urea, creatinine, electrolyte and calcium concentrations
liver biochemistry
full blood count
urine dipstick analysis (and urine microscopy and culture if appropriate).

Extended testing is performed in particular clinical situations based on features identified from history and
physical examination. Examples include:

computerised tomography (CT) head scan—there is a low threshold for this in the elderly and those on
anticoagulants
chest X-ray
cardiac enzymes
blood cultures.

Delirium may be a response to several concurrent insults to brain functioning, without a single main cause. In
some cases, no clear cause can be identified.

Drugs and drug groups commonly implicated in delirium (Box 8.24) [NB1]

Drugs and drug groups commonly implicated in delirium are:

anticholinergics (see Box 8.25)

benzodiazepines
opioids (including pethidine [NB2] and tramadol)
corticosteroids
nonsteroidal anti-inflammatory drugs (NSAIDs)
dopaminergic drugs (eg levodopa, dopamine agonists, catechol-O-methyltransferase [COMT] inhibitors)
sotalol and propranolol (unlikely with other beta blockers)
alcohol and illicit drugs (eg cannabis, methamphetamine).

NB1: This list is not exhaustive and all drugs that the patient is taking should be considered.

NB2: Pethidine is metabolised to norpethidine, which is neurotoxic and can cause delirium.

Drugs and drug groups with significant anticholinergic effects (Box 8.25)

Drugs and drug groups with significant anticholinergic effects are:

sedating antihistamines (eg promethazine, doxylamine)

drugs for bladder overactivity (eg oxybutynin, tolterodine)
some antipsychotics (see Table 8.21)
tricyclic antidepressants (eg amitriptyline)
benztropine and benzhexol
prochlorperazine
hyoscine hydrobromide.

Note 1: Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the
confusion assessment method. A new method for detection of delirium. Ann Intern Med 1990;113(12):941-8.
[URL]

Prevention of delirium
Up to a third of delirium episodes in hospitalised elderly patients can be prevented by the following evidence-
based interventions: adequate hydration and nutrition; adequate pain relief; promotion of sleep; correction of visual
and hearing impairments; avoidance of restraints; provision of lighting appropriate to the time of day; quiet; use of
single rooms; availability of a clock and calendar; and close involvement of family members. In patients with a hip
fracture, applying these principles preoperatively and perioperatively, by a geriatrician-led ‘orthogeriatric’ service,
has been shown to reduce postoperative delirium.

Prophylaxis with haloperidol has been shown to have no effect on the incidence of delirium.
Management of delirium
Principles of management
Prevention of delirium is ideal, but when delirium is present the key principle in its management is to identify and
treat the underlying cause(s) (see Diagnosis), and to implement nonpharmacological measures. Pharmacological
management is unnecessary for most delirious patients.

It is impossible to emphasise enough how often delirium is due to drugs. It is essential to review the patient's
medication history, as well as other medicines that may have been deliberately or unintentionally taken. While
anticholinergic drugs (see Box 8.25) and psychotropic drugs are often implicated in delirium, many other drugs
can also cause the syndrome (see Box 8.24). Most patients recover without specific treatment once the drugs are
withdrawn.

If the delirium has not resolved in under a week, the underlying cause(s) and their treatment should be reviewed.
Consider, for instance, whether a fungal infection may be the infective cause of the delirium, and whether more
investigations are required. Also consider whether there is a significant underlying dementia, especially dementia
with Lewy bodies, and whether the symptoms of the two are overlapping.

Up to half of all delirious patients are not recovered completely from their delirium at the time of hospital
discharge. This makes close liaison between the hospital and other care providers (eg general practitioner,
residential care staff) at the time of discharge essential, together with ongoing vigilance about medication,
environmental changes and sensory problems. It is essential to ensure appropriate information is given to both the
patient and family members. Often patients who have been delirious are troubled by frightening memories of and
misconceptions about their time in hospital. This distress can be reduced by careful explanation and reassurance
including the provision of written materials. The Hospital Elder Life Program (HELP) website is a useful source of
information about delirium for patients and their family [URL].

For management of delirium in patients receiving palliative care, see the Palliative Care guidelines. For discussion
of delirium in elderly patients with developmental disabilities, see Management Guidelines: Developmental
Disability.

Nonpharmacological management
Delirious patients must be nursed in a setting where they can be observed at all times, as their behaviour may be
unpredictable. Vital signs should be monitored closely and careful attention paid to ensuring adequate hydration,
nutrition and pain relief. A calm and quiet atmosphere, frequent prompts concerning orientation, clear and precise
communication, and a night-light are helpful. Delirious patients should be approached from the front, not the side,
as peripheral stimuli are more likely to be misinterpreted as hostile. Staff should clearly state their identity, role (eg
nurse, doctor) and the purpose of their approach each time they interact with the patient. The patient is likely to be
more settled in the presence of a familiar person (eg relative or friend). Very disturbed patients may need
individual care from a trained staff member.

The delirious patient must be observed at all times.

Explaining the nature of the diagnosis and the reasons for any unusual behaviours or ideas to the patient's close
relatives is likely to reduce their bewilderment and distress.

Pharmacological management

Frequently no medication will be needed to manage delirium if there is prompt treatment of underlying cause(s) and good
nonpharmacological management.

While pharmacotherapy is unnecessary for most delirious patients, it is sometimes required to control anxiety,
agitation, aggression, delusions and/or hallucinations. At the time of writing, there are no drugs specifically
approved by the Australian Therapeutic Goods Administration (TGA) for the treatment of delirium and high
quality evidence for their use is also lacking. However, clinical experience indicates that there is a place for
pharmacological intervention in patients with delirium where distress or agitation is significant.

Delirium can sometimes be caused by alcohol withdrawal, so a therapeutic trial of thiamine should always be
considered when the cause of the delirium is unknown. For management of delirium associated with alcohol use,
see Acute alcohol withdrawal.

Delirium can deteriorate into a behavioural emergency, or present as such. The management of behavioural
emergencies and delirium are markedly different. For management of behavioural emergencies, see Behavioural
emergencies.

If delusions or hallucinations are causing distress, or if behavioural disturbance threatens the patient's treatment or
care, or is causing significant threat to others, an antipsychotic is indicated. Use:

1 haloperidol 0.5 mg orally, as a single dose

OR

1 olanzapine 2.5 mg orally, as a single dose

OR

1 risperidone 0.5 mg orally, as a single dose.

If oral administration is impossible and symptoms are severe, use:

1 haloperidol 0.5 mg IM, as a single dose

OR

1 olanzapine 2.5 mg IM, as a single dose.

Half of the above doses may be adequate in the very frail and elderly person.

These antipsychotics are sedative, but not strongly so. They are eliminated slowly so repeat doses may have
cumulative effects. As their onset of action can be delayed from 30 to 60 minutes after administration, second
doses should not be given for at least 30 minutes. After the first dose is given, the patient should be gently
encouraged to a safe space and allowed to walk around if possible. All threatening stimuli should be minimised
and staff should maintain a respectful distance as they may exacerbate the patient's feeling of agitation.

A single dose of the indicated antipsychotic is usually adequate. Further doses may be required, but should be a
trigger to review the diagnosis and management plan. In particular, ensure that appropriate nonpharmacological
measures have been instituted. Ongoing delirium may also be an adverse effect of the antipsychotic.

A single dose of the indicated antipsychotic is usually adequate.

There is limited evidence for the use of quetiapine (25 mg orally, as a single dose) and amisulpride (50 mg orally,
as a single dose) in delirium.

All antipsychotic drugs have significant adverse effects (including the aggravation of delirium). First-generation
antipsychotics have a higher incidence of extrapyramidal adverse effects than second-generation antipsychotics;
however, when drugs are used for the short-term treatment of the hyperactive symptoms of delirium, these effects
are usually limited. All of the recommended antipsychotics in delirium, but particularly risperidone, are associated
with orthostatic hypotension and this effect may be evident acutely, especially if higher doses are administered.
See Box 8.26 for cautions in the use of psychotropic drugs in patients with delirium and Management of
antipsychotic adverse effects for a detailed discussion of antipsychotic adverse effects.

As second-generation antipsychotics have a lower incidence of extrapyramidal adverse effects, they are sometimes
used to ameliorate the drug-induced delirium of dopaminergic therapy in Parkinson disease. While this may enable
the motor benefits of the dopaminergic drugs to be maintained, there is an increased risk of medication adverse
effects due to polypharmacy and this approach should be monitored and reviewed carefully.

Except for the specific indications of delirium related to alcohol withdrawal or to seizures, benzodiazepines
should be avoided because complications are common and long-acting benzodiazepines increase the risk of
delirium.
Cautions in the use of psychotropic drugs in patients with delirium (Box 8.26)

Use the oral route of administration if possible.

Monitor vital signs closely during and after the administration of psychotropic drugs.

Avoid the use of ‘as needed’ (prn) orders unless both the indication for administration and the maximum dose
per 24 hours are clearly specified. Use of ‘as needed’ medication must be reviewed daily because of the changing
clinical situation.

In general, benzodiazepines should be avoided in delirium (especially in patients with significant respiratory
depression) except for cases due to alcohol withdrawal or seizures.

Monitor the patient intensively if repeat doses of psychotropic drugs are given.

A record of medications given should be kept and must accompany the patient if they are moved to another
location.

Further reading
Clinical Epidemiology and Health Service Evaluation Unit Melbourne Health in collaboration with the Delirium
Clinical Guidelines Expert Working Group. Clinical practice guidelines for the management of delirium in older
people. Melbourne: Victorian Government Department of Human Services; 2006. [URL]

National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management.
London: NICE; 2010. [URL]

Yew T, Maher S. Australian and New Zealand Society for Geriatric Medicine. Position statement 13. Delirium in
older people. Sydney: Australian and New Zealand Society for Geriatric Medicine; 2012. [URL]

Young J, Inouye SK. Delirium in older people. BMJ 2007;334:842-6. [URL]

Key references
Delirium: awareness of risk

Clinical Epidemiology and Health Service Evaluation Unit Melbourne Health in collaboration with the Delirium Clinical
Guidelines Expert Working Group. Clinical practice guidelines for the management of delirium in older people.
Melbourne: Victorian Government Department of Human Services; 2006. [URL]

National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management. London:
NICE; 2010. [URL]

Delirium: diagnosis

Clinical Epidemiology and Health Service Evaluation Unit Melbourne Health in collaboration with the Delirium Clinical
Guidelines Expert Working Group. Clinical practice guidelines for the management of delirium in older people.
Melbourne: Victorian Government Department of Human Services; 2006. [URL]

Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment
method. A new method for detection of delirium. Ann Intern Med. 1990;113(12):941–8. [ ]

National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management. London:
NICE; 2010. [URL]

Delirium: prevention

Clinical Epidemiology and Health Service Evaluation Unit Melbourne Health in collaboration with the Delirium Clinical
Guidelines Expert Working Group. Clinical practice guidelines for the management of delirium in older people.
Melbourne: Victorian Government Department of Human Services; 2006. [URL]

Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ, et al. Haloperidol prophylaxis for
elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc.
2005;53(10):1658–66. [ ]
Marcantonio ER, Flacker JM, Wright RJ, Resnick NM. Reducing delirium after hip fracture: a randomized trial. J Am
Geriatr Soc. 2001;49(5):516–22. [ ]

National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management. London:
NICE; 2010. [URL]

Delirium: management

Clinical Epidemiology and Health Service Evaluation Unit Melbourne Health in collaboration with the Delirium Clinical
Guidelines Expert Working Group. Clinical practice guidelines for the management of delirium in older people.
Melbourne: Victorian Government Department of Human Services; 2006. [URL]

National Institute for Health and Clinical Excellence (NICE). Delirium: diagnosis, prevention and management. London:
NICE; 2010. [URL]

Published March 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Dementia
Diagnosis and features of dementia
Dementia is a clinical syndrome that is characterised by a progressive deterioration in cognition with resulting
decline in function. Because dementia is an age-related disorder, whose prevalence doubles every 5 years from age
60 to 90 years, its prevalence is rising in most countries as their populations age. In Australia it is projected that
the current number of people with dementia (278 707 in 2012) will rise to 942 624 by 2050.

While the most common initial symptom is an impaired ability to learn and remember new information, there is
also deterioration in abstract thinking, judgment, verbal fluency, orientation, comprehension and the ability to
perform complex tasks. The diagnosis is made when deficits are demonstrated in two or more areas of cognition
causing a significant decline in function.

In addition to cognitive changes, people with dementia experience behavioural change and noncognitive
symptoms. These features of dementia are referred to as behavioural and psychological symptoms or
neuropsychiatric symptoms of dementia. They can include personality change, loss of impulse control, impaired
social and occupational functioning, and deterioration in personal care. A variety of mood changes can occur;
including shallow euphoria with associated poverty of thought. Mild depressive symptoms occur frequently,
especially in the early stages of dementia. More severe depressive disorders do occur in the context of dementia,
but are less common. Apathy may appear early in the course of the disorder but tends to be prominent in the late
phases.

Delusions, often persecutory in nature, are present in up to 30% of patients. Misidentification of friends and
relatives may occur, and mirror images or television may be misperceived as real. Although visual hallucinations
can occur in dementia, delirium is a more likely cause of these. Agitation and resistance to care interventions are
common in moderate-to-severe dementia.

To confirm the diagnosis of dementia, cognitive impairment should be verified in at least two domains. These
include impaired new learning, apraxia, agnosia, language disturbance and loss of executive functions. Executive
functions are controlled by the frontal lobes and include the ability to solve problems or change the focus of
attention in planning or action. Impairment is particularly evident in complex tasks such as driving a car, using
money, or carrying out a sequence of actions (eg cooking a meal). Attention and concentration usually are
unimpaired in mild-to-moderate dementia.

The most important causes of dementia are degenerative, including Alzheimer disease (50% to 70%), primary
frontal dementias (up to 10%), dementia with Lewy bodies and Parkinson disease dementia (up to 10%), vascular
dementia (10% to 20%), and alcohol-related dementia (up to 5%). Dementia also may be due to acquired
immunodeficiency syndrome (AIDS). Often dementia is due to a combination of some of the above causes. Many
cases of presumed Alzheimer disease also exhibit cerebrovascular pathology at autopsy, and the majority of
individuals diagnosed with vascular dementia during life have significant numbers of the plaque and tangle lesions
that characterise Alzheimer disease at post mortem.

Brief syndromal descriptions of the characteristics and differential diagnosis of the various dementia syndromes
are given in Box 8.1, but these are only a summary of the cardinal features of the common dementia syndromes.
For detailed information consult the references listed in Dementia: Further reading.

In depressive pseudodementia, severely depressed patients present with a dementia-like syndrome; however, this is
relatively uncommon and when it occurs there is usually a history of depression. Clarify the possibility of
depression by a detailed mental state examination and clinical history from the patient and significant others. In
contrast, depressive symptoms are common in people with true dementia, especially in the early stages, and
sometimes require treatment.

Consider other medical causes of memory impairment including hypothyroidism, B group vitamin deficiencies,
sleep apnoea, neurosyphilis, cerebral space occupying lesions and normal pressure hydrocephalus. Take care to
minimise use of drugs that may adversely affect cognitive function, notably the benzodiazepines, other sedative
hypnotics and drugs with anticholinergic properties (see Box 8.25).

In making a diagnosis of dementia, the most critical factor is a report of progressive cognitive decline from a
person who knows the patient well. There are no diagnostic tests that confirm the presence of dementia to a high
degree of sensitivity and specificity early in the clinical course.

Brief tools for assessing cognition include the Mini-mental State Examination (MMSE), Abbreviated Mental Test
Score (AMTS), General Practitioner Assessment of Cognition (GPCOG) and Montreal Cognitive Assessment
(MoCA). Some tools have been developed for use in particular settings, such as Rowland Universal Dementia
Assessment Scale (RUDAS) for multicultural settings and Kimberley Indigenous Cognitive Assessment (KiCA)
tool for use with remote Indigenous Australian people. To access these tools, see Appendix 8.2. The diagnosis of
the dementia syndrome is based both on the report of cognitive decline from a reliable informant and the presence
of typical cognitive deficits on direct examination.

It is vital to diagnose the cause of the dementia and to evaluate patients for the presence of treatable causes of
cognitive impairment. A full medical history from an informant (including drug and alcohol intake) should be
obtained, and physical and mental state examinations and appropriate investigations done. When the person with
dementia is young, the onset of the dementia rapid or the presentation atypical, tests for major organ failure
(kidney function and liver biochemistry), human immunodeficiency virus (HIV), blood glucose, thyroid function,
urinalysis, blood film, plasma vitamin B12 and folate concentrations, syphilis serology, chest X-ray and cerebral
imaging are especially indicated. Specific physical findings may point to the need for other investigations,
particularly considering that most people with dementia are older and many have concomitant physical illness or
disability.

Patients with dementia who are newly diagnosed or are entering residential care should also be assessed for their
nutritional status, dental and gum health, and for sleep problems. A thorough medical review is indicated because
many people with dementia fail to present to a doctor even though they may have a treatable medical condition.

Features of the common dementia syndromes (Box 8.1)

Alzheimer disease is characterised by an insidious onset of symptoms with initial forgetfulness progressing over
time to profound memory impairment with accompanying dysphasia, dyspraxia and personality change.

In frontal dementias, personality change and alteration in behaviour are the earliest manifestations of the
condition. Social disinhibition and insightlessness may be a problem. A small number of frontal dementia
patients present with word finding difficulty, which progresses to a profound nonfluent dysphasia (semantic
dementia). Many patients with a frontal dementia are apathetic and withdrawn, especially in the later stages of
the illness. As the dementia progresses, memory deficits may become more prominent.

Dementia with Lewy bodies is characterised by a dementia syndrome with any two of the following: visual
hallucinations, spontaneous motor parkinsonism, fluctuation in the mental state in the absence of a clear cause
for delirium. Dementia seen in Parkinson disease is likely to represent part of the same disease spectrum.

Pure vascular dementia usually starts suddenly and will be accompanied by focal neurological signs with
imaging evidence of cerebrovascular disease. Many patients with vascular dementia have evidence of
atherosclerotic disease elsewhere. However, many dementia patients with some cerebrovascular disease have a
mixed picture with elements of both Alzheimer and vascular pathology present.

Patients with dementia associated with excessive alcohol consumption tend to have predominant deficits in
new learning and in frontal function.

Overview of management of dementia

While cholinesterase inhibitors or memantine may be helpful for the treatment of cognitive impairment caused by
Alzheimer disease, and psychotropic drugs are sometimes indicated for the treatment of some psychological
symptoms and behaviours seen in people with dementia, the care and management of the patient with dementia
predominantly involves nonpharmacological measures, such as family education and support, and adjustment of
the environment.

Nonpharmacological management of dementia

Support for families and carers is an important part of the management strategy because dementia is a heavy
burden for both the patient and the family.

Cognitive and behavioural abnormalities need careful, calm explanation to family members, carers and advocates.
Behavioural and psychological symptoms of dementia, including sleep inversion, incontinence, excessive
inappropriate motor activity (eg pacing), shouting and agitation, affect over 90% of people with dementia at some
stage and all need individual management. Careful analysis of the cause of the behaviour, initiation of individually
tailored behavioural management strategies and good environmental design may ameliorate these symptoms of
dementia. An appropriately stimulating environment with personal belongings and orientation cues, as well as
attention to spectacles and hearing aids, can assist in preventing behavioural disturbance.

All Australian states and territories have a Dementia Behaviour Management Advisory Service (DBMAS), which
has a 24-hour helpline with trained staff who can advise on strategies to manage challenging behaviours in people
with dementia [Note 1].

Aged care assessment teams can provide useful evaluation and assistance. Soon after diagnosis of any type of
dementia, it is important to put carers in touch with the local branch of Alzheimer's Australia for provision of
information, care advice, support groups and counselling as required (see Appendix 8.1 for contact details). If the
patient's capacity to entrust enduring power of attorney and guardianship to a relative or friend remains intact, this
should be done. Review driving ability and report to relevant authorities in keeping with current regulations [Note
2].

For any new behavioural symptoms, care must be taken to exclude treatable causes such as delirium, pain or
constipation. Patients with dementia are vulnerable to superimposed delirium, often due to acute medical illness
(eg infection) or prescribed drugs. Suspect delirium if a stable patient becomes acutely disturbed (see Delirium).

Note 1: Dementia Behaviour Management Advisory Service, telephone: 1800 699 799, [URL]

Note 2: See Austroads website [URL]

Treatment for cognitive impairment in dementia

Cholinesterase inhibitors offer modest benefits to patients with dementia due to Alzheimer disease. These drugs
improve alertness and function and can maintain cognitive scores at or above the baseline for up to 12 months;
however, they do not modify the underlying progression of pathology. Open-label trials yielded results consistent
with continued benefit for up to 4 years. Six-month studies suggest that between five and fifteen patients need to be
started on treatment to see a significant improvement in one patient.

Patients should be treated for at least 2 months at the maximum recommended dose (if tolerated) before a final
assessment of response is made. Not all patients benefit from cholinesterase inhibitors; some have modest benefit
and a few show significant improvement. Adverse effects, particularly gastrointestinal, prevent the use of these
drugs in some patients.

If patients tolerate and appear to benefit from cognitive enhancing drugs then the drug should not be ceased until
the patient is in an advanced state of dementia, usually having lost independent mobility. A study indicated that
cessation of donepezil in moderate-to-severe dementia caused by Alzheimer disease is associated with a
measurable decline in function and/or cognition, compared to patients who are maintained on therapy [Note 3].

In Australia, the rules for obtaining and continuing subsidised cholinesterase inhibitors are complex; consult the
Pharmaceutical Benefits Scheme website for up-to-date information.

There is no convincing evidence that any of the available cholinesterase inhibitors is more efficacious than any
other; however, a once-daily dosing regimen and limited requirements for dose titration make donepezil,
prolonged-release galantamine and rivastigmine transdermal patch easier to use than oral rivastigmine. In the event
of no response, there is a lack of clear evidence that switching to another cholinesterase inhibitor will produce
improvement. However, individual cases of patients who respond to one drug but not to another have been
described. In addition, individuals vary in their susceptibility to the adverse effects of the available cholinesterase
inhibitors.

If considered appropriate, use:

1 donepezil 5 mg orally, at night for 4 weeks, increase to 10 mg at night if tolerated

OR

1 galantamine prolonged-release 8 mg orally, in the morning for 4 weeks, increase to 16 mg

daily if tolerated. If the patient deteriorates after an initial good response, increase further
to 24 mg daily if tolerated

OR

1 rivastigmine 4.6 mg transdermally, once daily applied for 24 hours. After 4 weeks
increase to 9.5 mg daily if tolerated [Note 4]

OR

2 rivastigmine 1.5 mg orally, twice daily for 2 weeks, increase to 3 mg twice daily;
subsequent dose increases to 4.5 mg and then 6 mg twice daily should be based on
 tolerability and may be considered every 4 weeks.

The cholinesterase inhibitors are associated with prominent gastrointestinal adverse effects, particularly anorexia,
nausea and vomiting. Other adverse effects include diarrhoea, insomnia, vivid dreams, cramps, dizziness,
depression, lethargy, fatigue, drowsiness, tremor, weight loss, urinary incontinence and sweating. Most adverse
effects are dose-related and can be minimised by slow titration of the dose.

Take care when introducing these drugs in patients with asthma, chronic obstructive pulmonary disease, cardiac
conduction abnormalities (particularly atrioventricular block) or peptic ulcer disease, and when administering
muscle relaxants to patients already taking a cholinesterase inhibitor.

There is some evidence that patients who have dementia with Lewy bodies show significant sustained
improvement in neuropsychiatric symptoms when treated with rivastigmine. There is limited evidence that some
patients whose dementia has a vascular component may benefit from treatment with donepezil or galantamine.

Memantine, an antagonist of N-methyl-D-aspartate (NMDA), is approved by the Therapeutic Goods

Administration as a treatment for moderate-to-severe Alzheimer disease. There are conflicting data on whether
memantine provides benefit when added to a cholinesterase inhibitor in patients who are deteriorating following an
initial response to a cholinesterase inhibitor.

If considered appropriate, use:

memantine 5 mg orally, in the morning in the first week, 5 mg twice daily in the second
week, 10 mg in the morning and 5 mg at dinnertime in the third week, and then 10 mg
twice daily.

Memantine is excreted by the kidney so reduce dose in kidney failure. Adverse effects can include confusion,
dizziness, drowsiness, headache, insomnia, agitation and hallucinations but the drug is usually well tolerated. If
insomnia is a problem, memantine can be taken earlier in the day.

Note 3: Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, et al. Donepezil and memantine
for moderate-to-severe Alzheimer's disease. N Engl J Med 2012;366(10):893-903. [URL]

Note 4: Two patch sizes are available, rivastigmine 4.6 mg/24 hours (9 mg) and rivastigmine 9.5 mg/24 hours
(18 mg).

Treatment of mood and behavioural disturbances in dementia

The mainstay of the treatment of mood and behavioural disturbances is nonpharmacological, with an emphasis on
supporting families and carers. However, there are specific instances where pharmacological treatment is used.
Psychotropic drugs should only be given for specific indications, based on assessment of specific symptoms and
when nonpharmacological interventions have not alleviated symptoms distressing for the patient, their family or
co-residents (see Dementia: nonpharmacological management).

Use low starting doses for all psychotropic drugs in people with dementia and increase slowly as necessary. In the
early treatment phase there should be at least weekly review of the target behaviour or symptoms and close
observation for adverse effects including sedation, postural hypotension, extrapyramidal symptoms and
anticholinergic effects (eg dry mouth, constipation, urinary hesitancy, delirium).

Behavioural and psychological symptoms in patients with dementia will often be temporary. Psychotropic drugs
should be reviewed after no more than 3 months and the dose reduced and stopped when possible, with the goal of
using the lowest effective dose for the shortest period of time.

Never use first-generation antipsychotics if dementia with Lewy bodies is suspected, or for patients with Parkinson disease.

If dementia with Lewy bodies is suspected, first-generation antipsychotics should never be used, nor should they
be used in patients with Parkinson disease.

In dementia, second-generation antipsychotics, such as risperidone and olanzapine, have fewer extrapyramidal
adverse effects and they have been more extensively studied in this population than the first-generation drugs, such
as haloperidol. There is some evidence that risperidone and perhaps olanzapine may have efficacy in the treatment
of aggression and psychosis complicating dementia. However, not all treated patients will improve, and in some
studies the majority have not improved and response has not been significantly different to that seen with placebo.

There is an increased risk of mortality and cerebrovascular adverse effects in patients with dementia treated with
risperidone and olanzapine in trials, and this risk appears to be at least as great or greater with first-generation
antipsychotics. The risk of cerebrovascular adverse effects is highest in those with poorly controlled vascular risk
factors (atrial fibrillation, hypertension or diabetes) or a history of previous stroke. Use of these drugs in patients
with dementia should be limited to those with intractable aggression or psychosis that has not responded to
psychosocial interventions and who have low or moderate risk of stroke. When individuals with a high risk of
stroke have intractable behavioural disturbances, seek advice from a psychiatrist with expertise in the psychiatry of
old age.

Due to the possible harms associated with these drugs in people with dementia, careful consideration should be
given to informed consent. Most people with moderate-to-severe dementia are too impaired to give informed
consent and it will often need to be sought from the patient's designated guardian, medical power of attorney or
next of kin (see Informed consent in mental illness).

If pharmacotherapy is considered necessary to control hallucinations, delusions or seriously disturbed behaviour,

use:

1 risperidone 0.25 mg orally, twice daily initially. Increase if needed by 0.25 mg every 2 or
more days. Maximum dose 2 mg daily [Note 5]

OR

2 olanzapine 2.5 mg orally, daily initially. Increase if needed by 2.5 mg every 2 or more
days to maximum of 10 mg daily in 1 or 2 divided doses [Note 6].

To relieve symptoms of severe anxiety and agitation, use:

oxazepam 7.5 mg orally, 1 to 3 times daily.

Benzodiazepines should not be used for longer than 2 weeks. They exacerbate cognitive impairment and increase
the risk of falls and associated injuries in older people.

Depression may occur in dementia, and if pervasive and persistent, it should be treated (see Depression). However,
studies of the efficacy of antidepressants in patients with depression in the context of dementia are limited by small
numbers and less than ideal methodology. The most recent and best conducted study failed to show efficacy for
either sertraline or mirtazapine [Note 7]. Avoid antidepressants with anticholinergic adverse effects as they have
the potential to exaggerate the cognitive deficits due to central acetylcholine deficiency in Alzheimer disease.

There is no convincing evidence that antiepileptic drugs are helpful for the behavioural and psychological
symptoms of dementia; however, some patients with dementia may develop seizures in which case these drugs
may be of use.

Note 5: Risperidone is licensed in Australia for the treatment of psychotic symptoms, or persistent agitation or
aggression unresponsive to nonpharmacological approaches, in patients with moderate to severe
Alzheimer disease. Maximum licensed treatment duration 12 weeks.

Note 6: At the time of writing, olanzapine is not approved by the Australian Therapeutic Goods Administration
(TGA) for treatment of behavioural disturbance associated with dementia. See the TGA website for current
information.

Note 7: Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, et al. Sertraline or mirtazapine for
depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet
2011;378(9789):403-11. [URL]

Other pharmacotherapies for dementia

Treat folate and vitamin B12 deficiency if present, but these are more often a result rather than a cause of dementia.
Vitamin E should not be used; evidence for efficacy is flawed and in trials high-dose vitamin E was associated with
a slightly increased death rate from haemorrhagic causes. A variety of other unproven herbal remedies and other
medications are used by some patients.

Further reading
Ames D, Burns A, O'Brien J. Dementia. 4th ed. London: Hodder Arnold; 2010.

Ames D, Chiu E, Lindesay J, Shulman KI. Guide to the psychiatry of old age. Cambridge, UK: Cambridge
University Press; 2010.
Ritchie C, Ames D, Masters C, Cummings J, editors. Therapeutic strategies in dementia. Oxford: Clinical
Publishing; 2007.

Key references
Dementia: diagnosis and features

Ames D, Burns A, O'Brien J, editors. Dementia. 4th ed. London: Hodder Arnold; 2010.

Ames D, Chiu E, Lindesay J, Shulman KI. Guide to the psychiatry of old age. Cambridge, UK: Cambridge University
Press; 2010.

Ritchie C, Ames D, Masters C, Cummings J, editors. Therapeutic strategies in dementia. Oxford: Clinical Publishing;
2007.

Dementia management: introduction and nonpharmacological

Ames D, Burns A, O'Brien J, editors. Dementia. 4th ed. London: Hodder Arnold; 2010.

Ames D, Chiu E, Lindesay J, Shulman KI. Guide to the psychiatry of old age. Cambridge, UK: Cambridge University
Press; 2010.

Kong E-H, Evans LK, Guevara JP. Nonpharmacological intervention for agitation in dementia: a systematic review and
meta-analysis. Aging & Mental Health. 2009;13(4):512–20. [ ]

O'Connor DW, Ames D, Gardner B, King M. Psychosocial treatments of psychological symptoms in dementia: a
systematic review of reports meeting quality standards. Int Psychogeriatr. 2009;21(2):241–51. [ ]

Ritchie C, Ames D, Masters C, Cummings J, editors. Therapeutic strategies in dementia. Oxford: Clinical Publishing;
2007.

Dementia: pharmacological management

Ames D, Burns A, O'Brien J, editors. Dementia. 4th ed. London: Hodder Arnold; 2010.

Ames D, Chiu E, Lindesay J, Shulman KI. Guide to the psychiatry of old age. Cambridge, UK: Cambridge University
Press; 2010.

Devanand DP, Mintzer J, Schultz SK, Andrews HF, Sultzer DL, de la Pena D, et al. Relapse risk after discontinuation
of risperidone in Alzheimer's disease. N Engl J Med. 2012;367(16):1497–507. [ ]

Herrmann N, Lanctot KL. Pharmacologic management of neuropsychiatric symptoms of Alzheimer disease. Can J
Psychiatry. 2007;52(10):630–46. [ ]

Kales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C, et al. Risk of mortality among individual
antipsychotics in patients with dementia. Am J Psychiatry. 2012;169(1):71–9. [ ]

McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;
(2):CD003154. [ ]

National Prescribing Service (NPS). Balancing the benefits and harms of antipsychotic therapy. Prescribing Practice
Review. 2011;(PPR 55 ). [URL]

Ritchie C, Ames D, Masters C, Cummings J, editors. Therapeutic strategies in dementia. Oxford: Clinical Publishing;
2007.

Rodda J, Carter J. Cholinesterase inhibitors and memantine for symptomatic treatment of dementia. BMJ.
2012;344e2986. [ ]

Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic
drugs in patients with Alzheimer's disease. N Engl J Med. 2006;355(15):1525–38. [ ]

Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of evidence for the efficacy of memantine in mild
Alzheimer disease. Archives Of Neurology. 2011;68(8):991–8. [ ]

Published July 2013. Amended October 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Anxiety and associated disorders
Overview of anxiety disorders
Anxiety symptoms may be primary or secondary to other psychiatric (eg depression) or physical disorders (eg
hyperthyroidism). For secondary anxiety, treatment of the underlying problem is the appropriate approach. In
addition, short-term symptomatic treatment of the anxiety with psychological interventions may also be required.

For treatment of childhood anxiety disorders, see Anxiety disorders in childhood and adolescence.

Anxiety disorders are generally separated into a number of discrete conditions (as described in DSM-IV-TR).
However, there is significant comorbidity between the different anxiety disorders, and with mood disorders and
problem drug use or dependence. It is important to characterise the range of anxiety symptoms presented by the
patient and ensure that treatment strategies appropriately address all of them.

Anxiety symptoms may be very prominent in depressive disorders. Lack of response to anxiolytic therapy may
reflect an underlying depressive illness requiring antidepressant treatment.

For all anxiety disorders, the first step in management is to define the type of anxiety disorder. It is important to
identify and address any possible psychological factors which may cause or exacerbate the disorder, eg financial or
relationship difficulties. In addition, lifestyle factors (eg alcohol use, excessive caffeine intake, illicit drug use,
excessive work, inadequate sleep) may exacerbate the problem and should be addressed.

Anxious patients with anxiety-related physical symptoms may attend many different medical practitioners seeking
an explanation for their symptoms and treatment of the assumed physical disorder. Sometimes careful examination
and assessment, then reassurance about the absence of physical disease, will reduce these anxiety symptoms.
Psychological interventions (including eTherapy) such as cognitive behavioural therapy (CBT) are the most
appropriate initial treatment choice in most cases. Although cognitive approaches for the anxiety disorders may be
as effective as drugs (and have fewer adverse effects) for those with mild-to-moderate disorders, patients with
more severe or persistent anxiety disorders usually need pharmacotherapy as well. Patient support organisations
are listed in Appendix 8.1 and eTherapy resources in Psychological interventions: eTherapy.

It is important to educate the patient about their disorder and its treatment, and in particular to emphasise that
symptoms may not completely disappear irrespective of whether psychological or pharmacological treatments are
used. It is also important to emphasise the need to persist with psychological interventions for sufficient time for
the benefits to be evident. Anxiety disorders are usually relapsing or chronic conditions that require ongoing
treatment, with psychological interventions being most beneficial when patients persist with and practise the
strategies long term.

Pharmacotherapy (eg selective serotonin reuptake inhibitors [SSRIs]) is used when psychological interventions are
not sufficiently effective or are not available. Although commonly used to treat anxiety in the past,
benzodiazepines are not recommended for the treatment of these disorders other than in exceptional circumstances.
The apparently innocuous nature of benzodiazepines has lulled many clinicians into prescribing them widely and
for long periods but there has been a slow recognition that large numbers of patients develop problems of tolerance
and abuse.

If considering prescribing benzodiazepines:

always check for a history of problem alcohol or drug use

be wary of prescribing to unfamiliar patients, especially if asking for a particular drug by name (may
indicate drug-seeking behaviour)
carefully discuss the potential for addiction with the patient
avoid using short-acting drugs as they are the most highly addictive
only prescribe small quantities of medication at a time
use only as short-term treatment
ensure regular review of the patient and continuity of care.

When patients have been taking benzodiazepines long term for the treatment of anxiety consider trying to wean the
patient off the drug. Instead, manage the disorder with a combination of psychological interventions with or
without alternative medication. A very gradual reduction of benzodiazepines over several months may be needed
(see Benzodiazepine withdrawal). If there is a return of symptoms, distinguish between the following:

a medication withdrawal (discontinuation) syndrome manifesting as new symptoms occurring soon after the
drug is stopped (anxiety, irritability, insomnia, palpitations, hypersensitivity to sensory stimuli, nausea,
 headache, tremor, sweating), but reducing spontaneously within 1 to 4 weeks of stopping the benzodiazepine
a re-emergence of the underlying anxiety, sometimes rebounding with greater than the original intensity.

If there are concerns about management of a patient who has been inappropriately taking benzodiazepines long
term, see Benzodiazepines, zolpidem and zopiclone: problem use.

Adjustment disorder with anxious mood

Adjustment disorder with anxious mood is the most common presentation of anxiety symptoms. It is a time-
limited syndrome with onset and resolution related to exposure to a stressor. By contrast, most anxiety disorders
are chronic conditions, albeit with symptoms varying in severity over time.

Diagnostic criteria for adjustment disorder with anxious mood include the onset of anxiety symptoms within 3
months of identifiable psychosocial stressor(s), which:

are time-limited, ie persist for less than 6 months, once the stressor or its consequence have terminated
are in excess of normal expectations of reaction to the stressor(s)
are not due to another identifiable mental disorder
are not part of a continuing pattern of overreaction to stress
impair social or occupational functioning.

The primary interventions for adjustment disorder with anxious mood are psychological, including counselling,
relaxation, problem solving, stress management, and cognitive behavioural therapy (CBT) (see Cognitive
behavioural therapy).

There is a place for short-term pharmacotherapy (usually less than 2 weeks) if the symptoms are severe, there is
significant impairment of functioning and there is inadequate response to psychological interventions. Most drugs
used to treat anxiety (eg selective serotonin reuptake inhibitors [SSRIs]) take a number of weeks to produce an
effect, thus in this situation the use of a benzodiazepine may be appropriate, taking into account the precautions
listed previously (see Anxiety and associated disorders: general information).

If pharmacotherapy is required, use a long-acting benzodiazepine, such as:

diazepam 2 to 5 mg orally, as a single dose, which may be repeated, if required, up to

twice daily, for up to 2 weeks.

Intermittent use, on occasional days when there is a severe exacerbation of anxiety, may suffice and is preferable to
continuous treatment.

If continuous treatment is required, the lowest effective dose should be used for up to 2 weeks. Daily doses should
not exceed diazepam 20 mg. Other long-acting benzodiazepines can be substituted for reasons of allergy, adverse
effects or for different pharmacokinetics.

Generalised anxiety disorder

Introduction

Generalised anxiety disorder (GAD) has a fluctuating course, but it tends to be a long-term disorder. It affects up to
5% of the population. Diagnostic criteria for GAD include excessive anxiety and pervasive and uncontrollable
worry about a number of events or activities, and which occurs for a period of 6 months or longer. Associated
symptoms include:

restlessness or feeling ‘keyed up’ or ‘on edge’

being easily fatigued
difficulty concentrating or mind ‘going blank’
irritability
muscle tension
sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep).

Other criteria are that the focus of the anxiety and worry is not confined to features of another psychiatric disorder;
also, that the anxiety, worry or physical symptoms cause clinically significant distress or impairment in social,
occupational or other important areas of functioning.

There is overlap between GAD and other anxiety disorders, and it often coexists with and may mask major
depressive disorder and/or dysthymic disorder.

Organic factors (eg hyperthyroidism, caffeine intoxication, stimulant use, alcohol/drug discontinuation syndrome)
or adverse effects of prescribed drugs or over-the-counter medication must be excluded. An adjustment disorder, as
defined in Adjustment disorder with anxious mood, must also be excluded.

When middle-aged or older patients first present with anxiety symptoms, exclude depression or dementia as the
primary cause of the anxiety symptoms.

On the available evidence, both psychological interventions and pharmacotherapy options are of moderate efficacy.
For treatment of GAD in childhood and adolescence, see Anxiety disorders in childhood and adolescence.

Psychological interventions are first-line therapy for generalised anxiety disorder.

The first-line treatments for generalised anxiety disorder are psychological.

Psychological interventions

Initial treatment for generalised anxiety disorder (GAD) should include information about the anxiety disorder and
education on relaxation techniques and coping skills. Stress management approaches including activity scheduling,
modifying lifestyle factors, problem-focused counselling, and other more specific approaches, such as structured
problem solving, are often beneficial. Ongoing supportive psychotherapy is important.

More specialised psychotherapies, particularly cognitive behavioural therapy (CBT), can be especially effective.
An experienced, trained clinician should provide the CBT.

When symptoms are more severe, pharmacotherapy is usually also required.

Pharmacotherapy
When psychological interventions do not provide sufficient benefit, pharmacotherapy may be added. While many
patients with generalised anxiety disorder (GAD) require long-term treatment, a trial of reduction and cessation of
medication should be attempted after the patient has been symptom free for at least 6 months. The chance of return
of symptoms is reduced if psychological interventions are used concurrently.

Selective serotonin reuptake inhibitors (SSRIs) are the most effective pharmacotherapy for GAD. In addition, the
serotonin and noradrenaline reuptake inhibitors venlafaxine and duloxetine have demonstrated efficacy for GAD.
Both classes of antidepressant take some weeks before efficacy is apparent, similar to the onset of response for
depression. Choice of drug should take into account the tendency to produce a withdrawal (discontinuation)
syndrome, and likelihood of toxicity in overdose (venlafaxine) as well as the adverse effect profile and potential
for drug interactions. Doses required for treating GAD are generally at the lower end of the recommended dose
range. If considered appropriate, use:

1 an SSRI orally, see Table 8.1 [Note 1]

OR

2 duloxetine 30 mg orally, daily initially, increasing according to tolerability and patient

response. Maximum dose 120 mg daily

OR

2 venlafaxine controlled-release 75 mg orally, in the morning after food, increasing

according to tolerability and patient response. Maximum dose 225 mg daily.

Tricyclic antidepressants are effective but are not considered first-line treatment due to adverse effects. They
should be used with caution if there is coexisting depression or ideas of self-harm because they are toxic in
overdose. If considered appropriate, an example would be to use:

imipramine 25 mg orally, at night, increasing gradually to 75 mg at night.

Buspirone is a further alternative treatment. It has negligible potential for tolerance or dependence and no
discontinuation syndrome. Response to buspirone may take 2 to 4 weeks, though initial response may be apparent
within 7 to 10 days. The mean effective daily dose of buspirone is 20 to 25 mg daily. If considered appropriate,
use:

buspirone 5 mg orally, 3 times daily initially, increasing if necessary to 20 mg 3 times

daily.
Several studies have shown that pregabalin, a presynaptic inhibitor of the release of excitatory neurotransmitters, is
effective in the treatment of GAD. The initial dose is 150 mg daily and increases gradually after 1 to 2 weeks to
450 to 600 mg daily. Effects are seen within a week. Adverse effects include somnolence, dizziness and dry mouth,
and are more prominent when higher doses (600 mg daily) are used. There is no rebound anxiety when it is
discontinued; however, when stopping, gradually decrease the dose to avoid precipitating a seizure. Pregabalin
does not have Therapeutic Goods Administration approval for use in Australia for GAD.

Existing data and current guidelines do not support the use of second-generation antipsychotics for the treatment of
GAD. While monotherapy with quetiapine does seem to be efficacious in reducing symptoms of GAD, this
efficacy must be weighed against its possible adverse effects. Data examining the use of second-generation
antipsychotics for augmentation treatment have shown limited benefit and greater risk of discontinuation due to
adverse effects.

Benzodiazepine use may be associated with a variety of adverse effects (eg dependence, cognitive impairment,
psychomotor effects including the risk of falls in older patients, somatic symptoms). Benzodiazepines may be used
for the treatment of GAD as a short-term measure during crises, when anxiety is severe and disabling or causing
the patient unacceptable distress, and taking into account the precautions listed previously (see Anxiety and
associated disorders: general information). If necessary, consider use of:

diazepam 2 to 5 mg orally, as a single dose, which may be repeated, if required, up to

twice daily.

Treatment should be for up to 2 weeks followed by gradual reduction of dose to zero within 6 weeks. Some
patients can reduce the dose in a shorter period. Subsequent use should be on an ‘as required’ basis.

Long-term treatment of GAD with benzodiazepines should only be considered when both psychological
interventions and alternative pharmacotherapies have failed to provide significant improvement. If long-term use is
contemplated, specialist review and advice should be sought first and a drug with a long half-life should be chosen
and the lowest effective dose should be prescribed. If considered appropriate, use:

diazepam 2 to 5 mg orally, as a single dose, which may be repeated, if required, up to

twice daily.

Patients with a diagnosis of an anxiety disorder may, over a period of time, develop depression requiring an
antidepressant (see Depression).

Note 1: At the time of writing, citalopram, fluoxetine, fluvoxamine and sertraline are not approved by the
Australian Therapeutic Goods Administration (TGA) for treatment of generalised anxiety disorder. See the TGA
website for current information.

Dosing regimens of selective serotonin reuptake inhibitors (SSRIs) for anxiety disorders (Table
8.1) [NB1]

Drug
Initial daily dose [NB2] Maximum daily dose

citalopram 10 mg 40 mg
escitalopram 5 mg 20 mg
fluoxetine 10 mg 80 mg
fluvoxamine 50 mg 300 mg [NB3]
paroxetine 10 mg 60 mg
sertraline 25 mg 200 mg
NB1: Not every SSRI has Australian TGA approval for use for each anxiety disorder; however, there is insufficient evidence to differentiate between
efficacy of the individual SSRIs.
NB2: Dose orally in the morning after food. Increase dose according to tolerability and patient response.
NB3: Doses above 150 mg daily may be given in 2 divided doses for better tolerability.

Panic attack
Introduction
Isolated panic attacks are common, occurring in around 15% of the population. A panic attack is defined as a
discrete period of intense fear or discomfort, in which four (or more) of the following symptoms develop abruptly
and reach a peak within 10 minutes:

palpitations, pounding heart or accelerated heart rate

 sweating
trembling or shaking
sensations of shortness of breath or smothering
feeling of choking
chest pain or discomfort
nausea or abdominal distress
feeling dizzy, unsteady, light-headed or faint
derealisation (feelings of unreality) or depersonalisation (being detached from oneself)
fear of losing control or going crazy
fear of dying
paraesthesiae (numbness or tingling sensations)
chills or hot flushes.

A single panic attack is not the same as panic disorder.

A single panic attack is not the same as panic disorder.

Treatment

Treat isolated panic attacks with psychological interventions.

Treat isolated panic attacks with psychological interventions.

Panic attacks may initially suggest an acute medical condition, eg heart attack, stroke, hyperthyroidism or a
respiratory condition, such as asthma. Patients presenting for the first time with symptoms of a panic attack,
especially with a clear physical element, should be carefully evaluated for significant acute physical illness.
Clinicians can be more confident of an accurate diagnosis of panic disorder with repeated presentations with
multisystem symptoms after prior negative investigations, but should be aware of changed symptoms that can
suggest acute physical illness.

Explanation, support and stress management advice are effective for some people and, where relevant, their
families and close friends. This is especially important on the first presentation following a panic attack.

People experiencing panic attacks should be told of the techniques of breathing slowly and deeply or of
rebreathing into a hand-held bag placed over the mouth. Both techniques raise arterial carbon dioxide
concentration and abolish many acute symptoms. However, although both are effective, breathing slowly and
deeply is less socially embarrassing than rebreathing into a bag and can be used to help control future episodes.
Also, rebreathing into a bag is usually inappropriate in medical practice as the acute hyperventilation has typically
passed by the time the patient presents to the clinician. It is important to carefully evaluate the patient to exclude
other illnesses such as asthma.

Panic disorder
Introduction
Panic disorder affects 2% to 3% of the population and is more common in women than men (3:1). It is
characterised by recurrent panic attacks, in which the onset of the attack is not associated with a situational trigger
(ie the attacks occur spontaneously or ‘out of the blue’), and not due to the direct physiological effects of a
substance, medication, general medical condition or another psychiatric disorder (eg depression).

Associated symptoms include:

anticipatory anxiety (ie persistent concern about having additional attacks)

elevated levels of generalised anxiety or tension
somatic preoccupation
phobic avoidance (agoraphobia 80%, social phobia 10%).

Psychological interventions

Psychological interventions are first-line treatment for panic disorder.

First-line treatment for panic disorder is with psychological interventions.

Education about the disorder, in particular explaining the way in which the panic attack produces physical
symptoms, is essential. The breathing control strategies described for panic attack treatment and relaxation
strategies are also important first steps.

Cognitive behavioural therapy (CBT) is the treatment of choice for panic disorder. There are several versions used
for panic disorder. The most commonly used is panic control treatment, which involves exposure to deliberately
induced symptoms, together with techniques (such as controlled slow breathing) for controlling symptoms and
reattribution of symptoms to benign causes (eg palpitations are not due to cardiac arrest). For further information
on CBT, see Cognitive behavioural therapy.

Pharmacotherapy

Psychological interventions are first-line treatment for panic disorder.

First-line treatment for panic disorder is with psychological interventions.

When CBT is not available or not effective, pharmacotherapy may be required. Various groups of drugs have
demonstrated efficacy in the treatment of panic disorder: selective serotonin reuptake inhibitors (SSRIs),
venlafaxine, tricyclic antidepressants (TCAs), irreversible nonselective monoamine oxidase inhibitors (MAOIs)
and some benzodiazepines. Antidepressants are considered the most appropriate long-term pharmacotherapy.
Choice of drug depends on factors such as adverse effect profile and general tolerability, presence of coexisting
depression, history of problem alcohol or drug use, and risk of overdose (TCA toxicity).

Pharmacotherapy for panic disorder may need to be continued for 6 to 12 months in the first instance. After this
period, the dose should be slowly reduced and, if possible, the drug stopped. Every effort should be made to use
psychological interventions to minimise the need for prolonged pharmacotherapy. However, some patients need
ongoing medication. Recurrence of symptoms may be reduced, and the chance of successfully ceasing the drug
increased, if the patient can effectively use CBT concurrently. If symptoms do not remit then refer to a psychiatrist.

SSRIs and venlafaxine are regarded as first-line pharmacotherapy. If considered appropriate, use:

1 an SSRI orally, see Table 8.1 [Note 2]

OR

2 venlafaxine controlled-release 75 mg orally, in the morning after food, increasing

according to tolerability and patient response. Maximum dose 225 mg daily.

On initiation of treatment there may be a transient increase in anxiety, which usually resolves after several days. It
is lessened with lower initial doses or, if patient distress is problematic, with short-term coadministration of a
benzodiazepine. If a benzodiazepine is used in the initial phase of treatment, prescribe with caution (see Overview
of anxiety disorders) and ensure that the dose is tapered and then ceased as soon as possible (no longer than 1
month).

Response to the antidepressant drug may not be apparent for several weeks (12 weeks is considered an adequate
treatment trial) and higher doses than those usually needed for depression may be required.

The following drugs would in general only be used after unsuccessful trials of at least one first-line drug. However,
these drugs should be considered first line for those who responded well to them previously. Some patients only
respond to second-line therapy. Use a TCA, such as:

1 clomipramine 50 to 75 mg orally, at night, increasing every 2 to 3 days according to

tolerability and patient response to 150 mg at night. Maximum dose 300 mg at night

OR

1 imipramine 50 to 75 mg orally, at night, increasing every 2 to 3 days according to

tolerability and patient response to 150 mg at night. Maximum dose 300 mg at night.

If there is no response to the TCA after 1 to 2 weeks, the dose can be increased at weekly intervals by increments
of 25 to 50 mg per day up to the maximum dose. Doses of TCAs for treating panic are often higher than for
treating depression and must be raised gradually as complaints of adverse effects are frequent. Use lower doses in
older patients and in the physically ill. The risk of adverse effects, including seizures and increasing the QTc
interval with associated cardiac risk, increases at higher doses but may occur at lower doses. Intolerance
commonly limits the use of TCAs and toxicity in overdose must be considered. In general, the maximum doses in
the product information should not be exceeded. As with the SSRIs, there may be a mild but self-limiting
exacerbation of anxiety when the TCA is started.

Initiating MAOIs should generally be restricted to specialist psychiatric practice. These drugs are effective;
especially phenelzine where a commonly used dosage range is 45 to 60 mg daily in 2 to 3 divided doses, up to a
maximum of 90 mg daily. The last dose each day should be given no later than early afternoon to minimise the risk
of insomnia.

MAOIs are generally well tolerated, but orthostatic hypotension is a common dose-limiting factor. The patient
must be able to reliably comply with drug use and the strict low-tyramine diet (see Table 8.22), as well as avoid
interacting drugs.

The role of benzodiazepines in treating panic disorder has been replaced by the antidepressants; however,
infrequently they may be used in patients who have not responded to or cannot tolerate antidepressants. The
benzodiazepines that have been shown to be the most effective are the high-potency benzodiazepines but these
also have the highest risk of the development of dependence. Seek specialist review and advice before considering
prescribing benzodiazepines.

Due to the duration of treatment and doses needed, patients usually exhibit withdrawal symptoms if the
benzodiazepine is abruptly stopped. Dependence is greater at higher doses and with longer duration of treatment,
and with drugs of shorter half-life with associated inter-dose anxiety and strong withdrawal phenomenon. The
benzodiazepine should be reduced slowly when ceasing (see Benzodiazepine withdrawal).

Note 2: At the time of writing, citalopram, fluoxetine, fluvoxamine and sertraline are not approved by the
Australian Therapeutic Goods Administration (TGA) for treatment of panic disorder. See the TGA website for
current information.

Obsessive compulsive disorder

Introduction
Obsessive compulsive disorder (OCD) has a lifetime prevalence of 2% to 2.5%. Obsessions are recurrent and
persistent intrusive ideas, thoughts, impulses or images that are usually resisted by the person and are recognised
as the product of their own mind and not imposed from outside.

Compulsions are repetitive, stereotyped behaviours in response to an obsession, to prevent discomfort or some
dreaded event with which it is not connected in a realistic way. The person generally recognises that their
behaviour is excessive or unreasonable.

These obsessions or compulsions may cause marked distress and significantly interfere with the person's life. As
symptoms frequently also affect those living with, or working with, the person with OCD, education and support
for family and close friends are important.

For treatment of OCD in childhood and adolescence, see Anxiety disorders in childhood and adolescence:
obsessive compulsive disorder.

Most people with OCD respond best to a combination of psychotherapeutic and pharmacological treatment.

Most people with OCD respond best to a combination of psychotherapeutic and pharmacological treatment.

Psychological interventions
Some patients with OCD respond adequately to specialised psychotherapeutic measures. The psychological
intervention of choice is cognitive behavioural therapy. Generally this includes two key elements: exposure to the
cues or triggers which cause anxiety, together with prevention of rituals which are usually performed to reduce
anxiety. However, many patients, particularly those with more severe symptoms, cannot engage in psychological
interventions until they have had some initial response to pharmacotherapy.

Pharmacotherapy
Drugs which have an effect on the serotonergic system (the selective serotonin reuptake inhibitors [SSRIs] and
clomipramine) have demonstrated efficacy for OCD. Doses required for all the drugs recommended below usually
need to be higher than those used for depression and response may not be seen for 6 to 12 weeks.
Pharmacotherapy will normally be continued for 6 to 12 months in the first instance. If the patient's condition is
improved and stable, then the drug can be reduced slowly, then stopped. However, many patients relapse on drug
withdrawal and require long-term pharmacotherapy. Patients with this disorder may best be managed by a
psychiatrist.
If considered appropriate, for first-line pharmacotherapy use:

an SSRI orally, see Table 8.1 [Note 3].

Clomipramine is approved for use in OCD and may be uniquely effective for some patients, but its lesser
tolerability and potential toxicity in overdose limit its use as a first-line drug. If considered appropriate, use:

clomipramine 50 to 75 mg orally, at night, increasing every 2 to 3 days according to

tolerability and patient response to 150 to 250 mg at night. Maximum dose 300 mg at
night.

If there is no response to clomipramine after 4 to 6 weeks, the dose can be increased at weekly intervals by
increments of 25 to 50 mg per day, up to the maximum dose. Use lower doses in older patients and in the
physically ill. The risk of adverse effects, including seizures and increasing the QTc interval with associated
cardiac risk, increases at higher doses but may occur at lower doses. An electrocardiogram (ECG) before and
during treatment may be prudent.

Note 3: At the time of writing, citalopram is not approved by the Australian Therapeutic Goods Administration
(TGA) for treatment of obsessive compulsive disorder. See the TGA website [URL] for current information.

Overview of phobic disorders

Phobic disorders are characterised by intense fear of an object(s) or situation(s), which:

is out of proportion to the apparent stimulus

cannot be explained or reasoned away
leads to avoidance of the object or situation.

These disorders may be named for the nature of the situation or object, eg agoraphobia, social phobia (social
anxiety disorder), specific phobia.

For all phobic disorders, treatment should generally be with psychological interventions.

For all phobic disorders, treatment should generally be with psychological interventions (eg cognitive behavioural
therapy).

Agoraphobia
Agoraphobia is the fear and avoidance of being in places or situations from which escape might be difficult or
embarrassing (eg theatre, public transport, queues), or in which help might not be available in the event of
suddenly developing a symptom that could be incapacitating or embarrassing (eg dizziness, derealisation, loss of
bladder or bowel control, or a panic attack). As a result of this fear, the person either restricts activities, or endures
agoraphobic situations despite intense anxiety.

The majority of people with agoraphobia (90%) develop this as a response to the onset of recurrent panic attacks.
Treatment involves the control of panic attacks and then, once anxiety is sufficiently reduced, behavioural therapy
with graduated in vivo exposure to overcome the phobic avoidance. See Panic disorder for drugs that are effective
for panic disorder.

When agoraphobia develops without associated panic attacks, pharmacotherapy is usually not indicated.

Social anxiety disorder (social phobia)

Introduction

Social anxiety disorder, also known as social phobia, is a persistent fear of one or more social or performance
situations in which the person is exposed to possible scrutiny by others (eg speaking in public), anticipates that
they will be negatively evaluated by others, and fears that they may say something or act in a way that is
humiliating or embarrassing. The phobic situation(s) is avoided or is endured with intense anxiety or distress.
There are two subtypes of this disorder:

generalised social anxiety—fear of numerous social situations, including both performance and interactional
situations
non-generalised social anxiety—fear of one or just a few situations of performance type.
 Treatment is quite different for the two types of social anxiety disorder.

Treatment is quite different for the two types of social anxiety disorder.

Treatment of generalised social anxiety disorder

In generalised social anxiety disorder, cognitive behavioural therapy (CBT) incorporating exposure-based therapy,
social skills training and cognitive therapy is the treatment of choice. However, for many people CBT alone is not
sufficient to reduce symptoms to a manageable level, so a combination of pharmacotherapy and psychological
intervention is needed.

Three groups of drugs have shown efficacy in the symptomatic relief of generalised social anxiety disorder:
selective serotonin reuptake inhibitors (SSRIs), irreversible nonselective monoamine oxidase inhibitors (MAOIs)
and venlafaxine.

Pharmacotherapy for social anxiety disorder may need to be continued for 6 to 12 months in the first instance.
After this period, the dose should be slowly reduced and, if possible, the drug stopped. Every effort should be
made to use psychological interventions to minimise the need for prolonged pharmacotherapy. However, some
patients need ongoing medication. Re-emergence of symptoms may be reduced, and the chance of successfully
ceasing the drug increased, if the patient can effectively use CBT concurrently.

When a drug is needed, SSRIs are the treatment of choice. If this is not effective, try venlafaxine. If considered
appropriate, use:

1 an SSRI orally, see Table 8.1 [Note 4]

OR

2 venlafaxine controlled-release 75 mg orally, in the morning after food, increasing

according to tolerability and patient response. Maximum dose 225 mg daily.

Many regard MAOIs as the most powerful pharmacotherapy for generalised social anxiety disorder. Their use is
generally restricted to specialist psychiatric practice because MAOI use is complicated by their adverse effect
profile, significant interactions with many other drugs and the need to avoid all foods containing tyramine (see
Table 8.22). For phenelzine, a commonly used dosage range is 45 to 60 mg daily in 2 to 3 divided doses, up to a
maximum of 90 mg daily. The last dose each day should be given no later than early afternoon to minimise the risk
of insomnia.

Note 4: At the time of writing, citalopram, fluoxetine and fluvoxamine are not approved by the Australian
Therapeutic Goods Administration (TGA) for treatment of generalised social anxiety disorder. See the
TGA website for current information.

Treatment of non-generalised social anxiety disorder

Control of hyperventilation and other measures to deal with panic symptoms, together with cognitive strategies,
form the basis of psychological interventions for non-generalised social anxiety disorder (including performance
anxiety).

The goal of pharmacotherapy is to reduce the specific physiological symptoms (manifestations of sympathetic
overactivity) of tremor, palpitations and sweating, which are distressing or unpleasant during a particular task. Beta
blockers are widely used for this purpose. To assess any possible adverse effects, advise patients to take a trial dose
at home before they take a dose to reduce symptoms in a social situation. Use:

propranolol 10 to 40 mg orally, 30 to 60 minutes before the social event or performance.

Propranolol should be avoided in patients with asthma or severe peripheral vascular disease and some patients with
heart failure. It should be used cautiously in patients with diabetes. Propranolol does not directly relieve the mental
aspects of social phobia.

A short-acting benzodiazepine taken just before the performance situation may be an option. However, adverse
effects include sedation, impaired coordination, or disinhibition, all of which may impair performance. If
prescribing a benzodiazepine consider the precautions listed in Overview of anxiety disorders and issue a
prescription for a limited supply.
Specific phobias
Specific phobias are divided into four subgroups: animal type (eg dogs, moths, birds); natural environment type
(eg heights, storms, water, lightning); blood-injury injection type; and situational type (eg aeroplanes, lifts and
enclosed spaces).

Ongoing pharmacotherapy has almost no place in treating specific phobia.

For specific phobia there is almost no place for ongoing pharmacotherapy.

Occasionally the specific phobia is so severe that the patient cannot overcome it with psychological interventions
alone. In these circumstances there may be some help in using diazepam for a brief period until some control is
achieved over the phobia.

Pharmacotherapy may also be useful in situations where a specific phobia needs to be overcome for a particular
event or at a particular time. A common example is the need to manage a phobia of enclosed spaces
(claustrophobia) in a patient who requires a magnetic resonance imaging (MRI) examination. In this type of
situation, diazepam can be given as a single dose before the examination to control anxiety.

Posttraumatic mental health disorders

Introduction
Exposure to traumatic events commonly results in a degree of psychological distress. In most instances
psychological symptoms of distress settle down in the days to weeks following the event. However, a minority of
people exposed to traumatic events have persisting symptoms and develop acute stress disorder and/or
posttraumatic stress disorder (PTSD).

Acute stress disorder may occur during the early weeks following exposure to a severe traumatic event. Symptoms
of re-experience, heightened arousal, avoidance, and dissociative symptoms such as detachment or being in a daze,
and depersonalisation are common. These spontaneously remit in the majority of people.

PTSD is characterised by three main clusters of symptoms, which persist for more than 1 month after exposure to a
traumatic event. The three clusters comprise:

re-experiencing symptoms—intrusive thoughts, dreams, nightmares, flashbacks

hyperarousal phenomena—exaggerated startle response, irritability, anger, sleep disturbance, poor
concentration and memory
avoidance and numbing—deliberate attempts to keep the traumatic event out of mind, loss of interest in
activities that formerly brought enjoyment, detachment or estrangement from others, restricted emotional
responses.

Comorbid drug and alcohol problems, as well as major depression, are very common in these disorders and often
require treatment in their own right (see Alcohol and other drug problems and Depression).

Early intervention following trauma exposure

In the first few days following a traumatic event, intervention should be limited to provision of practical and
emotional support. Structured interventions such as psychological debriefing should not be offered on a routine
basis. Pharmacotherapy does not have any role as a preventive intervention.

Pharmacotherapy is rarely indicated for acute stress reaction. There have been no controlled drug trials specifically
for acute stress disorder. Research does not support the use of medication to prevent the onset of PTSD, nor to treat
PTSD symptoms in the first 4 (some believe 8) weeks following trauma, as the vast majority remit spontaneously.

Use specialist-administered trauma-focused psychological therapy, not medication, as a routine first-line treatment.

Use specialist-administered trauma-focused psychological therapy, not medication, as a routine first-line treatment.

Psychological interventions

The effective psychological interventions for both acute stress disorder and PTSD are specialist-administered
trauma-focused psychological interventions; either trauma-focused cognitive behavioural therapy, or Eye
Movement Desensitisation and Reprocessing that includes in vivo exposure. These interventions must be
undertaken with an experienced clinician specialised in performing trauma-focused psychological interventions.

When PTSD has developed as a result of exposure to prolonged and/or severe traumatic events, attention to
teaching emotional regulation skills and a more gradual approach to exposure therapy may be required.

In chronic PTSD, exposure therapy is also less successful and the main focus may be on enabling the patient to
cope better with symptoms, rather than on symptom remission. Techniques such as anger and anxiety
management, stress reduction, relaxation therapy and advice on good sleep practices are often helpful.
Comorbidity, especially of depression and problems with alcohol use, is extremely common, and requires
treatment in its own right (see Depression and Alcohol: problem use).

Pharmacotherapy

The evidence base for pharmacological treatments in acute stress disorder and PTSD is very limited.
Pharmacotherapy may be used as an adjunct to psychotherapy, or as an alternative when psychological
interventions are unavailable. The selective serotonin reuptake inhibitors (SSRIs) are now accepted as first-line
drug treatment. There is no good evidence of differing efficacy between drugs in this class.

Response of PTSD to all antidepressants is often slower than for depression; any drug trial should be for at least 8
to 12 weeks and, if beneficial, the drug usually continued for 12 months. Some studies find sustained, and even
increasing, improvement over periods of several months.

If pharmacotherapy is indicated, first line would be:

an SSRI orally, see Table 8.1 [Note 5].

Limited evidence supports the use of mirtazapine, tricyclic antidepressants (TCAs) and irreversible nonselective
monoamine oxidase inhibitors (MAOIs). Mirtazapine and TCAs are considered as a second-line option. If
considered appropriate, use:

1 mirtazapine 15 mg orally, at night, increasing according to tolerability and patient

response. Maximum dose 60 mg at night

OR

2 amitriptyline 50 to 75 mg orally, at night, increasing every 2 to 3 days according to

tolerability and patient response to 150 mg at night. Maximum dose 250 mg at night.

Phenelzine (a MAOI) could be considered for individuals with treatment-resistant symptoms receiving specialist
care. A commonly used dosage range is 45 to 60 mg daily in 2 to 3 divided doses, up to a maximum of 90 mg
daily. The last dose each day should be given no later than early afternoon to minimise the risk of insomnia.

MAOIs are generally well tolerated, but orthostatic hypotension is a common dose-limiting factor. The patient
must be able to reliably comply with drug use and the strict low-tyramine diet (see Table 8.22), as well as avoid
interacting drugs.

Limited evidence supports the use of second-generation antipsychotics (risperidone, quetiapine, olanzapine) to
augment response to SSRIs in PTSD, with most benefit being seen for intrusive and hypervigilance symptoms.
However, there is insufficient evidence to recommend the use of second-generation antipsychotics in general
practice settings.

Note 5: At the time of writing, citalopram, escitalopram, fluoxetine, fluvoxamine and sertraline are not approved
by the Australian Therapeutic Goods Administration (TGA) for treatment of posttraumatic stress disorder. See
the TGA website for current information.

Further reading
Andrews G, Creamer M, Page A, Hunt C, Lampe L, Crino R. The treatment of anxiety disorders: clinician guides
and patient manuals. 2nd ed. Cambridge: Cambridge University Press; 2003.

Key references
Anxiety and associated disorders: general information

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

Adjustment disorder with anxious mood

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

Generalised anxiety disorder

Baldwin D, Woods R, Lawson R, Taylor D. Efficacy of drug treatments for generalised anxiety disorder: systematic
review and meta-analysis. BMJ (Clinical Research Ed.). 2011;342d1199–d. [ ]

Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, et al. Azapirones for
generalized anxiety disorder. Cochrane Database Syst Rev. 2006;(3):CD006115. [ ]

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders. Cochrane
Database Syst Rev. 2010;(12):CD008120. [ ]

Kapczinski F, Lima MS, Souza JS, Schmitt R. Antidepressants for generalized anxiety disorder. Cochrane Database
Syst Rev. 2003;(2):CD003592. [ ]

National Collaborating Centre for Mental Health. Generalised anxiety disorder and panic disorder (with or without
agoraphobia) in adults: management in primary, secondary and community care (CG113). London: National Institute for
Health and Clinical Excellence; 2011. [URL]

Panic attack

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

National Collaborating Centre for Mental Health. Generalised anxiety disorder and panic disorder (with or without
agoraphobia) in adults: management in primary, secondary and community care (CG113). London: National Institute for
Health and Clinical Excellence; 2011. [URL]

Panic disorder

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

National Collaborating Centre for Mental Health. Generalised anxiety disorder and panic disorder (with or without
agoraphobia) in adults: management in primary, secondary and community care (CG113). London: National Institute for
Health and Clinical Excellence; 2011. [URL]

Obsessive compulsive disorder

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

National Collaborating Centre for Mental Health. Obsessive-compulsive disorder: core interventions in the treatment of
obsessive-compulsive disorder and body dysmorphic disorder (CG31). London: National Institute for Health and
Clinical Excellence; 2005. [URL]

Phobic disorders

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.

de Menezes GB, Coutinho ESF, Fontenelle LF, Vigne P, Figueira I, Versiani Mr. Second-generation antidepressants in
social anxiety disorder: meta-analysis of controlled clinical trials. Psychopharmacology. 2011;215(1):1–11. [ ]

Stein DJ, Ipser JC, Balkom AJ. Pharmacotherapy for social phobia. Cochrane Database Syst Rev. 2004;
(4):CD001206. [ ]

Posttraumatic mental health disorders

Ahearn EP, Juergens T, Cordes T, Becker T, Krahn D. A review of atypical antipsychotic medications for posttraumatic
stress disorder. International Clinical Psychopharmacology. 2011;26(4):193–200. [ ]

Australian Centre for Posttraumatic Mental Health. Australian guidelines for the treatment of adults with acute stress
disorder and posttraumatic stress disorder. Melbourne: Australian Centre for Posttraumatic Mental Health; 2007. [URL]

Craske M, Barlow D. Mastery of your anxiety and panic 4th ed. New York: Oxford University Press; 2007.
 National Collaborating Centre for Mental Health. Post-traumatic stress disorder (PTSD): the management of PTSD in
adults and children in primary and secondary care (CG26). London: National Institute for Clinical Excellence; 2005.
[URL]

Stein DJ, Ipser JC, Seedat S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst
Rev. 2006;(1):CD002795. [ ]

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Insomnia, parasomnias and jet lag
Insomnia
Introduction
Insomnia is defined as the inability to initiate or maintain sleep, or lack of refreshing sleep. It may be a symptom
of other disorders (eg depression, problem drug use), due to somatic symptoms (eg pain), or a primary disorder in
itself. Insomnia is also seen as part of some organic disorders such as sleep apnoea, and episodic movement
disorders such as restless legs syndrome.

Whether primary or secondary, insomnia is often associated with daytime sequelae (eg fatigue, irritability,
impaired concentration and memory, pervasive malaise), which affect many aspects of daytime functioning.
Despite the known strong relationship between sleep loss and subsequent sleepiness, patients with insomnia do not
have a greater propensity to fall asleep during the day. There may be an association between chronic insomnia and
subsequent development of depression.

Population-based studies suggest about 30% of the general population has complaints of sleep disruption, while
approximately 10% has associated symptoms of daytime functional impairment consistent with the diagnosis of
insomnia.

Acute insomnia may occur in anyone. It commonly occurs in healthy people, who were previously good sleepers,
following a short-term stressor (eg emotional or financial stress, physical illness), which triggers the insomnia. The
distinction between acute and chronic insomnia is not clear, but the disorder is generally regarded as chronic if the
duration is greater than 30 days.

A sleep diary can assist patients with persistent insomnia to monitor their sleep habits, and provides valuable
information for the clinician.

Treatment

Aim to improve sleep quality and quantity, and relieve insomnia-related daytime impairment.

Primary treatment goals are to improve sleep quality and quantity, and to relieve insomnia-related daytime
impairment.

Management of underlying problems

Common causes of insomnia include psychosocial and environmental stressors, medical disorders (eg dyspnoea,
oesophageal reflux, nocturia, pain), psychiatric disorders (eg depression, anxiety), problem drug use (eg alcohol,
caffeine, nicotine, illicit drugs), and adverse effects of prescribed drugs. When insomnia is related to other
illnesses, treatment is usually directed at the underlying medical or psychiatric problem. Management of any
underlying problem can often improve insomnia; however, secondary insomnia may still require treatment.
Insomnia related to medications or problem drug use needs attention to the substance in question. The latter may
not be apparent unless a drug and alcohol history is taken.

Sleep disturbance secondary to intrinsic sleep disorders (eg restless legs, sleep apnoea) requires specific treatment.

Referral to a sleep specialist may be indicated if:

the diagnosis is unclear

further investigation and advice on treatment is required
the patient has a long history of sleep difficulties
the patient fails to respond to therapy
the patient has an intrinsic sleep disorder.

Good sleep practices

It is important to educate patients about normal sleep and provide counselling about good sleep practices and
habits (see Box 8.2).
 Advice on good sleep practices (Box 8.2)

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Sleep–wake activity regulation

go to bed at the same time each day

arise at a regular time
avoid lying in bed for long periods of time worrying about sleeping
avoid oversleeping
avoid napping (if necessary, limit to afternoon ‘powernap’ of 10 to 15 minutes)

Sleep setting and influences

avoid bright light exposure in late evening or night

seek exposure to bright light after rising
avoid heavy meals within 3 hours of bedtime
undertake regular daily exercise but avoid vigorous physical activity within 3 hours of bedtime
ensure a quiet, dark room for sleeping (remove TV, music player, laptop, mobile phone)
avoid having pets and highly illuminated digital clocks in the bedroom
use a suitable mattress and pillow for comfort and support
reserve bedroom for sleep and intimacy
avoid alerting, stressful ruminations before bedtime. Allocate time earlier in the evening to go through
worrying issues
avoid caffeine after midday
reduce excessive alcohol intake
avoid tobacco, especially in the evening
avoid illicit drugs

Sleep-promoting adjuvants

have a light snack or a warm milk drink before bed

have a warm bath before bed
ensure a comfortable temperature for sleep and maximal darkness

Psychological and behavioural interventions

Psychological and behavioural interventions are effective in treatment of insomnia.

Psychological and behavioural interventions are effective in the treatment of insomnia. They are most often used
for chronic insomnia as they do not work immediately and require practise and persistence. However, relaxation
therapy is easily taught and can be of benefit for both acute and chronic problems.

Relaxation therapies

Relaxation therapies such as hypnosis, meditation, deep breathing and progressive muscle relaxation are effective
in reducing physiological hyperarousal. They are useful for people who have trouble relaxing or winding down for
a range of reasons such as stress, worry or overactive mind after work.

Relaxation techniques are most effective if practised during the day, before going to bed and also in the middle of
the night if the person is unable to go back to sleep. Usually several weeks of practise are required to improve
sleep.

Cognitive therapy

People with insomnia often have dysfunctional beliefs and attitudes and unrealistic expectations about sleep. It is
important to reassure them that most people with insomnia get more sleep than they perceive and that insomnia
does not cause major physical health problems. Cognitive therapy targets the anxiety-producing maladaptive
beliefs and attitudes about sleep and sleep loss that serve to maintain insomnia. Beliefs about the negative effects
of not sleeping are very common and often people with insomnia develop a vicious cycle of ‘worry about not
sleeping’ and ‘not sleeping’.

Stimulus control
Stimulus control is useful for people who have difficulty falling asleep because they have come to associate the
bed or bedroom with frustration, worry and poor sleep. The main aim of stimulus control is to have the person
limit the amount of time spent in bed awake and for them to learn to associate the bed and bedroom with sleep and
nothing else. They should exclude from the bedroom activities that do not go well with sleep such as reading,
eating, using computers, watching TV, and worrying.

This therapy requires the person to go to bed only when sleepy and to get out of bed if worrying or sleepless for
more than 15 to 20 minutes, rather than remain in bed while awake. The person returns to bed when sleepy, and
leaves if they again remain awake. The role of the bedroom for sleeping and not for worrying is reinforced; they
are instructed to do any worrying in another room.

Sleep restriction

Sleep restriction programs are suitable for people who have difficulty staying asleep due to poor sleep drive. They
are designed to build on the body's natural drive to sleep. Their goal is to reduce the amount of time spent awake in
bed.

An example of a sleep restriction program is shown in Box 8.3. Sleep restriction is based on information from a
sleep diary in which the person records the amount of time they estimate they are asleep. The time spent in bed is
then restricted to the total sleep time estimated from the diary. Initially this results in sleep deprivation, but after a
few nights this sleep deprivation helps consolidate sleep thus improving sleep efficiency. Eventually, the length of
time in bed can be increased, with increments based on improved sleep efficiency.

Example of a sleep restriction program (Box 8.3)

A person with insomnia feels they sleep only 4 hours per night, despite generally being in bed from 10.00 pm
until 8.00 am.

Instruct the person to start restricting their sleep to only 4 hours per night, as this is the length of time they think
they are sleeping (eg go to bed at 2.00 am and wake up at 6.00 am).

The person must comply with this schedule until they are regularly sleeping solidly throughout the 4 hours and
feel increasingly sleepy, wanting to go to bed earlier.

Once this target is reached, they can increase the time in bed by 30 minutes until they are sleeping through and
craving sleep at an earlier time. Again the reward of an extra 30 minutes sleep will occur when the person is
sleeping through their allocated time.

Pharmacological treatment

Pharmacological treatment with a hypnotic drug (a benzodiazepine, zolpidem or zopiclone) or melatonin may be
indicated for short-term management of acute insomnia, and for chronic insomnia when the nonpharmacological
strategies described above are not effective.

The decision to prescribe a hypnotic or melatonin for acute insomnia should be guided by consideration of:

the cause(s) of the insomnia (see Management of underlying problems, above)

the level of distress caused by lack of sleep
the degree of impairment due to the daytime sequelae of insomnia
the likely benefits balanced against the possible harms of prescribing hypnotics.

Before starting treatment, the limitations and potential problems of hypnotics, including the risk of impaired
daytime alertness, tolerance and dependence with long-term use, should be explained. Unlike the hypnotics,
melatonin does not appear to cause impaired daytime alertness or have potential for abuse.

If hypnotics or melatonin are prescribed, the duration of therapy should be for the shortest time possible
(preferably dosed intermittently and for less than 2 weeks) and a definite duration of use agreed with the patient at
the outset. When prescribing hypnotics limit the quantity prescribed. For further information on precautions when
prescribing benzodiazepines, see Overview of anxiety disorders. Patients with acute insomnia should be reviewed
regularly and provided with support and, if appropriate, specific interventions to address the causes underlying
their acute sleep problem.

Continuous treatment with hypnotics, if needed at all, should normally be limited to less than 2 weeks. Intermittent
therapy may be considered for those with severe longstanding insomnia that is not relieved by nonpharmacological
management.
Explain to the patient that broken sleep with vivid dreams may occur when hypnotics are stopped and that it takes
several days or weeks for a normal sleep rhythm to be re-established. This rebound insomnia may indicate falsely
to the patient that a further prescription is needed.

If pharmacological treatment is considered necessary, use:

1 temazepam 10 mg orally, before bedtime

OR

1 zolpidem controlled-release 6.25 mg orally, at bedtime

OR

1 zolpidem immediate-release 5 mg orally, at bedtime

OR

1 zopiclone 3.75 mg orally, before bedtime

OR

2 melatonin prolonged-release 2 mg orally, before bedtime [Note 1].

When taking hypnotics, many people find their sleep is not refreshing. Benzodiazepines, particularly those with
longer duration of action (eg diazepam), may cause impairment of daytime alertness and performance including
impairment of driving. Zolpidem and zopiclone have similar sedative properties to the benzodiazepines but
minimal anxiolytic, muscle relaxant and antiepileptic properties. Compared with benzodiazepines, they generally
cause less morning sedation and have less disruptive effect on normal sleep patterns.

Zolpidem, and possibly all hypnotic drugs, can induce potentially dangerous complex sleep-related behaviours,
and can cause paradoxical reactions (eg hallucinations, acute rage, agitation). Stop treatment if these effects occur
[Note 2]. Avoid taking hypnotics with alcohol or other drugs that depress the central nervous system because they
can increase the risk of these potentially serious adverse effects.

Melatonin, an endogenous hormone associated with the control of circadian rhythms and sleep regulation, is
available in Australia as a prolonged-release formulation for treatment of primary insomnia characterised by poor
sleep quality in patients aged 55 years or older. Data from clinical trials showed that some patients gain clinically
significant improvements in quality of sleep and morning alertness with prolonged-release melatonin, but many
patients in the clinical trials did not respond to treatment. At present there is insufficient evidence to support
treatment beyond 3 weeks.

Sedating antidepressants, such as the tricyclic antidepressants, mirtazapine and agomelatine, are sometimes used to
improve sleep. Generally, evidence of effectiveness of antidepressant use in treating insomnia unrelated to
depression is lacking. Avoid using antidepressants in the absence of a depressive disorder.

Sedating antihistamines are frequently used to improve sleep. There is no evidence for efficacy and they may cause
significant adverse effects including daytime sedation, impaired cognitive function, delirium and paradoxical
agitation (especially in children). The long-term effects of regular use have not been evaluated. Rapid tolerance to
the sedative effect has been reported with diphenhydramine.

Antipsychotic drugs are sometimes prescribed for the treatment of insomnia. They can cause serious adverse
effects and have no role in the management of insomnia.

Note 1: At the time of writing, melatonin prolonged-release is only approved by the Australian Therapeutic
Goods Administration (TGA) for short-term treatment of insomnia in patients aged 55 years or more. See the
TGA website for current information.

Note 2: See the Therapeutic Goods Administration warning for zolpidem at [URL].

Management of long-term hypnotic use

Often clinicians encounter people who have been taking hypnotics for a prolonged period, especially older people
(see Management for older people, below). These people are likely to have unwittingly become dependent.
Stopping long-term hypnotic therapy should be discussed and trialled whenever possible.

Cessation will require a tailored dose reduction, regular contact between the patient and the treating clinician, and
the provision of nonpharmacological alternatives to assist with sleep (see Psychological and behavioural
interventions, above). A dose reduction plan can be downloaded from the National Prescribing Service (NPS) at
[URL].

Patients may need a lot of support and encouragement to help them through the period without medication, while
their sleep cycle stabilises.

Continued treatment with a hypnotic may be acceptable for a small number of people who continue to sleep well
with the same dose of medication and for whom:

a detailed history shows there are no adverse effects present

the patient is aware that they may be dependent
a reduction program has repeatedly been unsuccessful or is against the patient's wishes.

Such patients should have regular reviews considering any lifestyle and health changes that may reduce their need
for, or increase the risk of continued use of, hypnotics. Should they wish to stop the drug, this needs to be done
gradually, as explained above.

Management for older people

The same general principles (see Treatment, above) apply to the management of older people with insomnia. Good
sleep practices and nonpharmacological approaches should always be first-line therapy. Often, hypnotic drugs in
the older person are initiated during a hospital admission or in residential care facilities when nonpharmacological
approaches are unavailable or impractical. When this occurs it is essential to ensure the drug is not inadvertently
continued when the person is discharged from hospital or when they settle into a new care routine.

The highest rates of benzodiazepine use are in the older population even though they are most at risk of harm from
adverse effects of benzodiazepines, such as falls and cognitive impairment. Dependence, confusion and
incontinence can also be associated with long-term use. Discontinuing long-term benzodiazepine use can often be
achieved gradually, with cooperation from the patient, family, carers and/or nursing staff. Behavioural therapies,
above, can assist older people to stop.

Older patients with dementia often experience marked sleep fragmentation, dozing during the day and sundowning
(ie becoming agitated, wandering and wakeful in the early evening or at night). Endeavour to manage sundowning
through nonpharmacological interventions.

Parasomnias
Introduction
Parasomnias are dysfunctions associated with sleep, sleep stages or partial arousal, with abnormal motor,
behavioural or sensory experiences. Parasomnias are most common in children and decrease in frequency with
increasing age, but are reported in approximately 4% of adults. Parasomnias are classified into three broad groups,
those:

occurring in non-rapid eye movement (non-REM) sleep, eg sleepwalking, sleep terrors

associated with rapid eye movement (REM) sleep, eg nightmares, REM sleep behaviour disorder
that occur with either non-REM or REM sleep, eg sleep-related eating disorder, sleep-related enuresis.

Sleep terrors and sleepwalking

The non-REM parasomnias sleep terrors and sleepwalking are part of the same spectrum of sleep disorders and
typically occur in the first half of the sleep period.

Sleep terrors are characterised by sharp screams, violent thrashing movements and autonomic discharge with
sweating and tachycardia. The subject may or may not wake up and there is usually no recall of the event.

Sleepwalking is a complex motor activity that occurs when the sleeper performs some repetitive activity in bed or
walks freely from the bed. It is much more common in children (see Sleep disorders in childhood and adolescence
for further information). Usually no treatment is required but if sleepwalking is frequent, and presents a danger to
the sleeper, the sleeping environment should be made safe. Adults with recurring episodes may need to seek
specialist assistance.

Making an accurate diagnosis is essential. The major differential diagnosis in individuals with non-REM
parasomnias is sleep-related epilepsy. Specialist evaluation is recommended. Once the diagnosis is confirmed,
treatment of non-REM parasomnias includes counselling and support, improving sleep practices, and educating the
person and their family about the condition. Pharmacotherapy is not usually indicated for those with mild or
infrequent episodes.

Hypnotics may be considered for both sleep terrors and sleepwalking in some people, particularly those:

who have injured themselves or others

who are at serious risk of doing so
whose quality of life is significantly affected.

Nightmares and REM sleep behaviour disorder

Nightmares usually occur later in the sleep period and are best described as dream-related anxiety episodes. They
can be associated with the discontinuation of REM-suppressing drugs, such as alcohol, antidepressants and some
hypnotics. A number of drugs can also cause vivid dreams or nightmares (eg beta blockers, selective serotonin
reuptake inhibitors, benzodiazepines, levodopa).

Recurrent stereotyped nightmares are commonly associated with posttraumatic stress disorder (see Posttraumatic
mental health disorders). Psychological evaluation and therapy are required.

REM sleep behaviour disorder (RBD) is characterised by complex and elaborate motor activity in association with
dreams. This may result in violent behaviour during sleep. RBD affects men more than women (ratio 9:1) and is
seen predominantly in older males and frequently in those with neurodegenerative disorders. Differential diagnosis
includes nocturnal frontal lobe seizures, posttraumatic stress disorder, and other parasomnias.

Diagnosis can be made by a sleep study and specialist evaluation is recommended. Treatment includes
reassurance, improving sleep practices and interventions as necessary to address safety issues. If more severe, and
particularly if there is concern about physical injury occurring, pharmacotherapy may be required. RBD usually
responds well to low-dose clonazepam.

Notably, parasomnias such as sleepwalking, sleep-related eating disorder and sleep-driving can coexist and are rare
adverse effects of zolpidem [Note 3].

Note 3: See the Therapeutic Goods Administration warning for zolpidem at [URL].

Jet lag
Jet lag commonly affects air travellers who cross several time zones, particularly in an easterly direction. It results
from the body's internal rhythms being out of step with the day–night cycle at the destination. The severity of jet
lag symptoms largely depends on the number of time zones crossed and the direction of travel. In addition,
symptoms may be worsened by coexisting sleep loss due to flight schedules and environmental difficulties in
sleeping on flights.

Melatonin, a pineal hormone, plays a central part in regulating bodily rhythms. Trials have shown that melatonin,
taken close to target bedtime at the destination, decreases jet lag after flights crossing five or more time zones.

A short-acting hypnotic facilitates sleep on flights and can be taken up to 3 subsequent nights at bedtime. There
may be additive sedation if it is used with melatonin. No data exist on the efficacy of these treatments in children
or older people.

If there is evidence that the person is at increased risk of deep vein thrombosis (DVT), or there are concerns that
the hypnotic may impair the person in the event of an in-flight emergency, it is best to reserve the drug until night-
time at the final destination when it can be taken to help establish the sleep cycle in the new time zone. Hypnotics
are not recommended if the person has severe obstructive sleep apnoea.

Key references
Insomnia

Melatonin prolonged-release tablets (Circadin) for primary insomnia in older people. NPS Radar. 2010;(May). [URL]

National Institutes of Health State of the Science Conference statement on manifestations and management of chronic
insomnia in adults, June 13–15, 2005. Sleep. 2005;28(9):1049–57. [ ]

Zolpidem and sleep-related behaviours. NPS RADAR. Sydney: National Prescribing Service Ltd; 2008. [URL]

Zolpidem: continued reporting of abnormal sleep-related events and amnesia. Medicines Safety Update. 2012;3(3).
[URL]

Hajak G, Rodenbeck A, Voderholzer U, Riemann D, Cohrs S, Hohagen F, et al. Doxepin in the treatment of primary
insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001;62(6):453–63. [
]

National Institute for Clinical Excellence (NICE). Guidance on the use of zaleplon, zolpidem and zopiclone for the
short-term management of insomnia (TA77). London: NICE; 2004. [URL]

Roth T, Rogowski R, Hull S, Schwartz H, Koshorek G, Corser B, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and
6 mg in adults with primary insomnia. Sleep. 2007;30(11):1555–61. [ ]

Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of
chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487–504. [ ]

Siebern AT, Suh S, Nowakowski S. Non-pharmacological treatment of insomnia. Neurotherapeutics. 2012;9(4):717–

27. [ ]

Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin
Investig Drugs. 2008;17(10):1567–72. [ ]

Parasomnias

Zolpidem and sleep-related behaviours. NPS RADAR. Sydney: National Prescribing Service Ltd; 2008. [URL]

Zolpidem: continued reporting of abnormal sleep-related events and amnesia. Medicines Safety Update. 2012;3(3).
[URL]

American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual
(ICSD-2). 2nd ed. Westchester: American Academy of Sleep Medicine; 2005.

Avidan AY, Kaplish N. The parasomnias: epidemiology, clinical features, and diagnostic approach. Clin Chest Med.
2010;31(2):353–70. [ ]

Hoque R, Chesson AL, Jr. Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-
18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical
effects of zolpidem. J Clin Sleep Med. 2009;5(5):471–6. [ ]

Jet lag

Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;
(2):CD001520. [ ]

Published July 2013. Amended June 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Eating disorders
Overview of eating disorders
Eating disorders are a notable source of morbidity and only a minority present for treatment.

Patients with anorexia nervosa are characterised by:

a relentless pursuit of thinness, resulting in weight loss or failure to gain weight during growth
a refusal to maintain a normal body weight
an extreme fear of gaining weight or becoming fat
physiological effects of starvation, such as amenorrhoea (in women) and bone loss
in some, binge eating and/or extreme weight control behaviours, such as self-induced vomiting or laxative
abuse.

The essential features of bulimia nervosa are:

regular episodes of uncontrolled overeating of large amounts of food, namely binge eating
extreme weight control methods to counteract the perceived and feared effects of overeating, such as self-
induced vomiting, purging (laxative and/or diuretic abuse), driven exercise and/or fasting
weight in the normal or overweight/obese range.

The third major group is ‘eating disorder not otherwise specified’ (EDNOS), which refers to any eating disorder
that fails to meet criteria for anorexia nervosa or bulimia nervosa. EDNOS includes binge eating disorder. The
essential features of binge eating disorder are:

recurrent episodes of binge eating with associated distress

the absence of regular use of inappropriate weight control or compensatory behaviours characteristic of
bulimia nervosa.

An intense preoccupation with weight and shape issues as an expression of self-worth is common to all people
who suffer from anorexia nervosa or bulimia nervosa.

Anorexia nervosa is relatively uncommon. Worldwide, the community point prevalence is no more than 0.5% of
women over 15 years old; it is much lower in males. The community prevalence of bulimia nervosa is higher,
between 0.5% and 1%, with an even social class distribution. In addition, around 2% to 3% of young women may
suffer binge eating disorder and up to 5% EDNOS. Approximately 90% of people with anorexia nervosa and
bulimia nervosa are women but there is much less of a gender imbalance for binge eating disorder.

Early identification of eating disorders is very important and it is known that outcomes are better when treatment
starts early in the illness course. Most adults with an eating disorder, particularly bulimia nervosa or binge eating
disorder, present many years after onset. General practitioners should be aware that it is common for young
women with eating disorders to present with other problems such as weight concern (whether they are normal
weight or overweight) and concomitant depression and anxiety symptoms. Presentations with medical problems
such as infertility also occur not infrequently.

Guided cognitive behavioural therapy (CBT) self-help (ie nonspecialist guidance in CBT following a self-help
manual) by general practitioners or other nonspecialists has proven efficacious in bulimia nervosa and binge eating
disorder. There are several suitable self-help books and websites available to use (see Appendix 8.1).

General practitioners are also in a key position to increase public awareness about the risks of restrictive dieting
and compulsive exercise. This can be done in a number of ways, including the promotion of healthier attitudes
towards weight and shape, and provision of sound nutritional and healthy exercise advice in waiting rooms and
surgeries.

Anorexia nervosa
General management

Treatment must be tailored to the needs of the patient and the severity of the illness. Denial of the severity or even
existence of a problem is extremely common in this condition, and the early phases of treatment will often be
difficult.
The guiding principles of treatment are:

first, the restoration to a normal weight range for height and age
second, the identification, and management, of any contributing family and personal problems.

Comorbid anxiety and depression are common. This includes depression secondary to starvation, which most often
responds to nutritional restoration of normal weight and psychological interventions (see also Pharmacological
treatment, below). A multidisciplinary approach is necessary, including individual and family therapy, dietary
advice and, where appropriate, pharmacotherapy. Family therapy has been shown to improve the outcome of
adolescent patients still residing with their families. While its status for older patients is less certain, it may be
helpful in conjunction with individual therapy.

Checking for physical complications, such as hypokalaemia or dehydration, is mandatory and may be lifesaving.

Checking for physical complications, such as hypokalaemia or dehydration, is mandatory and may be lifesaving.
Anorexia nervosa is a potentially fatal condition with significant mortality levels and a high morbidity. Around
40% of patients make a good 5-year recovery, 40% remain symptomatic but with limited disability, and 20% of
patients remain severely symptomatic with chronic disability. Outcomes are notably better with treatment early in
the illness course and in children and adolescents. Therefore, referral to a specialised service should always be
contemplated, even in those individuals whose weight loss is not yet marked. However, access to such services
may be particularly difficult for patients in rural or remote areas.

The treatment of anorexia nervosa in many units has evolved from long-term inpatient programs with outpatient
follow-up, to shorter- or medium-term hospital admissions for supervised weight restoration followed by more
intensive outpatient programs with hospital backup. It is now more common to begin treatment on an outpatient
basis and to reserve inpatient care for those individuals who fail to make progress or are at physical risk (including
young patients, where it is essential to gain weight to allow normal physical development), or who are at risk of
suicide (see Assessing suicide risk). Insisting on admission to hospital is a difficult decision, but can be lifesaving.
Such admissions to hospital should preferably be in consultation with members of the ongoing treatment team.

Families of patients are commonly disrupted by the behaviour of the patient with anorexia nervosa, and will need
support and advice. It is important to provide ongoing information and to ensure that families continue to maintain
their child's safety, despite a child's insistence that he or she will best recover by being left alone.

Outcome studies have found severe medical complications are associated with a poorer outcome, and younger age
at presentation and good interpersonal function are associated with a better outcome.

Pharmacological treatment

Drugs are of no proven benefit for the primary anorexia nervosa itself.

Starvation can be associated with symptoms of depression and specialist advice may be helpful to differentiate this
from a comorbid major depressive illness. The former is treated with nutritional restoration but the latter may
require antidepressant treatment. Antidepressants would be prescribed if a patient has a persistently depressed
mood, neurovegetative features such as late insomnia, diurnal mood variation and anhedonia, and depressive
ideation such as guilt, hopelessness and worthlessness. Because of the increased risk of cardiovascular
complications in patients with anorexia nervosa, the dose regimen should be modified (eg start at half the usual
dose). Antidepressants with a low rate of cardiovascular adverse effects are preferred. Tricyclic antidepressants
and irreversible nonselective monoamine oxidase inhibitors should be used rarely. See Depression for information
on treatment.

People with anorexia nervosa may have electrocardiogram changes such as prolonged QTc intervals.

People with anorexia nervosa may have electrocardiogram (ECG) changes such as prolonged QTc intervals so
caution is required with concurrent drug treatment as some antidepressants and some antipsychotics can also
prolong the QTc interval.

If a patient is extremely agitated, low doses of an antipsychotic drug may be used. There have been small,
randomised trials of low-dose olanzapine (eg 2.5 to 5 mg daily) and other second-generation antipsychotics
(quetiapine and amisulpride). The trials suggest these drugs may have some effect on reducing anorexic
ruminations, psychological distress and improving weight gain. However, findings are mixed and antipsychotics
should be used with caution and only under specialist supervision.

Hormone replacement therapy and/or bisphosphonates may be used for continued osteopenia in a small number of
selected cases on specialist referral but their efficacy is unclear. Vitamin D and dietary calcium supplementation is
recommended, but in itself is probably insufficient to reverse bone loss in anorexia nervosa.
Replacement of other essential nutrients is usually incorporated into the nutritional program. Iron, B-group
vitamins and zinc may be prescribed when there is a deficiency and/or in times of increased nutritional demands
such as refeeding. Life-threatening hypophosphataemia can occur at commencement of refeeding, and
supplementation is essential; this should be with B-group vitamins, magnesium and calcium prophylactically, and
electrolytes as required. In addition, there should be provision of sufficient fat and protein in the refeeding diet. For
further information see Refeeding syndrome.

Hypokalaemia (and subsequent cardiac dysrhythmia) is an important complication of purging and/or self-induced
vomiting; potassium replacement can be lifesaving. For further information on management, see Hypokalaemia.

Bulimia nervosa
Nonpharmacological treatment
Although bulimia nervosa is a more recently recognised disorder than anorexia nervosa, there has been extensive
research into its treatment. The nature of treatment is important to outcome, and current research indicates that a
solely behavioural approach is likely to be less effective than full cognitive behavioural therapy (CBT).

There is good evidence from controlled studies that CBT is an effective approach in bulimia nervosa, resulting in
improvement in the eating disorder and other psychological aspects, such as depression. It aims to change not only
the eating habits and weight control behaviours, but also the preoccupation with shape and weight. Manualised
CBT has been favoured over control therapies, such as supportive psychotherapy, and in one study has been
reported to have greater speed of response than interpersonal psychotherapy (IPT). Techniques used include:

education about nutrition, shape and weight issues, and eating disorders (including important complications,
such as hypokalaemia)
the daily self-monitoring of relevant thoughts and behaviours
the prescription of a normal eating pattern and proscription of restrictive dieting
the gradual introduction of avoided foods into the patient's diet
cognitive restructuring procedures to identify and challenge problematic thoughts and attitudes
problem-solving
relapse prevention strategies.

However, it is recognised that for some patients, CBT is unnecessarily intensive; for others it is not sufficient and
other psychological therapies may be appropriate. For example, longer-term or other specific psychotherapies,
such as dialectical behaviour therapy, may be needed in patients with severe personality disturbance or other
problems, such as posttraumatic stress disorder, often following sexual or other abuse in their formative years.
CBT-enhanced (CBT-E) has been developed to address other common problems, namely mood intolerance, low
self-esteem, clinical perfectionism and interpersonal deficits [Note 1].

Patients with bulimia nervosa are rarely admitted to hospital but this should be considered if they are at risk of
suicide, medically unwell, in the first trimester of pregnancy (because of the risk of spontaneous abortion), or if
their symptoms are refractory to outpatient care. A short period in hospital can sometimes be useful to help the
patient obtain control over their symptoms.

Outcome studies have found that about 50% of patients make a full recovery, about 30% make a partial recovery
and 20% continue to be notably symptomatic. Good interpersonal function, an absence of a history of problem
drug use and/or obesity, and early response to treatment are associated with a better outcome.

Note 1: Details of CBT and CBT-E are given in Fairburn C. Cognitive behaviour therapy and eating disorders.
New York: Guilford Press; 2008.

Pharmacological treatment

In some patients, antidepressants may be used in the short term, specifically for their effect in reducing binge
eating frequency, and/or as an adjunctive treatment to psychotherapy. The action of antidepressants in bulimia
nervosa and binge eating disorders appears to be in addition to, and independent of, their effect on mood, and may
be related to a specific serotonin modulating effect on satiety mechanisms.

The selective serotonin reuptake inhibitor (SSRI) fluoxetine has received research attention, and is probably the
antidepressant of first choice. There are five very small studies of other SSRIs: citalopram, sertraline and
fluvoxamine. Their effectiveness in long-term maintenance of change is not established and they may be less
acceptable to people than psychotherapy as attrition rates have been high in clinical trials. Higher doses (eg 60 mg
fluoxetine) than those generally used in depression have been found to be more effective in controlled trials, but to
mitigate adverse effects patients can start on a lower dose and slowly titrate up. It is also helpful to advise patients
not to take their SSRI at a time when they are likely to vomit.
If considered appropriate, the following SSRIs may be used but comparative dose regimens have not been
empirically evaluated in controlled trials. Use:

1 fluoxetine 20 to 60 mg orally, daily in the morning

OR

2 citalopram 10 to 40 mg orally, daily in the morning

OR

2 fluvoxamine 50 to 300 mg orally, daily in the evening. Doses above 150 mg daily may be
given in 2 divided doses for better tolerability

OR

2 sertraline 50 to 200 mg orally, daily in the morning.

There is evidence from randomised controlled trials to support the use of the antiepileptic topiramate in bulimia
nervosa, which in doses of 250 mg daily has been reported to reduce bingeing and purging behaviours and improve
quality of life in people with bulimia nervosa. However, it is not widely used. Topiramate also causes significant
adverse effects.

Binge eating disorder

In contrast to bulimia nervosa, less is known about the treatment of binge eating disorder. It is generally agreed
that psychotherapeutic strategies, such as cognitive behavioural therapy (CBT) and interpersonal therapy (IPT),
that are successful in bulimia nervosa, are applicable to the treatment of binge eating disorder. However, these
treatments are unlikely to be associated with weight loss, and obesity is a common problem in people with binge
eating disorder.

For people who are overweight, behavioural weight loss treatments may be at least as effective as IPT or CBT in
the short term but long-term maintenance of change is less clear. In addition, weight loss drugs (such as orlistat)
and newer drugs (such as topiramate) may enhance behavioural interventions, but their use is experimental and it
is also not known if effects are sustained in the long term. Antidepressants, particularly SSRIs, may be useful as an
adjunctive treatment to psychotherapy, particularly in those with depressive comorbidity.

For further information on management of obesity, see Overweight and obesity.

Further reading
Fairburn C. Cognitive behaviour therapy and eating disorders. New York: Guilford Press; 2008.

Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet 2010;375(9714):583–93. [URL]

Yager J, Andersen AE. Clinical practice. Anorexia nervosa. N Engl J Med 2005;353(14):1481–8. [URL]

Key references
Eating disorders: general information

Fairburn C. Cognitive behaviour therapy and eating disorders. 1st ed. New York: Guilford Press; 2008.

Hay PJ, Claudino AM. Clinical psychopharmacology of eating disorders: a research update. Int J
Neuropsychopharmacol. 2012;15(2):209–22. [ ]

Hudson JI, Hiripi E, Pope HG, Jr., Kessler RC. The prevalence and correlates of eating disorders in the National
Comorbidity Survey Replication. Biol Psychiatry. 2007;61(3):348–58. [ ]

Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet. 2010;375(9714):583–93. [ ]

Wilson GT, Zandberg LJ. Cognitive-behavioral guided self-help for eating disorders: effectiveness and scalability. Clin
Psychol Rev. 2012;32(4):343–57. [ ]
Anorexia nervosa

Fairburn C. Cognitive behaviour therapy and eating disorders. 1st ed. New York: Guilford Press; 2008.

Hay PJ, Claudino AM. Clinical psychopharmacology of eating disorders: a research update. Int J
Neuropsychopharmacol. 2012;15(2):209–22. [ ]

Steinhausen HC. The outcome of anorexia nervosa in the 20th century. Am J Psychiatry. 2002;159(8):1284–93. [
]

Treasure J, Alexander J. Anorexia nervosa: a recovery guide for sufferers, families and friends. 2nd ed. Abingdon, UK:
Routledge; 2013.

Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet. 2010;375(9714):583–93. [ ]

Treasure J, Smith G, Crane A. Skills-based Learning for caring for a loved one with an eating disorder: the new
Maudsley method. Abingdon: Routledge; 2007.

Wilson GT, Zandberg LJ. Cognitive-behavioral guided self-help for eating disorders: effectiveness and scalability. Clin
Psychol Rev. 2012;32(4):343–57. [ ]

Yager J, Andersen AE. Clinical practice. Anorexia nervosa. N Engl J Med. 2005;353(14):1481–8. [ ]

Bulimia nervosa

Fairburn C. Cognitive behaviour therapy and eating disorders. 1st ed. New York: Guilford Press; 2008.

Hay PJ, Claudino AM. Clinical psychopharmacology of eating disorders: a research update. Int J
Neuropsychopharmacol. 2012;15(2):209–22. [ ]

Schmidt U, Treasure J. Getting better bit(e) by bit(e): a survival kit for sufferers of bulimia nervosa and binge eating
disorders. Hove, UK: Lawrence Erlbaum; 1993.

Steinhausen HC, Weber S. The outcome of bulimia nervosa: findings from one-quarter century of research. Am J
Psychiatry. 2009;166(12):1331–41. [ ]

Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet. 2010;375(9714):583–93. [ ]

Treasure J, Smith G, Crane A. Skills-based Learning for caring for a loved one with an eating disorder: the new
Maudsley method. Abingdon: Routledge; 2007.

Wilson GT, Zandberg LJ. Cognitive-behavioral guided self-help for eating disorders: effectiveness and scalability. Clin
Psychol Rev. 2012;32(4):343–57. [ ]

Binge eating disorder

Fairburn C. Cognitive behaviour therapy and eating disorders. 1st ed. New York: Guilford Press; 2008.

Hay PJ, Claudino AM. Clinical psychopharmacology of eating disorders: a research update. Int J
Neuropsychopharmacol. 2012;15(2):209–22. [ ]

Schmidt U, Treasure J. Getting better bit(e) by bit(e): a survival kit for sufferers of bulimia nervosa and binge eating
disorders. Hove, UK: Lawrence Erlbaum; 1993.

Treasure J, Claudino AM, Zucker N. Eating disorders. Lancet. 2010;375(9714):583–93. [ ]

Treasure J, Smith G, Crane A. Skills-based Learning for caring for a loved one with an eating disorder: the new
Maudsley method. Abingdon: Routledge; 2007.

Wilson GT, Zandberg LJ. Cognitive-behavioral guided self-help for eating disorders: effectiveness and scalability. Clin
Psychol Rev. 2012;32(4):343–57. [ ]

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Personality disorders
Overview of personality disorders
The personality of an individual is defined by their automatic patterns of thinking, emotions and behaviours,
the manner in which they relate to others, and their response to their environment.

Personalities are determined by the interaction of developmental experiences with innate tendencies or traits.
The innate component of personality is referred to as temperament, which is strongly genetically determined.

Personalities are said to be disordered when they deviate markedly from that expected in their cultures.
People with personality disorders show lifelong, maladaptive responses to their environment, often associated
with recurrent or persisting distress for those with the personality disorder and/or for others suffering from
the consequences of their aberrant behaviour. Historically, there has been some pessimism about treatments
and outcomes for people with personality disorders. However, a number of prospective longitudinal studies
that are still ongoing have demonstrated that considerable improvement is possible for many people in terms
of symptoms and functioning. Since 1996, the Collaborative Longitudinal Personality Disorders Study has
followed 733 people seeking treatment with one of four personality disorders (borderline, avoidant,
obsessive-compulsive and schizotypal) [Note 1]. While the personality disorders show consistency as
syndromes over time, the study suggests that rates of improvement are far greater than previously expected.

While estimates vary about the prevalence of personality disorder in the general population, it is likely that it
is around 11% to 12%. The broad personality clusters have been subdivided into various personality disorders
of which borderline personality disorder is among the most common and problematic.

Borderline personality disorder is encountered in up to 43% of psychiatry inpatients, 25% of female

prisoners and 1% to 2% of the general population. It is characterised by:

an unstable sense of self and identity manifesting in chronic inner emptiness and boredom
a severe disturbance of interpersonal function
developmental immaturity
mood instability
recurrent impulsive and maladaptive behaviours such as binge eating, stealing, drug use problems, and
deliberate self-harm.

Antisocial personality disorder (ASPD) is reported as occurring in about 1% to 2% of the general

population while being much more common among people in prison. Studies suggest that about 1 in 2 males
and 1 in 5 females in prison meet criteria for ASPD. The key features of ASPD are that the person routinely
disregards the rights of others as demonstrated by deceitfulness, impulsivity and lack of remorse as well as
repeated criminal acts, disregard for the safety of others, failure to meet obligations and aggressive behaviour.
A developmental history reveals that this is a longstanding pattern with conduct disorder (aggression to
others, destruction of property, deceitfulness and serious violations of rules) also occurring before the age of
15.

Paranoid personality disorder (PPD) is estimated to occur in around 1% to 1.5% of the general population.
A person with PPD is typified by pervasive distrust of others, interpreting their motives as being malevolent.
They are excessively sensitive, quick to take offence, often feel slighted and then will counterattack as well as
hold longstanding grudges. Sufferers may doubt the sexual fidelity of their partner without justification and
perceive attacks on their character, which are not apparent to anyone else. As a result they may be socially
isolated and reluctant to share information with others, fearing that it will be misused against them.

Consideration should be given to the distinction between PPD and a paranoid psychosis (delusional disorder
or schizophrenia). This relies on testing the degree of impairment in perception of reality; people with PPD
can at least entertain the possibility that they have misinterpreted a situation or that they may be overreacting.
In PPD the perceived threats are more likely to be from people personally known to the individual or from an
institution that they have dealt with, rather than from unlikely or bizarre sources.

People with personality disorders are vulnerable to the development of other psychiatric disorders. For
example, a patient with obsessive compulsive personality disorder may also have a major depressive disorder.
Personality disorder and drug use problems are common comorbidities. Additionally, there may be a blurring
between a specific psychiatric clinical disorder and a personality disorder category; for example, the link
between avoidant personality disorder and the generalised form of social anxiety disorder.

Sometimes the categories of personality disorder are inappropriately used in a pejorative manner. This may
serve to stigmatise and thus lead to inadequate assessment and treatment or even denial of service.
Furthermore, although medication may have little role in management of the underlying personality disorder,
the patient should not be denied treatment for a coexisting illness (eg depression) because of the presence of
their personality disorder. Treatment of those with a moderate-to-severe personality disorder, especially with
pharmacotherapy, is best started by a specialist.

Note 1: Gunderson JG, Shea MT, Skodol AE, McGlashan TH, Morey LC, Stout RL, et al. The
Collaborative Longitudinal Personality Disorders Study: development, aims, design, and sample
characteristics. J Pers Disord 2000;14(4):300-15. [URL]

Issues in diagnosis and treatment of personality disorders

A key issue in treatment is making a diagnosis that is consistent with accepted classifications of personality
disorders. To make the diagnosis, it is helpful to not only take a longitudinal history from the patient but to
also seek other sources of information that add to the diagnostic formulation. These could include previous
clinical records and collateral information from family and carers as well as from previous treating clinicians.
In particular, look for patterns of behaviour and difficulties in interpersonal relationships and functioning that
have persisted over the patient's lifetime and are often exacerbated at times of stress and during life events.

The treatment of personality disorders requires the patient's active involvement. However, because some
personality disorders are egosyntonic (cause the patient no distress), patients may lack the motivation to
change. This is a particular problem with antisocial personality disorder where the impact of the disorder is
often much more keenly felt by other people.

Treatment is multifaceted. It involves a range of psychotherapeutic interventions including individual, group

and family approaches as well as social support and environmental manipulation. Pharmacological treatment
usually has little part to play in the management of personality disorders, but in particular individuals (eg
those severely distressed or at risk of self-harm), it may be useful. However, pharmacotherapy must always
be only one component of an often complex management plan. If a decision is taken to use pharmacotherapy,
this should be accompanied by a discussion that such treatment is adjunctive to, not an alternative to,
psychological therapies, which are the mainstay of treatment.

A symptom of some personality disorders is limited functional coping strategies to manage emotional pain
and stress, which results in dysfunctional acting-out behaviours. Hence, effective therapy includes assisting
patients to develop constructive (cognitive reframing, mindfulness, distraction) rather than dysfunctional
(alcohol or drug use, binge eating, gambling) responses. Patients need to learn these skills, practise using
them and develop some confidence in themselves as a result. It is important that the use of medication does
not send the wrong message to the patient that drugs are an alternative to psychological therapies, or that
emotional pain cannot be tolerated to any extent. Patients often attribute changes in mood to medication that
they are taking but the effect, if any, is likely to be modest.

Personality disorders need a long-term treatment strategy based in the community where the person faces
their stressors and learns to deal with them effectively. Inpatient treatment should be reserved for comorbid
conditions when they warrant it, or in certain circumstances when there is an acute crisis presentation;
however, this is not without risk. Admitting the person to hospital may have a negative impact because
hospitalisation may be seen as an answer in itself and allow the person to avoid working collaboratively with
their counsellor in their own environment. In addition, inevitably the person will be faced with discharge and
this may be perceived as rejection or abandonment, particularly for people with borderline personality
disorder.

If pharmacotherapy is to be trialled for symptoms of a personality disorder then this should be undertaken in
a targeted way using one drug at a time. The patient should be monitored for the balance between benefits
and adverse effects, and should be given sufficient information to allow them to participate in making an
informed decision about the use of pharmacotherapy considering this balance. Adverse effects of
psychotropic medications should be discussed with the patient, including the likelihood of weight gain and
metabolic syndrome with antipsychotics, lithium and antiepileptics.

For women of childbearing age, it is always important to consider the likelihood of teratogenicity with
medication and to discuss this with the woman and her partner. This is particularly important in patients with
personality disorder where impulsivity is a feature of some conditions thus increasing the likelihood of
unplanned pregnancy. This likelihood needs to be balanced against the potentially marginal benefits of
medication. Topics for discussion should also include contraception, pregnancy plans and what action the
patient would take in the event of an unplanned pregnancy.

In the pharmacotherapy of people with personality disorders there is a need to pay particular attention to the
risk of occurrence of drug dependence, abuse and overdose (see Alcohol and other drug problems), and also
poor concordance (see Concordance, adherence and compliance with psychotropic treatment).
Benzodiazepines are not helpful because problems with dependence and tolerance commonly overshadow
any benefit.

When people with personality disorders present in a crisis, clinicians often feel the need to offer them
something to assist and hence may feel compelled to offer medication because there is no apparent
alternative. However, most people respond well to being given support and time to talk about their concerns,
with simple problem-solving strategies to address immediate precipitants if appropriate. Involving family and
carers may also be helpful. If these strategies are not successful then a single dose of a drug for sedative and
tranquillising effect may be helpful but drugs should not be provided beyond this point.

Before prescribing medications for patients in crisis it is helpful to consider the transference and
countertransference phenomena. There may be a tendency for over-reliance on medication, to ‘rescue’ the
patient or to ‘do something’. It is important to consider the meaning to the patient of the prescribing of the
medication and to ensure that all the issues raised above are taken into consideration, balancing the perceived
benefits of medication (which are most likely to be marginal) against the range of potential harms.

Psychological interventions for personality disorders

Various forms of psychotherapy and behavioural approaches are used for people with personality disorder
and related problems such as deliberate self-harm. Learning how to relate better to others through the positive
experience of a therapeutic relationship has face validity. In addition, specific approaches may target
problematic traits, for example cognitive therapy may be used to modify extreme perfectionism.

The best evidence for any approach is for two specific psychotherapies in borderline personality disorder.
Dialectical behaviour therapy may improve general psychiatric symptoms and decrease self-harm and
hospital presentations. Psychoanalytic (or psychodynamic) oriented psychotherapy may decrease the need for
hospital care, improve general psychiatric symptoms, reduce the need for medication, and improve social
adjustment. Both these therapies should be administered by clinicians with specialised training and expertise.

In addition, meta-analyses have supported the use of psychodynamic therapy, cognitive behavioural therapy
(CBT) and interpersonal therapies for a range of personality disorders. These treatments lead to improvement
in symptoms and social and occupational functioning. Effect sizes were larger for psychodynamic therapy
than for CBT. However, studies in different psychological therapies have been limited in scope and
comparability such that it is not possible to recommend one specific therapy over another. Treatment is
generally long term (over a number of years) and may be complicated by lack of treatment engagement and
fluctuations in motivation.

Pharmacological treatment of personality disorders

Psychological interventions are first-line treatment.

Psychological interventions are first-line treatment for the management of personality disorders. There is a
very limited role for the use of medications in their management. Pharmacotherapy may be used to treat
specific symptoms; however, the evidence is weak and specialist advice should be sought.

There is little research evidence for pharmacotherapy in personality disorders except when the person has a
comorbid condition that responds to medication. There have been some studies suggesting that lithium,
antiepileptics, antipsychotics, antidepressants and omega-3 fatty acid supplements may have some benefit in
borderline personality disorder; however, the findings are not sufficiently robust or significant to allow any
recommendations.

Psychiatric conditions associated with personality disorders

Differentiating between personality disorders and other psychiatric disorders may be difficult. A
comprehensive longitudinal history, particularly involving information from key informants (family, other
clinicians, medical records), will assist in understanding the features of a person's presentation that are due to
the personality disorder (ie features present in different situations over much of the person's life) and those
that have arisen anew (and hence may indicate the development or recurrence of a comorbid mental illness
such as depression). In some situations a person may present for assessment with behaviours and symptoms
that appear typical of a personality disorder (eg self-harming, rapid mood fluctuations, argumentativeness,
and anti-authority attitudes); however, on occasion these will be new symptoms and represent atypical
manifestations of an affective disorder or organic mental illness.

If a patient with a personality disorder develops another psychiatric disorder, such as major depression or
schizophrenia, both disorders should be treated in the usual way while recognising that concordance and
treatment response may be affected by the presence of the personality disorder. It is important that adjustment
to life events is not mistaken for major depression because the failure to respond to antidepressants can lead
to multiple futile trials of pharmacotherapy or electroconvulsive therapy.

There is a high risk of alcohol and drug problems in people with personality disorders, with studies reporting
the lifetime prevalence of alcohol use problems at 43% to 77% and with other drug use problems affecting
about 50% to 60%. It is important that misuse of alcohol, prescribed and/or illicit drugs is detected, assessed
and treated (see Alcohol and other drug problems). Be aware that the patient may conceal or minimise drug
or alcohol use. The possibility of an underlying personality disorder should be considered in patients
presenting with drug use problems and drug dependence, and in patients with apparently treatment-resistant
psychiatric disorders.

Further reading
Beatson J, Rao S, Watson C, Spectrum Personality Disorder Service for Victoria. Borderline personality
disorder: towards effective treatment. Melbourne: Victorian Medical Postgraduate Foundation; 2010.

Gunderson JG, Links PS. Borderline personality disorder: a clinical guide. 2nd ed. Washington, DC:
American Psychiatric Press; 2008.

Key references
Personality disorders

Borderline personality disorder: a resource booklet for GPs. Hobart: General Practice South; 2008. [URL]

Practice guideline for the treatment of patients with borderline personality disorder. American Psychiatric
Association. Am J Psychiatry. 2001;158(10 Suppl):1–52. [ ]

Beatson J, Rao S, Watson C, Spectrum Personality Disorder Service for Victoria. Borderline personality disorder:
towards effective treatment. Melbourne: Victorian Medical Postgraduate Foundation; 2010.

Binks CA, Fenton M, McCarthy L, Lee T, Adams CE, Duggan C. Psychological therapies for people with
borderline personality disorder. Cochrane Database Syst Rev. 2006;(1):CD005652. [ ]

Binks CA, Fenton M, McCarthy L, Lee T, Adams CE, Duggan C. Pharmacological interventions for people with
borderline personality disorder. Cochrane Database Syst Rev. 2006;(1):CD005653. [ ]

Gunderson JG, Stout RL, McGlashan TH, Shea MT, Morey LC, Grilo CM, et al. Ten-year course of borderline
personality disorder: psychopathology and function from the Collaborative Longitudinal Personality Disorders
study. Arch Gen Psychiatry. 2011;68(8):827–37. [ ]

Gunderson JG, Links PS. Borderline personality disorder: a clinical guide. 2nd ed. Washington, DC: American
Psychiatric Press; 2008.

Morana HC, Camara FP. International guidelines for the management of personality disorders. Curr Opin
Psychiatry. 2006;19(5):539–43. [ ]

National Health and Medical Research Council. Clinical practice guideline for the management of borderline
personality disorder. Melbourne: National Health and Medical Research Council; 2013. [URL]

Oldham JM, Skodol AE, Bender DS, editors. The American psychiatric publishing textbook of personality
disorders. Arlington: American Psychiatric Publishing; 2005.

Skodol AE, Gunderson JG, Shea MT, McGlashan TH, Morey LC, Sanislow CA, et al. The Collaborative
Longitudinal Personality Disorders Study (CLPS): overview and implications. J Pers Disord. 2005;19(5):487–504.
[ ]

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Alcohol and other drug problems
Overview of alcohol and drug problems
Problems can arise from the self-administration of psychoactive substances. In most societies a number of drugs
are used for their psychological effects, for example alcohol, cannabis, opioids, benzodiazepines and stimulants
such as caffeine and amphetamine. For information on use of these psychoactive drugs in pregnancy and
breastfeeding, see Psychotropic drug use during pregnancy and Psychotropic drug use while breastfeeding.

Problems arising from use of licit and illicit drugs include:

intoxication and overdose

chronic physical health problems from the toxicity of the drug
social problems and criminal activity as dependence emerges
physical dependence and subsequent withdrawal
precipitation or exacerbation of psychiatric illness.

The route of administration is also important. In particular, there is a risk of contracting infections including
human immunodeficiency virus (HIV), hepatitis B, hepatitis C and other agents from sharing needles, syringes and
other injecting equipment.

When any drug use problem is identified, take a history of other substance use, as multiple drug use is very
common.

For many patients, brief counselling focusing on the assessed problems may be sufficient. This could be concerned
with reducing intoxication or, at least, the level of risk while intoxicated, or reducing overall consumption to
minimise the risk to health. For the patient who is likely to continue injecting drugs, advise on the use of new
needles and syringes (obtainable from needle syringe programs and some pharmacies).

A range of psychiatric disorders also occurs with greater frequency among patients with problem drug use. The
most common are depression, anxiety disorders (particularly social phobias), posttraumatic stress disorder and
personality disorders. It should also be recognised that many (perhaps the majority of) psychiatrically ill patients
use drugs such as alcohol, tobacco, cannabis and amphetamines in ways detrimental to their health.

Psychosocial interventions should incorporate general principles of counselling and cognitive behavioural therapy,
but also need to recognise issues and strategies important in the treatment of people who use drugs. In the initial
stages of treatment there is commonly ambivalence by those who use alcohol and drugs towards changes in their
pattern of use. Motivational interviewing may be used to facilitate open communication and patient participation in
goal-setting and decision-making. Relapse prevention is an important focus of therapy and strategies need to be
developed to respond to relapses when they occur.

When a patient is dependent on a drug, long-term treatment is required. The general practitioner is best placed to
treat most patients with alcohol and drug problems as they have a much better knowledge of the family and local
circumstances. Referral to a specialist treatment centre may be necessary if withdrawal is likely to be severe, or if
management proves difficult.

Relapse is common and many people dependent on a drug require multiple episodes of treatment (often over
several years) before achieving abstinence or controlled use. Relapse occurs for a variety of reasons including a
protracted withdrawal phase of some months' duration that frequently follows acute withdrawal, as well as from
psychological factors such as the effects of drug-related cues. Self-help groups such as Narcotics Anonymous
(NA), Alcoholics Anonymous (AA) and SMART Recovery are helpful for many people. Considerable assistance
is also readily available by telephone and online. For further information, see Appendix 8.1.

Observe state and territory statutory health regulations about notification of and prescribing for drug-dependent
people.

Alcohol: problem use

Introduction

According to the National Health and Medical Research Council (NHMRC) guidelines, average daily consumption
of alcohol in excess of two standard drinks is a health risk for men and women [Note 1]. In addition, they state that
on any given day consumption should not exceed four standard drinks, a lower maximum alcohol consumption
than previously. A standard drink contains 10 g of alcohol, the amount in 285 mL of full-strength beer, 100 mL of
wine, 60 mL of fortified wine and 30 mL of spirits. Significant dependence associated with a withdrawal syndrome
on cessation is more likely in those whose regular consumption is greater than eight standard drinks per day, and is
increased if they also use other sedatives.

Note 1: National Health and Medical Research Council. Australian guidelines to reduce health risks from
drinking alcohol. Canberra: Commonwealth of Australia; 2009. [URL]

Acute alcohol intoxication and overdose

Alcohol overdose is potentially fatal; death is usually due to inhalation of vomitus or to respiratory depression. The
average lethal blood alcohol concentration (BAC) is around 0.45% to 0.5% (450 to 500 mg/100 mL). However,
people who have developed high tolerance to alcohol will be able to cope with higher BACs. Death may result
from a much lower BAC if other sedative drugs have been taken.

Clinical estimation grossly underestimates the prevalence and severity of alcohol intoxication so a breathalyser
should be used routinely to estimate the BAC. Observe the patient at least until the BAC falls below 0.2%. Ideally,
monitoring should continue until the BAC has dropped to 0.05% and there is no evidence of the onset of a
withdrawal syndrome. Withdrawal may begin at a BAC of 0.1% and usually starts before the BAC reaches zero.
BAC normally declines at a rate of 0.015% to 0.02% per hour, although the rate of decline may be increased in
heavy drinkers. However, it should be noted that alcohol in the gastrointestinal tract may continue to be absorbed
and hence the BAC could rise even if there is no further alcohol ingestion.

Treatment of intoxication and overdose is supportive and symptomatic, with careful monitoring of the BAC,
airway, level of consciousness and responsiveness, and oxygen saturation. Alcohol overdose may cause
hypoglycaemia and metabolic acidosis. Stimulants should not be given.

Acute alcohol withdrawal

The alcohol withdrawal syndrome is characterised by anxiety, tremor, sweating, nausea and vomiting, agitation,
headache and perceptual disturbances. Seizures are occasionally observed. Fifty per cent of patients who
experience a seizure only suffer a single fit. Some highly dependent patients will progress to an alcohol withdrawal
delirium. Symptoms usually appear within 6 to 24 hours of the last consumption of alcohol and typically persist
for up to 72 hours, but may last for several weeks.

Many alcohol-dependent people require no medication when withdrawing from alcohol. Supportive care including
information on the withdrawal syndrome, monitoring, reassurance and a low-stimulus environment are effective in
reducing withdrawal severity.

If medication is required, a benzodiazepine loading dose technique may be used. The patient is given repeated
doses of diazepam until symptoms have diminished to an acceptable level. Diazepam is effective in the prevention
and treatment of acute alcohol withdrawal seizures. Because of the relatively large doses usually given, and the
long half-life of diazepam, it may not be necessary to give any further medication for withdrawal relief. Use:

diazepam 20 mg orally, every 2 hours until symptoms subside. A cumulative dose of 60

mg daily is usually adequate.

If the patient has not settled with 60 mg diazepam, review the diagnosis and consider the possibility of other
conditions. Do not exceed 100 mg daily without seeking specialist advice. Free telephone advice is available 24
hours a day from drug and alcohol specialist advisory services for all Australian states and territories, see detail in
Appendix 8.2.

Diazepam may be administered over the subsequent 2 to 7 days if symptoms return but should not be continued
beyond that. Patients with favourable home conditions can be treated at home without admission for residential
care. If diazepam is needed, it can be collected daily by the patient or administration can be supervised by a
reliable person living with the patient.

In patients with severe liver disease, a short-acting benzodiazepine without active metabolites should be
considered (eg oxazepam). Specialist advice and hospitalisation would be preferred.

As alcohol-dependent patients are usually deficient in thiamine, use:

thiamine 300 mg IM or IV, daily for 3 to 5 days then thiamine 300 mg orally, daily for
several weeks [Note 2].

Initial dosing is with parenteral thiamine as absorption of oral thiamine is slow and may be incomplete in patients
with poor nutritional status. Higher doses and a longer period of parenteral administration may be appropriate in
those with Wernicke encephalopathy or suspected malnutrition, see Thiamine supplementation.
 Always give thiamine before administering glucose (including dextrose 5% IV) for hypoglycaemia.

Give thiamine before administering glucose (including intravenous 5% dextrose) for hypoglycaemia because
giving glucose in the presence of thiamine deficiency may precipitate Wernicke encephalopathy.

Consideration should also be given to the setting in which withdrawal occurs. In all cases careful monitoring of
withdrawal severity is essential and more severe withdrawal requires inpatient care. Specialist alcohol treatment
services and most hospitals can provide charts to be used in the monitoring of symptom severity, although a
common error is to assume that higher scores are diagnostic of alcohol withdrawal. Filling in monitoring charts
should not be used as a substitute for talking with the patient and engaging them in their recovery.

Note 2: If thiamine ampoules are unavailable, ‘B-Dose Forte’ ampoules (containing 250 mg/2.5 mL thiamine)
are a suitable alternative.

Alcohol withdrawal delirium

Alcohol withdrawal delirium (also known as delirium tremens) is the most severe manifestation of alcohol
withdrawal. It usually commences 72 to 96 hours after cessation of drinking and is characterised by gross tremors
and fluctuating levels of agitation, hallucinations (usually tactile), disorientation and impaired attention. Fever,
tachycardia and dehydration may be present. It is a medical emergency that always requires hospitalisation and, if
inadequately treated, has a high mortality rate, mainly from heart failure. Alcohol withdrawal delirium is rarely
uncomplicated; it is usually associated with infections, anaemia, metabolic disturbances and head injury. It may be
associated with a range of other disorders including Wernicke encephalopathy and hepatic encephalopathy.

The principles of treatment (including appropriate supportive care and the use of thiamine and diazepam) are the
same as those for milder withdrawal syndromes (see Acute alcohol withdrawal, above). Use:

diazepam 20 mg orally, every 2 hours until symptoms subside.

Very high doses of diazepam (greater than 100 mg daily) may be required, but seek specialist advice. Free
telephone advice is available 24 hours a day from drug and alcohol specialist advisory services for all Australian
states and territories, see detail in Appendix 8.2. See above for thiamine regimen.

Intravenous injection of diazepam should be avoided if possible. Onset of action is not much faster than with oral
administration and there is a greater likelihood of causing severe adverse effects such as respiratory depression. If
an injection of diazepam is necessary, it must not be diluted and it must be given slowly over several minutes to
minimise the risk of respiratory depression or arrest. Close cardiorespiratory monitoring is essential.

An alternative would be to cautiously use parenteral midazolam as given for agitation in behavioural emergencies
(see Behavioural emergencies: acute medical settings).

If an antipsychotic drug is required, use:

haloperidol 0.5 to 2 mg orally, repeated every 2 hours and titrated to clinical response, up
to 10 mg in 24 hours.

For severe psychotic symptoms when oral administration is not possible, cautiously use:

1 droperidol 5 mg IM, as a single dose (see droperidol warnings, Box 8.21)

OR

1 haloperidol 5 mg IM, as a single dose.

Droperidol is similar to haloperidol but is more sedating; haloperidol is less likely to lower seizure threshold.
Avoid chlorpromazine as it lowers seizure threshold. If extrapyramidal adverse effects emerge with droperidol or
haloperidol, use:

1 benztropine 1 to 2 mg orally

OR

1 benztropine 1 to 2 mg IM.
 Diazepam and, to a lesser extent, haloperidol and droperidol, may worsen symptoms of hepatic encephalopathy.

Administration of diazepam and, to a lesser extent, haloperidol and droperidol, may worsen the symptoms of
hepatic encephalopathy.

Long-term management of alcohol dependence

Introduction

Group or individual support and counselling programs form the basis of long-term management of alcohol
dependence.

Three drugs with different modes of action may be used in treatment: disulfiram, acamprosate and naltrexone.
Choice of drug needs to be individualised, depending on the person's circumstances. Disulfiram gives good results
but treatment must be closely supervised. It may be hard to achieve compliance with acamprosate because of the
need to take six tablets daily; however, it will not affect treatment for pain relief. Naltrexone can interfere with
treatment for pain relief but dosing with one tablet daily may aid compliance. For each of these drugs, treatment
duration of 6 months or more is recommended.

Disulfiram

Disulfiram can give good results for highly motivated, physically fit individuals who are capable of compliance
with an abstinence-based program. Where disulfiram forms part of a structured therapeutic program including
supervised dosing, outcomes have been good, for example, a reduction in the number of drinking days has been
documented.

Ensure that the person understands that they must not have any alcohol with the disulfiram. Dispense the
disulfiram dose daily under supervision of a clinic or of a trusted person such as a spouse or employer. If
appropriate, use:

disulfiram 100 mg orally, once daily initially for 1 to 2 weeks, increase as required and as
tolerated up to 300 mg daily.
Do not start disulfiram unless the patient fully understands the risks involved.

Disulfiram should not be started unless the patient fully understands the risks involved and has not consumed
alcohol in the previous 24 hours.

Increase disulfiram dose slowly because people vary in the efficiency of their acetaldehyde dehydrogenase enzyme
(which metabolises alcohol) so some are more sensitive to disulfiram's effect than others. Disulfiram interacts with
alcohol by blocking its metabolism. Ingestion of alcohol results in a raised blood acetaldehyde concentration,
giving rise to the aldehyde reaction (ie intense flushing, sweating, palpitations, tachycardia, dyspnoea,
hyperventilation and the development of a pounding headache). Chest pains, restlessness and a sense of impending
doom may develop. There is an associated steep rise in blood pressure followed by hypotension. Severe reactions
may have an effect on the heart, or be associated with seizures and loss of consciousness. Occasionally death may
occur from cardiorespiratory failure. Treatment of the interaction involves intensive supportive therapy.

Acamprosate

Acamprosate reduces the neuronal hyperexcitability characteristic of alcohol withdrawal. While not an effective
treatment for the acute phase, acamprosate reduces the symptoms of protracted alcohol withdrawal (eg anxiety,
irritability, insomnia, craving). It has been shown to increase the time to first drink, prolong abstinence, and reduce
the number of drinking days. Acamprosate combined with psychosocial treatment has been shown to significantly
improve treatment outcomes when compared to psychosocial treatment alone.

In conjunction with a counselling program, acamprosate should be started following cessation of the acute phase
of alcohol withdrawal, ie approximately 1 week after cessation of drinking. If considered appropriate, use:

1 acamprosate (patient less than 60 kg) 666 mg orally, in the morning, 333 mg at midday
and 333 mg at night

OR

1 acamprosate (patient 60 kg or more) 666 mg orally, 3 times daily.

Supervision of dosing should be encouraged. There is no evidence of any potential for dependence with
acamprosate. It is cleared by the kidneys hence is contraindicated where serum creatinine is greater than 120
micromol/L.

Naltrexone

Naltrexone blocks the effect of endogenous opioids released following alcohol intake. As a result, the person who
drinks alcohol reports less pleasurable effects, even though alcohol-induced impairment remains unaffected. Some
studies report fewer cravings for alcohol. Because naltrexone reduces rate of relapse to heavy drinking and
increases the number of abstinence days it may be most effective in patients with a history of binge drinking and
those who have been drinking heavily. It is also suitable for those who have a stable social support and living
situation.

Liver biochemistry should be assessed before beginning treatment and monitored according to the product
information. If considered appropriate and in conjunction with a psychosocial treatment program, use:

naltrexone 50 mg orally, once daily.

Supervision by a trusted person may help ensure compliance.

Naltrexone does not precipitate a withdrawal syndrome in alcohol-dependent people who do not use opioids. There
are no adverse effects from combining alcohol and naltrexone.

Naltrexone blocks the effect of opioid analgesics and is thus contraindicated in people who require chronic opioid
therapy. Acute pain relief can be provided by nonopioid drugs, such as nonsteroidal anti-inflammatory drugs
(including parenteral ketorolac), or by using local or regional anaesthesia.

Acamprosate and naltrexone

Some trials suggested that the combination of naltrexone and acamprosate may be more effective in preventing
relapse than either drug alone. The combination is safe but is not yet recommended as a standard treatment. It
would be reasonable to prescribe the combination when treatment with a single drug has not achieved the desired
result.

Other drugs

Baclofen, ondansetron and topiramate have been shown to assist in reducing alcohol relapse but further research is
needed before these more expensive drugs can be recommended for use as first-line treatments.

Opioids: problem use

Introduction
While heroin is the opioid most frequently associated with problems, other opioids such as codeine and controlled-
release formulations of oxycodone and morphine are becoming more commonly associated with problem use.

Dependence on prescription opioids can arise following treatment of chronic pain. See Analgesics used in chronic
nonmalignant pain: opioids for information on issues to consider before prescribing an opioid for chronic pain.
Clinicians prescribing opioids should always check with local regulatory authorities, comply with regulations
about opioid prescription, and be particularly wary of prescribing to patients who are not well known to them.

People who use heroin initially seek the euphoric and emotional numbing effects, but once dependent will also be
motivated by avoidance of withdrawal. Heroin is most commonly administered intravenously but is also used
intranasally and by vapour inhalation.

Opioid overdose
Opioid overdose is characterised by respiratory depression, a stuporous or comatose state, and constricted pupils.
Pulmonary oedema may also occur. The main treatment is with the opioid antagonist naloxone. For information on
assessment and management of opioid overdose, see Toxicology: opioids.

Opioid withdrawal
Opioid withdrawal symptoms include agitation, sweating, musculoskeletal pain, abdominal cramps, diarrhoea,
nausea and vomiting, seizures and goose flesh. Following cessation of heroin use, these effects peak at around day
2 to day 3 and are largely resolved after 5 to 7 days. The syndrome is not life-threatening but clinicians should be
guided by patient reports of severity of their symptoms and treat accordingly. The objective signs are usually
modest, even in severe withdrawal.

Use of the partial opioid agonist buprenorphine has largely replaced the use of clonidine and of tapered doses of
methadone for the treatment of opioid withdrawal. The first buprenorphine dose may precipitate opioid withdrawal
and therefore should be delayed until at least 6 to 8 hours after last heroin use and when objective signs of
withdrawal are evident; this allows monitoring of effect.

Buprenorphine can be used for the management of withdrawal in either an inpatient or an outpatient setting. The
doses and duration of use should be titrated according to withdrawal severity. An approximate guide is:

buprenorphine 4 to 8 mg sublingually, as a single dose on the first day, increasing to a

maximum of 12 mg as a single dose on the third day, then decreasing the dose over the
following 2 to 5 days. In an inpatient setting, because of the extra benefit of psychosocial
engagement, considerably smaller doses may be sufficient.

Opioid withdrawal can also be treated symptomatically with a range of drugs. For treatment of anxiety and
agitation, use:

diazepam 5 to 20 mg orally, 4 times daily.

Caution should be exercised in prescribing benzodiazepines in the outpatient setting because dependence on these
drugs is common among people who use opioids and their use in combination with heroin increases the risk of
fatal overdose. If diazepam is considered to be necessary, it can be collected daily by the patient or administration
can be supervised by a reliable person.

Avoid prescribing benzodiazepines unless supervision is available.

Avoid prescribing benzodiazepines unless supervision is available. Other symptomatic treatments include
loperamide for control of diarrhoea, metoclopramide for reduction of nausea and vomiting, and paracetamol or
ibuprofen for relief of musculoskeletal pain. These should be administered when needed, with doses determined by
symptom severity.

Opioid dependence may present covertly in a general hospital setting when there is intercurrent illness in an
opioid-dependent person. These patients may need to be administered an opioid during admission to prevent
opioid withdrawal symptoms. Use buprenorphine as for treatment of withdrawal (see Opioid withdrawal, above).

Observe state and territory statutory health regulations on the prescription of buprenorphine.

Long-term pharmacotherapy of opioid dependence

Introduction

In addition to psychosocial interventions (such as counselling, cognitive behavioural therapy, social support),
methadone and buprenorphine have been widely used in the long-term treatment of opioid dependence. Methadone
has robust evidence supporting its use. The rationale for maintenance treatment, with either the full agonist
methadone or the partial agonist buprenorphine, is to substitute for heroin or other short-acting opioids. It prevents
the development of withdrawal symptoms, reduces craving, and decreases the euphoric effects of heroin if relapse
occurs. Maintenance opioid treatment allows the patient to make positive changes to their lifestyle. An alternative
approach is to use the opioid antagonist naltrexone for the prevention of relapse on completion of withdrawal.

People who are taking methadone, buprenorphine or naltrexone may require treatment for episodes of acute pain,
see Acute pain in patients with an opioid addiction for information on management.

Observe the legal requirements for prescribing opioids to drug-dependent people. Most jurisdictions have rigid
constraints on the prescription of these drugs.

Methadone

Methadone maintenance, the long-term substitution of oral methadone for heroin and other opioids, has proven
effectiveness in reducing opioid use.

Before starting a patient on methadone seek specialist advice. Approval from the state or territory Department of
Health is required before starting treatment. The methadone dose needs to be determined individually, taking into
account the amount of opioid used before starting and the initial response to methadone. Stabilisation of the dose is
normally achieved over many weeks. Outcomes are usually better when higher maintenance doses are provided for
longer periods, with many patients maintained in the range 60 to 120 mg daily. The usual maximum dose is 120
mg but some patients need higher doses.

Methadone, like many other drugs, causes QTc interval prolongation but whether or not this is a serious problem is
still debated. Regular review is required during the induction phase, observing for any signs of opioid toxicity.
‘Start low, go slow, aim high’ is the helpful maxim, as it may take a week for blood levels to stabilise after a dose
change. For information on management of methadone overdose, see Toxicology: opioids.

It is important for physical health to be investigated before starting methadone. Liver biochemistry and hepatitis B,
hepatitis C and HIV serology are useful tests to consider. Deaths have occurred, usually in patients with poor
physical health and in the early weeks of treatment.

Buprenorphine

Buprenorphine is effective in reducing opioid use. Because it is a partial agonist it has a lower risk of overdose and
physical dependence compared to methadone; however, the lower agonist activity is not suitable for some patients.
While normally administered once daily as buccal film or sublingual tablets, some people find that alternate-day
administration of buprenorphine provides a sufficiently stable blood concentration to avoid withdrawal symptoms.

Before starting a patient on buprenorphine seek specialist advice. Approval from the state or territory Department
of Health is required before starting treatment. The buprenorphine dose needs to be determined individually, taking
into account the amount of opioid used before starting and the initial response to buprenorphine. Stabilisation of
the dose is usually achieved over 2 to 3 weeks. Maintenance doses are normally in the range 8 to 24 mg once daily,
or up to 32 mg on alternate days.

Buprenorphine can precipitate withdrawal if used too soon in an opioid-dependent person. This needs to be
considered when starting buprenorphine treatment. For those who have been using heroin, buprenorphine should
be started after the effects of the last heroin dose have subsided and early signs of withdrawal have started.
Pupillary dilatation is a very helpful sign to monitor. If patients are transferring from methadone, the methadone
dose is normally reduced to 30 mg and buprenorphine started at least 24 hours after the last methadone dose.

Because of buprenorphine's high affinity for opioid receptors, reversal of buprenorphine overdose with the opioid
antagonist naloxone may require considerably higher doses (up to 12 mg naloxone) than those used for heroin or
methadone overdose. See Toxicology: opioids for information on management of buprenorphine overdose.

Buprenorphine blocks the effects of opioid analgesics used for pain relief. Acute pain may be treated with
nonopioid drugs or by use of additional doses of buprenorphine.

Buprenorphine is increasingly used as a combination product with naloxone to diminish its utility if diverted and
injected. Naloxone is only clinically effective when injected. This oral combination is available in most
jurisdictions for ‘takeaway doses’.

When prescribing takeaway doses, monitoring is more intensive initially and then can be reduced as more evidence
becomes available of increasing patient stability, such as no illicit drugs on urine drug tests, involvement in
education, training, employment or child care, attending appointments punctually, signs of self care and behaving
politely to staff.

Naltrexone

Naltrexone is a long-acting, orally effective opioid antagonist. A dose of 50 mg daily blocks the effects of opioid
drugs; however, even when used as maintenance treatment for carefully selected people who use opioids, only a
very small proportion of patients are compliant. Oral naltrexone is rarely used to treat opioid dependence because
of its limited effectiveness and an observed high death rate from opioid overdose.

Extended-release preparations of naltrexone are available but are not approved by the Australian Therapeutic
Goods Administration (TGA) or regulatory bodies in other countries, except for the US and Russia. In 2011 a
National Medical Health and Research Council (NHMRC) review concluded that there was limited evidence of
effectiveness or safety [Note 3]. In addition, providing pain relief for patients treated with oral or extended-release
naltrexone is difficult.

Note 3: See the NHMRC website at [URL].

Cannabis: problem use

Cannabis intoxication is characterised by sedation, euphoria, increased appetite, elevated heart rate, reddening of
the eyes, cognitive (including memory loss) and psychomotor impairment and altered time perception. Transient
panic, anxiety and paranoia can occur, more often in naive users. There is growing concern about an increased risk
of psychosis.

Dependence can develop with regular, frequent use. Patterns of high-level use, eg 30 or more ‘cones’ per day, may
be becoming more common but the vast majority of people who use cannabis consume relatively small amounts.
With chronic use, cannabis has a longer duration of action. Slight cognitive impairment may occur briefly, but
changes are largely reversible on cessation. Accurately estimating the nature and extent of adverse consequences is
complicated by the controversy and politicisation of the subject. Cannabis is said to account for 0.2% of the burden
of illness in Australia (compared to 2.0% for all illicit drugs, 2.3% for alcohol and 7.8% for tobacco).

Cannabis use may increase the likelihood of a subsequent diagnosis of schizophrenia, with heavier consumption
and earlier use conferring greater risk.

Many clinicians encounter young patients who have mental health or ill-defined social problems and are using
considerable quantities of cannabis. For patients with severe mental illnesses (eg schizophrenia, bipolar disorder,
depression), cannabis use can increase the likelihood of relapse of their illness. Charting episodes of cannabis use
and episodes of relapse may be used as a tool to educate patients, showing how the two interact and lead to
hospitalisation and other adverse outcomes.

Young patients often do not want to stop consuming cannabis but their parents are adamant that abstinence is
essential. The clinician may need to broker an agreement within the family. Ideally, a clinician should encourage
cessation or the lowest possible use of cannabis or other powerful psychoactive substances. It is important to
consider this as an ongoing dialogue with the patient and to keep lines of communication open. Goals that are not
attainable immediately (eg complete cessation) may become attainable in the future.

Preliminary evidence suggests that cognitive behavioural therapy (CBT) may be effective in treatment of cannabis
dependence. There is no evidence for pharmacological treatment of cannabis withdrawal or relapse prevention.

An increasing range of new synthetic cannabinoid-like agents are becoming available on the black market, for
example ‘Kronic’. These are likely to continue to appear on the market but the nature and extent of the risk of
harm have not been identified. Theoretically, they may have similar qualities and cause similar complications to
cannabis.

Benzodiazepines, zolpidem and zopiclone: problem use

Introduction
Problems arising from the use of benzodiazepines are insidious and diverse. These include overdose, particularly
from the use of benzodiazepines together with other sedative drugs, and dependence as a result of long-term use.
Zopiclone and zolpidem also attach to the benzodiazepine binding site of the GABAA receptor and have most of
the same adverse effects.

Benzodiazepine consumption exceeding 1 month, particularly at high doses, risks development of dependence.
The risk increases with the duration of treatment. About a third of patients who have been prescribed
benzodiazepines long term may have difficulty in reducing or stopping them. There is little, if any, justification for
prescribing benzodiazepines beyond a few days. Clinicians encountering patients taking benzodiazepines long
term should encourage them to slowly reduce the dose to zero.

Severe benzodiazepine dependence is seen in some polydrug-dependent patients. Their pattern of drug use tends to
be chaotic, with benzodiazepines used to augment or substitute for intoxication with other drugs, notably opioids.
Benzodiazepines may also be used to terminate a stimulant binge. An escalation in ‘doctor shopping’ in the years
before overdose death has been noted in this group. Every effort should be made to engage these patients in
treatment for drug dependence. Direct or oblique requests for benzodiazepines should be treated with caution and,
as a general rule, prescriptions should not be issued to patients not well known to the clinician.

Clinicians can specify when prescribing that dispensing is to be supervised by a pharmacist, partner or parent and
that there is frequent urine drug testing to monitor other drug use. Benzodiazepines may also be prescribed for
daily pick up to provide an opportunity for ongoing patient monitoring. Among benzodiazepines, only clobazam
can be individually identified on urine drug testing. Thus, although clobazam is more expensive, it provides a
means of checking whether the patient is taking other benzodiazepines.

Patients on long-term prescribed benzodiazepines are likely to be dependent even if the dose is stable and they are
not at risk from consuming other psychoactive drugs. The highest rate of benzodiazepine use is in the older
population despite this being the group of patients that is most at risk of harm from adverse effects of
benzodiazepines (eg falls, cognitive impairment). Clinicians should discuss the problem with the patient and
encourage them to become abstinent over a couple of months (see Anxiety and associated disorders: general
information for information on alternative treatments for anxiety disorders).

Patients with current or previous alcohol and drug problems are at increased risk of developing benzodiazepine
dependence.
The safety of zolpidem and zopiclone is uncertain; some patients may be at risk of bizarre and sometimes
dangerous sleep-related behaviours after taking these drugs.

Benzodiazepine overdose

Overdose on benzodiazepines alone is not usually life-threatening. Overdose is most dangerous when
benzodiazepines have been combined with other sedative drugs, such as alcohol or opioids. Treatment with the
antagonist flumazenil is rarely indicated. It may be dangerous to use flumazenil to reverse benzodiazepine effects
in mixed overdoses of benzodiazepines and tricyclic antidepressants, amphetamines or other proconvulsants
because this may result in uncontrollable seizures and death. Furthermore, rapid reversal of benzodiazepine effects
in dependent individuals may precipitate severe withdrawal symptoms and seizures. Treatment is generally
supportive. For further information on management of overdose, see Toxicology: benzodiazepines.

Benzodiazepine withdrawal

The benzodiazepine withdrawal (discontinuation) syndrome is highly variable. Common symptoms include
anxiety, insomnia, irritability, myoclonic jerks, palpitations, and sensory disturbances such as hyperacusis and
photophobia. Abrupt discontinuation in patients taking high doses (eg greater than 50 mg diazepam daily or
equivalent) may be accompanied by seizures.

After short-term use, benzodiazepines can usually be stopped without problem. When a person has been
consuming a benzodiazepine within or only slightly above the therapeutic dose range for several months or more,
reduction of the dose at a rate of 15% of the starting dose per week is likely to be well tolerated. However, there is
considerable variability in withdrawal symptom severity. The rate of decrease should be titrated against symptoms.

For those people using higher doses, stabilisation on an equivalent dose of diazepam is recommended before dose
reduction (see Table 8.2). If several different benzodiazepines are being used concurrently, sum the various
diazepam equivalents to obtain the stabilisation dose. This diazepam stabilisation dose should not normally exceed
80 mg daily. Sometimes patients overestimate their unsanctioned consumption hoping to obtain higher prescribed
doses. It is common practice to prescribe 40% of the stated dose of unsanctioned benzodiazepines.

The diazepam equivalent should be given in divided daily doses. Following a few days stabilisation, dose
reduction should occur at a rate determined by symptom severity. Reductions of 10% of the diazepam dose per day
can be achieved in inpatient settings, but much slower reductions, often over a period of 2 months, are more
common in the outpatient environment.

Patients who present in severe benzodiazepine withdrawal should be treated in an inpatient setting with diazepam,
using a dose equivalent to their total daily benzodiazepine consumption (see Table 8.2). If this is not known, use:

diazepam 20 mg orally, every 2 hours until withdrawal symptoms are controlled.

Gradually taper dose over subsequent days.

Supportive care, including a low-stimulus environment and reassurance, is helpful.

Comparative oral doses of benzodiazepines (Table 8.2)

Approximate equivalent dose (mg) [NB1] to diazepam 5

Drug
mg
alprazolam 0.5
bromazepam 3
clobazam 10
clonazepam 0.25 [NB2]
diazepam 5
flunitrazepam 0.5
lorazepam 1 [NB3]
nitrazepam 5
oxazepam 15
temazepam 10
NB1: The widely varying half-lives and receptor-binding characteristics of these drugs make exact dose equivalents difficult to establish.
NB2: Particular care is needed if changing from clonazepam to a different benzodiazepine because there is a wide variety of reported equivalences.
NB3: Lorazepam may be relatively more potent at higher doses.

Quetiapine: problem use

There is growing concern about inappropriate use of quetiapine, in particular in the prison setting. It is possible
that quetiapine is being prescribed for its anxiolytic properties because it is seen as a safer option than
benzodiazepines. However, its long-term adverse effects (see Management of antipsychotic adverse effects) should
be considered as well as its potential for misuse. There are reports of excessive doses being taken for their sedative
effect and of tablets being diverted for illicit supply. People who misuse quetiapine are often taking multiple other
drugs such as opioids, alcohol or benzodiazepines.

At the time of writing, there have not been reports of problems with use of other second-generation antipsychotics.

Stimulants: problem use

Introduction
The psychomotor stimulants include amphetamines (amphetamine, methamphetamine, dexamphetamine) as well
as methylphenidate, ephedrine, cocaine and some appetite suppressants (eg phentermine). Methamphetamine, the
most widely used, is known as ‘speed’, ‘meth’, ‘ice’, ‘shabu’ or ‘p’. A number of synthetic stimulants (so-called
designer drugs) such as: methylenedioxymethamphetamine (MDMA, ‘ecstasy’); paramethoxyamphetamine (PMA,
‘ecstasy’, ‘death’); and methylene dioxypyrovalerone (MDPV); also have amphetamine-like properties. The actual
ingredients of some preparations of the synthetic stimulants may be unknown (eg ‘bath salts’, ‘shaman's dust’)
[Note 4]. They may cause a prolonged psychosis lasting for weeks during which the person can exhibit disturbed
behaviour and be extremely agitated.

The effects sought by people who use stimulants include euphoria, self-confidence, increased sexual behaviour,
increased concentration and appetite suppression. The routes of administration vary but include oral, intravenous,
intranasal and vapour inhalation.

Some people can use large quantities of stimulants for long periods without developing adverse consequences.
Others develop severe physical and mental health problems or severe social difficulties after consuming smaller
quantities for a shorter period.

In particular, all patients who present with symptoms of stimulant toxicity should be treated calmly and with
respect. The strategies described in the topic Behavioural emergencies, including avoiding escalation, de-
escalation and sedation, should be adopted. Clinicians should keep discussion short and use the opportunity to
emphasise their readiness for future discussion and assistance. Inexperienced staff whose anxiety and discomfort is
very obvious may unsettle some patients.

Note 4: See ‘legal high’ facts on the Australian Drug Foundation website [URL].

Amphetamine and cocaine overdose and toxicity

Overdose of amphetamine, cocaine and other stimulant drugs can produce a range of symptoms including anxiety,
insomnia, confusion, paranoid psychosis, tremors, seizures, rapid respiration, hyperthermia, rhabdomyolysis,
hypertension, tachycardia and cardiac arrhythmias. Strokes may result in ongoing disability, while death can result
from cardiac arrest and hyperthermia. Scratching a perceived skin irritation can cause deep excoriation of the skin
that may be difficult to heal.

See Behavioural emergencies for possible management strategies. In all cases, supportive care including a cool,
low-stimulus environment is important. Attention should be given to hydration and nutrition, particularly for those
who have been using the stimulant(s) continuously over a period of days. These patients will be very tired and
anxious to sleep.

For further information on the management of overdose, see Toxicology: stimulant drugs.

Ecstasy overdose and toxicity

Overdose of an amphetamine derivative such as ecstasy (MDMA or PMA) is potentially, albeit rarely, fatal. While
the signs and symptoms are similar to those described for amphetamine (see Amphetamine and cocaine overdose
and toxicity, above), hyperthermia and hyponatraemia are the most significant toxic effects. Core body temperature
may exceed 42°C and, in such cases, secondary pathological events (eg rhabdomyolysis, disseminated
intravascular coagulation, acute kidney failure and metabolic disturbances) are likely to be present.

The magnitude and direction of change in core body temperature is profoundly affected by ambient temperature.
Hyperthermia is much less likely in cool environments, while hypothermia can result if the person is exposed to
cold.

Treatment depends on the signs and symptoms, but may include reduction in body temperature, correction of fluid
and electrolyte disturbances, and management of the secondary pathological events. Deaths can occur because of
long delays between onset of symptoms and presentation for treatment. Overdose on these drugs is a medical
emergency and patients should be taken directly to an emergency department.

Liver damage can occur shortly after administration of MDMA or as a delayed effect. The cause is unknown. Most
cases resolve spontaneously, but some progress to liver failure.

Antidepressants (eg selective serotonin reuptake inhibitors, moclobemide) are sometimes taken in combination
with ecstasy to magnify its effect. There is significant risk of toxicity with such combinations.

Stimulant discontinuation (withdrawal) syndrome

Discontinuation or withdrawal states are commonly associated with abstinence following high-dose stimulant use.
Withdrawal is characterised by hypersomnia, hyperphagia, irritability and aggression, depression and craving.
Stimulant withdrawal syndromes are poorly understood. They are not just the mirror image of depressant
withdrawal syndromes, such as from alcohol or opioids.

Anhedonia and depression may last for many months after stopping stimulant use. This may be associated with
elevated risk of suicide (particularly in the first few weeks after stopping) necessitating appropriate observation
and treatment.

No medication has been shown to be particularly effective in the treatment of amphetamine withdrawal.
Benzodiazepines may be useful to reduce irritability. Antidepressants may be helpful for treatment of depression
arising from stimulant withdrawal. Doses and guidelines are the same as those used generally for treatment of
depression (see Depression).

Treatment of stimulant dependence

There is little conclusive evidence on the effectiveness of pharmacotherapeutic interventions for amphetamine
dependence or cocaine dependence. However, psychological interventions, such as cognitive behavioural therapy
are effective in treating cocaine dependence and appear promising for the treatment of methamphetamine
dependence. Cocaine dependence may be responsive to disulfiram.

Many clinicians are nihilistic about treating people who use stimulants. However, there is evidence that support
and encouragement are far more effective than generally appreciated and that they prolong the period to the next
relapse. There has been some research evaluation of agonist replacement treatments.

Other psychoactive drugs: problem use

Anticholinergic drugs and antihistamines
Anticholinergic drugs such as benztropine and benzhexol, plants containing anticholinergic agents, eg Angel's
Trumpet (Brugmansia spp.), and antihistamines with anticholinergic adverse effects, are sometimes consumed for
their hallucinogenic effects. In high doses they may produce acute toxic psychosis. For further information on
toxicity, see Toxidromes: anticholinergic (antimuscarinic) agents.

Betel nut
Betel nuts, which contain the active ingredient arecoline, are chewed by some people in Australia. They can have a
mildly hallucinogenic effect as well as a mildly stimulatory effect. A fact sheet on betel nut can be obtained from
the Australian Drug Foundation website [Note 5].

Note 5: See betel nut facts on the Australian Drug Foundation website [URL].

Gamma-hydroxybutyrate
Gamma-hydroxybutyrate (GHB), also known as ‘GBH’ or ‘fantasy’, is a sedative and anaesthetic drug that is used
therapeutically in Europe (as sodium oxybate), but is not approved by the Australian Therapeutic Goods
Administration for therapeutic use. GHB has been used by body-builders to enhance growth hormone release, but
most use now occurs as one of the so-called ‘party drugs’. It has also been implicated as a ‘date rape’ drug.

Effects are very similar to those for alcohol and include sedation, euphoria, disinhibition and amnesia. In addition
to these effects, overdose may be characterised by confusion, agitation, hallucinations, respiratory depression,
hypotension, bradycardia, involuntary movements (sometimes interpreted as seizures) and coma. GHB overdoses
may be common among people who use the drug and fatalities have occurred. Respiratory depression can be
worsened if alcohol or other sedatives are combined with GHB.

There is no specific antidote for overdose, and treatment is supportive. The duration of action is very short and the
effects wear off, often very suddenly, within a few hours of ingestion. Patients may display aggressive behaviour
on awaking from coma. For further information on overdose, see Toxicology: gamma-hydroxybutyrate.

GHB is relatively easy to manufacture from the widely used chemicals gamma-butyrolactone (itself metabolised to
GHB if ingested) and sodium hydroxide. Residual sodium hydroxide may cause burns to the mouth and
oesophagus in people taking GHB solutions. GHB is usually distributed as a colourless liquid and is taken orally.

There are case reports of physical dependence on GHB; the discontinuation syndrome is similar to alcohol
withdrawal.

Hallucinogens
The hallucinogens include a number of drugs such as lysergic acid diethylamide (LSD), psilocybin (from
mushrooms) and certain analogues of amphetamine. They are usually taken orally.

The effects include hallucinations, depersonalisation, hypersensitivity to external stimuli and changes in perception
of time; psychotic behaviour may be observed. Panic and feelings of loss of control may be prominent, with
lability of mood. Sympathomimetic effects (eg hypertension, tremor) may be prominent in overdose. The duration
of action depends on the particular drug consumed and the dose taken. In some instances hallucinations and other
effects may persist for several days.

While the patient is under the influence of hallucinogenic drugs, treatment with benzodiazepines may be helpful,
particularly if the patient exhibits fear or anxiety. The dose of oral diazepam is titrated to response; however, seek
specialist advice if no response is apparent.

If psychotic symptoms are persistent, treatment with an antipsychotic drug is appropriate, see Schizophrenia and
related psychoses: first psychotic episode for doses of oral antipsychotics. However, caution must be exercised
with antipsychotics that have anticholinergic effects as they may add to the anticholinergic effects of some
hallucinogens.

Hallucinogenic drugs are normally used sporadically and withdrawal symptoms are not seen. Flashbacks may
occur, ie recurrence of experiences simulating those of the previous intoxicated state arising some time after the
initial experience.

Kava

Kava is a plant native to the Pacific Islands, which has been available in parts of Australia for some years. The
roots are processed and then taken as a beverage; extracts of kava can also be obtained. The effects include
analgesia, muscle relaxation, sedation and reduced anxiety. Many effects are similar to benzodiazepines and
alcohol, and combining kava with these drugs produces at least additive effects. Chronic use has been associated
with an ichthyosiform kava dermopathy. There is some evidence to suggest that it may be hepatotoxic.

Ketamine

Ketamine (‘K’, ‘super K’, ‘vitamin K’, ‘special K’) is an anaesthetic used illicitly by a variety of routes of
administration for its dissociative and hallucinogenic properties. Overdose, typically of 1 to 2 hours duration, is
characterised by hallucinations, delirium, cardiovascular and respiratory stimulation, and hypothermia. Respiratory
depression can occur, particularly with intravenous administration, but it is uncommon. Treatment of overdose is
symptomatic.

Ketamine has the potential to produce physical dependence, but cessation of use does not usually present a
problem. As is the case with other hallucinogens, flashbacks may occur some time after cessation of use.

Khat
Khat is a mild stimulant commonly used by people from the Horn of Africa. A fact sheet on khat can be obtained
from the Australian Drug Foundation website [Note 6].

Note 6: See khat facts on the Australian Drug Foundation website [URL].

Nicotine
Tobacco use in people with alcohol and drug problems is common and occurs at a higher rate than in the general
Australian population. Smoking cessation should be particularly encouraged in this group because as well as
improving their current and future health, it may assist them in abstaining from other problematic drug use. For
further discussion on interventions for smoking cessation, see Smoking cessation.
Volatile substances: problem use
A wide variety of volatile substances is consumed, mainly by young people. Substances include petrol and solvents
such as toluene and acetone, found in glues, paints, paint thinners and correction fluids. Other volatile substances
include nitrous oxide and propellants in aerosols. Problems arise as a result of both acute intoxication and chronic
consumption. Volatile solvents are readily available, and with rare exceptions reducing their availability is
unrealistic.

Acute intoxication varies according to the substance; it is frequently characterised by euphoria, disinhibition and
excitation, but also by drowsiness, disorientation, hallucinations and ataxia, particularly at high doses. Most cases
of solvent intoxication can be treated with removal of the causal agent and bed rest. Deaths are rare, but may arise
through asphyxia, ventricular fibrillation and other cardiac arrhythmias.

Chronic, high-level exposure to some solvents can result in a diffuse neurotoxicity, which may be manifest as one
of a number of neurologic symptoms, most commonly peripheral neuropathy and encephalopathy. Other organ
systems, including the kidney and liver, may also be affected. For further information about management of
volatile substance use, see the National Health and Medical Research Council (NHMRC) clinical practice
guideline [Note 7].

Note 7: National Health and Medical Research Council. Consensus-based clinical practice guideline for the
management of volatile substance use in Australia. Melbourne: National Health and Medical Research Council;
2011.

Key references
Problem use of alcohol: introduction

Haber P, Lintzeris N, Proude E, Lopatko O. Guidelines for the treatment of alcohol problems. Sydney: Commonwealth
of Australia; 2009.

National Collaborating Centre for Mental Health. Alcohol-use disorders: diagnosis, assessment and management of
harmful drinking and alcohol dependence (CG115). London: National Institute for Health and Clinical Excellence; 2011.
[URL]

Alcohol withdrawal

Haber P, Lintzeris N, Proude E, Lopatko O. Guidelines for the treatment of alcohol problems. Sydney: Commonwealth
of Australia; 2009.

National Collaborating Centre for Mental Health. Alcohol-use disorders: diagnosis, assessment and management of
harmful drinking and alcohol dependence (CG115). London: National Institute for Health and Clinical Excellence; 2011.
[URL]

Acute alcohol intoxication and overdose

Haber P, Lintzeris N, Proude E, Lopatko O. Guidelines for the treatment of alcohol problems. Sydney: Commonwealth
of Australia; 2009.

National Collaborating Centre for Mental Health. Alcohol-use disorders: diagnosis, assessment and management of
harmful drinking and alcohol dependence (CG115). London: National Institute for Health and Clinical Excellence; 2011.
[URL]

Long-term management of alcohol dependence

Haber P, Lintzeris N, Proude E, Lopatko O. Guidelines for the treatment of alcohol problems. Sydney: Commonwealth
of Australia; 2009. [URL]

Kiefer F, Wiedemann K. Combined therapy: what does acamprosate and naltrexone combination tell us? Alcohol
Alcohol. 2004;39(6):542–7. [ ]

National Collaborating Centre for Mental Health. Alcohol-use disorders: diagnosis, assessment and management of
harmful drinking and alcohol dependence (CG115). London: National Institute for Health and Clinical Excellence; 2011.
[URL]

Opioids: problem use

 Lintzeris N, Clark N, Winstock A, Dunlop A, Muhleisen P, Gowing L, et al. National clinical guidelines and procedures
for the use of buprenorphine in the treatment of opioid dependence. Canberra: Commonwealth of Australia; 2006.
[URL]

The Royal Australasian College of Physicians (RACP). Prescription opioid policy: improving management of chronic
non-malignant pain and prevention of problems associated with prescription opioid use. RACP Sydney: 2009.

Cannabis: problem use

Barratt MJ, Cakic V, Lenton S. Patterns of synthetic cannabinoid use in Australia. Drug Alcohol Rev. 2012. [ ]

Wells DL, Ott CA. The “new” marijuana. Ann Pharmacother. 2011;45(3):414–7. [ ]

Benzodiazepines, zolpidem and zopiclone: problem use

UK Medicines Information (UKMi). What are the equivalent doses of oral benzodiazepines? London: National
Electronic Library for Medicines; 2010. [URL]

Virani AS, Bezchlibnyk-Butler KZ, Jeffries JJ, Procyshyn RM. Clinical handbook of psychotropic drugs. Virani AS,
Bezchlibnyk-Butler KZ, Jeffries JJ, Procyshyn RM, editors. 19th ed. Ashland, Oh: Hogrefe; 2012.

Quetiapine: problem use

Heilbronn CE, Lloyd B, McElwee P, Eade A, Lubman DI. Quetiapine-related harms are on the rise. Aust N Z J
Psychiatry. 2012;46(3):279–80. [ ]

McKean A, Monasterio E. Off-label use of atypical antipsychotics: cause for concern? CNS Drugs. 2012;26(5):383–90.
[ ]

McLarnon ME, Fulton HG, Macisaac C, Barrett SP. Characteristics of quetiapine misuse among clients of a
community-based methadone maintenance program. J Clin Psychopharmacol. 2012;32(5):721–3. [ ]

Paparrigopoulos T, Karaiskos D, Liappas J. Quetiapine: another drug with potential for misuse? A case report. J Clin
Psychiatry. 2008;69(1):162–3. [ ]

Reeves RR, Brister JC. Additional evidence of the abuse potential of quetiapine. South Med J. 2007;100(8):834–6. [
]

Tcheremissine OV. Is quetiapine a drug of abuse? Reexamining the issue of addiction. Expert Opin Drug Saf.
2008;7(6):739–48. [ ]

Stimulants: problem use

Joksovic P, Mellos N, van Wattum PJ, Chiles C. “Bath salts”-induced psychosis and serotonin toxicity. J Clin
Psychiatry. 2012;73(8):1125. [ ]

Rasimas JJ. “Bath salts” and the return of serotonin syndrome. J Clin Psychiatry. 2012;73(8):1126–7. [ ]

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Gambling problems
Overview and management of gambling problems
There is a high prevalence of gambling in the Australian population. It ranges from people placing an
occasional wager through to people for whom gambling impinges severely on their life.

There is emerging evidence that problem gambling represents a heterogenous disorder with diversity in its
clinical presentation. This heterogeneity is due in part to the high comorbidity with other psychiatric
disorders, such as depression, anxiety, alcohol and drug use problems, and personality disorders. These
comorbid conditions may influence the choice of treatment and impact on the effectiveness of treatment for
people with gambling problems. It is also possible that gambling problems are more severe in people who
have a comorbid psychiatric condition than in people who do not.

The National Health and Medical Research Council have approved the Guideline for screening, assessment
and treatment in problem gambling, which gives information on people who should be screened for problems
with gambling and suggestions for treatment of people who are at-risk or who have a gambling problem
[Note 1].

Trials have shown cognitive behavioural therapy is effective in reducing gambling behaviour and severity,
and reducing psychological stress in people with gambling problems. However, the durability of therapeutic
effect is unknown. Motivational interviewing, motivational enhancement therapy and other psychological
interventions have also been used to reduce gambling behaviour and severity. These interventions should
preferably be delivered by appropriately trained practitioners.

Online and telephone resources are available to provide assistance for people with a gambling problem [Note
2].

At the time of writing, no drugs have been approved by the Australian Therapeutic Goods Administration for
treatment of problem gambling. Antidepressants have not been shown to reduce gambling severity in people
with a gambling problem but who do not have comorbidities such as depression or anxiety. Naltrexone has
been shown to reduce gambling severity in some people with gambling problems but should only be used
under specialist supervision as further research is needed to identify optimal treatment.

Note 1: The problem gambling research and treatment centre. Guideline for screening, assessment and
treatment in problem gambling. Clayton: Monash University; 2011. [URL]

Note 2: Gambling Help Online, telephone 1800 858 858. [URL]

Key references
Gambling problems

Cowlishaw S, Merkouris S, Dowling N, Anderson C, Jackson A, Thomas S. Psychological therapies for

pathological and problem gambling. Cochrane Database Syst Rev. 2012;11CD008937. [ ]

Grant JE, Kim SW. Medication management of pathological gambling. Minn Med. 2006;89(9):44–8. [ ]

Grant JE, Kim SW, Hartman BK. A double-blind, placebo-controlled study of the opiate antagonist naltrexone in
the treatment of pathological gambling urges. J Clin Psychiatry. 2008;69(5):783–9. [ ]

Kim SW, Grant JE, Adson DE, Shin YC. Double-blind naltrexone and placebo comparison study in the treatment
of pathological gambling. Biol Psychiatry. 2001;49(11):914–21. [ ]

Thomas SA, Merkouris SS, Radermacher HL, Dowling NA, Misso ML, Anderson CJ, et al. Australian guideline
for treatment of problem gambling: an abridged outline. Med J Aust. 2011;195(11–12):664–5. [ ]
Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Smoking cessation
The benefits of stopping smoking
Tobacco smoking is a major risk factor for coronary heart disease, stroke, peripheral vascular disease, chronic
obstructive pulmonary disease, cancer and a variety of other diseases and conditions. It is estimated that 40% of
heart disease is attributable to smoking (population attributable risk) which is comparable to dyslipidaemia (around
24%) or elevated blood pressure (around 31%). The relationship between smoking and cardiovascular disease is
well established, with the risk depending on a range of factors—such as age, sex, amount of tobacco smoked, and
baseline cardiovascular risk (see also Cardiovascular disease risk stratification). Second-hand smoke also carries
significant health risks for nonsmokers.

The overall smoking rate has continued to fall in Australia with 15.1% of Australians aged 14 years or more
smoking tobacco daily in 2010. However, smoking rates are much higher among certain groups, such as those with
mental illness (32%) and Aboriginal and Torres Strait Islander people (50%). Other groups with high smoking
rates are prisoners, people with alcohol or other drug use problems, and some people from culturally and
linguistically diverse backgrounds, including refugees. The latter may not be aware of harms of smoking and
hence may respond well to intervention.

Health benefits from smoking cessation are well documented and quitting smoking before 35 years of age avoids
almost all excess risk for developing smoking-related diseases. Quitting smoking has immediate as well as long-
term benefits, reducing the risk for developing smoking-related diseases. However, the risk for developing
cardiovascular and cerebrovascular disease will never quite reach the level of risk of a person who has never
smoked, and people with severe lung disorders (eg chronic obstructive pulmonary disease) may have already
sustained irreversible damage to their lungs.

Evidence suggests that the beneficial impact of quitting smoking after an acute coronary syndrome or cardiac
surgery can decrease that person's risk of death by at least one-third, which may be as great as or greater than other
possible interventions (eg lipid-modifying therapy). See Table 8.3 for a patient information sheet listing some of
the health benefits associated with smoking cessation.

Smoking cessation interventions are both effective and cost-effective. It has been estimated that approximately
70% of smokers of any age wish to stop.

Health benefits associated with smoking cessation (Table 8.3)

Print-friendly PDF

Time since stopping smoking Health benefits

almost all nicotine will be out of the bloodstream
level of carbon monoxide in the blood will drop and
within a day
more oxygen will reach the heart and muscles

the lung's natural cleaning system will start to recover

and become better at removing mucus, tar and dust from
the lungs
within a week
there will be higher blood levels of protective
antioxidants (eg vitamin C)

there will be less coughing and wheezing

the immune system will have started to recover
blood will be less thick and sticky and blood flow to the
within 2 months
hands and feet will improve
the body will be better at healing cuts and wounds

lungs will no longer produce the extra phlegm caused by

within 6 months smoking

lungs will be healthier and breathing will be easier,

after 1 year making it easier to exercise

there will be a large drop in risk of heart attack and

within 2 to 5 years stroke; this risk will continue to gradually decrease
 risk of cervical cancer will return to the same as for a
within 5 years woman who has never smoked

risk of lung cancer will be markedly lower than that of a

continuing smoker; this risk will continue to decline
after 10 years
(provided the disease is not already present)

risk of heart attack and stroke will be close to that of a

after 15 years person who has never smoked

The 5As framework for stopping smoking

Introduction

The stages of intervention of the 5As framework—ask, assess, advise, assist and arrange follow-up—can be
applied for smoking cessation. The Royal Australian College of General Practitioners (RACGP) document
Supporting smoking cessation: a guide for health professionals gives a clear algorithm for applying the 5As
structure to smoking cessation [Note 1].

Note 1: ‘Supporting smoking cessation: a guide for health professionals’ is available on the RACGP website
[URL].

Ask about smoking

Ask people about their smoking and document their tobacco use.

Assess motivation and nicotine dependence

Obtain a smoking history. This should include:

the number of cigarettes smoked per day—‘How many cigarettes a day do you smoke?’
the time to first cigarette after waking—‘How soon after waking up do you smoke your first cigarette?’
readiness to quit—willing to make a quit attempt in the next month, in 6-months' time, or not interested in
quitting
any previous quit attempts and perceived reasons for the failure of these attempts.

Consider the relationship of smoking to other health problems.

Assessment also involves consideration of the relationship of smoking to other health problems such as mental
health and/or drug and alcohol problems.

Indicators of a person's level of nicotine dependence include:

high dependence—waking at night to smoke or smoking within the first 5 minutes after waking; usually
smokes more than 30 cigarettes daily
moderate dependence—smoking within 30 minutes after waking; usually smokes 20 to 30 cigarettes daily
low-to-moderate dependence—not needing to smoke within the first 30 minutes after waking; usually
smokes 10 to 20 cigarettes daily
low dependence—not needing to smoke in the first hour after waking; usually smokes fewer than 10
cigarettes daily.

Advise the smoker to quit

Advise all smokers to quit, using language that is clear but nonconfrontational. Inform smokers of the benefits of
quitting and reassure them that it is never too late to quit.

For example, pregnancy or planning to become pregnant is an opportunity for the clinician to discuss modification
of smoking behaviour and every effort should be made to capitalise on a woman's motivation to engage with
treatment during this time. See Psychotropic drug use during pregnancy: nicotine for further information.

A hospital admission is another opportunity for smoking cessation intervention. For example most mental health
units are now smokefree, with nicotine replacement therapy being offered to manage nicotine withdrawal
symptoms.
Assist with smoking cessation
Offer assistance and encouragement to smokers at all stages of readiness to quit.

Advice may range from restating the value of quitting (for smokers not ready to quit), to setting a quit date and
providing support for the decision (ready to quit), to summarising the benefits achieved by those who have recently
quit. Explore the health benefits of quitting for that particular person and discuss other advantages of quitting (eg
financial benefits, the deleterious effects of smoking on skin ageing and sexual attractiveness).

Brief medical advice (3 to 5 minutes) can result in a 12-month quit rate of up to 7.5%. A higher quit rate (20% to
24%) can be achieved if a range of effective interventions is included (eg follow-up, pharmacotherapy, enlisting
support, dealing with relapse, targeting smokers who are interested in quitting).

It is important to use whatever time is available, as the effectiveness of an intervention is not a linear function of
the time spent. Quit rates are increased by spending as little as 1 minute on strategies with good evidence (such as
assessing interest and dependence, suggesting pharmacotherapy, arranging a follow-up appointment, referring to
QUIT), and negotiating some form of support in the person's own network (such as with their partner).

If the smoker expresses a wish to quit, help should be offered. Assist the smoker to plan the quit attempt. Key
issues are enlisting social and professional support. QUIT runs a very effective multilingual quitline (137 848) and
provides QUIT books free of charge to smokers and health care providers. There is evidence for the effectiveness
of telephone counselling services, particularly if the smoker opts for proactive telephone counselling. Referral to
QUIT takes very little time and is a strategy that can easily be offered. Some quitlines provide feedback to
referrers, which can help the clinician to tailor further advice to the patient.

Most smokers aiming to quit have had failed quitting attempts in the past. These attempts can be used as learning
experiences and explored to identify triggers for relapse, danger situations and strategies that have helped
previously. Reassure smokers that most former smokers have progressed through a number of quitting attempts
and relapses before achieving long-term cessation.

Explore the smoker's fears concerning weight gain, depression and irritability, and plan ways to deal with these.
Reassure the smoker that any weight gain (which may be around 4 to 5 kg after 12 months) is likely to be
temporary and is much less harmful than continued smoking.

It is useful to discuss other potentially difficult areas including dealing with stress, the habit and cravings. Many
relapses occur because of a lack of awareness that even one puff substantially increases the chance of relapsing;
many relapses are related to alcohol use. Plans must be made in advance for dealing with these situations.

Some smokers have great belief in the use of hypnosis and acupuncture and may find them effective. However, in
controlled clinical trials these interventions have not been shown to be effective.

Consider the use of pharmacotherapies (see Smoking cessation: pharmacological interventions).

Arrange follow-up to maintain nonsmoking

Review the person about a week after the quit date, and arrange further consultations at regular intervals.
Clinicians can refer to QUIT, or arrange follow-up with themselves or a practice nurse. There is a dose–response
relationship between the intensity of support offered and quit rates.

Relapse is most likely to occur within the first 2 weeks and is more likely if motivation is poor, if family and
friends continue to smoke, or if the person uses alcohol significantly. People should try to develop a strategy for
coping with high-risk situations without avoiding them completely. If craving occurs, the person should take
physical action and leave the environment if possible.

Smoking cessation can be associated with neuropsychiatric symptoms such as irritability, poor concentration, sleep
disturbance and mood changes. People with a past history of depression are at risk of a recurrence of depression
and should be monitored for mood changes.

Tobacco smoking can interact with drugs taken for psychiatric conditions. Monitoring and dose adjustment may be
needed following smoking cessation, see Psychotropic treatment in people who smoke for further information.

Overview of pharmacological interventions for stopping smoking

Dependence on cigarettes has both ritual and addictive components. If judged by quit rates in motivated
individuals, nicotine seems to be one of the most addictive substances yet discovered.
 Recommend pharmacotherapy for moderately to highly nicotine-dependent smokers who express an interest in quitting, unless
contraindicated.

Pharmacotherapy is recommended for moderately to highly nicotine-dependent smokers who express an interest in
quitting, except when contraindicated. See Assess motivation and nicotine dependence for indicators of a person's
level of nicotine dependence.

The choice of pharmacotherapy is based on clinical suitability and patient preference, taking into account factors
such as potential for adverse effects, possible drug interactions, patient's previous experience with
pharmacotherapy, convenience and cost. The Royal Australian College of General Practitioners (RACGP)
provides a clear treatment algorithm for smoking cessation, including a table showing suitability of
pharmacotherapy to use in special populations [Note 2].

Best results are usually achieved when pharmacotherapy is combined with counselling and support, although the
effectiveness of nicotine replacement therapy (NRT) appears to be largely independent of the intensity of support
provided. Provision of more intense levels of support, although generally beneficial in aiding quitting, is not
essential to the success of NRT.

NRT, varenicline and bupropion are registered by the Australian Therapeutic Goods Administration (TGA) to aid
smoking cessation. There is also evidence for effectiveness of nortriptyline although it is not TGA-approved for
smoking cessation. Varenicline produced better quit rates than bupropion in several clinical trials but indirect
comparisons between varenicline and NRT gave inconclusive results. In one prospective study, more people taking
varenicline were continually abstinent after 3 months than people using NRT, but at 12 months the difference in
response was no longer clinically significant [Note 3].

Note 2: ‘Supporting smoking cessation: treatment algorithm’ is available on the RACGP website [URL].

Note 3: Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB, Jr., Gong J, et al. Varenicline versus transdermal
nicotine patch for smoking cessation: results from a randomised open-label trial. Thorax 2008;63(8):717-24.
[URL]

Nicotine replacement therapy

General information
Nicotine replacement therapy (NRT) approximately doubles quit rates compared with controls, irrespective of the
intensity of other support and nonpharmacological intervention—in primary care, quit rates are doubled from
approximately 5% to 10%, and in more intensive settings from approximately 10% to 20%.

Offer NRT to all smokers with evidence of nicotine dependence (smoking within half an hour of waking and/or
smoking more than 10 cigarettes per day). See Assess motivation and nicotine dependence for indicators of a
person's level of nicotine dependence.

NRT is available without prescription in Australia as patches, inhalation cartridges, chewing gum, oral spray,
lozenges and sublingual tablets. Nicotine patches are subsidised by the Pharmaceutical Benefits Scheme. The
choice of NRT product is a personal one. Many people find the patches most convenient to use. Short-acting forms
of NRT (gum, inhalation cartridge, lozenge, oral spray and sublingual tablet) give a rapid increase in blood
nicotine concentration, similar to that associated with smoking, and may be helpful for the more nicotine-
dependent smokers. Nicotine patches do not produce this rapid increase, which people trying to quit may miss.

Smokers can be frightened by the ‘apparent’ doses quoted for both patches and short-acting forms of NRT, and
need to be reassured that the treatments are safe and deliver lower doses of nicotine than low-nicotine cigarettes.
Smokers tend to maintain average plasma nicotine at relatively constant concentrations regardless of the brand of
cigarette smoked. In the past, NRT was often given in doses that were inadequate to maintain the trough plasma
nicotine concentration, which may account for many treatment failures.

Smokers with high nicotine dependence who have been unsuccessful in their quitting attempt may benefit from a
combination of nicotine patches and a short-acting formulation of nicotine replacement (see Combination therapy,
below).

The risk of harm of using nicotine replacement must be balanced against the possible harms of smoking. This is
particularly important for patients with cerebrovascular, peripheral vascular or coronary heart disease. For patients
with recent myocardial infarction, severe arrhythmias, unstable angina or a recent cerebrovascular event, NRT is
listed as a contraindication; however, nicotine patches have been safely used in these patients. Before prescribing
for this patient group, for adolescents or for women who are pregnant, consider seeking specialist advice. See also
Psychotropic drug use during pregnancy: nicotine for further discussion.

In hospitalised patients, there are issues to consider in addition to the risks associated with continued smoking (eg
possibility of nicotine withdrawal effects in smokers with high nicotine dependence).

Smokers should generally be encouraged to stop smoking when using NRT because there is an increased risk of
adverse effects (including gastrointestinal and cardiovascular adverse effects, such as palpitations and chest pain).
However, see Use of nicotine replacement therapy before quitting, below, for information on use of NRT while a
person is still smoking.

Nicotine patches

There are a number of nicotine patches available, with various release rates.

When recommending nicotine patches, if the person weighs over 45 kg and smokes more than 10 cigarettes per
day, use:

1 nicotine 21 mg/24 hour transdermally, once daily applied for 24 hours

OR

1 nicotine 15 mg/16 hour transdermally, once daily applied for 16 hours in a 24-hour
period.

Aim to stop treatment within 12 weeks by either reducing the strength of patches or by stopping treatment
abruptly.

If the person weighs less than 45 kg, has cardiovascular disease or smokes fewer than 10 cigarettes per day, use:

1 nicotine 14 mg/24 hour transdermally, once daily applied for 24 hours

OR

1 nicotine 10 mg/16 hour transdermally, once daily applied for 16 hours in a 24-hour
period.

Aim to stop treatment within 12 weeks.

Nicotine patches are not usually recommended for those who smoke fewer than 10 cigarettes per day (the low-
dependence group).

Nicotine gum

When recommending nicotine gum, if the person smokes more than 20 cigarettes per day, use:

nicotine 4 mg gum, chew 1 piece every 1 to 2 hours initially. Maximum 40 mg (10 pieces)
in 24 hours.

After 4 to 8 weeks the gum strength may be reduced to 2 mg.

If the person smokes 10 to 20 cigarettes per day, use:

nicotine 2 mg gum, chew 1 piece every 1 to 2 hours initially. Maximum 24 mg (12 pieces)
in 24 hours.

Users should gradually cut down the number of pieces chewed each day until only 1 to 2 pieces of gum per day are
required, at which time they should stop. Aim to stop within 12 weeks.

In the final weeks of quitting, it may help the person to stay smokefree if they only chew a piece of gum when
strongly tempted to smoke.

Nicotine inhalation cartridges

Nicotine inhalation cartridges can be used when the urge to smoke occurs or to prevent cravings.

When using nicotine inhalation cartridges, the person can inhale up to 6 nicotine 15 mg cartridges per day for 12
weeks, then gradually taper use over a further 6 to 8 weeks.

Each session of inhaling can last for approximately 5 minutes; a single 15 mg cartridge lasts for approximately 40
minutes of intense use. The amount of nicotine from one puff of a cartridge is less than that from a cigarette, thus it
is necessary to inhale more often than when smoking a cigarette. Some people may prefer to inhale the cartridge
intensely or they may use a slower technique to mimic cigarette smoking. The method will depend on individual
preference and smoking habit.

Nicotine lozenges

When recommending nicotine lozenges, if the person has their first cigarette within 30 minutes of waking, use:

nicotine 4 mg lozenges, suck 1 lozenge every 1 to 2 hours initially, for up to 6 weeks.

Maximum 60 mg (15 lozenges) in 24 hours.

If the person has their first cigarette more than 30 minutes after waking, use:

nicotine 1.5 or 2 mg lozenges, suck 1 lozenge every 1 to 2 hours initially, for up to 6

weeks. Maximum 30 mg (20 of 1.5 mg or 15 of 2 mg lozenges) in 24 hours.

After 6 weeks, gradually cut down the frequency of use of lozenges. In the final weeks of quitting it may help the
person to stay smokefree if they only suck a lozenge when strongly tempted to smoke.

Nicotine oral spray

Nicotine oral spray can be used when the urge to smoke occurs or to prevent cravings. Use:

nicotine 1 mg/spray, 1 to 2 sprays into the mouth initially, up to 4 mg (4 sprays) per hour.
Maximum 64 mg (64 sprays) in 24 hours.

The spray (maximum 2 sprays per dose) must be directed into the mouth, avoiding the lips, and the user should not
inhale while spraying. After 6 weeks, taper the frequency of use of the spray. Aim to stop within 12 weeks. In the
final weeks of quitting it may help the person to stay smokefree if they only use a spray when strongly tempted to
smoke.

Nicotine sublingual tablets

When recommending nicotine sublingual tablets, for highly nicotine-dependent people or those who have not
succeeded in quitting using one 2 mg nicotine tablet, use:

nicotine 4 mg sublingually, every 1 to 2 hours. Maximum 80 mg (40 of 2 mg tablets) in 24

hours.

For low-to-moderately nicotine-dependent people, use:

nicotine 2 mg sublingually, every 1 to 2 hours. Maximum 80 mg (40 of 2 mg tablets) in 24

hours.

Usually nicotine 16 to 24 mg (8 to 12 of 2 mg tablets) per day is sufficient. Gradually taper the dose after 2 to 3
months of treatment. In the final weeks of quitting, it may help the person to stay smokefree if they only take a
tablet when strongly tempted to smoke.

Combination therapy
Controlled trials have shown that a combination of a transdermal nicotine patch and a short-acting form of NRT
(eg patch plus gum) can be more effective than using a single form of NRT. Combination NRT may be offered to
those people who are unable to remain abstinent or who continue to experience withdrawal symptoms when using
only one type of NRT.

At the time of writing, there is no conclusive evidence to support combining NRT with varenicline, bupropion or
nortriptyline to improve rates of smoking cessation.

Use of nicotine replacement therapy before quitting

There is evidence that NRT use before the quit date is safe and can assist the quitting process. Use of a pre-
cessation nicotine patch (usually for 2 weeks) followed by a standard course of nicotine patches (see Nicotine
patches, above, for dose) increases quit rates compared to standard therapy.
There is also evidence for benefit from NRT for smokers who are not willing to quit abruptly to help them reduce
their tobacco consumption and then to progress to quitting. The Australian TGA-approved approach suggests
smokers use NRT to reduce the number of cigarettes smoked before stopping completely within 6 months.

Varenicline for stopping smoking

Varenicline is a nicotine partial agonist that can more than double the chances of a smoker quitting. Nausea is the
most common adverse effect (30%) and can be reduced by taking varenicline with food.

There is concern about neuropsychiatric adverse effects and people taking varenicline should be monitored for
unusual mood changes, depression, behaviour disturbance and suicidal thoughts. There is limited evidence of
safety and efficacy in people with significant psychiatric illness; however, with appropriate clinical oversight,
varenicline can aid smoking cessation in people with schizophrenia and schizoaffective disorder. There have also
been concerns about a possible small elevation in risk of cardiovascular events. This risk should be weighed up
against the health benefits of smoking cessation. Varenicline is not known to have any clinically significant drug
interactions.

Varenicline is started while the person is still smoking, and a quit date is set for the second week of therapy but
there can be flexibility around the timing of beginning treatment. The usual dose is:

varenicline 0.5 mg orally, daily for 3 days, then 0.5 mg twice daily for 4 days, then 1 mg
twice daily for the remainder of a 12-week course.

For people with a creatinine clearance of less than 30 mL/min, start with varenicline 0.5 mg daily for 3 days and
then a maximum of 1 mg daily. Avoid varenicline in patients with end-stage kidney disease.

Follow up patients 2 to 3 weeks after starting treatment to monitor progress and adverse effects and to provide
additional smoking cessation support. Longer-term use (a second 12-week course) slightly reduces relapse for up
to 1 year in people who have successfully quit at the end of week 12.

Bupropion for stopping smoking

Bupropion is a non-nicotine oral therapy (originally developed as an antidepressant) with similar efficacy to NRT
in aiding smoking cessation. It is effective for smokers with depression, cardiac or respiratory diseases, and also to
improve short-term abstinence rates for people with schizophrenia.

The most significant, but uncommon, adverse effect is seizures. Bupropion is contraindicated in patients with a
history of seizures, eating disorders and those taking irreversible monoamine oxidase inhibitors. Caution is needed
if bupropion is used concomitantly with other drugs that lower seizure threshold (eg antipsychotics,
antidepressants). Drug interactions are also possible due to bupropion's effect on and metabolism by cytochrome
P450 enzymes.

Bupropion is started while the person is still smoking, and a quit date is set for the second week of therapy but
many people stop smoking sooner. It takes about a week for bupropion plasma steady-state concentration to be
reached and doses higher than bupropion 300 mg daily are not recommended because of the risk of dose-
dependent seizures. The usual dose is:

bupropion 150 mg orally, once daily for 3 days, then 150 mg twice daily for the remainder
of a 9-week course.

Follow up patients 2 to 3 weeks after starting treatment to monitor progress and adverse effects and to provide
additional smoking cessation support.

Nortriptyline for stopping smoking

A number of other drugs have been trialled to aid smoking cessation, including antidepressants. Nortriptyline has
been shown to aid long-term smoking cessation but selective serotonin reuptake inhibitors (eg fluoxetine) have not.
The mode of action of nortriptyline appears independent of its antidepressant effect.

Nortriptyline has a range of adverse effects including dry mouth, constipation, nausea, sedation and headache, and
a risk of causing arrhythmia in patients with cardiovascular disease. It can be toxic in overdose. Check for possible
interactions when other drugs are given concurrently as nortriptyline has many potential clinically significant
interactions.

If nortriptyline is to be used, start taking it 10 to 28 days before the quit date and continue it for 12 weeks after
stopping smoking. The usual dose is:
 nortriptyline 25 mg orally, once daily, increasing gradually to 75 mg once daily [Note 4].

Follow up patients 2 to 3 weeks after starting treatment to monitor progress and adverse effects and to provide
additional smoking cessation support.

Note 4: At the time of writing, nortriptyline is not approved by the Australian Therapeutic Goods
Administration (TGA) for treatment of smoking cessation. See the TGA website [URL] for current information.

Key references
Smoking cessation: introduction

The health benefits of stopping smoking. Melbourne: Quit Victoria. [URL]

Godtfredsen NS, Prescott E. Benefits of smoking cessation with focus on cardiovascular and respiratory comorbidities.
Clin Respir J. 2011;5(4):187–94. [ ]

Scollo M, Winstanley MH, editors. Tobacco in Australia: facts and issues. 3rd ed. Melbourne: Cancer Council Victoria;
2008. [URL]

Zwar N, Richmond R, Borland R, Peters M, Litt J, Bell J, et al. Supporting smoking cessation: a guide for health
professionals. Melbourne: The Royal Australian College of General Practitioners; 2011. [URL]

Zwar N, Richmond R, Borland R, Stillman S, Cunninghamm M, Litt J. Smoking cessation guidelines for Australian
general practice. Practice handbook. Canberra: Australian Department of Health and Ageing; 2004.

Smoking cessation: the 5As framework

Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting cigarettes: meta-analysis.
BMJ. 2012;345e4439. [ ]

Zwar N, Richmond R, Borland R, Peters M, Litt J, Bell J, et al. Supporting smoking cessation: a guide for health
professionals. Melbourne: The Royal Australian College of General Practitioners; 2011. [URL]

Zwar N, Richmond R, Borland R, Stillman S, Cunninghamm M, Litt J. Smoking cessation guidelines for Australian
general practice. Practice handbook. Canberra: Australian Department of Health and Ageing; 2004.

Smoking cessation: pharmacological interventions

FDA Drug Safety Communication: Safety review update of Chantix (varenicline) and risk of neuropsychiatric adverse
events. Silver Spring, MD: US Food and Drug Administration; 2011. [URL]

Aubin HJ, Bobak A, Britton JR, Oncken C, Billing CB, Jr., Gong J, et al. Varenicline versus transdermal nicotine patch
for smoking cessation: results from a randomised open-label trial. Thorax. 2008;63(8):717–24. [ ]

Castle D, Baker AL, Richmond R, Filia SL, Harris D, Pirola-Merlo AJ. Varenicline plus healthy lifestyle intervention for
smoking cessation in psychotic disorders. Ann Clin Psychiatry. 2012;24(4):285–91. [ ]

Eisenberg MJ, Filion KB, Yavin D, Belisle P, Mottillo S, Joseph L, et al. Pharmacotherapies for smoking cessation: a
meta-analysis of randomized controlled trials. CMAJ. 2008;179(2):135–44. [ ]

Hays JT. Varenicline for smoking cessation: is it a heartbreaker? CMAJ. 2011;183(12):1346–7. [ ]

Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2007;
(1):CD000031. [ ]

Richmond R, Zwar N. Review of bupropion for smoking cessation. Drug Alcohol Rev. 2003;22(2):203–20. [ ]

Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, et al. Nicotine replacement therapy for smoking
cessation. Cochrane Database Syst Rev. 2012;11CD000146. [ ]

Weiner E, Buchholz A, Coffay A, Liu F, McMahon RP, Buchanan RW, et al. Varenicline for smoking cessation in people
with schizophrenia: a double blind randomized pilot study. Schizophr Res. 2011;129(1):94–5. [ ]

Williams JM, Anthenelli RM, Morris CD, Treadow J, Thompson JR, Yunis C, et al. A randomized, double-blind,
placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with
schizophrenia or schizoaffective disorder. J Clin Psychiatry. 2012;73(5):654–60. [ ]

Zwar N, Richmond R, Borland R, Peters M, Litt J, Bell J, et al. Supporting smoking cessation: a guide for health
professionals. Melbourne: The Royal Australian College of General Practitioners; 2011. [URL]

Zwar N, Richmond R, Borland R, Stillman S, Cunninghamm M, Litt J. Smoking cessation guidelines for Australian
general practice. Practice handbook. Canberra: Australian Department of Health and Ageing; 2004.

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Disorders usually first diagnosed in childhood and
adolescence
Using psychotropic drugs in children
For brevity, the term children will be used to refer to both children and adolescents in this topic.

A wide range of psychotropic drugs is available. While many of these drugs have the potential to help children
with mental disorders, evidence of their efficacy and safety in children is often lacking. Furthermore, many do not
have approval from the Australian Therapeutic Goods Administration (TGA) to be used in childhood mental
disorders.

For unapproved uses, there are few placebo-controlled trials to base clinical decisions on. Furthermore, most trials
have generally enrolled only small numbers of children and been of short duration (eg 8 weeks). Clinicians should
refer to appropriate independent sources of relevant information, eg TGA AusPARs, National Prescribing Service,
and the Cochrane Library [Note 1], or advice may be sought from the Psychotropic Drug Advisory Service [Note
2].

Psychopharmacologic treatments for children cannot be readily extrapolated from studies of adults because
pharmacokinetic and pharmacodynamic effects may differ in children. How these differences affect long-term
neurodevelopment is unknown. When possible, assessment by a specialist is recommended before commencing
drug treatment. In addition, where possible, specialist annual review should be undertaken when a child is being
maintained on psychotropic drugs. Nonpharmacological treatment is preferred in preschool children.

Nonpharmacological treatment is preferred in preschool children.

When psychotropic drugs are used, identify clear behavioural goals and carefully monitor effectiveness and
adverse effects.

Obtain informed consent from older children and parents before treatment (see Informed consent in mental
illness). Agreement with their treatment should also be sought from younger children. Inform children and parents
of the potential benefits and possible harms of treatment and of receiving no treatment. They should also be
informed about the availability of nonpharmacological treatments and the benefits of combining behavioural and
drug treatments.

With the exception of the use of stimulants in the treatment of attention deficit hyperactivity disorder (ADHD), the
research evidence for pharmacological treatments in other childhood conditions is limited due to small numbers of
studies and small number of study subjects compared to the adult population. The use of drugs in some conditions
is under debate and some of the indications may not have regulatory approval. It is important to seek specialist
advice whenever possible.

Further, careful assessment and accurate diagnosis must precede the use of pharmacotherapy for childhood mental
disorders. In most instances, information from teachers as well as from parents and children is necessary to
accurately assess children's problems. Pharmacotherapy should always be used as part of a broader management
plan developed in conjunction with children and parents. Effective treatment generally requires a multimodal
approach that uses behavioural and educational management strategies in home and school settings, and careful
attention to possible learning disabilities.

Only one psychotropic drug should be prescribed at a time and when estimating drug dose in obese children, ideal
weight for the child should be used. After an appropriate trial, if one drug is ineffective an alternative may be
selected. Only after consultation with a child psychiatrist or paediatrician experienced in paediatric
psychopharmacology should more than one psychotropic drug be used concurrently.

Note 1: - TGA Australian Public Assessment Reports for prescription medicines (AusPARs): [URL]
- National Prescribing Service: [URL]
- Cochrane Library: [URL].

Note 2: Mental Health Research Institute Psychotropic Drug Advisory Service: Telephone (03) 9388 1633.
Attention deficit hyperactivity disorder
General information
The core symptoms of attention deficit hyperactivity disorder (ADHD) are persistent inattention and/or
hyperactivity/impulsivity. Children with ADHD exhibit these symptoms with greater frequency and severity than
other children at a comparable level of development. ADHD occurs in around 5% to 7% of school-aged children; it
is a chronic condition that can cause considerable disruption to the lives of children, parents and families. It also
has a major impact on the educational outcomes of children. Accurate diagnosis and treatment with a
comprehensive multimodal intervention using pharmacological and nonpharmacological treatments as appropriate
can make a significant difference to the child and their family.

To meet the criteria for the diagnosis, some symptoms that cause impairment must have been present before the
age of 7 years and some impairment from the symptoms must be present in at least two settings, eg home and
school. There must also be clear evidence of significant interference with social, academic or occupational
functioning. Finally, the symptoms should not occur exclusively during the course of autism spectrum disorder,
schizophrenia or another psychotic disorder, or be better accounted for by another mental disorder.

An accurate diagnosis needs to be made before treatment is started.

An accurate diagnosis needs to be made before treatment for ADHD is started. This should be confirmed by a
specialist experienced in assessing children with emotional and behavioural problems.

In children of preschool age, diagnosis of ADHD is more difficult, effectiveness of stimulants is not well
established and the risk of adverse effects is greater.

Evaluation should include taking a medical and developmental history, a mental status examination, a family
assessment and an appropriate physical examination. Children with ADHD commonly have comorbid mental
disorders, such as oppositional defiant disorder and conduct disorder. They also have higher rates of learning and
language problems than other children. It is essential that a comprehensive management plan is developed to
address these problems. Information about a child's behaviour should also be obtained from teachers during the
initial assessment and regularly over the course of a child's treatment.

Parent and teacher rating scales are not diagnostic tools but can be an important guide to ascertaining the
frequency and severity of a child's symptoms and to monitoring the efficacy of treatment in reducing symptoms.
Comprehensive evaluation of other conditions that might coexist is also indicated. These may be:

emotional (eg anxiety, depression)

behavioural (eg oppositional defiant disorder, conduct disorders)
developmental (eg learning and language disorders or other neurodevelopmental disorders)
physical (eg tics, sleep apnoea).

Nonpharmacological treatment
It is essential that an individualised multimodal management plan is made in collaboration with the child, parents
or carers and teachers. It includes psychoeducation about the nature of ADHD and comorbid conditions, and
provides information about the range of treatment approaches and about developmental outcomes.

Parents should be put in touch with relevant community supports where they can receive training in the use of
well-planned behavioural interventions (see Appendix 8.1). Close liaison with staff in children's schools is
essential to monitor the effectiveness of treatment and to ensure children receive additional help for learning and
other developmental problems as indicated.

Pharmacological treatment

General information

Before the initiation of pharmacological treatment, a personal and family cardiac and psychiatric history should be
obtained. All drugs with sympathomimetic effects (eg stimulants, atomoxetine) should be used cautiously when
combined with other drugs that can inhibit their metabolism or affect cardiovascular function (eg clonidine).

Stimulants

Stimulants (methylphenidate, dexamphetamine) can reduce symptoms of inattention and hyperactivity/impulsivity.

However, drugs alone may not have a longer-term benefit on academic performance. It is essential that drug
titration is done with care to maximise positive effects and minimise adverse effects. Monitoring should include
regular (eg monthly) contact with children and parents, contact with teachers before clinic visits, and careful drug
titration to identify the most effective dose for each child.

Either dexamphetamine or methylphenidate could be used to treat a child with attention deficit hyperactivity
disorder (ADHD). Both drugs have the capacity to improve attention, decrease impulsiveness and reduce activity.
General behaviour and interactions with peers and parents may also improve. There is no clear evidence to suggest
that one of these drugs is more effective than the other. However, a child who does not respond to or cannot
tolerate one of these drugs may still respond to or tolerate the other. The alternative stimulant should be considered
if the maximum dose of the first drug is reached and there is no significant improvement after a month of
treatment, or if there are major adverse effects.

It is essential to properly trial both stimulants before trying alternative less efficacious drugs. If a child does not
respond to adequate trials of either drug, review the diagnosis and consider possible comorbid diagnoses. Poor
concordance is another possible reason for inadequate response. Predicting the response to stimulants by
individual children is difficult. Behaviours relevant to attention span probably give the best indication of the likely
effectiveness of these drugs.

Preschool children and children with significant developmental delays are known to be less responsive to
stimulants and have more adverse effects.

With rare exceptions, do not use stimulants in children aged younger than 4 years.

With rare exceptions, stimulants should not be used in children aged younger than 4 years. Best practice is to start
with parent training / educational programs supported by behavioural intervention in the preschool setting as the
first-line treatment. If drugs are used in preschool children, small doses should be used to take into account
differences in pharmacokinetics in this age group.

Adverse effects of stimulants include headache or abdominal discomfort. However, many children become tolerant
to these effects without the need to reduce doses. Increased sleep latency and appetite suppression are common.
Although studies suggest that the adverse effect of stimulants on growth is relatively minor, the weight and height
of children should be monitored routinely during their treatment. When there is concern about a child's growth,
drug holidays may be appropriate at times when some increase in symptoms may be acceptable (eg weekends and
school holidays). Social withdrawal and tearfulness may be indicators of an excessive dose.

Rebound symptoms towards evening may occur with immediate-release formulations as the effect of the drug
wears off. Giving a low dose in the midafternoon, or changing to a long-acting formulation, may improve this.
Rebound symptoms may also be seen briefly after discontinuation of drugs.

Stimulants may precipitate tics in predisposed children and the appearance of tics should suggest a review of
therapy. The use of stimulants in those with a pre-existing tic disorder is not contraindicated but use should be
closely monitored.

Stimulants should be used with caution in children with structural cardiac abnormalities, serious heart problems or
those with conditions that may be exacerbated by increased pulse rate or blood pressure. An assessment by a
cardiologist is suggested before stimulants are prescribed for children with these conditions, hypertension, or a
family history of sudden death, syncope or other relevant cardiac disease. Pulse and blood pressure should be
measured at baseline, after dose increases and periodically. Promptly evaluate children who develop exertional
chest pain, unexplained syncope or other cardiovascular symptoms.

Psychiatric adverse effects reported include psychosis, mania, aggression and suicidal ideation; these conditions
may be precipitated or worsened by stimulants. Avoid stimulants in children with a history of psychosis as a
psychosis may be precipitated.

There are no established guidelines for the length of time a child should be maintained on stimulants. It seems
reasonable to suggest a trial without stimulants after the first year of treatment and at regular intervals thereafter.
Preferably the trial should not occur at the beginning of the school year when a child is starting in a new classroom
setting. With recommended doses, the drug can be stopped without tapering. If doses of stimulants substantially
higher than those recommended have been prescribed, avoid rapid discontinuation if possible. There is no evidence
that stimulant treatment for ADHD in childhood leads to an increased risk for stimulant abuse or dependence in
adulthood.

The immediate-release stimulants (short-acting) are rapidly absorbed, acting within 30 minutes. The response
peaks within 1 to 3 hours, but the effect is largely gone by 4 to 6 hours. Dexamphetamine generally has a slightly
longer duration of effect than methylphenidate.

Due to the anorectic properties of these drugs, doses should be given at or after breakfast and lunch. If immediate-
release stimulants are indicated, consider using:
 1 dexamphetamine (4 years or older) 2.5 mg orally, once or twice daily initially. Maximum
dose 0.5 mg/kg (up to 40 mg) daily in 2 divided doses

OR

1 methylphenidate immediate-release (4 years or older) 5 mg orally, once or twice daily

initially. Maximum dose 1 mg/kg (up to 60 mg) daily in 2 or 3 divided doses.

The daily dose may be increased in small increments (dexamphetamine 2.5 to 5 mg or methylphenidate 5 to 10
mg) at weekly intervals until optimal response is obtained or the maximum dose is reached. For smaller children
(eg under 25 kg), drugs should be started at the low end of the dose range and increased with small weekly
increments. Doses are gradually increased until satisfactory response occurs or adverse effects necessitate dose
reduction or cessation. In obese children, ideal weight should be used when estimating the drug dose.

There may be benefit in giving the drug in three divided doses rather than twice daily, especially with
methylphenidate. This can help reduce problems in the period of time after school.

Long-acting modified-release methylphenidate is available. The formulations provide both an immediate release
and a delayed release of methylphenidate to mimic the pharmacokinetics of taking multiple doses of immediate-
release methylphenidate. The advantage of the once-daily dose is in eliminating the need to take a drug at school,
which is disliked by many children, is difficult to oversee, and carries the potential of diversion for illicit use.

Therapy should be started with immediate-release methylphenidate.

Before they are started on long-acting stimulants, children should first demonstrate a response to immediate-
release methylphenidate, be stabilised on an optimum dose and have no evidence of serious adverse effects. A
switch may then be made to a single morning dose of a modified-release methylphenidate preparation. Choice of
preparation depends on previous control achieved with immediate-release methylphenidate and whether an 8-hour
or a 12-hour duration of action is desired.

If previous control was achieved with twice-daily dosing of the immediate-release preparation, consider using 8-
hour duration methylphenidate [Note 3]:

methylphenidate 8-hour modified-release (6 years or older) 0.5 to 2 mg/kg orally, once

daily in the morning (the dose should approximate the total daily dose of the immediate-
release preparation).

If previous control was achieved with three-times-daily dosing of the immediate-release preparation (eg morning,
lunchtime and after school), consider using 12-hour duration methylphenidate [Note 4]:

methylphenidate 12-hour modified-release (6 years or older) 0.5 to 2 mg/kg orally, once

daily in the morning (the dose should approximate the total daily dose of the immediate-
release preparation).

Observe state and territory statutory health regulations on prescription of stimulants.

Note 3: For example, Ritalin LA.

Note 4: For example, Concerta.

Atomoxetine

Atomoxetine is a selective noradrenaline reuptake inhibitor but its precise mechanism of reducing symptoms of
ADHD is unknown. It is not a stimulant so, unlike stimulants, there may be a lag time of 2 to 4 weeks before
ADHD symptoms are reduced.

Atomoxetine is more effective than placebo; however, there is limited information about the relative effectiveness
of atomoxetine versus stimulants. It can be considered for treating ADHD when stimulants have resulted in
adverse effects, treatment with stimulants is contraindicated, or when there is a history of problematic drug use,
comorbid motor tics or Tourette syndrome, or severe anxiety disorders.

The most common adverse effects in children are decreased appetite, initial weight loss, abdominal pain, nausea
and vomiting, dizziness, somnolence, early morning waking, pharyngitis, irritability and mood swings.
Atomoxetine, like selective serotonin reuptake inhibitor (SSRI) antidepressants, has been shown in trials to have a
small risk for increasing suicidal thoughts and behaviours in children aged 12 years or younger. Monitor patients
started on atomoxetine for suicidality (see Major depression in childhood and adolescence: suicidal ideation and
behaviour).

Use atomoxetine with caution in patients with mild hypertension, tachycardia, congenital or acquired QTc
prolongation, or with a family history of QTc prolongation, cardiovascular or cerebrovascular disease. It can cause
a modest increase in blood pressure and heart rate. Pulse and blood pressure should be measured at baseline, after
dose increases and periodically. Promptly evaluate children who develop exertional chest pain, unexplained
syncope or other cardiovascular symptoms. Atomoxetine should not generally be used in those with known
structural cardiac abnormalities.

Rare cases of severe liver injury have been reported with atomoxetine. In patients with jaundice or laboratory
evidence of liver injury, discontinue atomoxetine and do not restart it.

If treatment with atomoxetine is considered appropriate, use:

atomoxetine (6 years or older) 0.5 mg/kg (up to 40 mg) orally, daily as a single dose in the
morning or in 2 divided doses (morning and late afternoon) for at least 7 days, then
increasing to a target dose of 1.2 mg/kg (up to 80 mg). Maximum dose 1.4 mg/kg (up to
100 mg) daily.

If there is inadequate response after 4 weeks, daily doses may be increased if necessary and as tolerated to the
maximum dose (1.4 mg/kg [up to 100 mg] daily). However, some patients may need lower doses or may require
divided daily doses to reduce adverse effects. Taking atomoxetine with food may minimise stomach upset and
dividing the daily dose or taking it at night may help reduce tiredness. Data at present suggest that there are
unlikely to be safety concerns or risk of symptom rebound related to abrupt atomoxetine discontinuation.

Other pharmacological treatment

Clonidine may be useful in children with ADHD who have comorbid tics, are markedly aggressive, or in children
where sleep disturbance is a major problem that cannot be resolved by adjustment to the timing and dose of
stimulants.

There is concern about the safety of using clonidine in combination with stimulants, especially when using large
once-daily, night-time dosing with clonidine. Furthermore, the safety of clonidine is not known when used in
combination with other drugs that affect cardiac function (eg atomoxetine, clomipramine or other tricyclic
antidepressants), or with children who have a cardiac abnormality. If clonidine is considered appropriate, use:

clonidine (5 years or older) 1 microgram/kg (up to 50 micrograms) orally, daily initially.

Maximum dose 4 micrograms/kg (up to 300 micrograms) daily in 2 or 3 divided doses.

The dose may be increased by 25 to 50 micrograms every third day until optimum response is obtained or the
maximum dose is reached. Give doses more than 150 micrograms daily in 2 or 3 divided doses. Recommended
doses do not generally produce significant sedation or hypotension provided the initial dose is increased slowly.

Disadvantages of clonidine are that clinical effects may take several weeks to occur, it does not appear to affect
inattention symptoms and there is a potential risk of causing depression. Blood pressure and pulse rate should be
routinely monitored during treatment. Avoid suddenly stopping treatment as rebound hypertension may occur.

Evidence supporting the efficacy of tricyclic antidepressants (TCAs) to treat ADHD is limited and no TCA has an
approved indication for ADHD in Australia. TCAs can impair cardiac conduction and cause potentially fatal
arrhythmias. They should be prescribed only by a specialist with experience in their use, and after other treatments
have failed.

TCAs should be prescribed only by a specialist with experience in their use, and after other treatments have failed.

There is insufficient evidence to conclude that fish oil (polyunsaturated fatty acids comprising omega-3 and
omega-6 fatty acids) supplementation is of therapeutic benefit in children with ADHD.

Management in older adolescents and adults

There is limited information to guide clinicians about how long older adolescents should continue to receive
treatment with drugs for attention deficit hyperactivity disorder (ADHD). The decision should be based on the
extent to which symptoms of ADHD and social functioning have improved to a point that medication is no longer
needed. If older adolescents have been largely symptom-free for a year and are functioning well, a trial without
medication is warranted. This should be undertaken at times of low stress such as during holidays or in a period
when a school routine is well established.
ADHD needs to be considered in adults who present with longstanding symptoms suggestive of ADHD
(inattention, impulsivity, disorganisation) that appear to have started in childhood and are persisting into adult life.
Further, people with personality disorder and/or problems with drug use accompanied by a significant level of
impulsivity and inattention should be referred for evaluation by a psychiatrist with the training and skills required
to assess and treat ADHD. This expertise is necessary due to the overlap of ADHD symptoms with anxiety, mood
and personality disorders.

Major depression in children and adolescents

Diagnosis
The formal criteria used to diagnose major depression in children are essentially the same as for adults (see
Depression). However, when assessing children it is important to obtain information from children, parents and
teachers.

The key features are a period of at least 2 weeks during which there is either depressed mood or the loss of interest
and pleasure in nearly all activities. In children, irritability may be more prominent than sadness. To meet the
formal criteria for diagnosis, other symptoms such as changes in appetite and weight, sleep, energy and drive, and
psychological symptoms, such as difficulty with thinking and concentration, feelings of worthlessness, guilt and
hopelessness, should be present.

The risk of suicidal behaviour increases sharply in the second decade, especially for males. A careful assessment of
the suicidal risk of adolescents with depression is essential before initiating treatment (see Suicidal ideation and
behaviour, below). Dysthymic disorder and adjustment disorder with depressed mood are diagnosed in childhood
using similar criteria to those used with adults; however, antidepressants are seldom indicated in these disorders.

Suicidal ideation and behaviour

Adolescents with psychiatric disorders, particularly depressive disorders, have a greatly increased risk for suicidal
ideation and behaviour. It has been estimated that the prevalence of depressive disorders ranges from 49% to 64%
among adolescent suicide victims. As such, failure to effectively treat these disorders can lead to significant
morbidity and mortality among adolescents.

There has been concern about the potential for increased risk of suicidal ideation and behaviour among children
and adolescents being treated with selective serotonin reuptake inhibitors (SSRIs). While estimates vary, it appears
that SSRIs pose a 2-fold risk for suicidal ideation and behaviour (4% with SSRIs versus 2% with placebo), with
the reported risks greatest in the first few months of therapy. However, no suicides were reported in the drug trials
from which this information was obtained.

A careful assessment of risk for suicide is an important element of all psychiatric assessments. This entails taking a
thorough history from children and their parents or carers, and where relevant consulting with other significant
people in children's lives, such as their teachers. Subsequently, a comprehensive management plan should be
developed. This should include familiarising children and their parents with the risks of suicide and steps that can
be taken both to reduce this risk and to respond effectively in a crisis.

During the initial months of treatment with an SSRI, a minimum of weekly contact should be maintained with
children and their families in the first month and at least fortnightly for the second month, monitoring for adverse
effects and for progress. Other potential times of increased suicidal risk are when increasing doses of
antidepressants or if therapy is stopped suddenly.

For further information on assessment of suicide risk, see Assessing patients with depression: assessing suicide
risk.

Nonpharmacological treatment

Nonpharmacological management of childhood depression entails identifying and addressing factors in children's
environments that may be contributing to their disorder. These include, for example, loss and grief, physical and
sexual abuse (mandatory reporting guidelines must be followed), family conflict, school difficulties or problems
with peers. In the first instance, it is recommended that psychological therapies such as cognitive behavioural
therapy and interpersonal therapy are used to manage depression of mild or moderate severity.

Parents or carers and children must be educated about:

the nature of the depressive disorder and its typical course over time
the importance of ensuring that open and supportive communication is maintained between children and
their parents or carers
the importance of ensuring that children's home environment is safe and secure to reduce the risk of suicide
the immediate steps to take if suicidal ideation or behaviour is identified.
Pharmacological treatment

General information

The pharmacological treatment of childhood depression must be done in the context of a comprehensive
management plan. This should include careful monitoring to ensure that adverse effects, including the emergence
of suicidal ideation or behaviour, are rapidly identified and managed appropriately. Clinicians need to be cautious
with the use of antidepressants in children, as evidence about their effectiveness in childhood disorders is limited.
There is also limited knowledge about the long-term effectiveness and safety of treatment. If possible, seek advice
from a specialist.

If drugs are used for the treatment of major depression, accurate diagnosis is essential and a discontinuation trial
should be considered within 1 year of starting treatment in children who have achieved a marked reduction in
symptoms. Results from trials investigating the added effectiveness and safety of combining cognitive behavioural
therapy with antidepressant treatment in children with depression have been inconsistent. However, management
of moderate-to-severe depression in adolescents should be assertive and prompt, typically including a combination
of psychological and pharmacological interventions.

Selective serotonin reuptake inhibitors

There is evidence that selective serotonin reuptake inhibitors (SSRIs) are effective in treating major depression in
children. However, due to concerns about increased risk of suicidal ideation and behaviour (see Suicidal ideation
and behaviour, above), none of the SSRIs is approved in Australia for the treatment of major depression in
children. Fluoxetine is approved for this use in the US and European Union countries.

If SSRIs are used, treatment trials should last for 3 to 4 weeks before considering a dose increase, and 8 to 12
weeks before a change of therapy. Dosing is conservative due to the higher levels of drug-induced irritability in
children.

If an SSRI is considered appropriate, use:

fluoxetine (8 years or older) 0.25 mg/kg (up to 10 mg) orally, daily in the morning initially
for 4 to 7 days, increasing to 0.5 mg/kg (up to 20 mg). Maximum dose 1 mg/kg (up to 80
mg) daily.

The optimal dose of fluoxetine for most patients will be 0.5 mg/kg (up to 20 mg) daily. If there is inadequate
response after 3 to 4 weeks then daily doses may be increased by increments of 0.25 mg/kg (up to 10 mg) if
necessary and as tolerated. Doses more than 20 mg daily may be given in two divided doses, in the morning and at
noon.

There are few clear guidelines about the use of other SSRIs for treatment of children with major depression.
Sertraline (start with 25 mg daily and titrate dose to 50 mg daily; maximum dose 150 mg daily) and citalopram
(start with 5 mg daily and titrate dose to 20 mg daily; maximum dose 40 mg daily) are potential second-line
alternatives. Paroxetine is not recommended in this age group due to its greater safety concerns. As with adults, the
choice depends on the potential for drug interactions if children are taking other drugs, and past history of good
response to a particular SSRI. The potential for drug interactions between SSRIs and illicit drugs, as well as
complementary medicines (eg St John's wort), needs to be considered.

Monitor for SSRI adverse effects including nausea, restlessness, insomnia and behavioural disinhibition. Small
doses for the first 4 to 7 days may decrease initial nausea and restlessness. Taking the drug with food may also
decrease the initial nausea. Sexual dysfunction can be a significant adverse effect that decreases compliance in
adolescents. Rarely reported adverse effects in adults, such as extrapyramidal adverse effects including akathisia,
need to be considered, due to greater propensity for these problems in adolescents taking other psychotropic drugs.

SSRIs may cause withdrawal adverse effects and gradual tapering is recommended, especially if high doses are
used (see Antidepressant discontinuation).

Other antidepressants

The use of tricyclic antidepressants (TCAs) for the management of childhood depression is not appropriate, so
TCAs should not be used in children under the age of 16 years. Controlled clinical trials have consistently failed to
demonstrate the superiority of TCAs over placebo.

Newer antidepressants, which are approved for use in adults, may be an option for use in adolescents when SSRIs
have failed. However, advice should be obtained from a specialist familiar with the use of these drugs in young
people before they are used. Mirtazapine, due to its effects of sedation and weight gain, may cause problems in this
age group. Venlafaxine should not be used in children and adolescents due to increased reports of hostility and
suicide-related adverse effects such as suicidal ideation and self-harm.
Anxiety disorders in children and adolescents
General information
Anxiety disorders are the most common mental disorders experienced by children. Symptoms range from very
specific episodes of time-limited severe panic, to prolonged periods of generalised anxiety and worry. Only
separation anxiety disorder is currently identified as being specific to childhood, although recent data suggest that
separation anxiety disorder may persist into adulthood. The other anxiety disorders are considered to be
counterparts of the same conditions diagnosed in adults.

The most well-studied intervention for childhood anxiety disorders is cognitive behavioural therapy (CBT). CBT
focuses on changing maladaptive and overly rigid thinking patterns relevant to the onset and maintenance of
anxiety disorders. A range of approaches are used to help children achieve these changes including ‘coping self-
talk’, practice sessions with controlled exposure to the stimuli that give rise to anxiety, and relaxation training. The
emphasis of CBT is on the ‘here and now’, with children undertaking homework sessions between appointments.
Approaches using CBT should be trialled before the introduction of pharmacotherapy for the treatment of
childhood anxiety disorders. If a drug is required to treat children's anxiety disorders, it is recommended that
behavioural treatments are used concurrently.

Selective serotonin reuptake inhibitors (SSRIs) are emerging as the first line of treatment if drugs are used to treat
anxiety disorders. Obsessive compulsive disorder is the best studied of the anxiety disorders in children.

If drugs are used for treatment of anxiety disorders, a discontinuation trial should be considered within 1 year of
starting treatment in those who have achieved a marked reduction in symptoms.

Obsessive compulsive disorder

Childhood obsessive compulsive disorder (OCD) occurs in the same form as that seen in adults, ie recurrent
obsessions or compulsions sufficiently severe to cause distress and interfere with functioning (see Obsessive
compulsive disorder: introduction). In about one-third of all cases, onset is between 5 and 15 years of age.

Management includes a clear explanation of the nature of the disorder to children and their parents. Subsequently,
both CBT for children and support for children's families should be given. Children with more severe disorders
may not respond to these strategies alone and concurrent medication may be required. There is evidence from
double-blind studies that the SSRIs fluvoxamine, sertraline and fluoxetine [Note 5], and the tricyclic antidepressant
clomipramine are effective.

The SSRIs may cause nausea and restlessness, especially at the start of therapy. General support is an important
element of treatment for children and families because many patients do not have symptom relief until 6 to 12
weeks after starting the drug, and initial worsening of their OCD symptoms or adverse effects may occur. Drug
doses should be started low and increased slowly, with children being closely monitored for adverse effects
particularly suicidal ideation and behaviour as described in Major depression in childhood and adolescence:
suicidal ideation and behaviour.

If pharmacotherapy is undertaken, consider using:

1 fluvoxamine (8 years or older) 25 mg orally, daily in the evening initially. Increase dose
by 25 mg every 7 days, according to tolerability and patient response, to 2.5 mg/kg (up to
100 mg) daily. Maximum dose 200 mg daily

OR

1 sertraline (6 years or older) 25 mg orally, daily in the morning initially. Increase dose by
25 mg every 7 days, according to tolerability and patient response, to 1.5 mg/kg (up to 50
mg) daily. Maximum dose 200 mg daily.

Clinical effects may be noted after 2 weeks, but response should be monitored for 6 weeks before increasing the
dose above the initial maximum (fluvoxamine 100 mg daily or sertraline 50 mg daily). Dose adjustment in children
should take into account their lower body weight. Doses of fluvoxamine more than 50 mg daily may be given in 2
divided doses for better tolerability.

Due to its greater potential adverse effects, clomipramine should be reserved for those failing to respond to
adequate trials of an SSRI in combination with CBT.

Clomipramine may cause sedation and weight gain although the former usually resolves as treatment continues.
Clomipramine can also cause changes in cardiac conduction so monitor the electrocardiogram (ECG). An ECG
should be obtained before treatment is started and then repeated once the dose is stabilised, usually after 6 weeks.
If the ECG shows abnormalities, seek advice from a paediatric cardiologist.
If considered appropriate, use:

clomipramine (10 years or older) 25 mg orally, daily initially. Increase gradually to 2

mg/kg (up to 200 mg) daily in 1 or 2 divided doses.

Response to clomipramine should occur 4 to 10 weeks after an effective dose is reached.

Note 5: At the time of writing, fluoxetine is not approved by the Australian Therapeutic Goods Administration
(TGA) for treatment of obsessive compulsive disorder in children. See the TGA website for current information.

Separation anxiety disorder

Separation anxiety disorder is characterised by developmentally inappropriate and excessive anxiety related to
separation, or threat of separation, from home or from those to whom children are attached. The disturbance causes
clinically significant distress or impairment in social, academic or other important areas of functioning. At the time
of separation, anxiety may reach the point of panic. Children with the disorder often fear that some disaster may
befall them or their parents and prevent reunion. Nightmares are common with themes of separation. School
refusal may be present. Children may also present with somatic symptoms such as headache or abdominal pains
related to school attendance. It is likely that this condition is related to panic disorder and agoraphobia in adults.

Family and behavioural interventions are first-line treatments for children with mild anxiety.

Children with mild anxiety usually respond to family and behavioural interventions, and these should be used as
first-line treatments. If a child's anxiety is severe and longstanding, a trial of fluvoxamine may be appropriate. In
these circumstances, start at a low dose and increase slowly, with children being closely monitored for adverse
effects particularly suicidal ideation and behaviour as described in Major depression in childhood and adolescence:
suicidal ideation and behaviour.

Consider using:

fluvoxamine (8 years or older) 25 mg orally, daily in the evening initially. Increase dose by
25 mg every 7 days, according to tolerability and patient response, to 2.5 mg/kg (up to 100
mg) daily. Maximum dose 200 mg daily.

Response should be monitored for 4 to 6 weeks before increasing the fluvoxamine dose above 100 mg. Dose
adjustments in children should take into account their lower body weight. Doses of fluvoxamine more than 50 mg
daily may be given in 2 divided doses for better tolerability.

Early research suggested that imipramine was effective for the treatment of separation anxiety. More recent studies
have failed to replicate these earlier results. In the light of this, although evidence is still limited, the SSRIs are a
better option for treating children with severe anxiety because of the lower risk of severe adverse effects.

Generalised anxiety disorder

Generalised anxiety disorder was previously called overanxious disorder of childhood. As for adults, behavioural
approaches are the first line of treatment for this condition. If pharmacotherapy is necessary, an SSRI may be used
and most information favours fluvoxamine or sertraline. For further information on generalised anxiety disorder,
see Generalised anxiety disorder.

Autism spectrum disorder

Children with autism spectrum disorders (ASDs) show delays and deviations in reciprocal social interaction,
communication skills and/or stereotyped behaviour, interests and activities. An experienced paediatrician or a child
psychiatrist should confirm the diagnosis. Management focuses mainly on special education and programs to
modify behaviour, with family support and respite. For further information on management of ASD, see
Management Guidelines: Developmental Disability (PDF, 7MB).

Psychotropic drugs cannot cure ASDs but they can reduce the severity of some symptoms.

Some antipsychotics (such as risperidone) have been shown to reduce maladaptive behaviours such as
hyperactivity, aggressiveness, distractibility, temper tantrums and stereotypies (repetitive, purposeless actions) that
are experienced by children with ASD. It is important to discuss with parents the benefits and potential harm of
using antipsychotics in these situations. When antipsychotics are used this should be as a time-limited trial with
periodic review every 3 to 6 months to assess efficacy and to determine the need for their continuation. Use of
antipsychotics should only be undertaken in conjunction with an appropriate nonpharmacological management
program and long-term use should only be carried out under the supervision of a specialist.

Risperidone is approved in Australia for the treatment of behavioural disorders associated with autism in children
and therefore is considered first choice if an antipsychotic is thought necessary. There is limited evidence on the
effectiveness of the other second-generation antipsychotics in reducing irritability, hyperactivity, and stereotypies
in children with ASD. The first-generation antipsychotics such as pericyazine and trifluoperazine [Note 6] have
approval in Australia for treatment of children with severe behavioural disturbances; however, this is based on
very limited efficacy and safety data.

Children appear to be more prone to a wide range of antipsychotic adverse effects. Monitoring children for
antipsychotic-induced extrapyramidal, endocrine and metabolic adverse effects should occur to avoid both acute
and long-term adverse consequences (see Antipsychotic adverse effect monitoring). In particular, long-term effects
in prepubertal children are still largely unknown and extra caution is required.

If treatment with a psychotropic drug is necessary, consider using:

1 risperidone (5 years or older, less than 20 kg) 0.25 mg orally, daily initially. Increase if
needed after at least 4 days up to 0.5 mg daily, in 1 or 2 divided doses. Maximum dose 1.5
mg daily

OR

1 risperidone (5 years or older, 20 kg or more) 0.5 mg orally, daily initially. Increase if

needed after at least 4 days up to 1 mg daily, in 1 or 2 divided doses. Maximum dose 2.5
mg daily.

The risperidone dose of 0.5 mg (child less than 20 kg) or 1 mg (child 20 kg or more) should be maintained and
response assessed at approximately day 14. Only consider additional dose increases in patients not achieving
sufficient clinical response. Dose increases may proceed no more frequently than at 2-week intervals in increments
of 0.25 mg (child less than 20 kg) or 0.5 mg (child 20 kg or more).

Note 6: Trifluoperazine was discontinued in Australia in 2018.

Intellectual disability with comorbid mental disorder

Children with intellectual disability experience the full range of other psychiatric disorders. Initially, it is important
to use behavioural strategies where possible to manage children's problems. It should not be assumed that
symptoms of psychiatric disturbance are due to intellectual disability, rather treatment should be as indicated by
the diagnosis. Children with mild intellectual disability who fulfil the criteria for attention deficit hyperactivity
disorder (ADHD) often benefit from pharmacotherapy, although cases of exacerbation of stereotypies and
behavioural problems have been described, especially in the more severely intellectually disabled.

Risperidone reduces symptoms of disruptive behaviours in children with intellectual disability. Although other
drugs have been used, the evidence base to support their effectiveness is lacking. Management should include
discussion with parents or carers about the evidence to support treatment approaches, the benefits and potential
harm, and identification of clear treatment goals to be achieved. When antipsychotics are used, this should be done
as a time-limited trial with periodic review every 3 to 6 months to assess efficacy and to determine the need for
continuation. Structured recording of the frequency of target behaviours is helpful in guiding the review.

If treatment with a psychotropic drug is necessary, consider using:

1 risperidone (5 years or older, less than 50 kg) 0.25 mg orally, once daily initially. Increase
gradually if needed (not more frequently than on alternate days), according to tolerability
and patient response, up to 0.5 mg daily, in 1 or 2 divided doses. Maximum dose 0.75 mg
daily

OR

1 risperidone (5 years or older, 50 kg or more) 0.5 mg orally, once daily initially. Increase
gradually if needed (not more frequently than on alternate days), according to tolerability
and patient response, up to 1 mg daily, in 1 or 2 divided doses. Maximum dose 1.5 mg
daily.

After an adequate trial of risperidone at 0.5 mg (child less than 50 kg) or 1 mg (child 50 kg or more), doses may be
increased further to the maximum dose given daily in 1 or 2 divided doses.

Children appear to be more prone to a wide range of antipsychotic adverse effects. Monitoring children for
antipsychotic-induced extrapyramidal, endocrine and metabolic adverse effects should occur to avoid both acute
and long-term adverse consequences (see Antipsychotic adverse effect monitoring). In particular, long-term effects
in prepubertal children are still largely unknown and extra caution is required.

For further information on management of developmental disabilities, see Management Guidelines:

Developmental Disability (PDF, 7MB).

Tourette syndrome
General information
Transient simple motor tics of less than 6 months' duration are quite common in otherwise healthy children.
Advice and support for children and parents is the best management in these circumstances.

Gilles de la Tourette syndrome is a neuropsychiatric disorder with childhood onset which can cause significant
social disability. It is a clinical diagnosis characterised by multiple motor tics and one or more recurrent vocal tics.
They occur many times a day and are present over a period longer than 1 year. Typically, motor tics begin between
the ages of 3 and 8 years with vocal tics appearing several years later. Vocal tics can involve sniffing, grunting,
swallowing, coughing, barking, whistling or uttering expletives. There is often a waxing and waning pattern of
severity, intensity and frequency of tics. Severity typically peaks during adolescence with many children
experiencing a substantial reduction in severity by early adulthood.

Tourette syndrome is more common in boys. Diagnosis should be confirmed by an experienced clinician. Initial
treatment should include education about the condition. If there are specific environmental stresses or precipitants
that exacerbate the condition, they should be identified and addressed appropriately. The prevalence of attention
deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) is greatly increased among
children with Tourette syndrome. It is important to treat comorbid mental disorders because their treatment may
reduce tic intensity.

Nonpharmacological treatment
The most studied nonpharmacological intervention for childhood tic disorders is habit reversal training. There is
usually an urge to tic called the ‘premonitory sensation’ which is often relieved by performing the tic. For most
patients this is an automatic and involuntary process but through awareness training, patients can be taught to
become more aware of the urge and then use competing responses that oppose the tic movements. A range of
approaches are used to help children achieve this in Comprehensive Behavioural Intervention for Tics (CBIT)
including awareness training, habit reversal training and psychosocial support. Classroom interventions would also
be beneficial for tics and related behaviours.

Pharmacological treatment

Pharmacotherapy generally achieves modest suppression of tics. Effective treatment of comorbid ADHD and OCD
symptoms may help reduce tic severity (see Attention deficit hyperactivity disorder and Obsessive compulsive
disorder). Tic suppression with medication may be considered if the tics cause pain or injury, cause sustained
social difficulties for the child including classroom disruption, or interfere significantly with the child's functioning
in other areas.

The greatest evidence for efficacy in suppressing tics is with the antipsychotics haloperidol and risperidone.
However, tolerability and safety concerns due to extrapyramidal adverse effects, weight gain and sedation limit
their acceptability. This has led to clonidine being the drug of choice because it is considered potentially safer,
even though it is less efficacious. There is limited evidence on the efficacy of other second-generation
antipsychotics in relieving tic symptoms.

Drug doses should not be chosen with the expectation that all tics will be suppressed. Rather, the dose used should
be the lowest possible dose that appropriately reduces the tic frequency and severity, without significant adverse
effects. If pharmacotherapy is undertaken, consider using:

clonidine (5 years or older) 1 microgram/kg (up to 50 micrograms) orally, daily initially.

Maximum dose 4 micrograms/kg (up to 300 micrograms) daily in 2 or 3 divided doses.

The dose may be increased by 25 to 50 micrograms every 3 to 7 days until optimum response is obtained or
maximum dose is reached. Give doses more than 150 micrograms daily in 2 or 3 divided doses. Recommended
doses do not generally produce significant sedation or hypotension provided the initial dose is increased slowly.
Blood pressure and pulse rate should be routinely monitored during treatment. Avoid suddenly stopping treatment
as rebound hypertension may occur.

If clonidine is ineffective, a trial of risperidone may be warranted. It is considered more appropriate than
haloperidol because the risk of extrapyramidal adverse effects is lower, but monitoring for adverse effects is still
necessary, see Antipsychotic adverse effect monitoring. If risperidone is thought appropriate, consider using:

1 risperidone (5 years or older, less than 50 kg) 0.25 mg orally, once daily initially. Increase
by no more than 0.25 mg per week. Maximum dose 0.05 mg/kg (up to 2.5 mg) daily, in 1
or 2 divided doses

OR

1 risperidone (5 years or older, 50 kg or more) 0.5 mg orally, once daily initially. Increase
by no more than 0.5 mg per week. Maximum dose 0.05 mg/kg (up to 2.5 mg) daily, in 1
or 2 divided doses.

In short-term trials, higher doses of risperidone have been used but there are no long-term safety data for higher
doses in children.

In the past, high-potency first-generation antipsychotics at low doses were the best choice for tic suppression.
Haloperidol is the best studied and is approved for use in childhood Tourette syndrome. If haloperidol is thought
appropriate, consider using:

haloperidol (5 years or older) 0.25 to 0.5 mg orally, daily initially. Increase in gradual
increments at weekly intervals. Maximum dose 0.05 mg/kg (up to 2 mg) daily, in 2 or 3
divided doses.

If a child develops extrapyramidal adverse effects while taking haloperidol they may require benztropine. The dose
used would be:

benztropine (3 years or older) 0.02 to 0.05 mg/kg (up to 2 mg) orally, once or twice daily.
Maximum dose 0.1 mg/kg (up to 4 mg) daily.

If oral dosing is not possible, the intramuscular or intravenous dose for benztropine is 0.02 mg/kg. It may be
repeated in 15 minutes if necessary.

Benztropine should be discontinued within several weeks at most. If extrapyramidal symptoms persist, stop
haloperidol and switch to a second-generation antipsychotic.

Juvenile bipolar disorder

Diagnosis and management of children with juvenile bipolar disorder should only be undertaken by practitioners
with specialist knowledge of the condition and its treatment.

The term juvenile bipolar disorder is increasingly being used when children aged 6 to 18 years meet the criteria for
the diagnosis of bipolar disorder. However, there is a huge disparity in practice in the UK and the US. Lack of
consistency in clinical practice and a relatively weak evidence base mean that careful consideration must be given
before lithium, antiepileptics and/or antipsychotics are used to treat children.

When symptoms are comparable to those used to define bipolar disorder in adults, drug treatment should be based
on recommendations for adults (see Bipolar disorder). There is consistent evidence for the use of second-
generation antipsychotics in the treatment of acute mania and limited evidence favouring the use of the
combination of a second-generation antipsychotic with lithium or an antiepileptic to treat children. There is no
compelling evidence for monotherapy with lithium or an antiepileptic.

Inpatient treatment is generally required for the management of acute episodes of bipolar disorder, with the aim of
providing a safe and low-stimulation environment while stabilising the adolescent's illness. Many of the drugs used
have the potential to cause significant weight gain in children and this should be assessed regularly. In light of the
risks of teratogenicity and polycystic ovary syndrome, sodium valproate should be used cautiously for girls and
young women. For further discussion of drug use in pregnancy, see Psychotropic drug use during pregnancy: drugs
used in treatment of bipolar disorder.

Careful attention should also be given to the impact of the disorder and its treatment on children's education and
their social relationships. Separate individual appointments and joint meetings with parents or carers should be
provided for children requiring treatment for the disorder. Long-term management of children with juvenile bipolar
disorder should only be undertaken by practitioners with specialist knowledge of the condition and its treatment.

When lithium or antiepileptics are used to treat juvenile bipolar disorder, the following would be typical doses:

carbamazepine 5 mg/kg orally, daily initially, in 2 or 3 divided doses, increasing over 2

weeks according to patient tolerability and response, while monitoring as for adult doses
 (see Antiepileptic drugs)

OR

lithium carbonate immediate-release (12 years or older) 15 mg/kg orally, daily initially, in
2 or 3 divided doses, increasing every 3 to 5 days according to patient tolerability and
response, while monitoring as for adult doses (see Lithium)

OR

sodium valproate 10 mg/kg orally, twice daily initially, increasing every 3 days according
to patient tolerability and response, while monitoring as for adult doses (see Antiepileptic
drugs).

For information on monitoring for adverse effects of lithium and antiepileptics, see Considerations with drugs used
in prophylaxis of bipolar disorder.

Childhood schizophrenia and other psychoses

General information
Schizophrenia is rare before puberty. Criteria for diagnosis are the same as for adults, ie a period of 6 months or
greater of deterioration in functioning and the presence of psychosis (delusions, hallucinations, thought form
disorder) with no preceding mood disorder (see Schizophrenia and related psychoses). Early diagnosis and
treatment of children with schizophrenia is important (see Schizophrenia and related psychoses: principles of
treatment) and should be undertaken by an experienced practitioner.

Antipsychotic drugs have a similar range of efficacy in adolescents to that in adults; however, adolescents appear
to be more prone to a wide range of adverse effects including extrapyramidal adverse effects, effects due to
prolactin elevation, and weight gain. In particular, males appear more susceptible to acute dystonias and adolescent
males may experience breast enlargement caused by elevated prolactin. For further information on antipsychotic
adverse effects in children, see Antipsychotic adverse effect monitoring, below.

Antipsychotic adverse effect monitoring

It is important to monitor children for antipsychotic-induced extrapyramidal, endocrine and metabolic adverse
effects. Limited data suggest these problems may be worse in children than in adults. Preventive and interventional
strategies have the potential to prevent both short- and long-term sequelae [Note 7]. The importance of healthy
lifestyle aspects such as diet and exercise should be continually reinforced.

Assess at baseline and then periodically evaluate for the development of extrapyramidal adverse effects and signs
of prolactin elevation.

Measure body height and weight to calculate body mass index (BMI) and compare against BMI-for-age percentiles
at baseline and at each visit while antipsychotics are being taken. In adolescents, BMI and BMI-for-age percentiles
give a better indication of significant weight gain issues than by simply looking at weight. The following have
been proposed as criteria for significant abnormal weight gain in children and adolescents who are treated with
psychotropic drugs:

a greater than 5% BMI increase in the first 3 months

any child falling into the overweight category (85th to 95th BMI percentile) with the presence of one other
obesity-related complication (eg hypertension, dyslipidaemia, hyperglycaemia)
any child crossing into obesity (greater than 95th BMI percentile).

Regular monitoring and appropriate intervention is required for anyone meeting any of these criteria.

Obtain blood pressure, fasting blood glucose and fasting serum lipids at baseline, at 3 months and every 6 to 12
months if results are within normal limits and BMI percentile values are stable. Those with risk factors for
metabolic adverse effects such as smoking, family history of diabetes or heart disease, certain ethnic populations
(eg Aboriginal and Torres Strait Islander peoples) and those already overweight or obese may require more
frequent monitoring. Identify a key person (either the general practitioner, psychiatrist or paediatrician) to be
responsible for ongoing monitoring and for ensuring that regular monitoring does occur.

Note 7: Eapen V, Shiers D, Curtis J. Bridging the gap from evidence to policy and practice: Reducing the
progression to metabolic syndrome for children and adolescents on antipsychotic medication. Aust N Z J
Psychiatry 2013:47(5):435-42. [URL]
Disruptive behaviour disorders in children and adolescents
The term disruptive behaviour disorders is used to describe a group of mental health disorders that include
oppositional defiant disorder and conduct disorder. These disorders are relatively common in the community and
are often comorbid with other conditions (eg major depression, attention deficit hyperactivity disorder). Once
established, they commonly have a chronic course and a significant adverse impact on children and families.

Three principles of treatment are important:

nonpharmacological treatment is the preferred first-line treatment

careful assessment and treatment of comorbid conditions is essential
there is a limited role for pharmacological treatment.

Risperidone has an approval in Australia for the treatment of conduct and other disruptive behaviour disorders in
those with intellectual disability in whom destructive behaviours (eg aggression, impulsivity and self-injurious
behaviours) are prominent (see Intellectual disability with comorbid mental disorder). There is also some evidence
that lithium may help those with very severe problems. There is one study showing benefit in adding clonidine to
stimulants for hyperactive and aggressive children with comorbid oppositional defiant disorder or conduct
disorder. However, use of these drugs to treat disruptive behaviour disorders should only be undertaken by
specialists familiar with these disorders.

Sleep disorders in children and adolescents

General principles of good sleep practice (see advice on good sleep practices Box 8.2) can be applied to children's
sleep problems, which often present as night crying, often after a stressful event or an intercurrent illness.
Generally, it is important that children fall asleep in ambient conditions that will not change during the night. Some
clinicians prescribe melatonin for severe insomnia although it is not approved by the Australian Therapeutic
Goods Administration for use in children.

Nightmares in children are usually related to recent experience and usually resolve without resort to medication.
Sleep terrors and sleepwalking are related to disturbances of sleep stages 3 and 4 (see Parasomnias: sleep terrors
and sleepwalking). Generally, these occur in episodes of relatively brief duration and pharmacotherapy is seldom
indicated. As children do not recall these episodes, distress can be minimised by not waking them in these states,
which are usually characterised by high autonomic arousal.

Further reading
Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology. Principles and practice. 2nd ed.
Oxford: Oxford University Press; 2011.

Key references
Using psychotropic drugs in children

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

Attention deficit hyperactivity disorder: general information

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

National Collaborating Centre for Mental Health. Attention deficit hyperactivity disorder: diagnosis and management of
ADHD in children, young people and adults (CG72). London: National Institute for Clinical Excellence (NICE); 2008.
[URL]

National Health and Medical Research Council. Clinical practice points on the diagnosis, assessment and
management of attention deficit hyperactivity disorder in children and adolescents. Canberra: Commonwealth of
Australia; 2012. [URL]

Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, et al. ADHD: clinical practice guideline for the
diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics.
2011;128(5):1007–22. [ ]

Attention deficit hyperactivity disorder: nonpharmacological treatment

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

National Collaborating Centre for Mental Health. Attention deficit hyperactivity disorder: diagnosis and management of
ADHD in children, young people and adults (CG72). London: National Institute for Clinical Excellence (NICE); 2008.
[URL]

National Health and Medical Research Council. Clinical practice points on the diagnosis, assessment and
management of attention deficit hyperactivity disorder in children and adolescents. Canberra: Commonwealth of
Australia; 2012. [URL]

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management of attention deficit hyperactivity disorder in children and adolescents. Canberra: Commonwealth of
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diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics.
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Attention deficit hyperactivity disorder: management in older adolescents and adults

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Oxford University Press; 2011.

National Collaborating Centre for Mental Health. Attention deficit hyperactivity disorder: diagnosis and management of
ADHD in children, young people and adults (CG72). London: National Institute for Clinical Excellence (NICE); 2008.
[URL]

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management of attention deficit hyperactivity disorder in children and adolescents. Canberra: Commonwealth of
Australia; 2012. [URL]

Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, et al. ADHD: clinical practice guideline for the
diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics.
2011;128(5):1007–22. [ ]

Major depression in childhood and adolescence

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Oxford University Press; 2011.

National Collaborating Centre for Mental Health. Depression in children and young people: identification and
management in primary, community and secondary care (CG28). London: The British Psychological Society; 2005.
[URL]

Anxiety disorders in childhood and adolescence

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pediatricians. Cambridge, UK: Cambridge University Press; 2008.

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Autism spectrum disorder

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early intervention for children with autism spectrum disorders. Canberra: Australian Government Department of Health
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Sharma A, Shaw SR. Efficacy of risperidone in managing maladaptive behaviors for children with autistic spectrum
disorder: a meta-analysis. J Pediatr Health Care. 2012;26(4):291–9. [ ]

Intellectual disability with comorbid mental disorder

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Oxford University Press; 2011.
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Oxford University Press; 2011.

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disorder: a randomized controlled trial. JAMA. 2010;303(19):1929–37. [ ]

Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS. A placebo-controlled trial of risperidone in Tourette
syndrome. Neurology. 2003;60(7):1130–5. [ ]

Seida JC, Schouten JR, Boylan K, Newton AS, Mousavi SS, Beaith A, et al. Antipsychotics for children and young
adults: a comparative effectiveness review. Pediatrics. 2012;129(3):e771–84. [ ]

Juvenile bipolar disorder

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pediatricians. Cambridge, UK: Cambridge University Press; 2008.

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Oxford University Press; 2011.

Schizophrenia and other childhood psychoses

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

Seida JC, Schouten JR, Boylan K, Newton AS, Mousavi SS, Beaith A, et al. Antipsychotics for children and young
adults: a comparative effectiveness review. Pediatrics. 2012;129(3):e771–84. [ ]

Disruptive behaviour disorders in childhood and adolescence

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

Seida JC, Schouten JR, Boylan K, Newton AS, Mousavi SS, Beaith A, et al. Antipsychotics for children and young
adults: a comparative effectiveness review. Pediatrics. 2012;129(3):e771–84. [ ]

Sleep disorders in childhood and adolescence

Greydanus DE, Calles JL, Patel DR. Pediatric and adolescent psychopharmacology: a practical manual for
pediatricians. Cambridge, UK: Cambridge University Press; 2008.

Martin A, Scahill L, Kratochvil CJ, editors. Pediatric psychopharmacology: principles and practice. 2nd ed. Oxford:
Oxford University Press; 2011.

Published July 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Psychiatric conditions in pregnancy and the
postpartum
Overview of psychiatric conditions in pregnancy
The peak incidence of many psychiatric disorders coincides with the childbearing years. Pregnancy and the
postpartum are not protective periods for women. Therefore, many pregnant women and new mothers will
require treatment for psychiatric disorders, whether they have an existing or a new onset of illness. There are
some conditions such as anxiety where there are nonpharmacological options for treatment, whereas for
psychotic illnesses antipsychotic drugs are the mainstay of treatment.

Psychotropic drugs are among the more commonly prescribed groups of medicines in pregnant and lactating
women. There are important harm–benefit considerations in providing psychiatric management during the
perinatal period to optimise the health and safety of mothers and their infants.

When treating any woman of childbearing age, clinicians need to keep in mind reproductive issues.
Contraception should be discussed, as unplanned pregnancies are more challenging to manage. The second-
generation antipsychotics are less likely to lead to elevated prolactin and reduced fertility than first-generation
antipsychotics; therefore, when switching from an older to a newer antipsychotic drug, it is an opportune time
to discuss contraceptive options with the patient.

The choice of management modality of psychiatric conditions in the perinatal period needs to be made with
consideration of both the evidence-based treatment of the psychiatric condition and also the variable safety
profiles of individual drugs during pregnancy and lactation.

It is preferable for women to have their mental state optimised or in a state of remission before conception.
One of the major risk factors for postpartum relapse of a psychiatric condition is the patient being
symptomatic in the antenatal period. Pre-conception planning is recommended, particularly with bipolar
disorder where the treatments used are known to be teratogenic. Pre-conception planning allows for time to
trial a withdrawal of or change in parts of treatment (if preferred by the woman, her partner and clinician),
and to formulate a relapse management plan.

As half of all pregnancies are unplanned, there will be a number of women who become pregnant on a
regimen of psychotropic drugs. There is usually no need for hasty cessation of medication, which can lead to
a higher risk of relapse than a gradual withdrawal. Before switching or ceasing a drug, there needs to be
thoughtful discussion (preferably with the patient and her partner), research of current treatment information
and/or consultation with specialist services to tailor the most appropriate management plan for the individual
patient.

The management of women with psychiatric conditions in the perinatal period can be complex and a referral
to specialist services for an opinion, advice or treatment is strongly recommended. Often a multidisciplinary
team approach is required involving collaboration with the usual treating clinician, a specialist psychiatrist or
perinatal psychiatrist, the obstetric team and paediatrician. With judicious choice of drug type and dose,
careful monitoring of mother and fetus or infant, and delivery in a hospital with neonatal facilities, most
psychiatric illness can be safely and successfully treated during pregnancy with significant benefit for both
mother and child.

Schizophrenia in pregnancy and the postpartum

Specialist opinion, advice or treatment should be sought in managing women with schizophrenia in the
perinatal period due to the combination of psychiatric, obstetric and parenting risk issues outlined below.

The relative fertility of women with schizophrenia has increased in recent years, coinciding with
deinstitutionalisation and the introduction of second-generation antipsychotics (decreased incidence of
hyperprolactinaemia, improved negative symptoms). While the severity of illness during pregnancy is
variable, there is a reported increased risk of relapse in the first year postpartum.

Women with schizophrenia are at increased risk of adverse obstetric outcomes such as low birth weight
babies, small-for-gestational age babies, preterm labour and placental abruption. Some of these outcomes are
partially attributable to increased rates of smoking, problem drug use, poor nutrition, and lower
socioeconomic status among this population. Maternal schizophrenia may also be an independent risk factor
for minor congenital abnormalities in offspring.

Parenting capacity is often impaired in patients with schizophrenia. They have the highest rate of custody loss
compared with other maternal mental illnesses. Maternal schizophrenia has also been associated with
increased risk of neonatal mortality. These adverse outcomes must be considered and weighed against the
potential harms of antipsychotics during pregnancy and lactation.

The same guiding principles for best practice management of schizophrenia in the general population remain
applicable in the perinatal period. In fact, robust rather than undertreatment is preferable, in the best interest
of mother and child.

Because of the risk of relapse, women taking antipsychotics long term should not have their drug abruptly
stopped. The decision to continue antipsychotics should be made after weighing up the relatively uncertain
harms associated with antipsychotic exposure in the perinatal period against the potential harms associated
with relapse, including inpatient admission and exposure to polypharmacy during acute treatment.

For further information on treatment of schizophrenia in the general population, see Schizophrenia and
related psychoses: principles of treatment.

Bipolar disorder in pregnancy and the postpartum

The management of women with bipolar disorder in the perinatal period has been described as placing these
women and their clinicians between ‘a teratologic rock and a clinical hard place’. Specialist opinion, advice
or treatment should be sought.

This is the most challenging of the psychiatric disorders to manage in the perinatal period due to high rates of
relapse of the illness and the known risks of teratogenicity with treatment. Women who discontinue their
lithium or antiepileptic during pregnancy have a relapse rate of up to 85% compared with 37% who continue
their lithium and/or antiepileptic. Unfortunately these commonly prescribed drugs (sodium valproate,
carbamazepine, lithium) are human teratogens. Furthermore, lithium, which has the more favourable profile
during pregnancy, should be used with caution while breastfeeding. In contrast, sodium valproate is not
recommended during pregnancy, but is considered compatible with breastfeeding. See Psychotropic drug use
during pregnancy: drugs used in treatment of bipolar disorder for further information on use of these drugs
during pregnancy.

Ideally, pregnancies are planned to allow time for treatment choices to be considered and trialled. This may
include the withdrawal of lithium and/or antiepileptic and introduction of an antipsychotic. A relapse
management plan should be formulated.

A life-span approach is recommended when seeing any woman of childbearing age with bipolar disorder,
including discussion of contraception. As part of standard care, women should be given education about the
risks of illness and medication in the perinatal period to help prevent unplanned and unintended pregnancies.
Some guidelines recommend the avoidance of sodium valproate for treatment of bipolar disorder in any
woman of childbearing age.

Actually, about half of pregnancies are unplanned and it is then left to the clinician, the woman and her
partner to decide on an individual management plan. This plan will need to take into account the current
gestation, the severity of the illness, the responsiveness to treatment, the time taken to recovery and the level
of functional impairment and risks involved with a relapse (impulsivity, problem drug use, loss of reputation,
affect on relationships, self-harm and suicidality). At either ends of the spectrum of illness, the decision is
more straightforward. A woman who has only had a couple of relatively mild episodes of illness and is
currently stable, may consider a slow withdrawal (over 3 to 4 weeks) of lithium or antiepileptic. She can then
wait until she has symptoms of relapse before reinstating psychotropics. Alternatively, lithium, lamotrigine or
an antipsychotic can be reintroduced prophylactically after the first trimester.

In a woman with severe illness and who is currently symptomatic, the objective would be to optimise her
mental state, which may involve continuing with all her medications and/or the consideration of
electroconvulsive therapy (ECT). Withdrawal of medication may not be an option if it is likely to lead to
relapse, the possibility of psychiatric inpatient admission, and potential exposure to multiple drugs in the
setting of a behavioural emergency.

For women with moderate illness, the approach is to give the woman enough information so that she can
make an informed decision. This may involve a referral to a specialist perinatal psychiatrist or to genetic
services.
If the pregnancy is not discovered until the second trimester, the priority will be to undertake the necessary
investigations (high-resolution ultrasound) rather than to hastily cease the lithium or antiepileptic.

Regardless of the decisions made, the most important aspect of managing a woman with bipolar disorder in
the perinatal period is ongoing close monitoring.

Postpartum psychosis
Postpartum psychosis is a rare (1 to 2 cases per 1000 live births) but dangerous illness, associated with
significant risk of maternal suicide and infanticide. The presentation is acute and usually requires inpatient
management. Symptoms include: agitation, confusion, thought disorganisation, sleep disturbance, psychosis
(hallucinations and delusions) and affective symptoms. Risk factors include a previous episode of postpartum
psychosis and a family history of bipolar disorder. There is an association between postpartum psychosis and
bipolar disorder. Women with bipolar disorder are at increased risk of developing a psychotic episode in the
postpartum period. Conversely, the first episode of postpartum psychosis may evolve into a bipolar illness.

The treatments involved are similar to those for an acute mania: antipsychotics, lithium, antiepileptics and
electroconvulsive therapy (ECT) (see Acute mania for further information on treatments). For those who
have had a previous episode of postpartum psychosis, there is evidence that the prophylactic use of lithium
after delivery reduces the likelihood of a recurrence.

Depression in pregnancy and the postpartum

Depression during pregnancy is as common as postnatal depression. Moreover, in developed countries
suicide is a leading cause of death in women during pregnancy and the postpartum period, exceeding causes
directly related to childbirth or its complications. Hence, while there is general agreement that effort should
be made to minimise drug doses, it is equally important not to undertreat the psychiatric illness.

The majority of women will relapse if their antidepressant, lithium or antiepileptic is stopped on confirmation
of pregnancy [Note 1].

In addition to the risks of mental illness, untreated maternal depression during pregnancy is associated with
increased risk of adverse obstetric and neonatal outcomes. These include spontaneous abortion, low birth
weight babies, smaller head circumference, premature delivery and increased neonatal cortisol concentration
at birth. Depressed women are more likely to report increased pain, nausea, gastrointestinal symptoms and
dizziness. There is also a decreased rate of health-related behaviour: lower attendance to antenatal
appointments, poorer nutrition, higher rates of smoking, alcohol and illicit drug use, and lower likelihood to
take vitamin supplements. Poor neonatal adaptation is associated with untreated depression and anxiety
during pregnancy. This latter association makes it very difficult to determine if neonatal problems are
attributable to maternal depression during pregnancy or to drugs used to treat it (see Selective serotonin
reuptake inhibitors: poor neonatal adaptation). The adverse consequences for the fetus of not treating
antenatal depression may have been insufficiently emphasised in the past. Furthermore, antenatal depression
is the most important risk factor for postnatal depression.

The prevalence of postnatal depression is 10% to 15%. In addition to the risks of maternal suicide and
infanticide, postnatal depression leads to an impairment of the mother–infant relationship, and poorer
cognitive and behavioural outcomes in the child. Along with the usual symptoms of major depression, other
symptoms include difficulty coping with the baby, guilty thoughts about being a bad mother, excessive
anxiety about the wellbeing of the baby and irritability towards the family. There can be comorbid symptoms
of anxiety and obsessive compulsive disorder.

In both the antenatal and postnatal period, mild-to-moderate depression should be treated with psychological
therapies—there is evidence for cognitive behavioural therapy, interpersonal therapy and group therapy, see
Psychological interventions.

For severe depression, antidepressants should be considered (see Treatment of depression). Base the choice
of antidepressant on clinical factors, particularly previous efficacy, tolerability and patient preference. In
those who are medication naive, selective serotonin reuptake inhibitors (SSRIs) are recommended as first
line. Some guidelines recommend more caution with the use of paroxetine (see Selective serotonin reuptake
inhibitors) and fluoxetine (due to its longer half-life).

There is currently a lack of evidence to support the use of antidepressants to prevent unipolar depression in
the perinatal period when current symptoms are not present.

Note 1: Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major
depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA
2006;295(5):499-507. [URL]

Anxiety in pregnancy and the postpartum

Anxiety disorders are common in the perinatal period, but relatively understudied. The most evidence is for
treatment of panic disorder, obsessive compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).
Less is known about generalised anxiety disorder and specific phobias in the perinatal period. There are very
high rates of comorbidity of anxiety symptoms with depression in the perinatal period. Antenatal anxiety is a
risk factor for postnatal depression.

There is a suggestion of a perinatal course of illness with panic disorder, where there is an improvement
during pregnancy and an increase in symptoms in the postpartum. However, this will not be the case for
every woman. Physical symptoms of pregnancy (tachycardia, sweating, dizziness, shortness of breath) may
mimic or precipitate a panic attack. Undertreatment of panic disorder can result in poorer attendance to
antenatal appointments.

The prevalence of OCD is lower during pregnancy and higher in the postpartum compared with general
population rates. Obsessional thoughts involving the infant have been reported in nearly half of women with
postnatal depression and so are not necessarily indicative of OCD. It is important to distinguish between
obsessional thoughts of harming the infant (which the patient finds intrusive and distressing) from either real
intentions or delusions of wanting to harm the infant. Referral for a second opinion may be indicated,
particularly when the assessment of risk to the infant is uncertain. In addition, OCD can lead to avoidance of
the infant (for fear of harming the infant), insensitive interactions (repetitively wiping and/or cleaning the
infant) or neglect because of time spent with cleaning rituals and other compulsions.

The course of existing PTSD during the perinatal period is unknown. Some women may develop either acute
stress disorder or PTSD following a perceived traumatic childbirth. This can lead to avoidance of the infant,
and sexual activity and fear of further childbearing—sometimes termed tocophobia. There have been reports
of requests for caesarean section, termination of unplanned pregnancies and sterilisation, all due to PTSD
following childbirth.

With all the anxiety disorders, treatment should proceed as for a nonpregnant patient, with consideration of
the specific risks associated with psychotropic drugs during pregnancy and the postpartum. For information
on treatment of anxiety disorders, see Anxiety and associated disorders.

Eating disorders in pregnancy and the postpartum

Eating disorders include: anorexia nervosa, bulimia nervosa and eating disorders not otherwise specified.
They occur more commonly in women and with the highest prevalence in the reproductive years. While
eating disorders are less prevalent in pregnant women than other psychiatric conditions, the mortality rate is
high. Furthermore, the medical and psychiatric complications impact on the health of the mother, the
pregnancy, the fetus and the mother–infant interactions.

The course of eating disorders during the perinatal period is not consistent for all women. Some find the
weight gain, food cravings and food aversions associated with pregnancy provoke anxiety and a fear of loss
of control. This may lead to a recurrence or worsening of restrictive eating, purging and excessive exercise.
Conversely, other women fear adverse outcomes from such behaviours on the pregnancy and this may lead to
a time-limited remission.

The literature about the association between eating disorders and adverse pregnancy and neonatal outcomes
has been mixed and inconsistent. The findings most often replicated are that bulimia nervosa is associated
with increased rates of spontaneous abortions and active anorexia nervosa is associated with smaller birth
weight babies. Other adverse outcomes reported include: increased anaemia, increased hyperemesis
gravidarum (though this may be masking purging behaviours), increased rate of caesarean section, more
problems with episiotomy repair and smaller head circumference of infants. It appears that outcomes are
worse if there is active current illness rather than a past history of an eating disorder. Therefore, it is
recommended that women with eating disorders delay conception until their symptoms are well controlled.

The treatment of eating disorders during pregnancy follows the same principles as for the nonpregnant
patient, see Eating disorders. However, it is advisable that the pregnancy care is undertaken by a
multidisciplinary team involving an obstetrician, psychiatrist (or a specialist eating disorder service), dietitian
and physician. A dietitian can educate the patient about normal pregnancy weight gain and the required
nutritional supplements. There may be an indication for more frequent medical surveillance of the physical
state of both the mother and fetus, using blood tests (watching for anaemia, thyroid dysfunction, electrolyte
disturbance, nutritional deficiencies) and ultrasounds (to monitor fetal growth).

In the postpartum period, women with eating disorders are at greater risk of relapse due to the combination of
stress, sleep deprivation and reduced motivation because the baby is no longer in utero. Women with eating
disorders are more likely to develop postnatal depression and they are less likely to persist with
breastfeeding. Furthermore, mother–infant interactions tend to involve more control and conflict, and the
projection of distorted body image onto their children. Children of mothers with eating disorders tend to
weigh less than their age-matched controls. Ongoing monitoring and management into the perinatal period is
essential for both mother and infant.

Electroconvulsive therapy during pregnancy

The use of electroconvulsive therapy (ECT) during pregnancy is often overlooked, due to the combination of
the stigma and the anxiety it provokes in clinicians and patients. However, there are several indications where
it is the most effective treatment: acute mania, major depression with severe melancholic features and major
depression with psychotic symptoms. In these cases, if untreated or ineffectively treated, there is significant
risk of harm to the patient (and fetus) due to suicidality, impulsivity, severe self-neglect and the lack of oral
intake.

Furthermore, ECT may be considered preferable during pregnancy in situations where ECT has a lower
teratogenicity risk than drug treatment for the disorder (eg some drugs to treat bipolar disorder). Anaesthetic
and muscle relaxant drugs are used during ECT but non-teratogenic options are available.

ECT may be the patient's preference based on previous experience.

The usual adverse effects of confusion, short-term memory loss, headache and muscle soreness can occur. In
addition, reported adverse outcomes with ECT use during pregnancy include: mild vaginal bleeding,
abdominal pain, transient benign fetal arrhythmias, uterine contractions and preterm delivery. While most of
the cases of uterine contractions were transient, there have been two cases where tocolytic therapy was
required. In all these cases, the infants were otherwise normal at delivery. There has also been one isolated
case of placental abruption with the infant safely delivered.

In preparation for ECT during pregnancy, women should have the standard medical workup and the usual
exclusion criteria apply, see Electroconvulsive therapy. The woman should give informed consent or the use
of ECT should comply with the conditions set out in the respective state or territory Mental Health Act. In
addition, there should be consultation with the treating obstetrician—conditions that lead to placental
compromise such as hypertension and diabetes should be treated with caution. The patient should also be
seen by an anaesthetist who commonly manages obstetric patients.

Psychotropic drug use during pregnancy

General information
For the latest updates on psychotropic drug use during pregnancy, and patient handouts, see MotherToBaby
[URL] or The Women’s Pregnancy and Breastfeeding Medicines Guide published by the Royal Women’s
Hospital [URL].

See also general background information on use of drugs during pregnancy.

Harm/benefit analysis
Table 8.4 can provide a framework to aid the practitioner to decide whether or not to prescribe a psychotropic
drug during pregnancy. It can also guide discussion with the woman, preferably in conjunction with her
partner.

There are five potential harmful effects to the fetus due to prescribing psychotropic drugs during pregnancy
as shown in Table 8.4. For the first four effects (death, congenital abnormality, intrauterine growth restriction,
neonatal toxicity), data (albeit of variable quality) indicating possibility of harm are available for the more
commonly used psychotropic drugs.

Long-term neurodevelopmental effects are largely unexplored and nonpharmacological interventions always
warrant consideration. However, although no psychotropic drug can be considered 100% safe in pregnancy,
this should not deter prescribing when this is otherwise indicated.
Unnecessarily high dose and prolonged duration of drug treatment should be avoided. However, there are
increases in total body water during pregnancy, as well as alterations in protein binding and changes in
cytochrome P450 enzyme activity, so some pregnant women may require higher doses of some drugs (eg
antidepressants) for an effective response. As with a nonpregnant patient, the dose of drug required is
primarily based on clinical response.

Harm/benefit analysis for prescribing during pregnancy (Table 8.4)

Fetus Mother
death
congenital
abnormality
growth restriction overdose
Possible harms of neonatal adverse effects
prescribing toxicity/withdrawal possible negative impact on therapeutic alliance
long-term
neurodevelopmental
effects

fetal abuse/neglect relapse of psychiatric illness

adverse impact of suicide/self-harm
Possible harms of
NOT prescribing maternal mental state family/relationship deterioration
on the fetus use of harmful substitutes

Antipsychotics

Introduction

There is not sufficient evidence to recommend any one antipsychotic over another during pregnancy. Drug
choice should be made with consideration of previous effective treatment and patient preference. During
pregnancy, switching from one antipsychotic to another puts the patient at risk of relapse and of potential
adverse effects to the fetus from exposure to multiple drugs.

Second-generation antipsychotics

The safety of the second-generation antipsychotics (amisulpride, aripiprazole, asenapine, clozapine,

olanzapine, paliperidone, quetiapine, risperidone, sertindole and ziprasidone) has yet to be established [Note
2]. However, on the basis of case reports and small series, there are no consistent reports of teratogenicity
associated with olanzapine, risperidone or quetiapine. Isolated case reports of congenital abnormalities have
been reported following clozapine use during pregnancy, but no definitive association has been established.

Olanzapine has been linked to an increased risk of maternal gestational diabetes, with associated risk to the
mother and fetus (macrosomia, increased rates of caesarean section).

There is minimal information on use of depot antipsychotic injections during pregnancy.

Unlike first-generation antipsychotics, some second-generation antipsychotics (eg clozapine, quetiapine,

aripiprazole) do not increase prolactin, and others (eg olanzapine) are less likely to increase prolactin, and
hence to reduce women's fertility. When changing from a first- to a second-generation antipsychotic,
informing women about this normalisation of their fertility and the potential for unplanned pregnancies and
discussing contraception is warranted.

Note 2: Sertindole was discontinued in Australia in January 2014.

First-generation antipsychotics

On the basis of the limited data available, first-generation antipsychotics do not appear to increase the risk of
teratogenicity or adverse obstetric outcomes. Opinions differ on the relative safety of individual drugs. Over
many decades, phenothiazines (eg chlorpromazine) have been prescribed to pregnant women for short
periods for the treatment of hyperemesis gravidarum. There are extensive data available about the safety of
haloperidol used as an antipsychotic. As a group, first-generation antipsychotics (in comparison with second-
generation antipsychotics) are only rarely associated with maternal gestational diabetes and fetal macrosomia.
However, first-generation antipsychotics may lead to extrapyramidal symptoms in the neonate: hypertonicity,
tremors, motor restlessness, spasticity and difficulty feeding. These symptoms will usually resolve within
days.

The few studies addressing the long-term developmental effects of in-utero exposure to antipsychotics have
to date found no difference between exposed infants and controls.

Drugs used to treat extrapyramidal adverse effects

Anticholinergic drugs have a Therapeutic Goods Administration pregnancy categorisation of B and there is
inconclusive evidence that they may be associated with an increase in congenital abnormalities and neonatal
adverse effects. They should be avoided if possible during pregnancy. Beta blockers may relieve akathisia;
however, possible cardiovascular adverse effects need to be taken into account.

Antidepressants

Selective serotonin reuptake inhibitors

General information

Selective serotonin reuptake inhibitors (SSRIs) are a very commonly prescribed class of drugs, and therefore
concern about harm–benefit analysis for their use in the perinatal period is commonly encountered. It is the
class of psychotropic drug with the most literature about use during pregnancy but unfortunately the literature
has made decision-making more complex rather than simpler. There are six areas of concern: teratogenicity,
spontaneous abortion and premature labour, low birth weight/small-for-gestational age, poor neonatal
adaptation, persistent pulmonary hypertension of the newborn, and neurodevelopmental difficulties in older
children.

There is no evidence to recommend any particular SSRI over another during pregnancy and the decision
should be based on previous response and adverse effect profile, in discussion with the woman. However,
some problems have been reported with use of paroxetine and fluoxetine (see Teratogenicity, Spontaneous
abortion and premature labour and Poor neonatal adaptation).

Teratogenicity

There is some inconsistency in published findings; however, no conclusive evidence has emerged of
teratogenicity caused by any individual SSRI, nor from analyses that have considered the SSRI group as a
whole. The Therapeutic Goods Administration pregnancy categorisation for paroxetine is D, following
unpublished reports of increased risk of cardiovascular malformations. Accumulated evidence from various
types of studies has not found an increased risk for cardiovascular malformations with paroxetine use during
pregnancy. Therefore, women who find themselves unexpectedly pregnant should not be advised to abruptly
stop the drug before thoughtful consideration of the harms and benefits of treatment versus untreated illness.

The risk of some rare malformations appears to be increased by SSRIs in some unreplicated studies; however,
the absolute risk is low, and there are a large number of potential confounding variables (including depression
itself), which could account for such findings. Concern about teratogenicity should not deter prescription of
SSRIs during pregnancy for treatment of moderate-to-severe major depression and anxiety disorders.

Spontaneous abortion and premature labour

The association between SSRIs and spontaneous abortion or premature labour is controversial because of
uncertain control for higher nicotine and alcohol use, age and other risk factors in depressed women, as well
as the influence of depression itself. In addition, several studies found no association. If there is a true
association, the increased relative risk is likely to be small and the clinical significance is unclear. In women
who have a history of recurrent spontaneous abortions or premature labour of otherwise unknown aetiology,
it is advisable to have a higher threshold for prescribing SSRIs.

Low birth weight/small-for-gestational age

The association of SSRI use with low birth weight/small-for-gestational age babies is controversial. As for
the association of SSRI use during pregnancy with spontaneous abortion and premature labour, (see above
Spontaneous abortion and premature labour), studies were confounded by maternal depression, which may
also contribute to low birth weight/small-for-gestational-age infants.
Poor neonatal adaptation

It is now well established that approximately 10% to 30% of neonates of mothers taking SSRIs in late
pregnancy will have a syndrome resembling serotonergic overstimulation, arising in the first 1 to 2 days
postpartum. There is ongoing debate over whether this is a result of SSRI toxicity or withdrawal. It is
therefore often termed neonatal adaptation syndrome and is characterised by:

central nervous system reactivity: irritability, restlessness, tremor, hyper-reflexia, myoclonus and
occasionally seizures
gastrointestinal disturbance (eg feeding difficulties)
respiratory difficulties
low Apgar scores
increased likelihood of admission to a neonatal unit.

In almost all cases the syndrome remits within 2 weeks with no apparent residual problems. Presently, the
data do not distinguish between levels of risk of the syndrome for different SSRIs.

One study specifically addressed the practice of tapering the SSRI 2 weeks before delivery and found no
differences in neonatal outcomes with cessation of SSRIs before delivery compared with neonates whose
mothers continued with SSRI treatment into the postpartum period. Furthermore, ceasing the drug increases
the risk of maternal relapse and there is poor predictability of delivery dates. Supportive care of the neonate is
preferable.

Persistent pulmonary hypertension of the newborn

Persistent pulmonary hypertension of the newborn (PPHN) is a rare condition affecting 1 to 2 infants per
1000 live births. PPHN is the failure of circulatory transition after birth, with persistence of high pulmonary
pressure (which usually falls at birth). It is a heterogenous condition with multiple aetiological risk factors
(the most common cause is meconium aspiration) and that manifests in a spectrum of illness severity. It has a
high rate of mortality (5%) and severe morbidity (60%).

There have been six studies addressing the association between exposure to SSRIs in the second half of
pregnancy and PPHN. Of these, half have been positive studies and half negative studies. One study found
that PPHN is associated with caesarean section rather than SSRI exposure and that this may have been a
confounder in previous studies. Caesarean section, maternal weight, asthma, diabetes, as well as infant
prematurity or postmaturity, are all known risk factors for PPHN. After review of the studies, the US Food
and Drug Administration (FDA) released a statement [Note 3] saying that it was premature to reach any
conclusion about the link between PPHN and SSRIs and that clinicians should not alter their clinical practice
due to concerns about PPHN.

Note 3: Statement available on the US FDA website at [URL].

Neurodevelopmental difficulties in older children

Several prospective studies have assessed small cohorts of children, in both the shorter (age 6 months) and
longer term (age 6 years), whose mothers were prescribed an SSRI in late pregnancy. One study found subtle
impairment in motor development compared to matched controls. However, it was not blinded and the
exposed group included mothers with higher alcohol and drug use during pregnancy. Other more
methodologically sound studies failed to detect any impairment. Ongoing maternal depression and its
consequent effect on parenting may be a potential confounder.

There has been a single study reporting an association between antenatal antidepressant use and autism in the
offspring [Note 4]. There were limitations in this study and the data need replication.

Note 4: Croen LA, Grether JK, Yoshida CK, Odouli R, Hendrick V. Antidepressant use during pregnancy
and childhood autism spectrum disorders. Arch Gen Psychiatry 2011;68(11):1104-12. [URL]
Commentary on the article, Levitt P. Serotonin and the autisms: a red flag or a red herring? Arch Gen
Psychiatry 2011;68(11):1093-4. [URL]

Tricyclic antidepressants

There is no evidence that exposure to tricyclic antidepressants (TCAs), even in the first trimester, carries any
significantly increased risk of malformation. Isolated case reports have suggested an increased risk with the
use of doxepin, but this evidence is inconclusive. However, the clinician needs to be aware of the much
higher lethality in overdose of TCAs compared to SSRIs, and their lower tolerability due to adverse effects.
Doses may need to be increased in late pregnancy to maintain efficacy.

Nortriptyline is sometimes regarded as the TCA of choice during pregnancy due to its lower likelihood of
causing anticholinergic adverse effects and orthostatic hypotension. In addition, maternal serum
concentration of this drug can be measured.

Maternal use of TCAs has occasionally been associated with anticholinergic adverse effects, and a rebound
reaction (irritability, insomnia, fever and colic) in the neonate. Abrupt discontinuation of clomipramine
during pregnancy has been associated with premature delivery, and subsequent seizures in the newborn.

Other antidepressants

Preliminary data suggest venlafaxine is not associated with congenital abnormality, but neonatal withdrawal
has been reported. The safety during pregnancy of agomelatine, desvenlafaxine, duloxetine, moclobemide
and reboxetine has not been adequately studied.

In a small number of case series where mirtazapine has been used short term as an antiemetic during
pregnancy, no increased teratogenicity has been noted.

The safety during pregnancy of mianserin and irreversible nonselective monoamine oxidase inhibitors
(MAOIs) has not been adequately studied. Most guidelines recommend these drugs are avoided.

Drugs used in treatment of bipolar disorder

General information

With the complexity in managing women with bipolar disorder in the perinatal period, specialist advice
should be sought. Furthermore, there should be a multidisciplinary approach involving the general
practitioner, psychiatrist, obstetrician and paediatrician.

Management of bipolar disorder in the general population is discussed in Bipolar disorder. For specific
discussion of bipolar disorder during pregnancy and the postpartum, see Bipolar disorder in pregnancy and
the postpartum. Drugs used in the treatment of bipolar disorder include lithium, sodium valproate,
carbamazepine and lamotrigine, as well as second-generation antipsychotics (see Psychotropic drug use
during pregnancy: antipsychotics). Women who discontinue their lithium or antiepileptic during pregnancy
have a relapse rate of up to 85% compared with 37% who continue their lithium or antiepileptic. The harms
versus benefits must be carefully weighed, taking into account the following information, and mindful that
polypharmacy should be avoided wherever possible due to substantial increases in teratogenic risk.

In circumstances where lithium or antiepileptics are required, lithium is preferable to sodium valproate or
carbamazepine. The high rates of teratogenicity and adverse neurodevelopmental outcomes for offspring
exposed to sodium valproate in utero have led several guidelines to advise against its routine use in any
woman of childbearing potential regardless of her immediate reproductive planning.

Lithium

Ideally, the management of a woman prescribed lithium during pregnancy should involve a multidisciplinary
approach with liaison between the general practitioner, psychiatrist, obstetrician and paediatrician.

The use of lithium within the first trimester has been associated with an increased risk of Ebstein's anomaly, a
cardiac defect involving the downward displacement of the tricuspid valve into the right ventricle and a
variable level of right ventricular dysfunction. Reviews have confirmed that earlier estimates of risk in
humans had been overestimated. Although the risk of Ebstein's anomaly is significantly increased, the
absolute risk remains low, approximately 1 in 1000 to 2000 compared with 1 in 20 000 in the general
population.

Patients who are on lithium and who wish to become pregnant should be informed of the possible harms, and
have their lithium gradually withdrawn before conception occurs. If the pregnant patient develops symptoms
and is in need of pharmacological treatment, then antipsychotics can be prescribed, especially during the first
trimester. Lithium may be reinstated after cardiogenesis, about 50 days postconception. For information on
treatment of bipolar disorder, see Acute treatment of bipolar disorder.

The benefits of lithium prophylaxis during pregnancy, in cases of severe bipolar disorder, may outweigh the
risks, and lithium has been considered as a first-line treatment during pregnancy for some such women.
As with any person on lithium, but particularly in the pregnant woman, there should be patient education, and
monitoring of hydration status and for signs of toxicity. More frequent blood tests for kidney function and
serum lithium concentration are recommended, especially for women who have hyperemesis or vomiting.

Any woman who has been exposed to lithium during pregnancy should have a high-resolution ultrasound at
around 18 to 20 weeks and be referred to a specialist centre for management if Ebstein's anomaly is detected.

Lithium has been associated with premature delivery, stillbirth and neonatal goitre in some isolated case
reports.

Renal clearance of lithium increases during pregnancy and falls abruptly after delivery. Careful monitoring of
serum lithium concentration (particularly in the third trimester) is indicated and dose adjustments of the order
of 25% are often required.

At delivery, lithium has been associated with the neonate being ‘floppy’ and less responsive in some case
reports. To reduce toxicity in mother and infant with the rapid reduction in vascular volume, lithium should
be stopped 24 to 48 hours before delivery (if the delivery is planned) or withheld at the onset of labour. After
delivery and when the patient is medically stable, lithium should be restarted at the prepregnancy dose.
Intrapartum and cord blood lithium concentrations may be considered if there are concerns about toxicity.
Furthermore, maternal serum lithium concentration should be taken 5 days after any dose change to ensure
that the patient is within the therapeutic range.

The puerperium is a time of high risk of relapse of mania or depression. Prophylactic treatment with lithium
immediately after delivery is sometimes appropriate for patients with bipolar disorder who have been well
controlled on lithium but who stopped it during pregnancy. There is also emerging evidence for the
prophylactic use of lithium in the postpartum period in women with a known history of postpartum
psychosis. However, the implications for breastfeeding must also be considered (see Drugs used while
breastfeeding in treatment of bipolar disorder: lithium).

There have only been two small studies looking at the long-term neurodevelopmental effects of in-utero
lithium exposure and both studies found lithium-exposed children to be similar to non-exposed controls.

Antiepileptics

Antiepileptics used in bipolar disorder include sodium valproate, carbamazepine and lamotrigine (see Bipolar
disorder). Sodium valproate and carbamazepine should only be used during pregnancy under exceptional
circumstances because of their risk of teratogenicity. The decision to continue or stop the drug should always
be in consultation with the woman and her partner. Women who discontinue their antiepileptic therapy during
pregnancy should be monitored regularly and closely. Relapse can be managed symptomatically using safer
therapy such as antipsychotics or electroconvulsive therapy. Alternatively women can be changed to lithium
after the period of fetal cardiogenesis, about 50 days postconception.

Sodium valproate has been associated with an up to 10-fold (from 0.2% to 2%) increased risk of spina bifida,
as well as other serious malformations (11% risk in total) and coagulopathies. These effects seem to be dose-
related, with increased risk from sodium valproate doses above 1000 mg daily.

Carbamazepine has also been associated with a significant increased risk of spina bifida in addition to
developmental delay and craniofacial defects. The overall risk of major malformations is approximately 6%.

If a decision is taken to continue these antiepileptics, animal data suggest that the risk of neural tube defects
may be reduced if larger than the standard oral dose of folic acid (5 mg daily instead of 0.5 mg daily) is taken
from at least 1 month before conception and continued until at least 3 months gestation. This has not been
demonstrated in humans. A number of studies suggest that vitamin K (10 to 20 mg orally daily) taken from
36 weeks of pregnancy reduces the risk of coagulopathies in neonates exposed to antiepileptics in utero.

Women taking sodium valproate or carbamazepine who become pregnant should be counselled and offered
antenatal screening. The latter can involve biochemical (alpha-feto protein), radiological and ultrasound
investigations, and expert opinion should be sought.

Early data has suggested that lamotrigine (if taken alone) may not be associated with increased risk of
congenital abnormality, even if used in early pregnancy; however, this should not be regarded as definitive.
The overall risk of major malformations with lamotrigine has been reported as 2.9%. Risk increases to 10%
to 15% if lamotrigine is combined with other more teratogenic antiepileptics, and monotherapy is highly
desirable for all antiepileptic treatment.

Lamotrigine clearance may be increased by up to 50% in late pregnancy requiring a substantially increased
dose, with corresponding dose reduction after delivery. See further information on dosing lamotrigine in
pregnant women.

Early data raise the possibility that sodium valproate and carbamazepine drug use at any time during
pregnancy may be associated with later developmental delay. However, these studies have been conducted in
women with epilepsy rather than bipolar disorder and epilepsy itself is a potential confounder.

Benzodiazepines, zolpidem and zopiclone

For anxiety and insomnia, the first-line treatment should be nonpharmacological, see Anxiety and associated
disorders: general information and Insomnia: treatment. In addition to the adverse effects associated with use
of benzodiazepines, zolpidem and zopiclone during pregnancy, there is also the risk of dependence occurring.

The issue of whether first trimester exposure to benzodiazepines is associated with increased risk of cleft lip
and/or palate is controversial. Pooled data from prospective cohort studies have shown no increase in
malformations. However, poorer quality, case-control studies have shown an association between exposure to
benzodiazepines and major malformations or oral cleft alone. The first 8 weeks of pregnancy appears to be
the period of highest risk. A high-resolution ultrasound examination at 18 to 20 weeks should be considered
for such women, and refer to a specialist centre if necessary.

If benzodiazepines (especially those with a long half-life) are taken in late pregnancy, they can cause neonatal
drowsiness, respiratory depression, poor temperature regulation, poor feeding and hypotonicity (the ‘floppy
infant syndrome’). Neonatal withdrawal symptoms have also been reported.

Small studies have found an association between zopiclone and reduced gestational age and low birth weight
babies. One of two studies has reported an association between zolpidem and an increased risk of adverse
pregnancy outcomes: small-for-gestational age and low birth weight babies, and preterm deliveries. The small
studies to date have not found an increased risk of malformations with either zopiclone or zolpidem. The
reported risk of abnormal sleep-related events with zolpidem must be considered when prescribing this drug
at any time [Note 5].

Note 5: See the Therapeutic Goods Administration warning for zolpidem at [URL].

Drugs for opioid dependence

Refer women with opioid dependence to a specialist addiction service.

Women with opioid dependence should be referred to a specialist addiction service to assist with management
during pregnancy and the postpartum.

Heroin use during pregnancy is associated with multiple adverse outcomes including: intrauterine growth
restriction, premature rupture of membranes, placental abruption, pregnancy-induced hypertension, stillbirth
and maternal and neonatal infections. Furthermore, there are the associated social risks of criminality,
prostitution and poor antenatal attendance. Opioid detoxification with medical assistance is controversial due
to concerns of possible increased obstetric complications. Furthermore, opioid detoxification is associated
with high rates of attrition and relapse.

Opioid substitution with methadone has been the standard recommended treatment for opioid dependence
during pregnancy. When compared with women with opioid dependence who are not taking methadone,
methadone use during pregnancy has benefits such as improved attendance to antenatal care, higher birth
weight babies, longer gestations and increased rate of the infant being discharged into the mother's care.
Infants of methadone-treated mothers tend to be smaller and have a smaller head circumference compared
with drug-free controls, and there is also an increased risk of stillbirths. However, the comparison with
opioid-dependent mothers is more clinically relevant.

The majority of infants exposed to methadone develop a neonatal abstinence syndrome but its severity does
not appear to be related to maternal methadone dose. Inform women taking methadone that dose increases
during pregnancy are likely to be required due to changes in pharmacokinetics, and reassure them that
neonatal abstinence syndrome is unrelated to maternal methadone dose. The presentation of this syndrome is
delayed with methadone (48 to 72 hours after birth) compared with heroin (within 24 hours). Therefore, an
extended stay in hospital for mother and baby is recommended to observe for emerging neonatal abstinence
syndrome.
Buprenorphine is currently gaining acceptance as an alternative to methadone, and placental transfer appears
less than with methadone. To date, no teratogenic effects or other increase in serious adverse effects have
been reported during pregnancy. The incidence and severity of neonatal withdrawal are probably lower
compared to methadone. There are no data to support the use of buprenorphine combined with naloxone
during pregnancy.

Nonprescribed psychoactive drugs

Introduction

Pregnancy may represent an opportunity for the clinician to discuss modification of maternal drinking and
smoking behaviours and other problem drug use. Every effort should be made to capitalise on a woman's
motivation to engage with treatment during this time.

Educational and behavioural interventions are the mainstay of treatment. Pharmacological treatments should
be considered only after specialist consultation.

Alcohol

Controversy and debate continue about how much, if any, alcohol consumption is ‘safe’ during pregnancy.
This is accompanied by efforts to define and detect the less severe presentations of the fetal alcohol spectrum
disorders (ie those without facial abnormalities). Australian guidelines [Note 6] have been made consistent
with those of the US in recommending total abstinence during pregnancy. This is based on human
longitudinal studies suggesting permanent adverse impacts on children's behavioural and neurocognitive
function at low levels of consumption (eg one to two standard drinks per week). Animal studies further
support the potential for low intake to interfere with normal brain development. However, in human studies,
numerous potential confounding variables (including psychosocial ones) render these longitudinal data
difficult to interpret. The clinician has to balance the communication of the deleterious irreversible effects of
alcohol to women of childbearing age, while not inciting panic in women who have inadvertently consumed
alcohol before knowing they are pregnant.

Ten to fifteen per cent of pregnant women continue to consume alcohol, despite it being a well-established
teratogen. The effects of alcohol on the fetus tend to be lifelong, and are best conceptualised as lying along a
continuum of severity known as the fetal alcohol spectrum disorder. The severe neurotoxic effects of ‘high’
consumption (especially binge drinking) have been well documented for over 40 years, ie the fetal alcohol
syndrome. The syndrome is characterised by growth restriction, developmental disability, neurological
damage and characteristic craniofacial abnormality. See Management Guidelines: Developmental Disability
[PDF, 7MB] for information on diagnosis and management of fetal alcohol syndrome. The harm does not
appear to be confined to first trimester alcohol consumption, and it is possible that the pattern of drinking may
be more important than the average number of drinks per week.

Neonatal withdrawal is associated with heavy alcohol use in late pregnancy. Alcohol has also been associated
with increased risk of spontaneous abortion, premature delivery and stillbirth.

There are some specialist addiction centres that will admit pregnant women for alcohol detoxification—if
available, this option should be explored. As usual, alcohol detoxification should be followed by counselling
to support ongoing abstinence. The safety during pregnancy of anticraving drugs such as naltrexone and
acamprosate has not been established. The safety of disulfiram is also unknown; while there are case reports
of normal pregnancies, there are also isolated reports of congenital malformations including a case of limb
reductions.

For information on treatment of alcohol dependence, see Alcohol: probem use.

Note 6: National Health and Medical Research Council. Australian guidelines to reduce health risks from
drinking alcohol. Canberra: Commonwealth of Australia; 2009. [URL]

Nicotine

Approximately 17% of Australian women report having smoked during pregnancy. Such women often have a
higher prevalence of other risk factors for adverse pregnancy outcomes (eg problem drug use, poor nutrition,
nonadherence with antenatal care and a suboptimal living environment). Nevertheless, there is substantial
evidence linking smoking itself with several adverse outcomes. Some significant adverse outcomes
associated with smoking during pregnancy are:
 spontaneous abortion
premature birth
intrauterine growth restriction
neonatal nicotine withdrawal syndrome
increased risk of sudden infant death syndrome (independent of postnatal exposure)
possible neurocognitive and neurobehavioural deficits in the older child.

For many of these outcomes there appears to be a dose-dependent relationship with the number of cigarettes
smoked. Mechanisms are less clear, but literature has highlighted the potential importance of other harmful
ingredients in cigarette smoke, apart from nicotine. In particular, carbon monoxide is a powerful
neuroteratogen, and can also induce fetal cellular hypoxia through formation of carboxyhaemoglobin. Fetal
blood concentration of the latter has been shown to be 1.8 times maternal blood concentration.

It appears that up to 25% of Australian women smokers quit smoking without professional help when
pregnancy is confirmed. However, this abstinence may not continue throughout the pregnancy, and the
majority of these women resume smoking after delivery.

The available evidence suggests that, for pregnant women, counselling may exert more influence on smoking
than pharmacological interventions. Nicotine replacement therapy (NRT) during pregnancy is controversial,
as nicotine itself has been linked to some of the above problems (excluding growth restriction but including
neurotoxicity) in animal studies. However, there is an emerging consensus that with NRT the level of nicotine
exposure to the fetus is less than that in women who continue to smoke heavily. Moreover, cigarette smoke is
known to contain a large number of other potentially harmful ingredients, which are avoided in successful
NRT. Unfortunately the randomised controlled trials to date have not clearly established the efficacy or safety
of NRT during pregnancy, largely due to the low adherence to therapy.

NRT can be used as an adjunct to counselling, especially in women smoking more than 10 cigarettes per day.
However, it is usually not started unless a trial of psychological interventions has failed.

If NRT is used, it should always be coupled with a psychological intervention. Care should be taken to ensure
that the initial dose is minimised but is consistent with the previous level of smoking; nicotine metabolism is
more rapid during pregnancy. When commencing NRT, intermittent regimens (eg nicotine gum or lozenge)
rather than continuous regimens (eg transdermal patch) are recommended. Transdermal patches can be
introduced if intermittent replacement fails but should be applied for 16 rather than 24 hours.

The small studies and registry data suggest that bupropion may be effective for smoking cessation during
pregnancy. There is a small increased risk of spontaneous abortion, while the findings about congenital
malformations have not been consistently replicated. Long-term developmental data following in-utero
bupropion exposure are also lacking. These uncertain factors must be weighed against the well-established
adverse outcomes of maternal cigarette smoking. There is no information on the efficacy and safety of
varenicline during pregnancy; therefore its use is not recommended.

For further information about nonpharmacological and pharmacological treatment, see Smoking cessation.

Caffeine

Studies suggest that the majority of pregnant women consume 100 to 300 mg of caffeine each day. Typical
amounts of caffeine found are around: 150 to 240 mg/250 mL for drip or percolated coffee, 80 to 120 mg/250
mL for instant coffee and 65 to 105 mg/250 mL for medium strength tea. Cola drinks contain 40 to 50
mg/375 mL, caffeine tablets contain 100 mg and energy drinks average 50 to 80 mg/250 mL of caffeine [Note
7].

There is no evidence that moderate caffeine intake presents a teratogenic risk. However, caffeine
consumption of greater than 200 mg per day has been linked to a significantly increased risk of spontaneous
abortion. The available evidence also suggests that high intake (in excess of 300 mg per day) may increase
the risk of preterm delivery and of intrauterine growth restriction. Whether lower intake also carries risk
remains controversial.

There is no evidence of long-term neurobehavioural toxicity in children of women with moderate intake of
caffeine during pregnancy.

Note 7: See caffeine facts on the Australian Drug Foundation website [URL].

Cannabis
In most developed countries, approximately 10% of women smoke cannabis at some point during pregnancy.
Animal and human research suggest that permanent neurobehavioural effects can result, and the nature of
these depends on the gestation at exposure. Cannabis use may be associated with increased risk of low birth
weight and small-for-gestational age babies. Longitudinal studies suggest that, compared to controls, such
children may have cognitive (especially visuospatial) deficits, greater impulsivity and hyperactivity, more
attention defects and higher rates of depression. Interpretation of these data requires caution owing to
possible confounding factors.

Methamphetamine

Animal studies are strongly suggestive of the potential teratogenicity of methamphetamine. In humans,
clefting and cardiac abnormalities have been described in case reports or small series. However, there are
numerous possible confounding factors in women with drug use problems and these findings have not been
confirmed. There is no evidence of a consistent syndrome with first trimester methamphetamine exposure.

More firmly established is the association between use of methamphetamine during pregnancy and increased
adverse fetal outcomes such as: smaller head circumference, small-for-gestational age and lower birth weight
relative to controls. Premature delivery has also been associated with methamphetamine use.

There is evidence of an association with long-term developmental neurobehavioural and neurocognitive

deficits in children up to 14 years of age (learning disabilities, poor attention and memory impairment).
Decreased volume of the associated subcortical structures has also been demonstrated in these children.
Although, once again, confounding biological and social factors cloud interpretation, methamphetamine is
likely to be neurotoxic to the developing brain.

Neonatal withdrawal (jitteriness, drowsiness, respiratory distress) has been frequently recorded but usually
appears to be mild and self-limiting.

Psychotropic drug use while breastfeeding

General information
Breastfeeding has multiple benefits and should be encouraged. Most psychotropic drugs are excreted in small
but detectable amounts into breastmilk. Therefore, women and their families will express understandable
concerns about the potential effect on their infant in both the short and long term. It is important to meet with
the woman and her family during pregnancy to discuss breastfeeding so that an informed choice can be made.
There are three options for a woman to consider. These are:

to continue the drug and breastfeed

to continue the drug and formula feed
to discontinue the drug and breastfeed.

The general guideline is that if the infant drug dose from breastmilk is less than 10% of the maternal drug
dose (adjusting for weight of the infant) then the drug is considered compatible with breastfeeding. See also
general background information on use of drugs while breastfeeding.

For the latest updates on psychotropic drug use while breastfeeding, and patient handouts, see:

Drugs and Lactation Database (LactMed) at [URL]

MotherToBaby at [URL]
The Women's Pregnancy and Breastfeedng Medicines Guide published by the Royal Women's
Hospital at [URL].

Harm/benefit analysis
Table 8.5 can provide a framework to aid the practitioner to decide whether or not to prescribe a psychotropic
drug while a woman is breastfeeding. It can also guide discussion with the woman, preferably in conjunction
with her partner.

The harmful effects to the infant can be conceptualised as short-term toxicity and long-term
neurodevelopmental effects (‘behavioural toxicity’). The risk of short-term toxicity depends on a variety of
complex factors, in addition to the drug itself. These include: timing of dose in relation to breastfeeding;
differing concentration in foremilk versus hindmilk; the weight both of the mother and the infant; and their
ability to metabolise and/or excrete the drug and its active metabolites. It is this complexity that accounts, in
part, for the conflicting findings about the extent of transmission of psychotropic drugs into breastmilk.
Nevertheless, most psychotropic drugs are excreted only to a minimal extent in breastmilk, and in most cases
the dose to which the infant is ultimately exposed is low and below that expected to have any significant
clinical effects. For this reason, there are few psychotropic drugs that are contraindicated while breastfeeding.

A significant number of infant adverse reactions attributed to breastfeeding are confounded by exposure in
utero. However, particular caution is required in the case of infants who are premature, have low birth weight,
are physically ill, or whose ability to metabolise and/or excrete drugs may be impaired.

Apart from a few exceptions (eg lithium, clozapine), psychotropic drugs used during pregnancy can generally
be continued while breastfeeding. In general, for most drugs the placental transfer exceeds the excretion into
breastmilk.

Infants whose mothers are taking psychotropic drugs should be monitored for excessive sedation, irritability,
agitation and gastrointestinal dysfunction (eg colic, poor feeding). However, given the high incidence of
some of these problems in infants in general, the practitioner should be cautious about attributing them
entirely to a drug. If severe, a trial of decreased dose, cessation or a formula feed may be appropriate.

Long-term neurodevelopmental effects are largely unexplored and nonpharmacological interventions always
warrant consideration. However, although no psychotropic drug can be considered 100% safe in lactation,
this should not deter prescribing when it is otherwise indicated.

Harm/benefit analysis for prescribing while breastfeeding (Table 8.5)

Infant Mother
short-term toxicity
overdose
Possible harms of long-term
adverse effects
prescribing neurodevelopmental
possible negative impact on therapeutic alliance
effects

Possible harms of
NOT prescribing
infant abuse/neglect
relapse of psychiatric illness
adverse impact of
suicide/self-harm/infanticide
maternal mental state
family/relationship deterioration
on the mother–infant
use of harmful substitutes
relationship

Antipsychotics
Definitive information on use while breastfeeding is lacking for the second-generation antipsychotics
(amisulpride, aripiprazole, asenapine, clozapine, olanzapine, paliperidone, quetiapine, risperidone, sertindole
and ziprasidone) [Note 8]. Preliminary data suggest that olanzapine and risperidone have low infant doses
relative to the maternal weight-adjusted dose and these drugs are being increasingly used during lactation.
However, additional studies are required to definitively establish safety, and the association of olanzapine
with some reversible adverse effects (jaundice, impaired weight gain, sedation, irritability and tremor) in a
small series of breastfed babies has led the manufacturer to recommend against breastfeeding while taking
olanzapine.

Clozapine should not be used while breastfeeding (due to high concentration in breastmilk and the theoretical
risk of agranulocytosis occurring in the infant). The usual clinical recommendation is for the continuation of
clozapine for maternal wellbeing and the use of formula feeding rather than breastfeeding.

Concurrent use of more than one antipsychotic while breastfeeding appears to substantially increase the
likelihood of adverse infant reactions.

The first-generation antipsychotics, especially at high dose, have occasionally been associated with adverse
reactions in breastfed infants (eg urinary retention, dystonic reactions). In lower dose, ie less than 10 mg
haloperidol daily or equivalent, they are usually regarded as safe.

Depot antipsychotic injections should be reserved for when there are no other antipsychotic treatment
options. If the infant suffers an adverse reaction to a depot antipsychotic, cessation of breastfeeding is
necessary.

Note 8: Sertindole was discontinued in Australia in January 2014.

Antidepressants
The placental transfer and fetal exposure to antidepressants in utero is much greater than breastmilk exposure
occurring after birth. Therefore, in circumstances where a woman has been taking an antidepressant during
pregnancy for treatment of depression or anxiety, this should be continued into the postpartum period.
Switching to an alternative antidepressant on the grounds of lower breastmilk concentration is not
recommended.

In the case of selective serotonin reuptake inhibitors (SSRIs), most studies suggest that infant plasma
concentrations are either low or not detected, with the exception of fluoxetine where clinically significant
concentrations have been measured. Fluoxetine and its metabolites with long half-lives have the potential to
accumulate in the breastfed infant, and fluoxetine has been associated with low weight gain, irritability,
difficulty settling and infant gastrointestinal dysfunction in several studies. There are now several published
studies on sertraline, citalopram, fluvoxamine and paroxetine that show acceptably low relative doses, and
minimal short-term toxicity, in breastfed infants. From published data, sertraline and paroxetine appear to
have the lowest transmission into breastmilk and fluoxetine, escitalopram and citalopram the highest.
Venlafaxine gives a higher mean relative infant dose than the SSRIs; however, for some women venlafaxine
may have been prescribed during pregnancy or earlier due to lack of efficacy of other antidepressants. For
these women, if they have a full-term infant who is otherwise well, breastfeeding should be encouraged.

Where infants breastfed by mothers taking SSRIs or venlafaxine have been assessed neurologically or
developmentally, no adverse outcomes have been noted. However, isolated cases of irritability, sleep
disturbance and colic, which remitted when breastfeeding or the antidepressant was stopped, have been
reported. The majority of these cases involved infants under 2 months and use of fluoxetine.

Breastmilk transfer of tricyclic antidepressants (TCAs) is low, and they are generally considered safe while
breastfeeding; however, compared with SSRIs they have a less favourable adverse effect profile for the
mother, and much higher lethality in overdose. The use of doxepin is not recommended because there have
been isolated case reports of sedation and respiratory depression in infants.

Nortriptyline is sometimes preferred on the grounds that maternal serum concentration can be monitored.

Regarding neurodevelopmental toxicity of TCAs in breastmilk, the only data are for dothiepin (15 infants
followed for 4 years). No adverse sequelae were found.

Moclobemide has very low transfer into breastmilk and is probably safe. Agomelatine, desvenlafaxine,
duloxetine, mianserin, mirtazapine, reboxetine and the irreversible nonselective monoamine oxidase
inhibitors (MAOIs) have not been adequately studied.

Drugs used in treatment of bipolar disorder

General information

Drugs used in the treatment of bipolar disorder include lithium, sodium valproate, carbamazepine and
lamotrigine, as well as second-generation antipsychotics. Discontinuation of these drugs in patients with
bipolar disorder is associated with a significant risk of relapse. The harms versus benefits must be carefully
weighed, taking into account the following sections on lithium and antiepileptics and the preceding section on
antipsychotics, see Psychotropic drugs while breastfeeding: antipsychotics, above.

Lithium

There is conflicting evidence about the safety of lithium while breastfeeding. The passage of lithium into the
breastmilk is highly variable. Moreover, the interpretation of infant serum lithium concentration, in terms of
safety, may be difficult. The American Academy of Pediatrics states lithium is contraindicated while
breastfeeding. However, this is not a consistent recommendation from other sources. In women with
moderate-to-severe bipolar disorder, the preference would be for the baby to have formula milk while the
woman is continued on lithium, because of the high rate of relapse in the postpartum if lithium is stopped.

If a woman chooses to breastfeed while on lithium, this should be done with caution. Regular monitoring of
infant serum lithium concentration, thyroid function and electrolytes is recommended, and taking blood is an
invasive procedure. Furthermore, the infant should have ongoing specialist monitoring while exposed to
lithium through breastmilk. Breastfeeding should be avoided or stopped if there are signs of infant sedation,
dehydration, hypothyroidism and/or respiratory depression.

Antiepileptics

No serious adverse report has been associated with sodium valproate while breastfeeding.
Occasional reports associate carbamazepine use while breastfeeding with infant jaundice and liver
dysfunction. However, most guidelines regard it as compatible with breastfeeding. Monitoring of infant liver
biochemistry and white cell count is worthwhile if the woman is taking either sodium valproate or
carbamazepine.

Unlike lithium, the American Academy of Pediatrics does not regard these two antiepileptics as
contraindicated while breastfeeding.

The safety of lamotrigine while breastfeeding is questionable. Potentially serious skin conditions have been
reported in young children treated with this drug. Lamotrigine has relatively high transmission to and slow
elimination from the neonate.

Benzodiazepines, zolpidem and zopiclone

In the postpartum period, as with any other time, the initial management of anxiety and insomnia should be
nonpharmacological, see Anxiety and associated disorders: general information and Insomnia: treatment.

‘Floppy infant syndrome’, with symptoms of hypotonia, lethargy and reduced suckling, has been reported
with the long-acting benzodiazepines (eg diazepam) since they may accumulate in the infant during chronic
use. If a benzodiazepine hypnotic is needed while breastfeeding, then those with a short half-life are
preferable (eg temazepam).

Particular caution should be exercised in the first 3 or 4 postnatal days, especially if the infant has
physiological jaundice.

Case series of zolpidem and zopiclone use while breastfeeding reported very low excretion into breastmilk
and no short-term adverse outcomes in the small number of exposed infants. However, the risk of abnormal
sleep-related events with zolpidem must be considered when prescribing this drug at any time [Note 9].

Note 9: See the Therapeutic Goods Administration warning for zolpidem at [URL].

Drugs for opioid dependence

Methadone is considered relatively safe to use while breastfeeding. The concentration in breastmilk is low,
regardless of maternal dose. Symptoms of withdrawal may occur in the first week in 60% of infants born to
mothers on methadone maintenance during pregnancy. The concentration of methadone in breastmilk is
insufficient to prevent this. Infants in withdrawal are often very difficult to breastfeed (irritable and
hypertonic with poor suck and swallow coordination) and involvement of a lactation consultant is desirable.

Maternal methadone use (irrespective of dose) is considered compatible with breastfeeding. Provided there
are no maternal medical contraindications (other illicit drug use, maternal HIV), women taking methadone
should be strongly encouraged to breastfeed. With the change in pharmacokinetics, women usually need to
have their methadone dose incrementally reduced in the postpartum. The dose needs to be optimised so that
women are not oversedated, especially when caring for their infants.

Buprenorphine has not been associated with adverse effects on the breastfed infant in a small number of
reports, and transmission to breastmilk is low. Breastfeeding with buprenorphine is not contraindicated;
however, there are a lack of data on long-term outcomes for exposed infants. There are no data to support the
use of buprenorphine plus naloxone while breastfeeding.

Nonprescribed psychoactive drugs

Introduction

The postnatal period is a priority time for intervention with alcohol, smoking and problem drug use. The
mode of intervention will depend on where the woman is in the stages of change cycle. Some women may
have already made significant changes during pregnancy that require consolidation, while others may still be
precontemplative. Every effort should be made to capitalise on a woman's motivation to engage with
treatment during this time and thus provide the safest environment for her child.

Educational and behavioural interventions should be the mainstay of treatment. Pharmacological treatments
should only be considered after specialist consultation.

Alcohol
Findings in this area are complicated by the fact that alcohol consumption while breastfeeding often
represents a continuation of consumption during pregnancy, making it difficult to separate adverse effects on
the infant from each period. Confounders such as smoking also make interpretation difficult.

Alcohol has been associated with delayed let-down reflex and reduced breastmilk supply, probably related to
inhibition of oxytocin and prolactin release. Thus, in contrast to a prevailing folklore in many cultures of the
benefits of alcohol for milk production, the opposite is more likely the case.

The infant's liver maturation is not complete until approximately 3 months, and the resultant reduced capacity
to metabolise alcohol could potentially lead to accumulation. Both excessive drowsiness and irritability have
been described in breastfed infants whose mothers consume alcohol.

Both animal and human studies point towards potential adverse long-term effects in the offspring.
Significantly poorer development of motor skills has been reported in breastfed infants of mothers who
consumed one standard drink per day. There is also evidence that exposure to alcohol in breastmilk is
associated with subsequent active seeking of alcohol. Whether this translates into earlier initiation of drinking
in later life (eg adolescence) is unclear.

A safe level of alcohol consumption while breastfeeding has not been defined. The clinician is faced with a
dilemma in terms of weighing up the relative harms and benefits of breastfeeding for women who regularly
consume alcohol.

The safety of the anticraving drugs naltrexone and acamprosate has not been established while breastfeeding.
There are no reports of disulfiram use in lactation therefore the potential effects on the infant are unknown.

Nicotine

In Australia, over half of women who quit smoking during pregnancy resume smoking in the postnatal
period. Women often see smoking as helpful for losing weight, and postnatal smoking may be perceived as
more socially acceptable compared to smoking during pregnancy. The powerful influence of having a partner
who smokes has also been emphasised.

There is a well-established dose–response relationship between the number of cigarettes smoked and reduced
likelihood or duration of breastfeeding.

Smoking has a number of adverse effects on lactation in terms of reduced milk production, interference with
the let-down reflex and altered taste of breastmilk (which the infant may refuse). The infant may be affected
through both nicotine in the milk and from second-hand smoke. The effects may include colic, diarrhoea,
tachycardia, irritability, apnoeic episodes and immune system impairment. These are especially likely if the
woman smokes more than 15 cigarettes per day.

There is debate as to whether the adverse effects of nicotine in breastmilk are outweighed by the benefits
(especially immunological ones) to the infant of being breastfed. It has been argued that if a woman cannot
stop smoking during the postnatal period she should nevertheless still breastfeed. The enhanced
immunological competence of the infant was shown, in some studies, to be protective against the increased
risk of respiratory tract infection caused by second-hand smoke.

By delaying smoking until just after breastfeeding, the nicotine present in milk at the time of the next
breastfeed is minimised.

Ongoing exposure to cigarette smoke in the postnatal period is a well-recognised risk factor for sudden infant
death syndrome (SIDS).

The use of nicotine replacement therapy (NRT) while breastfeeding is controversial. Serum concentration of
nicotine in breastfed infants of mothers using NRT is low (approximately 6% of maternal serum
concentration), possibly due to the infant's first pass metabolism of oral nicotine. Moreover, the milk will not
contain other cigarette-derived toxic substances. The additional benefits for a young baby in a nonsmoking
household should also be taken into account (eg reduced risk of SIDS). If nonpharmacological measures are
unsuccessful, consideration of the use of NRT is warranted. Rather than patches, intermittent regimens are
sometimes advocated to allow breastfeeding to precede the nicotine dose.

Data suggest that infant bupropion dose from breastfeeding is approximately 2% of maternal dose. Using the
guideline that less than 10% is likely to be safe for most drugs, this is reassuring. A small number of case
reports have found bupropion undetectable in the serum of breastfed babies whose mothers were taking the
drug. The risks associated with bupropion during lactation are low compared to the risk of ongoing cigarette
smoking.
There are no data on the efficacy and safety of varenicline to recommend its use during lactation.

Caffeine

Caffeine is readily transferred into breastmilk. Young infants have a lower capacity to metabolise caffeine,
which raises the possibility of caffeine toxicity. Infants breastfed by mothers ingesting more than 300 mg per
day may become jittery, restless and experience sleep difficulties. No long-term adverse effects have been
documented. Conflicting findings have emerged about the relationship between caffeine and SIDS.
Confounding factors (eg smoking) may explain the association found in one study, which could not be
replicated. For information on the approximate caffeine content in various drinks, see Psychotropic drug use
during pregnancy: caffeine.

Cannabis

Cannabis passes readily into breastmilk. Animal studies have repeatedly demonstrated adverse effects on the
rapidly developing infant brain. Human data are difficult to interpret due to confounding factors (including
second-hand smoke) but appear to support the detrimental neurocognitive impact. Several articles advise
against breastfeeding while continuing to use cannabis.

Methamphetamine

There are very little data on methamphetamine use while breastfeeding. One study of four babies breastfed by
mothers taking dexamphetamine reported that this was readily transferred into breastmilk, but the relative
infant dose was less than 10% (which is generally considered acceptable in the short term). No adverse infant
effects were observed.

Key references
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Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
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Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Field T, Diego M, Hernandez-Reif M. Prenatal depression effects on the fetus and newborn: a review. Infant
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Galbally M, Roberts M, Buist A. Mood stabilizers in pregnancy: a systematic review. Aust N Z J Psychiatry.
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Scottish Intercollegiate Guidelines Network (SIGN). Management of perinatal mood disorders: a national clinical
guideline (SIGN 127). Edinburgh: SIGN; 2012. [URL]

Vajda FJ, Horgan D, Hollingworth S, Graham J, Hitchcock AA, Roten A, et al. The prescribing of antiepileptic
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Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A, et al. Risk of recurrence in women
with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry.
2007;164(12):1817–24. quiz 923. [ ]

Postpartum psychosis

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Scottish Intercollegiate Guidelines Network (SIGN). Management of perinatal mood disorders: a national clinical
guideline (SIGN 127). Edinburgh: SIGN; 2012. [URL]

Depression in pregnancy and the postpartum

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Field T, Diego M, Hernandez-Reif M. Prenatal depression effects on the fetus and newborn: a review. Infant
Behav Dev. 2006;29(3):445–55. [ ]

Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during
pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry.
2010;67(10):1012–24. [ ]

Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and
postpartum. Dialogues In Clinical Neuroscience. 2011;13(1):89–100. [ ]

Scottish Intercollegiate Guidelines Network (SIGN). Management of perinatal mood disorders: a national clinical
guideline (SIGN 127). Edinburgh: SIGN; 2012. [URL]

Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, et al. The management of depression
during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians
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Anxiety in pregnancy and the postpartum

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Scottish Intercollegiate Guidelines Network (SIGN). Management of perinatal mood disorders: a national clinical
guideline (SIGN 127). Edinburgh: SIGN; 2012. [URL]

Eating disorders in pregnancy and the postpartum

Lowes H, Kopeika J, Micali N, Ash A. Anorexia nervosa in pregnancy. Obstetrician & Gynaecologist.
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Ward VB. Eating disorders in pregnancy. BMJ. 2008;336(7635):93–6. [ ]

Electroconvulsive therapy during pregnancy

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
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Psychotropic drug use during pregnancy: general information and harm/benefit analysis

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Galbally M, Snellen M, Lewis AJ. A review of the use of psychotropic medication in pregnancy. Current Opinion
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Psychotropic drug use during pregnancy: antipsychotics

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Galbally M, Snellen M, Lewis AJ. A review of the use of psychotropic medication in pregnancy. Current Opinion
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Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophrenia Bulletin.
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Psychotropic drug use during pregnancy: antidepressants

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related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Einarson A, Pistelli A, DeSantis M, Malm H, Paulus WD, Panchaud A, et al. Evaluation of the risk of congenital
cardiovascular defects associated with use of paroxetine during pregnancy. Am J Psychiatry. 2008;165(6):749–
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Field T, Diego M, Hernandez-Reif M. Prenatal depression effects on the fetus and newborn: a review. Infant
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Galbally M, Snellen M, Lewis AJ. A review of the use of psychotropic medication in pregnancy. Current Opinion
In Obstetrics & Gynecology. 2011;23(6):408–14. [ ]

Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A meta-analysis of depression during
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2010;67(10):1012–24. [ ]

Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and
postpartum. Dialogues In Clinical Neuroscience. 2011;13(1):89–100. [ ]

Occhiogrosso M, Omran SS, Altemus M. Persistent pulmonary hypertension of the newborn and selective
serotonin reuptake inhibitors: lessons from clinical and translational studies. The American Journal Of Psychiatry.
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related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
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Cohen LS, Rosenbaum JF. Psychotropic drug use during pregnancy: weighing the risks. J Clin Psychiatry.
1998;59 Suppl 218–28. [ ]

Field T, Diego M, Hernandez-Reif M. Prenatal depression effects on the fetus and newborn: a review. Infant
Behav Dev. 2006;29(3):445–55. [ ]

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2010;44(11):967–77. [ ]

Galbally M, Snellen M, Lewis AJ. A review of the use of psychotropic medication in pregnancy. Current Opinion
In Obstetrics & Gynecology. 2011;23(6):408–14. [ ]
Vajda FJ, Horgan D, Hollingworth S, Graham J, Hitchcock AA, Roten A, et al. The prescribing of antiepileptic
drugs for pregnant Australian women. Aust N Z J Obstet Gynaecol. 2012;52(1):49–53. [ ]

Viguera AC, Whitfield T, Baldessarini RJ, Newport DJ, Stowe Z, Reminick A, et al. Risk of recurrence in women
with bipolar disorder during pregnancy: prospective study of mood stabilizer discontinuation. Am J Psychiatry.
2007;164(12):1817–24. quiz 923. [ ]

Psychotropic drug use during pregnancy: benzodiazepines, zolpidem and zopiclone

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

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malformations: a critical overview. Gen Hosp Psychiatry. 2013;35(1):3–8. [ ]

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84. [ ]

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Physician. 2011;40(9):684–90. [ ]

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related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

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Psychotropic drug use while breastfeeding: prescribed psychoactive drugs

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Physician. 2011;40(9):684–90. [ ]

Gentile S, Rossi A, Bellantuono C. SSRIs during breastfeeding: spotlight on milk-to-plasma ratio. Arch Womens
Ment Health. 2007;10(2):39–51. [ ]

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postpartum. Dialogues In Clinical Neuroscience. 2011;13(1):89–100. [ ]

Moretti ME. Psychotropic drugs in lactation: Motherisk Update 2008. The Canadian Journal Of Clinical
Pharmacology = Journal Canadien De Pharmacologie Clinique. 2009;16(1):e49–e57. [ ]

Psychotropic drug use while breastfeeding: nonprescribed psychoactive drugs

Amir LH, Pirotta MV, Raval M. Breastfeeding: evidence based guidelines for the use of medicines. Aust Fam
Physician. 2011;40(9):684–90. [ ]

Austin M-P, Highet N, Guidelines Expert Advisory Committee. Clinical practice guidelines for depression and
related disorders: anxiety, bipolar disorder and puerperal psychosis in the perinatal period. A guideline for primary
care health professionals. Melbourne: beyondblue; 2011. [URL]

Moretti ME. Psychotropic drugs in lactation: Motherisk Update 2008. The Canadian Journal Of Clinical
Pharmacology = Journal Canadien De Pharmacologie Clinique. 2009;16(1):e49–e57. [ ]

Published July 2013. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Psychiatric disorders: patient resources and
support organisations (Appendix 8.1)
General information
Listed below are potentially useful patient resources and support organisations for people with psychiatric
disorders. Users should be aware that websites might not be vetted for the quality of information they
provide, and that many disease information and patient support organisations are sponsored by the
pharmaceutical industry. Therapeutic Guidelines Limited accepts no responsibility for the currency or
accuracy of the information found at these or linked websites.

General resources
National
Clinical Research Unit for Anxiety and Depression: [URL]

Lifeline: Telephone 131 114, [URL]

Medicines Line: Telephone 1300 633 424

MensLine Australia: Telephone 1300 789 978, [URL]

Mental Health Association Australia: [URL]

Mental Health Carers Arafmi Australia: [URL]

Mental Health Council of Australia: [URL]

Mental Illness Fellowship of Australia: [URL]

Mind Australia: [URL]

mindhealthconnect: [URL]

MiNetworks Australia: [URL]

Mental Health in Multicultural Australia: [URL]

National Mental Health Consumer and Carer Forum: [URL]

National Prescribing Service (NPS): [URL] (NPS has consumer medicine information sheets)

Psychotropic Drug Advisory Service: Telephone (03) 9388 1633.

The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for
consumers and carers: [URL]

SANE Australia: [URL]

Australian Capital Territory

Mental Health Triage Service: Telephone 1800 629 354

Mental Health Foundation ACT: [URL]

Mental Illness Fellowship Victoria: [URL]

New South Wales

ARAFMI NSW: [URL]

Mental Health Association NSW: Telephone 1300 794 991 (general) or 1300 794 992 (anxiety disorders),
[URL]

NSW Mental Health Line: Telephone 1800 011 511

Schizophrenia Fellowship of NSW Inc.: [URL]

Northern Territory
Mental Health Association of Central Australia: [URL]

Mental Health Carers NT: [URL]

Northern Territory Crisis Assessment Telephone Triage and Liaison Service: Telephone 1800 682 288

TEAMhealth: [URL]

Queensland

ARAFMI Queensland Inc.: [URL]

Mental Illness Fellowship of North Queensland Inc.: [URL]

Mental Illness Fellowship of Queensland

South Australia

Mental Health Triage Service: Telephone 131 465

Mental Illness Fellowship South Australia: [URL]

Tasmania
Mental Health Carers Tasmania: [URL]

Mental Health Services Helpline: Telephone 1800 332 388

Victoria
ARAFEMI: [URL]

Mental Health Foundation of Australia (Victoria): [URL]

Mental Illness Fellowship Victoria: [URL]

Victorian Mental Illness Awareness Council: [URL]

Western Australia
Mental Health Carers Arafmi (WA) Inc.: [URL]

Mental Health Emergency Response Line: Telephone 1300 555 788 (Perth metropolitan) or 1800 676 822
(Peel region)

Mental Illness Fellowship of Western Australia: [URL]

Western Australian Association for Mental Health: [URL]

Alcohol and other drug problems: resources

Alcohol and Other Drugs Council of Australia Help Lines:

Australian Capital Territory: Telephone (02) 6207 9977

New South Wales: Telephone (02) 9361 8000 (metropolitan) or 1800 177 833 (other areas)

Northern Territory: Telephone (08) 8922 8399 (Darwin) or (08) 8951 7580 (central Australia) or 1800 131
350

Queensland: Telephone (07) 3837 5989 (Brisbane) or 1800 177 833 (regional Queensland)

South Australia: Telephone 1300 131 340

Tasmania: Telephone 1800 811 994

Victoria: Telephone 1800 888 236

Western Australia: Telephone (08) 9442 5000 (metropolitan) or 1800 653 203

Alcoholics Anonymous Australia: [URL]

Counselling Online: [URL]

DrinkWise Australia: [URL]

Narcotics Anonymous Australia: [URL]

SMART Recovery Australia: [URL]

Anxiety and associated disorders: resources

beyondblue (support line): Telephone 1300 224 636, [URL]

headspace: [URL]

mindhealthconnect: [URL]

Reconnexion: [URL]

Dementia: resources
Alzheimer's Australia: National Dementia Helpline 1800 100 500, [URL]

The website lists contact numbers for helplines in all Australian states and territories.

Depression and bipolar disorder: resources

beyondblue (support line): Telephone 1300 224 636, [URL]

Black Dog Institute: [URL]

BluePages: [URL]

Griefline (services): Telephone (03) 9935 7400, [URL]

National Association for Loss and Grief (NSW) Inc.: [URL]

SuicideLine (Victoria): Telephone 1300 651 251, [URL]

Suicide Call Back Service: Telephone 1300 659 467, [URL]

Disorders usually first diagnosed in childhood and adolescence:

resources
headspace: [URL]

itsallright: [URL]
Kids Helpline: Telephone 1800 55 1800, [URL]

Lifeline: Telephone 131 114, [URL]

Attention deficit hyperactivity disorder (ADHD)

Every day with ADHD: [URL]

The website lists contact details for ADHD support groups in Australia and New Zealand.

Autism spectrum disorders

State autism associations provide information and support for parents, professionals and other interested
people.

Australian Capital Territory: [URL]

New South Wales: [URL]

Northern Territory: [URL]

Queensland: [URL]

South Australia: [URL]

Tasmania: [URL]

Victoria: [URL]

Western Australia: [URL]

Eating disorders: resources

Eating Disorders Association Inc: [URL]

Eating Disorders Victoria: [URL]

If not dieting: [URL]

Butterfly Foundation for Eating Disorders: [URL]

The Centre for Eating and Dieting Disorders: [URL]

Self-help books
Fairburn C. Overcoming binge eating. New York: The Guilford Press; 1995

Cooper P. Bulimia nervosa and binge eating. A guide to recovery. London: Robinson Press; 1995

Schmidt U, Treasure J. Getting better bitE by bitE: A survival kit for sufferers of bulimia nervosa and binge
eating disorders. Hove, UK: Psychology Press; 1993

Treasure J, Alexander J. Anorexia nervosa: A recovery guide for sufferers, families and friends. 2nd ed.
Abingdon, UK: Routledge; 2013

Treasure J, Smith G, Crane A. Skills-based learning for caring for a loved one with an eating disorder.
Abingdon: Routledge; 2007

Gambling problems: resources

Gamblers Helpline: Telephone: 1800 858 858, [URL]

Schizophrenia: resources
ARAFEMI: [URL]

Mental Health Carers NT: [URL]

Mental Health Carers Tasmania: [URL]

Mental Health Foundation ACT: [URL]

Mental Illness Fellowship of Australia Inc.: [URL]

Mental Illness Fellowship of North Queensland Inc.: [URL]

Mental Illness Fellowship Queensland

Mental Illness Fellowship South Australia: [URL]

Mental Illness Fellowship of Western Australia: [URL]

Orygen Youth Health: [URL]

Schizophrenia Fellowship of NSW Inc.: [URL]

Schizophrenia Research Institute: [URL]

Smoking cessation: resources

QUITline: Telephone 137 848, [URL]

The website includes contact details for smoking cessation resources in all Australian states and territories.

Published July 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Psychiatric disorders: sources of information and
assistance for health professionals (Appendix 8.2)
General information
Listed below are potentially useful sources of psychotropic information for health professionals. Users should
be aware that websites might not be vetted for the quality of information they provide, and that many disease
information and patient support organisations are sponsored by the pharmaceutical industry. Therapeutic
Guidelines Limited accepts no responsibility for the currency or accuracy of the information found at these or
linked websites.

General resources
Clinical Research Unit for Anxiety and Depression: [URL]

Mental Health in Multicultural Australia: [URL]

mindhealthconnect: [URL]

Psychotropic Drug Advisory Service: Telephone (03) 9076 8036.

The Royal Australian and New Zealand College of Psychiatrists: [URL]

Alcohol and other drug problems: resources

The following state and territory based telephone services provide 24-hour medical advice to health
professionals seeking advice for managing drug and/or alcohol affected patients.

Australian Capital Territory

Drug & Alcohol Specialist Advisory Service (DASAS): Telephone 1800 023 687 (country NSW and ACT)

New South Wales

Drug & Alcohol Specialist Advisory Service (DASAS): Telephone (02) 9361 8006 (Sydney metropolitan) or
1800 023 687 (country NSW)

Northern Territory

Drug and Alcohol Clinical Advisory Services (DACAS): Telephone 1800 111 092

Queensland

Alcohol and Drug Information Service: Telephone 1800 177 833

South Australia

Drug and Alcohol Clinical Advisory Services (DACAS): Telephone (08) 8363 8633

Tasmania

Drug and Alcohol Clinical Advisory Services (DACAS): Telephone 1800 630 093

Victoria

Drug and Alcohol Clinical Advisory Services (DACAS): Telephone 1800 812 804

Western Australia
Drug and Alcohol Clinical Advisory Service: Telephone (08) 9442 5042 or 1800 688 847 (country WA)

Alcohol and Other Drugs Council of Australia: [URL]

The website lists contact numbers for drug and alcohol information in all Australian states and territories.

Australian Drug Foundation: [URL]

Australian Government: [URL]

The website provides links to information about alcohol-related health issues and government policy.

Turning Point Alcohol and Drug Centre: [URL]

Anxiety and associated disorders: resources

beyondblue (support line): Telephone 1300 224 636, [URL]

mindhealthconnect: [URL]

Dementia: resources
Tools to aid in assessing cognition in particular settings can be found on the following websites.

Kimberley Indigenous Cognitive Assessment (KiCA): [URL]

Montreal Cognitive Assessment (MoCA): [URL]

Rowland Universal Dementia Assessment Scale (RUDAS): [URL]

Depression and bipolar disorder: resources

beyondblue (support line): Telephone 1300 224 636, [URL]

Black Dog Institute: [URL]

Disorders usually first diagnosed in childhood and adolescence:

resources
American Academy of Child and Adolescent Psychiatry Practice Parameters: [URL]

EPPIC-Early Psychosis Prevention and Intervention Centre: [URL]

Guidelines for Adolescent Depression in Primary Care (GLAD-PC) Tool Kit: [URL]

Personality disorders: resources

Borderline personality disorder. A resource booklet for general practitioners can be accessed from the
General Practice South, Tasmania website: [URL]

Spectrum, the personality disorder service for Victoria: [URL]

Psychiatric conditions in pregnancy and the postpartum: resources

beyondblue (support line): Telephone 1300 224 636, [URL]

Drugs and Lactation Database (LactMed): [URL]

MotherToBaby: [URL]

The Women's Pregnancy and Breastfeeding Medicines Guide published by the Royal Women's Hospital:
[URL]
Published July 2013. Amended March 2020. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Dietary guidelines for patients taking irreversible
nonselective monoamine oxidase inhibitors
(Appendix 8.3)
Dietary guidelines for nonselective MAOIs
The irreversible nonselective monoamine oxidase inhibitors (MAOIs), phenelzine and tranylcypromine,
may cause significant hypertension when combined with foods containing large amounts of tyramine so these
foods should be avoided (see Table 8.22). Tyramine is an indirectly acting sympathomimetic metabolised by
monoamine oxidase enzymes. A dose of at least 10 to 25 mg of tyramine is thought to be required to cause a
serious rise in blood pressure. A throbbing headache (usually occipital) is the first symptom. Any hypertensive
episode should be treated urgently (see Urgent reduction of blood pressure).

Interactions with tyramine-containing foods are unlikely at recommended doses of moclobemide, a reversible
inhibitor of monoamine oxidase type A (MAO-A), as tyramine is still metabolised by monoamine oxidase
type B (MAO-B). Risk of interaction is further minimised by taking moclobemide after meals. However,
when used at higher than recommended doses, moclobemide also inhibits MAO-B and dietary restrictions are
warranted (see Table 8.22).

Irreversible nonselective monoamine oxidase inhibitor dietary guidelines (Table 8.22)

Print-friendly PDF

This table should be used as a guide only. All food should be fresh or freshly frozen, stored properly and eaten soon
after purchase. Avoid food that is fermented or possibly ‘off’.

There is no way of knowing for certain the tyramine or other biologically active amine content of food or drink
without appropriate product analysis.

Food types Permitted Avoid [NB1] [NB2]

fresh cottage, cream and ricotta cheese;
cheese and other processed cheese slices; all fresh milk
matured, aged or out-of-date cheese
milk products products that have been stored correctly
(eg fresh cream, yoghurt, ice cream)
liver products (eg pâté); fermented,
matured or aged meat (eg salami,
meat, fish, poultry all permitted except those listed opposite
pepperoni, mortadella); pickled herring;
and eggs as avoid
improperly stored or spoilt meat, fish,
poultry or eggs
fava or broad bean pods (not beans),
all permitted except those listed opposite
fruit and vegetables banana peel (not pulp), sauerkraut,
as avoid
fermented soya beans
spirits, moderate quantities [NB3] of
bottled or canned beer (including
nonalcoholic beer), moderate quantities
alcoholic drinks [NB3] of wine (except Chianti wine made all tap and home-brewed beers [NB4],
by the governo process). Chianti wine made by the governo process

Red wine may cause a headache unrelated

to a rise in blood pressure
yeast extracts (eg Vegemite, Promite,
Marmite, Bovril); protein extracts; soy
Brewer's yeast; soy milk; commercial soup sauce and other soybean products (eg
miscellaneous bases, packet soups and tinned soups if miso, tofu); banana chips and banana-
used before their expiry date flavoured dessert (banana peel is used in
 flavouring)
NB1: These foods are known to contain large amounts of tyramine; however, any food high in aromatic amino acids can become high in tyramine
if spoilage occurs or after storage. Cooking does not inactivate tyramine.
NB2: Wait for 14 days after stopping phenelzine or tranylcypromine before eating any of these foods to allow new monoamine oxidase enzymes to
be synthesised.
NB3: Moderate quantities: beer–2 x 340 mL glasses, wine–2 x 110 mL glasses.
NB4: Home-brewed alcoholic drinks should be avoided as they have a highly variable tyramine concentration.

Key references
Dietary guidelines for patients taking irreversible nonselective monoamine oxidase
inhibitors (Appendix 8.3)

MAOIs or RIMAs + Food; Tyramine-containing. In: Baxter K, editor. Stockley's drug interactions (online). London:
Pharmaceutical Press; August 2012.

Monoamine oxidase inhibitors. In: Rossi S, editor. Australian medicines handbook (online). Adelaide: Australian
Medicines Handbook; July 2012.

Published March 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Management of common adverse effects of
psychotropic drugs (Appendix 8.4)
Summary table
With any drug causing adverse effects, determine the extent of the adverse effect burden and consider if a
change in medication is indicated. Also review the dose, timing of the dose, and potential drug interactions
that may be contributing to the adverse effect burden. If a decision is made to continue the medication, the
practical management strategies for common adverse effects given in Table 8.23 may be helpful where
appropriate.

Practical management strategies for common adverse effects of psychotropic drugs (Table
8.23)

Adverse effect Management strategies

ensure adequate hydration—drink (rather than sip) adequate amounts of
fluid, particularly tap water
chew sugarless gum or suck sugarless sweets (avoid fruit flavours)
dry mouth use artificial saliva products
use lip balm/gloss
see also Dry mouth

ensure adequate intake of noncaffeinated fluid and dietary fibre

constipation ensure adequate physical activity
consider the appropriate use of laxatives (see Functional constipation)

take medication after food

nausea
sit up in bed before getting up
have a chair by the bed to hold on to when first standing up
orthostatic hypotension if feeling dizzy, lie down, or sit down and bend head down to knees
ensure adequate hydration

take medication in the evening, or early evening if the feeling of sedation

sedation persists the next day

take medication in the morning

insomnia ensure good sleep practices (see Box 8.2)

consider timing of dose in relation to anticipated sexual activity

consider the use of medications for erectile dysfunction (eg sildenafil,
sexual dysfunction tadalafil) (see Erectile dysfunction)
see also Management of antipsychotic adverse effects:
hyperprolactinaemia

use a mug rather than a cup, only fill half way, and hold with two hands
tremor sit on hands or hold hands in lap when sitting

medications that stimulate appetite often increase the urge to eat in the
hour or two following administration so consider taking these medications
at bedtime
encourage healthy eating and physical activity
weight gain consider weight reduction programs (see Management of overweight and
obesity)
see also Management of antipsychotic adverse effects: weight gain and
other cardiometabolic effects
Published March 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Respiratory symptoms in children
Wheeze in children
Wheeze is produced by turbulent airflow in the lower airways. It is most commonly heard in expiration and
can be acute or chronic. Parents should be asked specifically about the presence of a high-pitched whistle on
expiration. In the first year of life, wheeze is commonly due to conditions other than asthma; wheezy infants
should not automatically be treated for asthma.

Asthma and acute bronchiolitis are the most common causes of acute expiratory wheeze in children; there are
a number of other conditions that can cause chronic wheeze. For example, in a thriving infant, ongoing daily
expiratory wheeze occurring from the first few weeks of life, without respiratory distress, sleep disturbance or
cough is likely to be due to mild tracheobronchomalacia rather than asthma. These children are often referred
to as 'fat happy wheezers'. Alternatively, wheeze that occurs for the first time at 3 to 4 months of age, worsens
with time, and is associated with increased work of breathing and choking or gagging on feeds, should trigger
referral to a specialist.

Referral is indicated for most infants with chronic persistent wheeze.

Cough in children
As in adults, the most common cause of cough in children is acute viral respiratory tract infection. The cough
can be wet or dry, and symptoms settle spontaneously in 7 to 10 days. Oral antibiotic treatment is not
required.

A daily wet cough that persists for longer than 4 weeks is suggestive of protracted bacterial bronchitis. A
chronic wet cough can also be a sign of suppurative lung disease such as Cystic fibrosis or Bronchiectasis.

Cough can occur in children with asthma. However, cough alone is a poor marker of asthma, which should
not be diagnosed in the absence of other symptoms of airway obstruction (eg recurrent wheeze, tachypnoea
and dyspnoea).

See Cough for further information on cough, including alarm symptoms and findings in Box 9.8.

Stridor in children
Stridor is a respiratory noise produced by turbulent airflow through the upper airways. It is most commonly
heard in inspiration and can be acute or chronic.

The most common causes of acute stridor in children include viral laryngotracheobronchitis (croup), acute
tonsillitis or pharyngitis (with or without peritonsillar abscess) and epiglottitis, which is rare since the
introduction of routine immunisation against Haemophilus influenzae type B. Foreign body inhalation should
be suspected in children who present with acute stridor after a choking episode.

Some children present with a chronic 'cog-wheel' high-pitched inspiratory stridor that has been present from
birth or the first few days or weeks of life. The most common cause is laryngomalacia. The stridor resolves
spontaneously at 1 to 2 years of age. Alternatively, inspiratory stridor that develops for the first time at 6 to 8
weeks of life, worsens and becomes biphasic (present in both inspiration and expiration) may be due to a
subglottic haemangioma.

Most cases of chronic stridor in infants need referral.

Key references
Respiratory symptoms occurring in children

Marchant J, Masters IB, Champion A, Petsky H, Chang AB. Randomised controlled trial of amoxycillin
clavulanate in children with chronic wet cough. Thorax 2012;67(8):689–93. [ ]
Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Asthma in children: general information and
diagnosis
General information on asthma in children
This topic addresses the management of asthma in children 12 years and younger; for adolescents, see
Asthma in adults and adolescents.

Most children diagnosed with asthma in Australia have intermittent symptoms triggered by viral respiratory
tract infection. Treatment with inhaled bronchodilators on an ‘as required’ basis is usually sufficient to control
symptoms, which improve with age. In the minority of children with asthma who require preventive
treatment, care should be taken to use the lowest dose that controls asthma symptoms.

Combination therapy with inhaled corticosteroids (ICS) + long-acting beta2 agonists (LABAs) should never
be used as first-line preventer therapy for children (see stepwise approach to treatment in children).

Children with recurrent cough alone are often misdiagnosed with asthma; see diagnosis, below, for further
information.

Diagnosis of asthma in children

There is no single reliable test or set of standardised diagnostic criteria for asthma in children. The diagnosis
should be made on a history of recurrent wheeze and dyspnoea (increased respiratory rate and work of
breathing), indicating large and/or small airway obstruction. Although cough can accompany these
symptoms, it is almost never the only symptom in childhood asthma.

Asthma is unlikely if cough is the only or predominant respiratory symptom.

Exposure to household tobacco smoke places an infant at increased risk of developing asthma. Smoking
during pregnancy may also cause abnormal fetal lung development and is a known risk factor for the baby
developing asthma.

Asthma often occurs without allergic rhinitis or atopic dermatitis in children.

Not all children can adequately perform lung function tests; success depends on various factors, including the
child's age, the equipment and the operator. In general, peak flow measurements are unreliable in children.
Preschool children require age-specific assessment; seek specialist advice before starting long-term preventer
treatment.

A summary of the key features of diagnosis of asthma in children is provided in Table 9.1.

Alternative diagnoses to consider in children are listed in Table 9.2.

The most common pattern of asthma symptoms in children is infrequent intermittent asthma (also called
virus-associated wheeze), where children experience symptoms up to once every 6 weeks but are
asymptomatic between flare-ups (exacerbations). In contrast, children with frequent intermittent asthma
exhibit symptoms more than once every 6 weeks on average but are also asymptomatic between flare-ups.

Children with persistent asthma experience symptoms on a regular basis, varying from 1 or 2 days or nights
per week to most or every day or night (see also Table 9.3).

The pattern of asthma symptoms is useful in determining appropriate therapy in children (see control-based
management for further information). Review the clinical diagnosis if the child is not responding to optimised
management.

Review the clinical diagnosis if management is ineffective.

Diagnosis of asthma in children (Table 9.1)

INITIAL CLINICAL ASSESSMENT

Focus the initial assessment in children suspected of having asthma on:

presence of key features in history and examination

careful consideration of alternative diagnoses (see Table 9.2).

CLINICAL FEATURES THAT INCREASE THE PROBABILITY OF ASTHMA

more than one of the following symptoms: wheeze, cough, difficulty breathing,
chest tightness—particularly if these:
are frequent and recurrent
are worse at night and in the early morning
occur in response to, or are worse after, exercise or other triggers, such as
exposure to pets, cold or damp air, or with emotions or laughter
occur apart from colds
personal history of atopic disorder, eg allergic rhinitis, atopic dermatitis
family history of atopic disorder and/or asthma
widespread wheeze heard on auscultation of the chest
history of improvement in symptoms or lung function in response to adequate
therapy.

CLINICAL FEATURES THAT LOWER THE PROBABILITY OF ASTHMA

symptoms with colds only, with no interval symptoms

isolated cough in the absence of wheeze or difficulty breathing
history of moist cough
prominent dizziness, light-headedness, peripheral tingling
repeatedly normal physical examination of the chest when symptomatic
normal spirometry when symptomatic (older children)
no response to a trial of asthma therapy
clinical features pointing to an alternative diagnosis (see Table 9.2).

Record the basis on which a diagnosis of asthma is suspected.

Adapted by permission from BMJ Publishing Group Limited. Scottish Intercollegiate Guidelines Network
(SIGN). British guideline on the management of asthma: a national clinical guideline (SIGN 141). Quick
reference guide. © 2014.

Alternative diagnoses than asthma to consider in children according to predominant

symptoms (Table 9.2)

Symptom Possible alternative diagnosis

postinfective cough (respiratory viruses, Bordetella pertussis or
Mycoplasma pneumoniae)
dry cough
habit cough, particularly if it resolves during sleep
virus-associated wheeze

in young children:

transient infant wheeze

wheeze
tracheobronchomalacia
airway lesion
inhaled foreign body (unilateral wheeze)
cardiac left-to-right shunt

chronic lung disease of prematurity (bronchopulmonary dysplasia)

difficulty breathing cardiac left-to-right shunt

upper airway dysfunction (vocal cord dysfunction)

chest tightness anxiety
persistent bacterial bronchitis
wet cough (with sputum production chronic suppurative lung disease (including bronchiectasis)
in older children)
cystic fibrosis

Key references
Asthma in children: general information and diagnosis

Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, et al. The importance of nurse-led home
visits in the assessment of children with problematic asthma. Arch Dis Child 2009;94(10):780–4. [ ]

Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, et al. FEV(1) is associated with risk of
asthma attacks in a pediatric population. J Allergy Clin Immunol 2001;107(1):61–7. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma
Council Australia; 2014. [URL]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Maintenance management of asthma in children
Overview of childhood asthma maintenance management
Most children with asthma will experience improvement in symptoms with age.

The most common pattern of asthma symptoms in children is infrequent intermittent asthma (also called virus-
associated wheeze). Symptoms usually improve with age, and preventer therapy is not indicated.

For children with frequent intermittent or persistent asthma, preventer treatment is indicated using the lowest dose
that controls symptoms. If symptoms are well controlled for 2 to 3 months, the dose of preventer should be
reduced; see stepping down treatment for further information.

Introduction to control-based management of asthma in children

The aim of asthma management in children is to achieve good symptom control and prevent flare-ups
(exacerbations) using the lowest effective preventer dose. Asthma symptom control is assessed according to the
frequency of asthma symptoms over the previous 4 weeks. This allows definition of control as good, partial or
poor; see Table 9.3.

Each child's risk factors for poor future asthma outcomes should also be assessed and taken into account in
management. Factors associated with increased risk of flare-ups may be independent of symptom control. Risk
factors for adverse asthma outcomes in children are listed in Table 9.4.

Levels of recent asthma symptom control in children (Table 9.3) [NB1]

Good control Partial control Poor control

Any of the following features:
All of the following features:
daytime symptoms (eg
wheezing or breathing
problems) on 2 or fewer days
per week, lasting only a few
minutes and rapidly relieved by
short-acting bronchodilator
no limitation of activities; child
is fully active, runs and plays
without symptoms
no symptoms during night or on
waking, including no coughing
during sleep
need for reliever on 2 or fewer
days per week [NB2]
daytime symptoms (eg
wheezing or breathing
problems) on more than 2 days
per week, lasting only a few
minutes and rapidly relieved
by short-acting bronchodilator
any limitation of activities;
wheeze or breathlessness
during exercise, vigorous play
or laughter
any symptoms during night or
on waking (eg waking with
symptoms of wheezing or
breathing problems)
need for reliever on more than
2 days per week [NB2]
Either of the following features:
daytime symptoms (eg
wheezing or breathing
problems) on more than 2 days
per week, lasting from minutes
to hours or recurring, and
partially or fully relieved by
short-acting bronchodilator
three or more features of
partial control within the same
week

NB1: Recent asthma symptom control is based on symptoms over the previous 4 weeks irrespective of the current treatment regimen.
NB2: Not including short-acting beta2 agonist taken prophylactically before exercise; record this separately and take into account when assessing
management.
Source: National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia; 2014. [URL]

Risk factors for adverse asthma outcomes in children (Table 9.4) [NB1]

Adverse asthma outcome Associated risk factors

uncontrolled asthma symptoms
inadequate ICS dose, which may be due to not being prescribed,
poor adherence or incorrect technique
one or more severe or life-threatening flare-ups in the past year
low FEV1, especially if less than 60% predicted [NB2]
Increased risk of flare-ups sputum or blood eosinophilia
(exacerbations) major psychological or socioeconomic problems for child or family
exposure to tobacco smoke, indoor or outdoor air pollution, or
 indoor allergens, especially in combination with viral infection
comorbidities, such as obesity, rhinitis or confirmed food allergy
lack of written asthma action plan
history of sudden-onset acute asthma

Increased risk of life-threatening confirmed food allergy

asthma
severe asthma with several hospitalisations
Development of fixed airflow history of bronchiolitis
limitation exposure to tobacco smoke or noxious chemicals

frequent courses of oral corticosteroids

Treatment-related adverse events high-dose and/or potent ICS
incorrect inhaler technique

FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid

NB1: Risk factors for adverse asthma outcomes in adolescents are outlined in Table 9.11.
NB2: Not all children can adequately perform lung function tests; success depends on various factors, including the child's age, the equipment and the
operator.
Source: Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. GINA; 2014. [URL]

Maintenance treatments for asthma in children

Overview
In children, the aim of asthma treatment is to maintain a normal quality of life, free of asthma symptoms and
without adverse effects of asthma treatment.

A stepwise approach to managing asthma in children is outlined in Stepwise approach to treatment in children.
Doses and other considerations for drugs are provided in Drug doses and administration in children.

Practical points
For long-term management of asthma, inhalation is the preferred route of drug administration. The advantage of
the inhaled route is deposition of the drug into the bronchial tree, resulting in the lowest effective dose and
minimal systemic adverse effects. Effective administration of inhaled drugs requires correct delivery device
technique. Inhaled drugs can be administered by pressurised metered dose inhalers (pMDIs) or dry powder
inhalers (DPIs). Nebulisers are rarely needed for long-term maintenance treatment.

The device and regimen depend firstly on the drug that meets the child's clinical needs; appropriate device choice
is then based on various factors including the child's preference and capabilities, age, and susceptibility to local
adverse effects. Less complicated treatment regimens can improve adherence to therapy.

A pMDI with spacer is the preferred delivery device in children younger than 8 years. All children using a pMDI
should use a spacer device. Spacers reduce problems with coordination, increase the relative dose delivered to the
lung and decrease oropharyngeal deposition of the drug, thereby reducing local adverse effects and systemic
absorption.

When using a spacer, ensure that one actuation is administered at a time, followed by:

four to five tidal breaths in preschool-aged children

one to two deep breaths followed by a breath-hold in older children.

Use a face mask with a spacer for infants and young children, and for older children who cannot form an airtight
lip seal around the spacer mouthpiece.

If there is poor adherence to use of a pMDI with spacer, a dry powder inhaler (DPI) is an alternative if the child
can be trained to use the device. For further information about inhalational delivery of drugs and considerations for
device choice, see Table 9.39.

To minimise the risk of oropharyngeal candidiasis and systemic corticosteroid absorption, children should be
advised, or helped, to rinse their mouth with water and spit out straight after using inhaled corticosteroids (ICS).
Ciclesonide has some advantages in this respect as it is a prodrug; it is relatively inactive in the oropharynx and is
associated with a reduced risk of dysphonia (hoarse voice). Using a spacer with ICS also reduces oropharyngeal
candidiasis and dysphonia.

Stepwise approach to treatment in children

Overview

A stepwise approach to treating asthma in children is shown in Figure 9.1. It applies to children with intermittent
asthma and persistent asthma (see diagnosis).

Intermittent asthma is the most frequent form of asthma seen in children. Infrequent intermittent asthma is treated
with an inhaled short-acting beta2 agonist (SABA) as required (ie Step 1 in Figure 9.1). Preventer therapy is not
indicated for children with infrequent intermittent asthma.

Frequent intermittent asthma and persistent asthma can often be well controlled with preventer therapy (a low-dose
inhaled corticosteroid [ICS] or montelukast or a cromone) in addition to as-required SABA (ie Step 2 in Figure
9.1). Children with frequent intermittent asthma are often affected only during winter and may require preventive
therapy only during those months.

Combination therapy with ICS + long-acting beta2 agonist (LABA) can be introduced if symptoms do not respond
to initial optimised preventer therapy (ie Step 3 in Figure 9.1); see stepping up treatment for further detail.
Combination ICS+LABA therapy should never be used as first-line preventer therapy, and LABAs should not be
used alone in any child with asthma.

Combination therapy with ICS+LABA should never be used as first-line preventer therapy for children.

There is no evidence to support the use of LABAs in children younger than 5 years and their use in this age group
is not recommended.

Montelukast can be added to low-dose ICS if asthma symptoms are not well controlled (ie Step 3 in Figure 9.1).

The level of symptom control of persistent asthma is determined by symptom frequency and the degree of impact
on daytime functioning, exercise capacity and sleep (see Table 9.3).

Asthma severity is defined by the intensity of treatment required to achieve good asthma symptom control. It is a
retrospective label that is applied after a child has been using preventer treatment for at least 3 to 6 months.
Children are considered to have mild asthma when good symptom control is achieved using optimised treatment at
Step 1 or Step 2 (see Figure 9.1). Children are considered to have moderate or severe persistent asthma when
symptoms do not respond to optimised treatment at Step 3 (see Figure 9.1); referral to a specialist is recommended.

For detail of drugs used to treat asthma in children, see drug doses and administration in children.

Stepped approach to adjusting asthma medication in children 12 years and younger (Figure 9.1)

ICS = inhaled corticosteroid; LABA = long-acting beta2 agonist; SABA = short-acting beta2 agonist

NB1: In addition, manage flare-ups with extra treatment when they occur, and manage exercise-related asthma symptoms as indicated.
 NB2: There is no evidence to support the use of LABAs in children younger than 5 years; use in this age group is not recommended.

Modified with permission from National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014.

Stepping up treatment

If initial preventer treatment does not improve symptoms within 2 weeks for children taking montelukast, or
within 4 weeks for children using ICS or cromones, review:

inhaler technique—all children using a pressurised metered dose inhaler (pMDI) should use a spacer (see
practical points, above)
adherence—explore reasons for, and strategies to overcome, nonadherence (see adherence)
diagnosis—if a dry cough is the only or predominant respiratory symptom and there are no signs of airway
obstruction such as wheeze or shortness of breath, a diagnosis of asthma is unlikely.

The vast majority of children with persistent asthma will respond to low-dose ICS, providing inhaler technique and
adherence are optimised, and the diagnosis is correct.

A small proportion of children may have persistent symptoms despite the above factors being satisfactory. In this
subgroup of children, treatment may need to be escalated as per Step 3 in Figure 9.1; consider specialist input at
this stage. If frequent SABA use is still required at Step 3, review the diagnosis and arrange referral; see failure to
respond to adequate treatment for further advice.

Stepping down treatment

When asthma has been stable for at least 2 to 3 months, gradually step-down the ICS dose to the lowest dose that
gives good asthma symptom control.

If the child is using combination preventer therapy with ICS+LABA, step-down preventer therapy by stopping the
LABA and continuing with low-dose ICS or other Step 2 treatment (see Figure 9.1).

If the child is on low-dose ICS or other Step 2 treatment, step-down treatment to SABA as needed (ie Step 1 in
Figure 9.1).

Drug doses and administration in children

Short-acting beta2 agonists

Short-acting beta2 agonists (SABAs) (salbutamol, terbutaline) are used as needed for symptom relief. In Australia
they are referred to as 'relievers'; the term 'rescue medication' may be used in the literature.

Almost all inhaled SABA treatment in children is now given via a pressurised metered dose inhaler (pMDI) with
spacer. In children unable to use a pMDI with spacer, a breath-actuated pMDI (eg Autohaler), dry powder inhaler
(DPI) or nebuliser may be required.

Use:

1 salbutamol 100 micrograms, 1 to 2 actuations by inhalation via pMDI with spacer, as

needed

OR

1 terbutaline 500 micrograms, 1 actuation by inhalation via DPI, as needed.

Inhaled corticosteroids

Inhaled corticosteroids (ICS) (beclomethasone, budesonide, ciclesonide, fluticasone propionate) are the most
effective preventive therapy in children with asthma. In Australia they are referred to as 'preventers' and are first-
line maintenance treatment.

For children requiring preventer treatment in addition to as-needed reliever treatment (ie Step 2 in Figure 9.1), use:

a low-dose ICS by inhalation, see Table 9.5.

Review treatment after 2 to 3 months to determine the level of asthma symptom control (see Table 9.3). Low and
high doses of ICS for children are presented in Table 9.5.

The effect of ICS on long-term growth in children is unclear. Most studies have focused on short-term growth
velocity and failed to show any reduction in final height. However, suppression of growth due to ICS remains a
concern, so always use the lowest effective dose of ICS that gives good symptom control. Children with severe
asthma may have improved growth velocity after starting ICS, perhaps by eliminating the growth-suppressive
effects of poorly controlled asthma and reducing the need for pulses of oral corticosteroids. There are also several
reports of significant systemic adverse reactions with high-dose ICS in children, including adrenal suppression and
acute adrenal crisis.

Ensure the minimum effective ICS dose is used in the long term.

To minimise oropharyngeal candidiasis and systemic absorption of corticosteroid, advise or help children to rinse
their mouth with water and spit out straight after using ICS.

ICS are the most effective therapy for maintenance control of persistent asthma in children; however, montelukast,
below, may be trialled first in some circumstance.

Low and high dosages of inhaled corticosteroids for asthma in children (Table 9.5)

Dosage [NB2] [NB3]

Drug Delivery device [NB1]
Low (Step 2) High (Step 3) [NB4]
50 to 100 micrograms, 100 to 200 micrograms,
beclomethasone [NB5] pMDI with spacer [NB6]
twice daily twice daily
100 to 200 micrograms, 200 to 400 micrograms,
budesonide multiple-dose DPI
twice daily twice daily
ciclesonide [NB7] pMDI with spacer 80 micrograms, once daily 160 micrograms, once daily
pMDI with spacer
50 to 100 micrograms, 100 to 250 micrograms,
fluticasone propionate or
twice daily [NB8] twice daily
multiple-dose DPI [NB8]
DPI = dry powder inhaler; pMDI = pressurised metered dose inhaler
NB1: See Inhalational drug delivery devices for advice about appropriate device choice.
NB2: See Figure 9.1 for steps in asthma management; see stepwise approach to treatment in children for further advice.
NB3: Number of actuations to deliver a dose depends on the dose formulation available.
NB4: Doses above the upper limit of the high dose range should not be prescribed without specialist advice.
NB5: Beclomethasone is not registered for use in children younger than 5 years.
NB6: Beclomethasone is also available as a breath-actuated pMDI, which is not compatible with a spacer.
NB7: Ciclesonide is not registered for use in children younger than 6 years.
NB8: Fluticasone propionate 50 micrograms can only be delivered via pMDI; minimum available dose per actuation of multiple-dose DPI is 100
micrograms.

Montelukast

Montelukast (a leukotriene receptor antagonist) is a tablet used as an alternative to inhaled corticosteroids (ICS) or
cromones (cromoglycate, nedocromil). It may be trialled if:

the child is unable to use inhaled therapy

the child also has significant allergic rhinitis
the parents have strong concerns about adverse effects of ICS.

If good symptom control is not achieved after a 4-week trial of montelukast, replace with low-dose inhaled
corticosteroids if possible; no treatment overlap period is required. If the child is unable to use ICS and does not
respond to montelukast, consider seeking expert advice.

Montelukast may also be added to ICS if needed to control asthma symptoms (ie Step 3 in Figure 9.1) [Note 1].
Before stepping up, ensure inhaler technique and adherence are optimised; consider specialist input at this stage
(see stepping up treatment for further information).

If considered appropriate, use:

montelukast (2 to 5 years) 4 mg orally, at night

or montelukast (6 to 14 years) 5 mg orally, at night.

 Note 1: See the Pharmaceutical Benefits Scheme website for subsidised indications for montelukast [URL]

Cromones

Cromones (cromoglycate, nedocromil) can be used as an alternative to low-dose inhaled corticosteroids (ICS) or
montelukast as first-line preventer therapy in children with frequent intermittent or persistent asthma. However,
cromones are not as effective as ICS and involve a more complex regimen (ie more frequent dosing and
meticulous daily care to prevent clogging of inhaler device).

If considered appropriate, use:

1 cromoglycate 20 mg, 1 actuation by inhalation via DPI, 4 times daily

or cromoglycate 5 mg, 2 actuations by inhalation via pMDI with spacer, 4 times daily

OR

1 nedocromil (child 2 years and older) 2 mg, 2 actuations by inhalation via pMDI with
spacer, 4 times daily.

Combination inhaler therapy

Overview

The vast majority of children with persistent asthma respond to first-line preventer treatment with low-dose
inhaled corticosteroids (ICS) providing inhaler technique and adherence are optimised, and the diagnosis is
correct.

There is no evidence to support the use of long-acting beta2 agonists (LABAs) (eformoterol, salmeterol, vilanterol)
in children younger than 5 years, and their use in this age group is not recommended. There is concern that
combination ICS+LABA therapy is greatly overprescribed as first-line preventer therapy for asthma in children in
Australia; discussion with a specialist is advisable before adding a LABA to paediatric treatment.

Children 5 years or older who remain symptomatic despite appropriate optimised doses of ICS alone may have a
LABA added to their regimen (see Step 3 in Figure 9.1). LABAs do not control underlying airway inflammation.
They should, therefore, only be used in combination with ICS [Note 2].

LABAs must only be used in combination with ICS.

Note 2: At the time of writing, fluticasone+salmeterol is the only ICS+LABA combination inhaler registered
by the Therapeutic Goods Administration (TGA) for use in children 5 to 12 years of age; see current information
[URL].

Fixed-dose combination inhalers

Fixed-dose combination inhalers used for asthma treatment contain an ICS+LABA in a single inhaler. They are
more convenient for children than separate inhalers and, importantly, ensure that the LABA is always accompanied
by an ICS.

If a fixed-dose combination ICS+LABA is indicated, for children 5 to 12 years of age [Note 3], use:

1 fluticasone propionate+salmeterol 50+25 micrograms, 2 actuations by inhalation via

pMDI with spacer, twice daily

OR

2 fluticasone propionate+salmeterol 100+50 micrograms, 1 actuation by inhalation via DPI,

twice daily.
Note 3: See the Pharmaceutical Benefits Scheme website for subsidised indications for combination inhalers
[URL]

Combination therapy using separate single-drug inhalers

Combination ICS+LABA therapy using separate single-drug inhalers is not recommended unless there is no fixed-
dose combination inhaler containing the corticosteroid that the child is using (such as ciclesonide or
beclomethasone).

Use of LABA or high dose of short-acting beta2 agonist (SABA) as monotherapy is not recommended—patients
are at high risk of flare-up due to uncontrolled airway inflammation, and an increased risk of death despite often
having few symptoms. Therefore, LABAs must only be prescribed concurrently with an ICS. If addition of a
LABA to ICS is considered necessary in children 5 years or older, but no fixed-dose combination inhaler is
available, eformoterol or salmeterol are appropriate LABAs. Consider referring for specialist input at this stage.

Although eformoterol has a rapid onset of action, it is not recommended for use as a reliever medication when
used as a single-drug inhaler.

Exercise-induced bronchoconstriction

In school-aged children with asthma, exercise is usually one of a number of triggers for bronchoconstriction. Less
commonly, it may be the only, or predominant, trigger. The level of physical activity needed to trigger exercise-
induced bronchoconstriction depends on the child, and also on ambient environmental factors (symptoms are more
likely in cold and dry conditions).

For children with persistent asthma, regular preventer therapy is the most important factor in controlling exercise-
induced bronchoconstriction. In children in whom exercise is the only trigger for asthma symptoms, pre-exercise
bronchodilator therapy is usually effective. Use:

1 salbutamol 100 micrograms, 1 to 2 actuations by inhalation via pMDI with spacer, 15

minutes before exercise

OR

1 terbutaline 500 micrograms, 1 actuation by inhalation via DPI, 15 minutes before

exercise.

Alternative pre-exercise therapies include cromoglycate, nedocromil and montelukast [Note 4] .

Note 4: At the time of writing, montelukast is not registered by the Therapeutic Goods Administration (TGA)
for as-needed use pre-exercise; see current information [URL]

Allergen immunotherapy for asthma in children

The place of specific allergen immunotherapy in children with asthma remains controversial, but it may be
effective, in addition to standard treatment, in some children with documented dust mite, cat or pollen allergy.
Poorly controlled asthma is a contraindication for immunotherapy.

Immunotherapy (either sublingual or subcutaneous) is expensive and may be required for 3 to 5 years. Treatment
must be supervised by a paediatric allergy specialist. There is a risk of anaphylaxis, particularly with subcutaneous
therapy.

Nondrug interventions for asthma in children

Avoiding triggers for children with asthma is important. Exposures that increase risk of children developing
asthma are discussed in diagnosis.

Respiratory viral infection is the most common trigger in childhood asthma. Exposure to airborne allergens can
also trigger asthma symptoms in sensitised children. Other possible triggers are listed in Table 9.15.

There is no good evidence for use of complementary medicines to treat asthma in children. Some complementary
medicines (eg royal jelly, echinacea) are known triggers for asthma and anaphylaxis; see complementary medicine
for further discussion.

Education and skills training for asthma in children

Overview
It is important to provide the parents or carers of children with asthma with information about the natural history
of asthma, the rationale for treatment, and the need for good adherence with preventer medication (when
prescribed). The difference between preventer and reliever therapy must be clearly explained.

A spacer device is vital for the delivery of all asthma drugs administered via pressurised metered dose inhaler
(pMDI) in children. Carefully demonstrate the appropriate spacer technique to both parent or carer, and the child.

A written asthma action plan is another important component of management.

Adherence

If asthma symptom control is poor despite apparently adequate treatment, consider poor inhaler technique and/or
poor adherence.

In addition to the child forgetting to use their treatment, a number of factors can affect adherence. Explore other
possible barriers such as cost, the home environment and parent or carer beliefs about the drug and its adverse
effects. Adherence often deteriorates with improvement in symptoms.

Strategies that may improve adherence include:

using an open, nonjudgmental approach when discussing adherence

allowing the parent, carer or child to express their concerns about possible drug adverse effects (eg risk of
growth suppression with inhaled corticosteroids), and addressing these concerns
improving the parent, carer and child understanding of asthma management over a period of time;
comprehensive information can rarely be retained after one visit
keeping treatment simple (eg using once- or twice-daily dosing where possible, using as few drugs and
different types of devices as possible)
identifying useful daily associations or medication reminders to improve drug adherence (eg using
preventive therapy before meals or in the bathroom before brushing teeth).

Written asthma action plan

Providing a written asthma action plan has been shown to reduce morbidity and is recommended for all children
with asthma.

Asthma action plans must be individualised to the child's current treatment regimen, their usual asthma symptoms
and pattern of reliever use, and their willingness and ability to self-manage worsening asthma.

The general principles of a written asthma action plan are outlined in Written asthma action plan and Box 9.2.

Asthma action plan templates that can be individualised are available from the National Asthma Council [URL].
The National Asthma Council also publishes other comprehensive and useful education material for patients,
available on their website.

Review and referral of children with asthma

Regular review

Regular review is important to ensure optimal control of symptoms with the lowest effective medication dose.
Check adherence and device technique at each visit, and perform spirometry if the child is capable. Consider
stepping down treatment in children with good symptom control in the previous 3 months.

Update the written asthma action plan at least yearly or when maintenance treatment is changed.

Provide information on avoiding triggers, where appropriate, and managing comorbid conditions (eg allergic
rhinitis). Advise on avoiding environmental tobacco smoke, and encourage physical activity and maintaining a
healthy weight.

Failure to respond to adequate treatment

Overview

Most children with asthma have intermittent symptoms and do not require treatment beyond Step 1 of the stepwise
approach, see Figure 9.1. Those who do require preventive treatment usually respond very well to first-line
preventer therapy (ie Step 2 in Figure 9.1). Failure to respond to optimised first-line preventer treatment (ie correct
technique and good adherence; see stepwise approach to treatment in children), should prompt reassessment of the
diagnosis, and exploration of possible complicating factors, such as:

exposure to aeroallergens or environmental tobacco smoke

psychosocial factors including parent or carer mental health problems, or financial hardship.
Referral may be warranted at this point; see below for further information about when specialist consultation is
recommended.

Referral

Refer children for specialist consultation when there has been:

a life-threatening asthma flare-up or asthma in conjunction with anaphylaxis

frequent flare-ups requiring oral corticosteroids
doubt about the diagnosis of asthma
failure to respond to therapy, indicated by
–
persistently impaired lung function (in children old enough to perform spirometry) despite control of
symptoms
–
the need for infants or toddlers to use oral or inhaled corticosteroids (ICS)
–
the need for older children to use maintenance ICS doses in excess of the upper limit of the high-dose
range (see Table 9.5).

Key references
Maintenance management of asthma in children: overview and control-based management

Fuhlbrigge AL, Kitch BT, Paltiel AD, Kuntz KM, Neumann PJ, Dockery DW, et al. FEV(1) is associated with risk of
asthma attacks in a pediatric population. J Allergy Clin Immunol 2001;107(1):61–7. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Maintenance management of asthma in children: drug treatment

CSM Update: Desensitising vaccines. Br Med J (Clin Res Ed) 1986;293(6552):948. [ ]

Babl FE, Sheriff N, Borland M, Acworth J, Neutze J, Krieser D, et al. Paediatric acute asthma management in Australia
and New Zealand: practice patterns in the context of clinical practice guidelines. Arch Dis Child 2008;93(4):307–12. [
]

Chuang S, Jaffe A. Cost considerations of therapeutic options for children with asthma. Paediatr Drugs
2012;14(4):211–20. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, et al. Effect of inhaled glucocorticoids in
childhood on adult height. N Engl J Med 2012;367(10):904–12. [ ]

Malling HJ. Comparison of the clinical efficacy and safety of subcutaneous and sublingual immunotherapy:
methodological approaches and experimental results. Curr Opin Allergy Clin Immunol 2004;4(6):539–42. [ ]

McMahon AW, Levenson MS, McEvoy BW, Mosholder AD, Murphy D. Age and risks of FDA-approved long-acting
beta(2)-adrenergic receptor agonists. Pediatrics 2011;128(5):e1147–54. [ ]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Sadatsafavi M, Lynd LD, Marra CA, FitzGerald JM. Dispensation of long-acting beta agonists with or without inhaled
corticosteroids, and risk of asthma-related hospitalisation: a population-based study. Thorax 2014;69(4):328–34. [
]

Schuh S, Johnson DW, Callahan S, Canny G, Levison H. Efficacy of frequent nebulized ipratropium bromide added to
frequent high-dose albuterol therapy in severe childhood asthma. J Pediatr 1995;126(4):639–45. [ ]

Maintenance management of asthma in children: nondrug interventions

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Maintenance management of asthma in children: education and skills training

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Maintenance management of asthma in children: review and referral

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute asthma in children
Introduction to acute asthma management in children
This topic provides advice for managing acute asthma in children 12 years and younger. For advice about managing
acute asthma in adolescents, see management of acute asthma in adults and adolescents.

In the event of an acute flare-up (exacerbation) of asthma, early intervention with inhaled bronchodilator therapy is the
best strategy to prevent further deterioration.

Educate parents, carers and children with asthma to recognise early symptoms of deterioration and to initiate the first
steps in treatment (see education and skills training).

Anaphylaxis is an important differential diagnosis for children presenting with acute wheeze. Anaphylaxis is a life-
threatening condition; the child can deteriorate exceedingly rapidly (ie within minutes). This diagnosis is likely if an
apparent asthma flare-up occurs with angioedema or rapid onset of a widespread rash. Also consider anaphylaxis if
there are marked abdominal symptoms or hypotension.

Manage anaphylaxis in children according to appropriate national guidelines or local clinical protocols; see the
Australian Prescriber anaphylaxis wallchart. The mainstay of therapy is intramuscular adrenaline.

First aid for acute asthma in children

If symptoms are severe or life-threatening (see Table 9.6), urgently call an ambulance and advise that the child is
having a ‘severe asthma attack’ (flare-up). Pending its arrival, administer high doses of inhaled short-acting beta2
agonist (SABA) via pressurised metered dose inhaler (pMDI) with spacer (if available) or via nebuliser.

In children younger than 6 years, use:

1 salbutamol 100 micrograms, 6 separate actuations by inhalation via pMDI with spacer,
repeated every 20 minutes or sooner if required

OR

1 salbutamol 2.5 mg by inhalation via nebuliser, repeated every 20 minutes or sooner if

required.

In children 6 years or older, use:

1 salbutamol 100 micrograms, 12 separate actuations by inhalation via pMDI with spacer,
repeated every 20 minutes or sooner if required

OR

1 salbutamol 5 mg by inhalation via nebuliser, repeated every 20 minutes or sooner if required.

If early signs of asthma deterioration are present, first-line treatment with a bronchodilator should be initiated by the
child, parent or carer. Call an ambulance if the child fails to improve significantly with first-line home treatment, or if
there are signs of a severe or life-threatening flare-up (see Table 9.6). Urgent medical review is also required if the child
initially responds but bronchodilator therapy is needed more than 3 to 4 hourly.

Call an ambulance if there are signs of a severe or life-threatening flare-up or if the child fails to respond rapidly to first-line treatment.

There is a ‘first aid plan’ for acute asthma, used by many community and sports organisations, called ‘4×4×4’, which
recommends salbutamol pMDI; if available, use:

4 separate actuations, with spacer if available, one actuation at a time

take 4 breaths from the spacer after each actuation
wait 4 minutes and then give another 4 separate actuations
if the child still cannot breathe normally, call an ambulance and continue giving 4 separate actuations every 4
minutes until the ambulance arrives.

Corresponding first aid advice if using terbutaline is available on the National Asthma Council website [URL].
Overview of management of acute asthma in children
When the patient arrives at the medical facility, perform a rapid assessment to evaluate the severity of the flare-up (see
Table 9.6), which determines initial management (see Figure 9.2).

Most cases of acute asthma in children are mild and can be successfully managed in the primary care setting. Treat
these children as for mild–moderate acute asthma (see Figure 9.2), with ongoing assessment of severity and response to
treatment. If the child's condition worsens, arrange urgent transfer to an acute care facility.

Ongoing monitoring of treatment response is the key to successful management of acute asthma flare-ups.

After starting initial therapy, a more detailed review can be undertaken to determine subsequent management (see Table
9.7 for children 5 years and younger, and Table 9.17 for children 6 years and older). The key to successfully managing
acute asthma is ongoing monitoring of the response to therapy.

If the child is not responding to treatment at the assessed level of severity, treat them according to the next level. Note
that some children may appear to respond initially and then relapse.

The aim of therapy is to stabilise the child within the first hour, then attempt to lengthen the interval between
salbutamol doses in a stepwise fashion.

Assessment of acute asthma in children

Initial rapid assessment
Undertake an initial rapid severity assessment as outlined in Table 9.6; this determines initial management (see Figure
9.2).

Wheezing is an unreliable indicator of the severity of an asthma flare-up in children.

Wheezing is an unreliable indicator of the severity of an asthma flare-up in children and may be absent in a severe flare-
up (ie ‘silent chest’). Cyanosis is only visible with marked hypoxaemia; it indicates life-threatening acute asthma but its
absence does not exclude life-threatening acute asthma (see Table 9.6).

The most important parameters of severity in acute childhood asthma are the child's general appearance or mental state,
and work of breathing (eg accessory muscles use, chest wall recession).

Initial rapid severity assessment of acute asthma in children (Table 9.6)

Life-threatening: any of the following Severe: any of the following Mild–moderate: all of the following
increased work of breathing (eg
altered conscious level
accessory muscle use, tracheal
exhaustion
tug, intercostal and subcostal can walk and can speak whole
cyanosis
recession) sentences in one breath
SpO2 less than 90%
unable to complete sentences in SpO2 more than 94%
poor respiratory effort one breath due to dyspnoea
soft or absent breath sounds SpO2 90 to 94%

Important additional information:

The severity category may change when more information is available (eg pulse oximetry) or over time. These
changes may be in either direction. Ongoing observation is required; see secondary severity assessment of acute
asthma, below.
If oxygen therapy has already been started, it is not essential to stop oxygen to measure oximetry.
Oxygen saturation levels are a guide only and are not definitive; clinical judgment should be applied.
While clinical features can help identify severity of an asthma flare-up, they are not specific (either in isolation
or in combination); their absence does not exclude a severe or life-threatening flare-up. Of note:
wheezing may be absent in severe acute asthma (ie ‘silent chest’)
pulsus paradoxus is not a reliable indicator of the severity of acute asthma
life-threatening acute asthma can occur without cyanosis.

SpO2 = oxygen saturation measured by pulse oximetry

Source: National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia; 2014. [URL]

Secondary severity assessment

Following initial administration of salbutamol according to Figure 9.2, reassess severity as outlined for children 5 years
or younger in Table 9.7 or for children 6 years or older in Table 9.17. Adjust management according to this secondary
severity assessment.

Manage children with acute asthma somewhere they can be seen and monitored frequently. For children with a severe
or life-threatening acute asthma flare-up, repeat secondary severity assessment frequently (eg after each dose of
salbutamol). In more severe cases, remain at the bedside until the child is stabilised. For children with a mild–moderate
acute asthma flare-up, reassess the severity after 1 hour of treatment or more frequently if their condition changes.

Secondary severity assessment of acute asthma in children 5 years or younger (Table 9.7) [NB1]

Note: If features of more than one severity level are present, treat according to the higher severity level.

Life-threatening: any of the Mild–moderate: all of the

Severe: any of the following
following following
Consciousness drowsy or unconscious not applicable [NB2] alert
unable to vocalise due to
Speech not applicable [NB2] can talk or vocalise
dyspnoea
Posture collapsed or exhausted lethargic can walk or crawl
paradoxical chest wall
movement: inward movement
on inspiration and outward
movement on expiration

severe respiratory distress or

respiratory distress is not
Breathing or use of accessory muscles of
severe
neck or intercostal muscles
poor respiratory effort (‘tracheal tug’)

or

subcostal recession
(‘abdominal breathing’)
Skin colour cyanosis not applicable [NB2] normal
bradypnoea (indicates
Respiratory rate tachypnoea [NB3] normal [NB3]
respiratory exhaustion) [NB3]
cardiac arrhythmia

or
Heart rate tachycardia [NB4] normal [NB4]
bradycardia (preterminal sign,
may occur just before
respiratory arrest) [NB4]
‘silent chest’ wheeze

Chest auscultation or not applicable [NB2] or

reduced air entry normal lung sounds

SpO2 less than 90%

Pulse oximetry or SpO2 90 to 94% SpO2 more than 94%

clinical cyanosis
clinical indications include, but are not limited to:

life-threatening asthma
suspicion of pneumothorax
Chest X-ray
sudden deterioration
failure to respond to appropriate therapy
if signs remain focal

Asthma history assess risk factors for asthma-related death, see Box 9.3
SpO2 = oxygen saturation measured by pulse oximetry
NB1: Secondary severity assessment for children 6 years or older is outlined in Table 9.17.
NB2: May be the same as mild–moderate and does not determine severity level.
NB3: Normal respiratory rate (breaths/min) for children: younger than 1 year, 30 to 40; 1 to 2 years, 25 to 35; 2 to 5 years, 25 to 30.
NB4: Normal heart rate (beats/min) for children: younger than 1 year, 110 to 160; 1 to 2 years, 100 to 150; 2 to 5 years, 95 to 140.
Source: National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia; 2014. [URL]
Treatment of acute asthma in children
Overview
This section provides a summary of the principles of drug treatment of acute asthma; see Figure 9.2 for further detail.
For dosing in children, see Table 9.8.

The early use of inhaled short-acting beta2 agonist therapy (such as salbutamol) is the cornerstone of successful
management of all children with acute asthma, regardless of severity (see Table 9.6 and Table 9.7 or Table 9.17).
Children assessed as having a life-threatening asthma flare-up usually require supplemental oxygen, and early initiation
of inhaled ipratropium is recommended.

Give oral corticosteroids within the first hour of management to children having a severe or life-threatening flare-up.
Corticosteroids may also be indicated in children with mild–moderate acute asthma who do not respond satisfactorily to
initial bronchodilator therapy.

Consider additional intravenous bronchodilator therapy (magnesium, salbutamol or aminophylline) in children with
life-threatening acute asthma and/or those who fail to improve, or deteriorate, following initial therapy (see Figure 9.2).

Failure to respond to therapy should prompt reassessment, including consideration of complications such as
pneumothorax and adverse effects of treatment.

Inhaled bronchodilators
Inhaled salbutamol is indicated for all episodes of acute asthma in children. Administration by pressurised metered dose
inhaler (pMDI) with spacer is recommended for those with mild–moderate acute asthma. For children unable to
cooperate with administration via pMDI with spacer, use nebulised salbutamol. In children with life-threatening
asthma, give salbutamol via continuous nebulisation.

If there is poor response to initial inhaled salbutamol, add inhaled ipratropium. Children with more severe asthma
benefit most from the addition of ipratropium.

Repeated high doses of salbutamol can cause adverse effects; see inhaled bronchodilators for advice about identifying
and managing adverse effects.

Corticosteroids
Oral prednis(ol)one is recommended within the first hour of management of children with an acute flare-up of asthma
that does not respond to initial inhaled bronchodilator therapy. If the oral route is not possible, intravenous
hydrocortisone or methylprednisolone can be used.

There is accumulating evidence that oral corticosteroids are of no benefit in preschool children, ie 5 years or younger,
with an acute episode of mild–moderate virus-associated wheeze. Therefore, oral corticosteroids are not indicated in
children 5 years or younger if wheeze responds to initial inhaled bronchodilator therapy.

Oral corticosteroids are not indicated in children 5 years or younger if wheeze responds to initial inhaled bronchodilators.

Oral corticosteroid therapy is more likely to be effective in the small number of preschool-aged children with an
established diagnosis of frequent episodic or persistent asthma requiring regular preventer therapy.

Oxygen

If oxygen saturation measured by pulse oximetry (SpO2) is less than 95%, give supplemental oxygen and titrate to a
target SpO2 of at least 95%. For advice on supplemental oxygen administration, see acute oxygen therapy.

Intravenous magnesium sulfate

Studies suggest that intravenous magnesium sulfate is a useful add-on bronchodilator in children with severe or life-
threatening acute asthma or those not responding to initial treatment with inhaled bronchodilator therapy (ie salbutamol
and ipratropium). Comprehensive monitoring is required in a high-dependency–type environment.

Intravenous salbutamol
Intravenous salbutamol may be useful in children with life-threatening acute asthma who fail to respond to inhaled
bronchodilators and intravenous magnesium sulfate. However, intravenous salbutamol is not used frequently because
the vast majority of children with acute asthma respond to inhaled salbutamol. Comprehensive monitoring is required
in a critical care environment.
Intravenous aminophylline
Studies suggest that intravenous aminophylline is a useful add-on bronchodilator in children with life-threatening acute
asthma. However, treatment in children is often complicated by nausea and vomiting. Theophylline plasma
concentrations must be monitored to ensure they are within the therapeutic range and the dose adjusted accordingly.
Comprehensive monitoring is required in a critical care environment.

Initial approach to managing an acute asthma flare-up in children (Figure 9.2) [NB1]

HDU = high-dependency unit; ICU = intensive care unit; IV = intravenous; pMDI = pressurised metered dose inhaler; SpO2 = oxygen saturation measured
by pulse oximetry

NB1: Doses for drugs used to manage acute asthma flare-ups in children are listed in Table 9.8, below.

NB2: In severe flare-ups, repeated secondary severity assessment should occur frequently within the first hour, eg after each dose of inhaled salbutamol. In
severe or life-threatening cases the clinician should remain at the bedside until the child is stabilised.

NB3: Corticosteroids are not indicated in children 5 years or younger if wheeze responds to initial inhaled bronchodilator therapy.

Drug dosages for acute asthma in children (Table 9.8)

Dosage
Drug [NB1] Delivery
5 years or younger 6 to 12 years
pMDI with spacer 100 micrograms × 2 to 6 separate 100 micrograms × 4 to 12 separate
 [NB2] actuations actuations
intermittent
2.5 mg 5 mg
nebulisation
salbutamol continuous
nebulisation driven by 2.5 mg × 2 nebules 5 mg × 2 nebules
oxygen [NB3]
5 micrograms/kg/minute for the first hour, then reduce to 1 to 2
IV infusion [NB4]
micrograms/kg/minute until breathing stabilises
pMDI with spacer 21 micrograms × 4 separate 21 micrograms × 8 separate
[NB2] actuations actuations
ipratropium
intermittent
250 micrograms 500 micrograms
nebulisation
avoid unless severe acute wheeze; prednis(ol)one 2 mg/kg (up to 50
oral if indicated, dose as for 6 to 12 mg) as an initial dose, then 1
years mg/kg on subsequent days
hydrocortisone 4 mg/kg (up to 100
mg) every 6 hours for the first 24
hours,

then every 12 hours on day 2,

corticosteroids then once on day 3 [NB5]

avoid unless severe acute wheeze;
IV [NB5] if indicated, dose as for 6 to 12 OR
years
methylprednisolone 1 mg/kg (up
to 60 mg) every 6 hours for the
first 24 hours,

then every 12 hours on day 2,

then once on day 3 [NB5]

oxygen [NB3] intranasal start if SpO2 is less than 95% and titrate to target SpO2 of at least 95%
child older than 2 years:
magnesium sulfate
IV infusion
[NB6] 0.1 to 0.2 mmol/kg (up to 10 mmol) diluted in sodium chloride 0.9%,
given over at least 20 minutes, as a single dose
IV loading dose [NB7]:

1 to 12 months: 5 mg/kg

1 to 12 years: 5 to 10 mg/kg (up to 500 mg); younger children are

more likely to require doses at the upper end of the range due to
increased drug clearance

IV loading dose FOLLOWED BY

[NB7],
aminophylline [NB4] IV infusion:
followed by IV
6 weeks to 6 months: 0.5 mg/kg/hour
infusion
6 to 12 months: 0.7 mg/kg/hour

1 to 9 years: 0.9 to 1.1 mg/kg/hour

9 to 12 years: 0.7 mg/kg/hour.

Target theophylline plasma concentration: 55 to 110 micromol/L (10 to

20 mg/L)
IV = intravenous; pMDI = pressurised metered dose inhaler; SpO2 = oxygen saturation measured by pulse oximetry
NB1: Drug, dose, frequency and delivery method depend on severity of acute asthma; see Table 9.6 for initial rapid severity assessment of acute asthma in
children and corresponding management in Figure 9.2.
NB2: Use a face mask with spacer in younger children and/or those unable to form a lip seal around the spacer mouthpiece.
NB3: Continuous nebulisation driven by oxygen is indicated in life-threatening acute asthma. Children with severe acute asthma using intermittent nebulisation
or pMDI with spacer may require oxygen; administer oxygen separately.
NB4: Only indicated in life-threatening acute asthma (see Figure 9.2); comprehensive monitoring is required in a critical care environment.
NB5: Change to oral corticosteroids once oral route is available.
NB6: Only indicated in severe and life-threatening acute asthma in children older than 2 years (see Figure 9.2); comprehensive monitoring is required in a high-
dependency–type environment.
NB7: For children already taking oral theophylline, omit the aminophylline loading dose.
Post-acute care of asthma in children
Many children presenting with an acute asthma flare-up may only ever have one such episode. However, a small
number of children are at risk of recurrent, potentially fatal episodes (see Box 9.3).

Consider the need for preventer therapy in children not currently prescribed preventer medication. Base assessment on
the pattern of asthma symptoms between flare-ups, rather than the severity of symptoms during the flare-up.

Review the child's asthma maintenance management before discharge, as outlined in Box 9.1. Oral corticosteroid
therapy may be required on discharge to complete a course of treatment; total course of treatment should be 3 to 5 days,
including the doses administered during the acute phase of the flare-up.

Reviews required before discharging a child after an acute asthma flare-up (Box 9.1)

Following the resolution of an acute asthma flare-up, review:

inhaler technique for all devices

adherence to prescribed drug regimen
triggers to identify the possible cause of this flare-up; discuss avoidance measures if necessary
exposure to environmental tobacco smoke
inhaled corticosteroid dose; adjust the child's maintenance therapy if necessary
written asthma action plan; educate the child and parent or carer about the action plan.

Follow-up after acute asthma attacks in children

It is essential that a child who suffers an acute asthma flare-up, of any severity, be followed up. Advise the parent or
carer to take the child to their general practitioner, preferably within 48 to 72 hours of discharge from the emergency
department or the ward. Provide a discharge summary to the child's general practitioner in time for this review,
including details of the:

severity of the flare-up

treatment administered
treatment prescribed on discharge
written asthma action plan provided to the patient.

Ongoing specialist review is required for children with near-fatal or brittle asthma (ie sudden and severe flare-ups).
Consider referring children who present with asthma for the first time to a specialist for review. Consider referring
children with ongoing poorly controlled asthma to a specialist; see Failure to respond to adequate treatment for further
information.

Key references
Management of acute asthma in children: overview

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Management of acute asthma in children: suspected anaphylaxis

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Management of acute asthma in children: first aid

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Medical management of acute asthma in children: overview and assessment

Babl FE, Sheriff N, Borland M, Acworth J, Neutze J, Krieser D, et al. Paediatric acute asthma management in Australia and
New Zealand: practice patterns in the context of clinical practice guidelines. Arch Dis Child 2008;93(4):307–12. [ ]
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Treatment of acute asthma in children

Babl FE, Sheriff N, Borland M, Acworth J, Neutze J, Krieser D, et al. Paediatric acute asthma management in Australia and
New Zealand: practice patterns in the context of clinical practice guidelines. Arch Dis Child 2008;93(4):307–12. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children
aged 1-5 years: randomised controlled trial. Lancet 2003;362(9394):1433–8. [ ]

Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al. Oral prednisolone for preschool children
with acute virus-induced wheezing. N Engl J Med 2009;360(4):329–38. [ ]

Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic
review with meta-analysis. Thorax 2005;60(9):740–6. [ ]

Starkey ES, Mulla H, Sammons HM, Pandya HC. Intravenous salbutamol for childhood asthma: evidence-based medicine?
Arch Dis Child 2014;99(9):873–7. [ ]

Medical management of acute asthma in children: post-acute care and follow-up

Babl FE, Sheriff N, Borland M, Acworth J, Neutze J, Krieser D, et al. Paediatric acute asthma management in Australia and
New Zealand: practice patterns in the context of clinical practice guidelines. Arch Dis Child 2008;93(4):307–12. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014. [URL]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Asthma in adults and adolescents: introduction and
diagnosis
Introduction to asthma in adults
This topic addresses the diagnosis and management of asthma in adults and adolescents; for advice about
children 12 years and younger, see asthma in children.

The Australian Asthma Handbook [Note 1] describes asthma as a ‘chronic lung disease, which can be
controlled but not cured’. The prevalence in Australian adults and children is 10% [Note 2].

Asthma is a common disease, with variable clinical presentations at different times over a patient's lifetime.
Appropriate recognition of disease activity and optimisation of acute and longer-term maintenance care is
challenging.

Asthma is diagnosed clinically, as outlined in diagnosis, below. Asthma is defined by a history of respiratory
symptoms that vary in intensity and over time, together with variable expiratory airflow limitation. It is
usually characterised by airway inflammation.

The goals of asthma management are to control symptoms and to reduce risk of future adverse outcomes.
Successful management involves drug therapies supported by nondrug interventions (see maintenance
management).

Significant changes to clinical practice have arisen from ongoing research and international expert consensus
guidelines, as well as from reflection on pitfalls in current prescribing practice. There is an increased
understanding and awareness of the risks of future adverse asthma outcomes, the cost of current prescribing
practices, and the high prevalence of poor adherence and incorrect inhaler technique. This has led to a new
focus on long-term low-dose inhaled corticosteroids (ICS), taken regularly and correctly, to optimise disease
control and minimise morbidity and mortality. The introduction of a variety of new drugs and devices offers
potential for more appropriately tailored care, but at the risk of patient and clinician confusion.

Note 1: National Asthma Council Australian Asthma Handbook is available at [URL]

Note 2: Data from Australian Centre for Asthma Monitoring. Asthma in Australia 2011. AIHW Asthma
Series no. 4. Cat. no. ACM 22. Canberra: AIHW; 2011. [URL]

Diagnosis of asthma in adults

General information

Asthma frequently presents in childhood, but can occur for the first time at any age. There are concerns about
both over- and under-diagnosis of asthma in children and adults.

There is no single diagnostic test for asthma.

There is no single diagnostic test for asthma; the clinical diagnosis in adults is made by:

considering asthma as a potential diagnosis for a variety of respiratory symptoms including wheeze,
dyspnoea (shortness of breath), cough and chest discomfort or tightness
taking a detailed history to identify the pattern of symptoms and to exclude other causes
documenting variable airflow limitation.

It is likely that asthma represents a spectrum of conditions with differing mechanisms and pathophysiology.
Asthma may coexist or have symptoms overlapping with chronic obstructive pulmonary disease in older
adults; see overlap of asthma and COPD.
Asthma is characterised by respiratory symptoms (wheeze, shortness of breath, chest tightness, cough) that
vary in intensity and over time. A summary of the key symptom patterns in adults and adolescents consistent
with asthma is provided in Table 9.9.

Alternative diagnoses to consider in adults and adolescents according to predominant symptoms are suggested
in Table 9.10.

In older people, key alternative diagnoses to exclude are chronic obstructive pulmonary disease (COPD), left
ventricular failure, bronchiectasis and lung cancer. Asthma and COPD may coexist in older patients and
awareness of this reduces the likelihood of mismanagement (particularly the use of inappropriate
medications); see overlap of asthma and COPD for further information.

Diagnosis of asthma in adults and adolescents (Table 9.9)

CLINICAL FEATURES THAT INCREASE THE PROBABILITY OF ASTHMA

more than one of the following symptoms: wheeze, breathlessness, chest
tightness, cough—particularly if these:
are worse at night and in the early morning
occur in response to exercise, allergen exposure or cold air
occur after taking aspirin or beta blockers
history of atopic disorder, eg allergic rhinitis, atopic dermatitis
family history of asthma and/or atopic disorder
widespread wheeze heard on auscultation of the chest
otherwise unexplained low FEV1 or PEF (historical or serial readings)
otherwise unexplained peripheral blood eosinophilia.

CLINICAL FEATURES THAT LOWER THE PROBABILITY OF ASTHMA

prominent dizziness, light-headedness, peripheral tingling

chronic productive cough in the absence of wheeze or breathlessness
repeatedly normal physical examination of chest when symptomatic
voice disturbance
symptoms with colds only
significant smoking history (more than 20 pack years [NB1])
cardiac disease
normal spirometry or PEF when symptomatic [NB2].

Record the basis on which a diagnosis of asthma is suspected.

FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow
NB1: Pack years is calculated using the formula (years of smoking × cigarettes per day) / 20; see also [URL]. Note that asthma and chronic
obstructive pulmonary disease (COPD) can coexist; see overlap of asthma and COPD.
NB2: Normal spirometry when not symptomatic does not exclude the diagnosis of asthma. Repeated measurements of lung function are often
more informative than a single assessment.
Adapted by permission from BMJ Publishing Group Limited. Scottish Intercollegiate Guidelines Network (SIGN). British guideline on the
management of asthma: a national clinical guideline (SIGN 141). Quick reference guide. © 2014.

Alternative diagnoses than asthma to consider in adults and adolescents according to

predominant symptoms (Table 9.10)

Symptom Possible alternative diagnosis [NB1]

lack of fitness

obesity

COPD

hyperventilation or dysfunctional breathing

upper airway dysfunction (vocal cord dysfunction)

heart failure

breathlessness pleural effusion

pulmonary fibrosis
 lung cancer

large airway stenosis

congenital heart disease

pulmonary hypertension

inhaled foreign body

COPD

bronchiectasis

upper airway dysfunction (vocal cord dysfunction)

wheeze
large airway stenosis

large airway malacia

inhaled foreign body

ischaemic heart disease

chest tightness hyperventilation or dysfunctional breathing

gastro-oesophageal reflux
postviral cough

upper airway cough syndrome (postnasal drip)

oesophageal disorders (eg gastro-oesophageal reflux)

drug-induced (eg ACEI)

dry cough COPD

chronic rhinosinusitis

lung cancer

inhaled foreign body

pulmonary fibrosis
COPD

chronic bronchitis

bronchiectasis

sputum production rhinitis

lung cancer

cystic fibrosis

inhaled foreign body

ACEI = angiotensin converting enzyme inhibitor; COPD = chronic obstructive pulmonary disease
NB1: Likelihood of alternative diagnoses will depend on other patient-specific factors such as age, comorbid conditions, smoking history and other
findings.

Variable airflow limitation

Evidence of variable expiratory airflow limitation should be obtained and documented in the patient's clinical
records. This should preferably be done before starting regular preventer treatment, as it is harder to confirm
the diagnosis of asthma once the patient is receiving treatment. In urgent asthma presentations, empirical
treatment with inhaled corticosteroids may be started, and the patient brought back for objective testing within
1 to 3 months.
In some patients, observing a response after 1 to 3 months of regular preventer treatment may help to confirm
the diagnosis, but lack of response to bronchodilators or inhaled corticosteroids does not rule out asthma.

The term ‘variable airflow limitation’ is used when the variation in expiratory airflow is more than that seen in
healthy people. However, there is some variation in lung function even in healthy people and patients with
chronic obstructive pulmonary disease (COPD) (up to 12% from week to week). In a patient with symptom
patterns consistent with asthma (see Table 9.9), the more times variable airflow limitation is seen, or the
greater the variation, the more likely the diagnosis of asthma.

Criteria for variable airflow limitation include:

clinically important bronchodilator reversibility; ie an increase of forced expiratory volume in 1 second

(FEV1) of at least 200 mL and 12% from baseline 10 to 15 minutes after giving a short-acting beta2
agonist (SABA) (200 to 400 micrograms inhaled salbutamol or equivalent). A larger increase in FEV1
(ie more than 400 mL) in response to a SABA is strongly suggestive of asthma
clinically important variation in lung function (at least 20% change in FEV1 or peak expiratory flow
[PEF]) when measured repeatedly over time
diurnal variation in PEF readings of greater than 10% [Note 3]. If PEF is being measured, use the same
meter on each occasion
positive bronchial provocation challenge or exercise challenge in a respiratory function laboratory
clinically important increase in FEV1 of more than 200 mL and 12% from baseline after a therapeutic
trial of inhaled corticosteroids for 4 weeks.

At least once during the diagnostic process, confirm the presence of expiratory airflow limitation (ie reduced
FEV1 to forced vital capacity [FVC] ratio [FEV1/FVC]). In most healthy adults, the FEV1/FVC is greater than
0.75 to 0.8 (sometimes expressed as a percentage [75 to 80%]) and for adolescents, greater than 0.85 (85%).
In older people, an FEV1/FVC as low as 0.70 (70%) may still be considered normal [Note 4].

Normal spirometry in the absence of symptoms does not exclude asthma. However, if the patient is
symptomatic (especially if short of breath) at a time when spirometry is normal, consider another diagnosis.
The clinical diagnosis should also be reviewed if management is ineffective.

Review the clinical diagnosis if management is ineffective.

For further information on other lung function tests that may require specialist referral, see pulmonary
function tests.

Note 3: Diurnal variability is calculated each day from twice-daily PEF readings (best of three each time) as
([the day's highest PEF minus the day's lowest PEF] divided by the mean of the day's PEF), and averaged
over 1 to 2 weeks.

Note 4: If the patient's FEV1/FVC is expressed as a percentage rather than a ratio, do not confuse this with
the percentage of predicted FEV1/FVC.

Key references
Asthma in adults and adolescents: introduction and diagnosis

Australian Centre for Asthma Monitoring. Asthma in Australia 2011. AIHW Asthma Series no. 4. Cat. no. ACM 22.
Canberra: AIHW; 2011. [URL]

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the
management of asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the
management of asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

LeMay KS, Armour CL, Reddel HK. Performance of a brief asthma control screening tool in community
pharmacy: a cross-sectional and prospective longitudinal analysis. Prim Care Respir J 2014;23(1):79–84. [
 ]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma
Council Australia; 2014. [URL]

Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung
function tests. Eur Respir J 2005;26(5):948–68. [ ]

Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry
for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324–43. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Maintenance management of asthma in adults and
adolescents
Overview of maintenance management of asthma in adults
Overview
A diagrammatic overview of control-based asthma management is shown in Figure 9.3.

The long-term goals of asthma management are:

symptom control; ie to achieve good control of symptoms and maintain normal activity levels
risk reduction; ie to minimise future risk of
–
flare-ups (exacerbations)
–
fixed airflow limitation
–
drug adverse effects.

These goals are achieved through:

accurate diagnosis
a partnership between the patient and healthcare professional(s) (see doctor–patient relationship)
control-based management, incorporating
–
drug treatment, managed with a cycle of assessment, adjustment and review of response
–
nondrug interventions
–
management of modifiable risk factors and comorbid conditions
education and skills training for asthma self-management
regular medical review.

The control-based asthma management cycle (Figure 9.3)

Modified with permission from the Global Strategy for Asthma Management and Prevention 2014, © Global Initiative for Asthma (GINA) all rights
reserved. Available from [URL]

Doctor–patient relationship
Effective asthma care requires a partnership between the patient and healthcare professional(s) so that patients can
participate in decisions about their management and gain confidence and skills to engage in self-management.
Patients vary in their willingness and ability to participate in self-management.

Good communication is an essential part of asthma management. Take the patient's health literacy into account
when providing education and skills training. Specific communication strategies can assist in reducing the impact
of low health literacy, eg ordering information from the most to the least important, and using the ‘teach-back‘
method to confirm understanding.

Control-based management

Overview

The aim of asthma management is to achieve good long-term asthma control. Asthma control refers to the extent to
which the manifestations of asthma have been reduced or removed by treatment; it has two components:

current level of symptom control

risk of future adverse outcomes.

Assessing asthma symptom control is different to assessing asthma severity.

Assessing asthma symptom control

Good asthma symptom control is characterised by:

absent or minimal daytime symptoms

no nocturnal symptoms
no limitation of activity by asthma
minimal need for short-acting beta2 agonists.

The patient's current level of symptom control can be summarised with a validated composite score, eg Asthma
Control Test (referred to as the Asthma Score in Australia; see [URL]). The Primary care Asthma Control
Screening tool (PACS) (see Australian Asthma Handbook [URL]) can be used to quickly identify patients who
need more detailed assessment of their asthma symptom control.

In some patients, symptoms and reliever use may be an unreliable indicator of the need for regular preventer
therapy. The following situations highlight the need to measure lung function as well as assess symptoms and
reliever use.

Symptoms and reliever use may be inappropriately infrequent, leading to undertreatment, in patients who are:

inactive, ie with insufficient activity to experience symptoms

poor perceivers of airway obstruction—consider if a substantial change in lung function (eg 20% increase
after bronchodilator or similar decrease after exercise or during bronchial provocation testing) is not
accompanied by a change in symptoms
using long-acting bronchodilator alone without inhaled corticosteroid (ICS). Using long-acting beta2 agonists
(LABAs) alone is dangerous and not recommended; patients may have few symptoms, but are at high risk of
flare-ups and an increased risk of asthma-related death due to uncontrolled airway inflammation.

Symptoms and reliever use may be inappropriately frequent, leading to overtreatment and risk of adverse effects, in
patients who are:

experiencing symptoms due to conditions other than asthma, eg shortness of breath due to obesity, or cough
due to chronic upper airway cough syndrome (postnasal drip)
overperceivers of airway obstruction
using excessive doses of short-acting beta2 agonist through habit or anxiety.

Assessing risk of adverse asthma outcomes

Assess patients for their risk of future adverse outcomes including flare-ups, faster than normal decline in lung
function and adverse effects of treatment.

Patients are at risk of adverse asthma outcomes, even if they have few asthma symptoms, if they:

have poor lung function

smoke or are exposed to environmental tobacco smoke
are using too much or too little of their prescribed therapy
are using high doses of ICS.
Other factors predictive of worse clinical outcomes include increased airway hyperresponsiveness and blood
eosinophilia.

A more extensive list of adverse asthma outcomes and associated risk factors is provided in Table 9.11. Review
patients at risk of adverse outcomes more frequently than usual (see regular review).

Risk factors for adverse asthma outcomes in adults and adolescents (Table 9.11)

Adverse asthma
Asthma history Investigation findings Other factors
outcome
exposure to tobacco
poor asthma symptom
smoke (personal or
control
second-hand smoking)
any asthma flare-up poor lung function
socioeconomic
during the previous 12 (even if few symptoms)
disadvantage
Increased risk of months peripheral blood
use of illegal substances
flare-ups lack of written asthma eosinophilia (suggests
major psychosocial
(exacerbations) action plan eosinophilic airway
problems
difficulty perceiving inflammation)
mental illness
airflow limitation or
other concurrent
severity of flare-ups
chronic lung disease

invasive ventilation or
admission to intensive
care unit due to asthma
inadequate treatment
(ever)
experience of adverse
two or more
effects of OCS (may
hospitalisations for
contribute to
asthma in past year
undertreatment or
three or more ED visits
delayed presentation to
for asthma in the past
hospital during flare-
year sensitivity to
ups)
hospitalisation or ED unavoidable allergens
Increased risk of socioeconomic
visit for asthma in the (eg Alternaria species
life-threatening disadvantage
past month of common moulds)
asthma living alone
high SABA use (more confirmed food allergy
mental illness
than one pMDI canister
use of alcohol or illegal
per month)
substances
history of delayed
poor access to health
presentation to hospital
care (eg rural or remote
during flare-ups
region)
history of sudden-onset
cardiovascular disease
acute asthma
lack of written asthma
action plan

chronic mucus
poor lung function
hypersecretion
peripheral blood exposure to tobacco
severe asthma flare-up
Accelerated decline eosinophilia (suggests smoke (personal or
in a patient not using
in lung function eosinophilic airway second-hand smoking)
ICS
inflammation)
occupational asthma

anxiety disorder (may

be associated with
increased sensitivity to
long-term high-dose
asthma symptoms and
Treatment-related ICS
adverse events reluctance to reduce
frequent use of OCS
ICS dose when asthma
well controlled)
euphoria with OCS use

ED = emergency department; ICS = inhaled corticosteroid; OCS = oral corticosteroid; pMDI = pressurised metered dose inhaler; SABA = short-acting
beta2 agonist.
Modified with permission from National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014.

Assessing asthma severity

Asthma severity is defined by the intensity of treatment required to achieve good asthma symptom control. It is a
retrospective label that is applied after a patient has been using preventer treatment for at least 3 to 6 months.

Asthma severity is defined by the intensity of treatment required to achieve good asthma symptom control.

Note that the term ‘severity‘ may also be applied to the severity of an acute flare-up (see medical management for a
discussion of severity and management of acute asthma).

Mild asthma is asthma that can be well controlled with occasional short-acting beta2 agonist alone or with low-
dose inhaled corticosteroid; ie Step 1 or 2 in Figure 9.4.

Severe asthma is asthma that requires high-intensity treatment (high-dose inhaled corticosteroid plus long-acting
beta2 agonist, with or without other therapy) to maintain good control, or when good control is not achieved despite
high-intensity treatment; ie Step 4 or higher in Figure 9.4.

It is possible for severe asthma to be well controlled because the patient is using high doses of medication; it is also
possible for mild asthma to be poorly controlled because the patient is not using sufficient preventer medication.

It is important to achieve good asthma symptom control. Maintain this for 3 months, then step-down to find the
minimum effective treatment (see stepwise approach to treatment in adults and adolescents), which is then used as
a guide to the severity of the patient's asthma. Review the severity and treatment at least annually.

Asthma is difficult to treat in some patients as it is not possible to completely resolve problems such as poor
adherence, poor inhaler technique, and comorbid conditions; for further information, see failure to respond to
adequate treatment.

General principles of maintenance treatment of asthma in adults

Overview
Specific strategies for asthma maintenance treatment include:

drug treatment—inhaled, oral and parenteral

nondrug interventions
managing modifiable risk factors including triggers and common comorbid conditions.

Route of administration
Inhalation is the preferred route of drug administration in asthma. Inhalation allows deposition of the drug into the
bronchial tree, resulting in the lowest effective dose and minimal systemic adverse effects. Inhaled drugs can be
administered by pressurised metered dose inhalers (pMDIs) or dry powder inhalers (DPIs). Nebulisers are only
rarely needed. Effective administration of inhaled drugs requires correct delivery device technique.

The device and regimen depends firstly on the drug that meets the patient's clinical needs; appropriate device
choice is then based on various factors including patient preference and capabilities, age, and susceptibility to local
adverse effects. For further information about inhalational delivery of drugs and considerations for device choice,
see Table 9.39.

Less complicated treatment regimens can improve adherence to therapy.

Spacers should be used by adults and adolescents using a pMDI for inhaled corticosteroids (ICS). A spacer reduces
problems with coordination, increases the relative dose delivered to the lung and decreases oropharyngeal
deposition.

To minimise the risk of oropharyngeal candidiasis and systemic corticosteroid absorption, advise patients to rinse
their mouth with water and spit out straight after using ICS (single drug or fixed-dose combination). Ciclesonide
has some advantages in this respect because it is a prodrug; it is relatively inactive in the oropharynx and is
associated with a reduced risk of dysphonia (hoarse voice). Using a spacer with ICS also reduces systemic
absorption, oropharyngeal candidiasis and dysphonia.

Initiating treatment

Once current level of symptom control and risk factors are identified, and baseline lung function is documented,
select appropriate initial treatment (see Figure 9.4). Some patients may have started self-treatment with an over-
the-counter short-acting beta2 agonist (SABA).
Choice of initial preventer treatment for adults and adolescents presenting with asthma depends on their recent
symptom pattern. For patients presenting with:

symptoms less than twice per month, and who have not had a flare-up (exacerbation) requiring oral
corticosteroids in the previous year, start (or continue) treatment with as-needed SABA
symptoms occurring at least twice per month, or who have woken due to asthma symptoms at least once in
the past month, and/or who have had a flare-up requiring oral corticosteroids in the previous year, start
preventer treatment with regular low-dose inhaled corticosteroid (ICS), plus SABA as needed
poorly controlled or very troublesome symptoms (eg frequent night waking, poor lung function) on initial
presentation, start preventer treatment with medium- to high-dose ICS. Combination ICS+LABA and/or
addition of a short course of oral corticosteroids may be considered. Start (or continue) as-needed SABA.
Step-down the ICS dose after symptoms improve and good asthma symptom control is maintained for 2 to 3
months (see stepping down, below).

For detail of drugs used to treat asthma, see drug doses and administration.

Stepwise approach to treatment in adults and adolescents

Overview

Treatment aims to achieve symptom control as quickly as possible. In some cases this may involve starting with a
higher-dose medication regimen and then stepping down treatment. Clearly advise the patient of the plan and the
need for follow-up to achieve this.

Ongoing treatment aims to use the lowest dose of drugs that maintains asthma symptom control and prevents flare-
ups. If inhaled corticosteroids (ICS) are indicated, low-dose regular treatment with ICS (plus short-acting beta2
agonist [SABA] as needed) is more effective than intermittent treatment and more likely to achieve control with a
lower total dose of ICS.

Low-dose regular ICS is more effective than intermittent treatment.

A stepwise approach to treating asthma in adults and adolescents is outlined in Figure 9.4. The steps reflect the
increased intensity of medication required to achieve good asthma symptom control for patients who have not
responded to the previous level despite good adherence and correct inhaler technique. See recommended drug
doses and administration for further detail.

Approximately three-quarters of adults with asthma have mild asthma that can be well controlled by Step 2
treatment. This is in contrast to current practice in Australia, where three-quarters of patients are prescribed
medium to high dose of ICS + long-acting beta2 agonist (LABA) combination therapy, suggesting that
overtreatment is common.

Most adults with asthma have mild asthma that can be well controlled with low-dose ICS preventer treatment and as-needed
SABA.

Stepped approach to adjusting asthma medication in adults and adolescents (Figure 9.4)
 ICS = inhaled corticosteroid; LABA = long-acting beta2 agonist; SABA = short-acting beta2 agonist

NB1: In addition, manage flare-ups with extra treatment when they occur, and manage exercise-related asthma symptoms as indicated.

NB2: If patients are started on low-dose budesonide+eformoterol combination as both maintenance and reliever at Step 3, as-needed SABA is not
required (see combination inhaler therapy for more information).

Modified with permission from National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council
Australia; 2014.

Stepping up treatment

After 1 to 3 months, if good asthma symptom control is not achieved, consider stepping up treatment only after
confirming:

symptoms are due to asthma

inhaler technique is correct
adherence is adequate.

Identify and manage any comorbid conditions that may be affecting asthma symptom control.

Stepping down treatment

Consider stepping down treatment if asthma is stable and well controlled for 2 to 3 months (see assessing asthma
symptom control). Check the patient's actual treatment regimen before stepping down treatment, remembering that
what the patient is using may not necessarily be what has been prescribed. Assess the patient's risk factors for flare-
ups (see Table 9.11), and choose an appropriate time to step-down. For example, do not step-down when the patient
has a cold and not before the patient's access to medical services will be limited, such as on public holidays or
when travelling internationally or to remote areas.

During pregnancy, therapy should not be stepped down due to the risk to mother and baby of any flare-ups (see
asthma and pregnancy for more information).

If stepping down treatment is considered appropriate, either:

reduce ICS dose (25 to 50% dose reduction every 2 to 3 months), or

stop LABA if ICS dose is already low.

Stopping ICS in adults is associated with a significant risk of asthma flare-up; if an adult has stopped ICS they
should be made aware of this risk. Adults using low-dose ICS should generally not be stepped down to SABA
alone; however, this may be warranted in some circumstances (eg confirming asthma diagnosis). In these cases, as
with any step-down in treatment, assess the risk of flare-up (see Table 9.11), and closely monitor and follow up the
patient.
Following any step-down in treatment, advise patients to step back up if there is deterioration in control. Update
the patient's written asthma action plan regularly during any change.

Maintenance treatments for asthma in adults

Introduction
Table 9.38 details the different delivery devices for inhaled drugs used to treat asthma. See also drug doses and
administration in children.

Short-acting beta2 agonists

Short-acting beta2 agonists (SABAs) (salbutamol, terbutaline) are used as needed for symptom relief. In Australia
they are referred to as ‘relievers’; the term ‘rescue medication’ may be used in the literature.

Beta2 agonists (long-acting or short-acting) should not be used regularly as monotherapy because patients are at
high risk of flare-up due to uncontrolled airway inflammation, and increased risk of asthma-related death despite
often having few symptoms.

Use:

1 salbutamol 100 micrograms, 1 to 2 actuations by inhalation via pMDI, as needed

OR

1 terbutaline 500 micrograms, 1 actuation by inhalation via DPI, as needed.

Most patients are able to use a pressurised metered dose inhaler (pMDI) plus spacer, breath-actuated pMDI (eg
Autohaler), or dry powder inhaler (DPI). Rarely, nebulised SABA may be required. See Table 9.38 for information
about available devices.

If nebulised treatment is necessary, use:

salbutamol 5 mg by inhalation via nebuliser.

Inhaled corticosteroids

Dosage

Inhaled corticosteroids (ICS) (beclomethasone, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate)
are first-line maintenance treatment. In Australia they are referred to as ‘preventers’.

Start with low-dose ICS in addition to as-needed short-acting beta2 agonist (SABA); use:

a low-dose ICS by inhalation, see Table 9.12.

Prescribing low-dose ICS is significantly cheaper, both for the patient and the government, compared with
combination inhaler therapy. Low, medium and high dose ranges for available ICS are presented in Table 9.12.

A long-acting beta2 agonist (LABA) may be added if good control has not been achieved despite correct inhaler
technique and good adherence; wherever possible a fixed-dose combination inhaler containing the two drugs
should be prescribed. See stepwise approach to treatment and combination inhaler therapy for more information.

Low, medium and high dosages of inhaled corticosteroids for asthma in adults and adolescents
(Table 9.12)

Delivery device Dosage [NB2]

Drug
[NB1] Low Medium High [NB3]
50 to 100 more than 200
200 micrograms,
beclomethasone pMDI micrograms, twice micrograms, twice
twice daily
daily daily
100 to 200 more than 400
micrograms, twice 400 micrograms, micrograms, twice
budesonide [NB4] multiple-dose DPI
 daily twice daily daily

80 to 160 more than 320

320 micrograms, once
ciclesonide pMDI micrograms, once micrograms, once
daily
daily daily
pMDI
50 to 100 125 to 250 more than 250
fluticasone or
micrograms, twice micrograms, twice micrograms, twice
propionate
multiple-dose DPI daily [NB5] daily daily
[NB5]
fluticasone furoate 100 micrograms, once 200 micrograms or
[NB6] [NB6]
[NB6] daily more, once daily
DPI = dry powder inhaler; pMDI = pressurised metered dose inhaler
NB1: See inhalational drug delivery devices for advice about appropriate device choice.
NB2: Number of actuations to deliver a dose depends on the dose formulation available.
NB3: Except for short periods, refer patients considered for high doses to a specialist.
NB4: Budesonide may be given once daily for patients needing 400 micrograms per day or less.
NB5: Fluticasone propionate 50 micrograms can only be delivered via pMDI; minimum available dose per actuation of multiple-dose DPI is 100
micrograms.
NB6: Fluticasone furoate is only available in combination with vilanterol, and is administered as one inhalation once daily. Fluticasone furoate +
vilanterol 100+25 micrograms daily is considered to contain medium-dose inhaled corticosteroid; at the time of writing there is no product available
containing low-dose fluticasone furoate.

Rate of response to treatment

Different clinical features of asthma respond to inhaled corticosteroid (ICS) treatment at different rates, with night-
time waking improving rapidly and reliever use improving more slowly; see Table 9.13.

Night-time symptoms improve rapidly with high-dose ICS, with 50% improvement within a few days and nearly
complete disappearance after 1 month; most patients do not need oral corticosteroids to control significant initial
symptoms. Combination ICS + long-acting beta2 agonist (LABA) improves symptoms more quickly than ICS
alone; however, there is no added benefit from ICS+LABA in reducing the risk of asthma flare-ups.

Rate of response of different measures of asthma control to inhaled corticosteroid (Table 9.13)
[NB1]

Measure of asthma control Average time to maximum improvement

night-time waking 1 week
FEV1 2 months
morning PEF 3 months
reliever use 6 months
airway hyperresponsiveness 18 months
FEV1 = forced expiratory volume in 1 second; PEF = peak expiratory flow
NB1: Based on data using high-dose inhaled corticosteroids; Reddel HK, Jenkins CR, Marks GB, Ware SI, Xuan W, Salome CM, et al. Optimal asthma
control, starting with high doses of inhaled budesonide. Eur Respir J 2000;16(2):226—35. [URL]

Combination inhaler therapy

Overview

For patients who remain symptomatic despite good adherence and correct technique with inhaled corticosteroids
(ICS) alone (Step 2 treatment) increase treatment to Step 3 (see Figure 9.4). Either add a long-acting beta2 agonist
(LABA) (eformoterol, salmeterol, vilanterol) to the maintenance treatment (see conventional fixed-dose
combination maintenance regimen with SABA as needed, below), or switch to a fixed-dose combination inhaler
containing low doses of budesonide + eformoterol as maintenance and reliever therapy (see fixed-dose combination
maintenance and reliever regimen).

LABAs should not be used without ICS.

Fixed-dose combination inhalers are more convenient for patients than separate inhalers and, importantly, ensure
that the LABA is always accompanied by an ICS. Use of LABA alone is not recommended—patients are at high
risk of flare-up due to uncontrolled airway inflammation, and an increased risk of asthma-related death despite
often having few symptoms.
Each fixed-dose combination product is available with different ICS doses to allow for ‘stepping up’, or ‘stepping
down’ once good control has been achieved. Various delivery devices are available (see Table 9.38).

Conventional fixed-dose combination maintenance regimen with SABA as needed

One option for asthma maintenance is the use of a fixed-dose combination ICS+LABA with short-acting beta2
agonist (SABA) as needed (Step 3 in Figure 9.4). This regimen is suitable for all fixed-dose combinations of
ICS+LABA.

The starting dose of a fixed-dose combination ICS+LABA is guided by the dose of ICS the patient was previously
using. Use:

a low-dose ICS+LABA by inhalation, see Table 9.14.

Depending on response, the fixed-dose combination ICS+LABA dose may then be stepped down; see stepwise
approach to treatment for further information.

For stepping up a fixed-dose combination ICS+LABA (Step 4 in Figure 9.4, see also stepwise approach to
treatment). If appropriate, use:

a medium- to high-dose ICS+LABA by inhalation, see Table 9.14.

Inhaled corticosteroid + long-acting beta2 agonist fixed-dose combination dosages for asthma in
adults and adolescents (Table 9.14)

Dosage [NB2] [NB3]

Drug combination Delivery device [NB1] Medium to high (Step 4)
Low (Step 3)
[NB4]
100+6 micrograms, twice
multiple-dose DPI daily
budesonide+eformoterol 400+12 micrograms, twice
or up to
[NB5] daily
pMDI 200+6 micrograms, twice
daily
100+25 micrograms, once
daily
fluticasone
multiple-dose DPI [NB6] up to
furoate+vilanterol
200+25 micrograms, once
daily
250+10 micrograms, twice
daily
fluticasone 100+10 micrograms, twice
pMDI up to
propionate+eformoterol daily
500+20 micrograms, twice
daily
250+50 micrograms, twice
multiple-dose DPI daily
fluticasone 100+50 micrograms, twice
or up to
propionate+salmeterol daily
pMDI 500+50 micrograms, twice
daily
DPI = dry powder inhaler; pMDI = pressurised metered dose inhaler
NB1: See inhalational drug delivery devices for advice about appropriate device choice.
NB2: See Figure 9.4 for steps in asthma management, and for further advice, see stepwise approach to treatment in adults and adolescents.
NB3: Number of actuations to deliver a dose depends on the dose formulation available.
NB4: Doses around the upper limit of the medium to high dose range should not be used without early reassessment and consideration of specialist
referral.
NB5: These doses apply to conventional fixed-dose combination maintenance regimen with short-acting beta2 agonist as needed; fixed-dose combination
maintenance and reliever regimen is discussed below.
NB6: Fluticasone furoate + vilanterol 100+25 micrograms, given as one inhalation once daily, is considered to contain medium-dose inhaled
corticosteroid; at the time of writing there is no product available containing low-dose fluticasone furoate.

Fixed-dose combination maintenance and reliever regimen

Fixed-dose combination budesonide + eformoterol as maintenance and reliever therapy is an alternative to
conventional fixed-dose combination maintenance regimen with SABA as needed. For patients whose asthma is
initially not well controlled on ICS alone or ICS+LABA maintenance therapy, studies have shown a fixed-dose
combination maintenance and reliever regimen is associated with lower ICS doses and fewer flare-ups. The
advantage of using only one type of inhaler device is that increased use as a reliever during flare-ups also increases
ICS dose early in the course of a flare-up.

At the time of writing, fixed-dose combination budesonide + eformoterol is the only combination that is registered
in Australia for the maintenance and reliever regimen. Use:

budesonide+eformoterol 100+6 or 200+6 micrograms, 1 to 2 actuations by inhalation via

DPI, twice daily for maintenance

plus 1 actuation of the same dose as needed for relief of symptoms; no more than 6 actuations on a single occasion

Maximum daily dose is 12 actuations

OR

budesonide+eformoterol 50+3 or 100+3 micrograms, 2 to 4 actuations by inhalation via

pMDI, twice daily for maintenance

plus 2 actuations of the same dose as needed for relief of symptoms; no more than 12 actuations on a single
occasion.

Maximum daily dose is 24 actuations.

Combination therapy using separate single-drug inhalers

Combination ICS+LABA therapy using separate single-drug inhalers is not recommended unless there is no fixed-
dose combination inhaler containing the corticosteroid the patient is using (such as ciclesonide or beclomethasone).

Use of LABA or high doses of SABA as monotherapy is not recommended—patients are at high risk of flare-up
due to uncontrolled airway inflammation, and an increased risk of asthma-related death despite often having few
symptoms. Therefore, LABAs must only be prescribed concurrently with an ICS.

If addition of a LABA to ICS is considered necessary, but no fixed-dose combination inhaler is available, use:

an ICS by inhalation, see Table 9.12

PLUS

1 eformoterol 6 or 12 micrograms, 1 actuation by inhalation via DPI, twice daily

OR

1 salmeterol 50 micrograms, 1 actuation by inhalation via DPI, twice daily.

Although eformoterol has a rapid onset of action, it is not recommended for use as a reliever unless used in fixed-
dose combination with an inhaled corticosteroid, as described in fixed-dose combination maintenance and reliever
regimen.

Other drug treatment

Cromones

Cromones (cromoglycate, nedocromil) are mast cell stabilisers. Cromoglycate is less effective than inhaled
corticosteroids in controlling asthma and improving lung function.

Cromones taken before exercise can be used to manage exercise-induced bronchoconstriction, but they are only
effective in approximately 50% of patients and are less effective than short-acting beta2 agonists.

Cromones have a good safety profile and tolerance does not occur when they are taken regularly. However,
cromones involve a more complex regimen (ie more frequent dosing and meticulous daily care to prevent clogging
of inhaler device).
If considered appropriate, use:

1 cromoglycate 20 mg, 1 actuation by inhalation via DPI, 4 times daily

or cromoglycate 5 mg, 2 actuations by inhalation via pMDI, 4 times daily

OR

1 nedocromil 2 mg, 2 actuations by inhalation via pMDI, 4 times daily.

Montelukast

In adolescents 14 years and younger, montelukast may be used as add-on therapy for patients who have frequent
exercise-related symptoms with Step 2 treatment (see Figure 9.4), despite otherwise good asthma symptom control.
This is an alternative to changing to inhaled corticosteroid + long-acting beta2 agonist [Note 1] .

The evidence does not support using montelukast as an alternative to adding long-acting beta2 agonist as add-on
therapy at Step 3 treatment (see Figure 9.4).

Montelukast may be considered as add-on therapy in adults and adolescents with severe asthma, ie uncontrolled
despite good inhaler technique and adherence with Step 4 treatment (see Figure 9.4 and failure to respond to
adequate treatment).

If considered appropriate, use:

montelukast (6 to 14 years) 5 mg orally, at night

or montelukast (15 years or older) 10 mg orally, at night.

Note 1: See the Pharmaceutical Benefits Scheme website for subsidised indications for montelukast [URL]

Anti-immunoglobulin E therapy

Anti-immunoglobulin E (IgE) (omalizumab) is a humanised monoclonal antibody for use in adults and adolescents
with uncontrolled severe asthma who are already using optimised inhaler treatment, are atopic, and have a serum
IgE concentration more than 76 IU/mL.

At the time of writing omalizumab is available for Pharmaceutical Benefits Scheme subsidy only on specialist
referral and if the patient fits a set of well-defined criteria, which includes the frequent need for systemic
corticosteroids [Note 2]. Omalizumab reduces flare-ups and asthma-related hospitalisations, improves symptoms
and quality of life, and reduces other medication needs. It has no significant effect on forced expiratory volume in 1
second (FEV1).

Note 2: See the Pharmaceutical Benefits Scheme website for subsidised indications for omalizumab [URL]

Allergen immunotherapy

The place of specific allergen immunotherapy in asthma remains controversial; it is not recommended as
monotherapy for asthma. It may be effective, in addition to standard treatment, in some patients with documented
dust mite, cat or pollen allergy. In general, allergen immunotherapy in asthma is most often used when there is
concurrent allergic rhinitis or allergic rhinoconjunctivitis.

There is a risk of anaphylaxis with subcutaneous allergen immunotherapy; it should only be administered under
supervision by a specialist in allergy and only if the patient has well-controlled asthma and a forced expiratory
volume in 1 second (FEV1) greater than 70%. Sublingual allergen immunotherapy has a better safety profile and
may be more convenient for the patient; it should also be supervised by a specialist in allergy. The cost-
effectiveness of allergen immunotherapy has not been assessed.

Modifiable risk factors for asthma in adults

Smoking

For patients with asthma, tobacco smoking results in:

 increased asthma symptoms
increased risk of flare-ups
reduced efficacy of inhaled corticosteroids—higher doses may be needed
faster than normal decline in lung function.

Smoking during pregnancy may cause abnormal fetal lung development and is a known risk factor for the baby
developing asthma. Exposure to household tobacco smoke places an infant at increased risk of developing asthma.

Ask about current smoking behaviour and provide access to smoking cessation strategies at every opportunity.

Triggers

Triggers for asthma vary widely and differ between patients. Multiple triggers may be involved concurrently for a
patient, so take a detailed history. Patients with poorly controlled asthma are more susceptible to asthma triggers.
Possible triggers for asthma are listed in Table 9.15.

Food allergies rarely trigger acute asthma; however, a confirmed food allergy is a risk factor for asthma-related
death. No individual food item triggers asthma in all people. Intolerance to food chemicals (ie dose-related,
non–IgE-mediated reactions) may affect asthma in some patients, but this appears to be rare. Specialist
investigation is usually necessary for accurate assessment and diagnosis, which often requires supervised
elimination diets and challenge.

Management of triggers for flare-ups of existing asthma (Table 9.15)

When to avoid Trigger [NB1] Major examples Comment

personal and second-hand
ALWAYS tobacco smoke See smoking for further information.
smoking
allergens such as:

animal danders
latex
wood, flour and grain
dusts
As well as triggering asthma flare-ups, most of
these substances (except for nonspecific irritants)
small molecules such as:
ALWAYS IF occupational may also cause occupational asthma.
POSSIBLE factors chlorine
If possible, refer to an occupational or respiratory
epoxy resins
physician for assessment [NB2].
formaldehyde
glutaraldehyde
soldering and
welding fumes

irritants (dust, smoke)

Advise patients that influenza vaccination protects
WHEN respiratory tract viral URTIs are the most against influenza but will not protect against
POSSIBLE infections common cause of flare-ups ‘colds’. Influenza vaccine does not trigger asthma
flare-ups.
dust

strong odours
WHEN Response to irritants is more common when
irritants
POSSIBLE asthma is poorly controlled.
fumes

air pollutants
WHEN Reduction is difficult to achieve, may be costly,
inhaled
POSSIBLE (if house dust mite and has not been shown to improve asthma
allergens [NB3]
relevant) symptom control in the majority of patients.
animal danders Removal of cats can sometimes be beneficial.
fungal allergens (mould) Removal of mould can sometimes be beneficial.
If allergic to pollens, exposure may be reduced
when pollen levels are high by remaining indoors
pollens
with windows and doors closed, especially during
thunderstorms if allergic to grass pollens.
WHEN Food allergy is an uncommon trigger of asthma.
foods and food allergies eg nuts, eggs,
POSSIBLE (if Asthma symptoms may occur as part of an
additives [NB4] fish, shellfish, some seeds
relevant) anaphylactic reaction to food.
 sensitivity to food Reactions to food chemicals are usually dose-
chemicals, including: related; patients may be able to tolerate small
amounts of the relevant substance.
preservatives such as Australian approved food additive numbers for
sulfites or benzoates sulfites are 220 to 228 and benzoates are 210 to
213.
colourings such as
Australian approved food additive number for
tartrazine
tartrazine is 102.
naturally occurring
Salicylates occur naturally in berries, pineapple,
salicylates in food
dried fruits, spices, curries and mints.
Always avoid NSAIDs if they have triggered
WHEN anaphylaxis or flare-ups in the past. See aspirin-
drugs aspirin and NSAIDs
POSSIBLE exacerbated respiratory disease for further
information.
Can trigger asthma regardless of beta1-specificity
or route of administration (oral, parenteral, eye
drops).
beta blockers
Seek specialist advice if beta blockers are
indicated for comorbid conditions (eg acute
coronary syndrome).
For example, royal jelly, echinacea, and those
some complementary
containing salicylates (eg willow bark) or salicin
medicines
(eg meadowsweet).
cholinergic agonists and For example, bethanechol, pyridostigmine, drugs
anticholinesterases used to treat dementia.
Rare reports with misoprostol and prostaglandin
prostaglandin analogues eye drops (eg bimatoprost, latanoprost,
travoprost).
Exercise is recommended in all people with asthma; however, it is a common
DO NOT
exercise trigger for bronchoconstriction. See exercise-induced bronchoconstriction for
AVOID
information including management advice.
DO NOT Laughter may cause cough and wheeze if asthma is poorly controlled, but do
laughter
AVOID not avoid.
NSAIDs = nonsteroidal anti-inflammatory drugs; URTI = upper respiratory tract infection
NB1: No individual item triggers asthma in all people.
NB2: Avoidance may reduce asthma symptoms in some sensitised patients, but take into account the cost and burden of an intervention and the evidence
for its effectiveness; see advice in Australian Asthma Handbook [URL]
NB3: See advice about allergen avoidance in Australian Asthma Handbook [URL]
NB4: See triggers, above, for further information.

Lifestyle factors

Diet

Encourage healthy eating for all patients with asthma [Note 3]. Dietary supplements have not been shown to be of
benefit for asthma [Note 4]. Dietary restrictions such as low-salt diets, or avoiding dairy foods or food additives are
not recommended without dietetic or medical supervision.

Note 3: See the National Health and Medical Research Council Australian Dietary Guidelines for further
information; available at [URL]

Note 4: For a summary of efficacy evidence for dietary supplements in asthma, see the Australian Asthma
Handbook [URL]

Exercise

Reassure patients that asthma is not a contraindication to physical exercise. Recommend regular physical exercise
for both adults and children for its beneficial effect on cardiopulmonary fitness and quality of life.

Symptoms such as breathlessness triggered by exercise may be due to lack of fitness rather than exercise-induced
bronchoconstriction. However, breathlessness that worsens in the minutes after stopping exercise is likely to be due
to asthma. Exercise-induced bronchoconstriction can be managed effectively and is not a reason to avoid physical
exercise.

Comorbid conditions

Overview

A number of comorbid conditions can worsen asthma symptom control, risk or management (see Figure 9.5).
Managing these conditions may improve symptom control and should be considered before stepping up asthma
treatment. This section provides advice about obesity, gastro-oesophageal reflux disease, rhinosinusitis and upper
airway dysfunction in the context of coexisting asthma. General advice on other conditions contained in Figure 9.5
can be found in relevant topics in Therapeutic Guidelines.

Conditions that can affect asthma symptom control, risk or management (Figure 9.5)

COPD = chronic obstructive pulmonary disease; GORD = gastro-oesophageal reflux disease; OSA = obstructive sleep apnoea

NB1: See overlap of asthma and COPD for further information.

Reproduced with permission from National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma
Council Australia; 2014.

Obesity

Obesity (defined as a body mass index [BMI] more than 30 kg/m2) is associated with an increased prevalence of
asthma. In addition, obese people with asthma report more dyspnoea and asthma-like symptoms than nonobese
people; therefore, it is important to confirm the diagnosis of asthma by documenting variable airflow limitation.
Obese patients are more likely to have obstructive sleep apnoea and gastro-oesophageal reflux, which can also
worsen asthma symptom control.

Weight loss of at least 5 to 10% may result in clinically significant improvements in asthma symptom control.

Gastro-oesophageal reflux disease

The relationship between asthma and gastro-oesophageal reflux disease (GORD) is complex. Patients with asthma
have higher rates of GORD based on symptoms or results of 24-hour pH monitoring. It is considered that the
presence of GORD may worsen asthma symptom control or contribute to symptoms of coughing. Asthma drugs
may cause relaxation of the lower oesophageal sphincter.

Symptomatic GORD should be treated; however, this will not necessarily improve asthma symptoms. See Gastro-
oesophageal reflux for management advice.

Rhinosinusitis

Rhinitis or chronic rhinosinusitus and asthma commonly coexist. Actively assess for and manage concurrent
conditions (see Rhinitis and rhinosinusitis for management advice).

Upper airway dysfunction

Upper airway dysfunction (vocal cord dysfunction) often mimics, and is misdiagnosed as, asthma. Variable upper
airway obstruction results from abnormal and intermittent adduction of the vocal cords or supraglottic muscles
during respiration. These episodes can be frightening to the patient. Symptoms do not respond to short-acting beta2
agonists.

Upper airway dysfunction may coexist with asthma, and this can worsen symptoms and lead to overtreatment of
asthma if it is not diagnosed and managed appropriately. If upper airway dysfunction is suspected, seek specialist
advice.

Nondrug interventions for asthma in adults

Breathing exercises
Various breathing exercises including the Butekyo breathing technique have been shown to improve asthma
symptoms in the short term, but have not been shown to improve lung function or reduce bronchial
hyperresponsiveness. The design of many studies of breathing exercises is problematic, and much of the benefit
may be due to the relaxation strategies that are often incorporated with breathing techniques. These exercises
should be used in conjunction with prescribed maintenance asthma therapy; dosage of existing therapy should not
be reduced or stopped.

Complementary medicine
Although there is no good evidence that complementary medicines are beneficial for asthma, patients frequently
use them. It is important to facilitate an open discussion and to know which complementary medicines patients are
taking because they may interact with prescribed medication. Provide information about the possible harms and
benefits of complementary medicine. Ensure patients trialling complementary medicine continue with their usual
medications.

For a summary of efficacy evidence for complementary therapies in asthma, see the Australian Asthma Handbook
[URL]. Some complementary medicines that should be avoided in patients with asthma are listed in Table 9.15.

Bronchial thermoplasty

Bronchial thermoplasty is a specialist invasive physical intervention. It delivers thermal energy (65°C) to the
proximal airways, resulting in smooth muscle ablation. It has been associated with a short-term increase and
longer-term decrease in flare-ups, but there is a very large placebo effect for outcomes such as asthma symptoms
and quality of life, and studies have been criticised for a lack of follow-up compared with sham-treated control
subjects.

Education and skills training for asthma in adults

Information

All patients require some core information about asthma and treatment, but the education must be personalised to
their asthma severity and their health literacy.

Key information includes:

an explanation of asthma
rationale for treatment, and differences between relievers and preventers
potential adverse effects of treatment
how to recognise worsening asthma and what to do.

Information alone does not appear to improve health outcomes in adults and adolescents with asthma, although
symptoms may improve.

Inhaler technique

Correct inhaler technique is essential for good asthma outcomes. Up to 90% of patients have incorrect inhaler
technique, but most are not aware that they have a problem. Correcting inhaler technique can lead to significant
improvement in asthma symptom control.

Up to 90% of patients use their inhaler devices incorrectly.

Before prescribing an inhaler device, train the patient in its use and confirm that they are able to use it correctly.
Check inhaler technique at every opportunity by watching the patient using their inhaler, and comparing with a
device-specific checklist [Note 5]. Correct technique using a physical demonstration, focusing on incorrect steps.
Avoid prescribing multiple different inhaler devices if possible, to reduce confusion. See inhaler technique for
further information.

Note 5: NPS MedicineWise have a checklist available at [URL]

Adherence
If asthma symptom control is poor or flare-ups continue to occur despite apparently adequate treatment, consider
poor inhaler technique and adherence. Adherence (compliance) often falls with improvement in symptoms.

Assess adherence using an empathic approach that acknowledges adherence is often incomplete. For example, ask
the patient if they find it easier to remember their inhaler in the morning or the evening, or ask them if they use
their preventer inhaler less or more than 3 days per week.

Strategies that may improve adherence include:

using an open, nonjudgmental approach when discussing adherence

allowing the patient to express their concerns about drugs and devices (including about adverse effects), and
addressing these concerns
improving the patient's understanding of asthma management over time; comprehensive information can
rarely be retained after one visit
explaining the goals of treatment and aiming for concordance with the patient's goals
keeping treatment simple (eg using once- or twice-daily dosing where possible, using as few devices as
possible)
identifying useful daily associations or medication reminders to improve drug adherence (eg using
preventive therapy before meals, or in the bathroom before brushing teeth, or setting reminders on phones or
other electronic devices)
enlisting support of the patient's family and peers
keeping in touch and using reminder letters or telephone calls.

Further advice about assessing adherence in asthma is available in the Australian Asthma Handbook [URL].

Guided self-management education

Overview

Guided self-management education that includes a written asthma action plan, self-monitoring and regular clinical
review, results in significant reduction in emergency healthcare use and asthma morbidity.

Conduct a structured program over time to teach skills for detecting and managing deteriorating asthma, and for
optimal use of drugs. Important components are:

information about asthma (written, verbal, visual and/or audio)

self-monitoring of symptoms and/or peak expiratory flow (PEF)
training in optimal inhaler technique
provision of an individualised written asthma action plan
regular medical review.

Self-monitoring

Teach patients to monitor their asthma symptoms and to take action if symptoms worsen.

Long-term PEF monitoring is needed by only a small minority of patients with asthma, including those with a
history of sudden severe flare-ups, with poor perception of airflow limitation, or with severe asthma. For patients
carrying out PEF monitoring, it is easier to see changes from a standardised PEF chart compared to a PEF diary
[Note 6]. Patients should consistently use the same chart format.

PEF self-monitoring is also used in the diagnosis of occupational asthma.

Note 6: A PEF monitoring chart is available from the National Asthma Council [URL]

Written asthma action plan

All patients should have an individualised written asthma action plan that outlines how and when to:
 recognise symptoms of asthma deterioration
start or change reliever and preventer treatment
seek medical attention.

Written asthma action plans may be based on asthma symptoms or PEF measurements or both. Plans should be
simple, individualised and based on two to four action points. While symptom-based action plans are suitable for
the majority of patients, an action plan based on PEF measurements is essential in the case of poor perceivers,
overperceivers and patients prone to sudden severe flare-ups (see control-based management for an explanation of
issues associated with poor perceivers and overperceivers). Plans based on PEF measurements should use personal-
best PEF rather than predicted PEF for action points.

The principles of written asthma action plans for worsening asthma are outlined in Box 9.2. All patients with
asthma must know how and when to obtain prompt medical assistance.

All patients with asthma must know how and when to obtain prompt medical assistance.

There is clear evidence of increased inflammation during flare-ups. Therefore, it is inappropriate to recommend
bronchodilator treatment alone until the flare-up is severe enough to require oral corticosteroids.

In the past, guidelines recommended no increase in preventer treatment when asthma worsened; this was on the
basis of three placebo-controlled trials that failed to show any benefit from doubling inhaled corticosteroid (ICS)
dose. However, in those studies complex criteria were used to identify the onset of a flare-up, patients were
required to attend on multiple occasions, adherence was strongly emphasised, and the extra medication was not
started until approximately 5 days after asthma had started to worsen.

For patients prescribed budesonide + eformoterol maintenance and reliever therapy, a rapid increase in dose as
soon as symptoms start to worsen is highly effective in reducing the risk of progressing to a severe flare-up; in this
context, high ICS doses are not needed.

For patients prescribed conventional maintenance preventer treatment, there is some clinical trial evidence in adults
to support quadrupling the dose of ICS in the management of flare-ups. Therefore the current recommendation is to
increase ICS to high dose soon after the onset of a flare-up.

Asthma action plans must be individualised.

Asthma action plans must be individualised to the patient's current treatment regimen, their usual asthma symptoms
and pattern of reliever use, and their willingness and ability to self-manage worsening asthma.

Asthma action plan templates that can be individualised are available from the National Asthma Council [URL].

Principles of written asthma action plans (Box 9.2)

The principles of written asthma action plans for worsening asthma are:

increase inhaled reliever dose and frequency

early increase in preventer dose
start prednis(ol)one for a severe flare-up or if already on a high dose of inhaled corticosteroid
obtain prompt medical attention
in an emergency:
immediately start first aid treatment using high doses of inhaled reliever; see first aid for dose
recommendations
call an ambulance and advise that the patient is having a severe asthma attack (flare-up)
continue to use the reliever until the ambulance arrives.

Review and referral of adults with asthma

Regular review
A formal review process requires the patient to agree to attend appointments on a regular basis. The medical review
should include assessment of:

asthma symptom control by

 –
monitoring symptom control including frequency of use of reliever medication
–
reviewing the diagnosis if there is poor response to current level of treatment
–
assessing risk factors for adverse asthma outcomes (see Table 9.11)
–
monitoring spirometry—if available measure lung function (3 to 6 months after preventer treatment
starts, then annually thereafter). Normal year-to-year variation in forced expiratory volume in 1 second
(FEV1) is up to 15%
treatment issues by
–
checking inhaler technique
–
checking adherence to treatment plan
–
reviewing current medications to determine if a trial of stepping up or stepping down treatment is
indicated
–
checking patient understanding of their written asthma action plan
comorbidities.

Frequency of review is determined by several factors including the patient's asthma severity. In general, inhaler
technique should be checked by a health professional at every opportunity (at least 6-monthly) and the written
asthma action plan should be reviewed annually. Additionally, patients should be reviewed within 48 to 72 hours
following discharge from an emergency department or ward after a flare-up (see follow-up). Patients should be
reviewed within a week following mild flare-ups that have been self-managed or managed in primary care.
Opportunistic review is also recommended (eg when patients attend for repeat prescriptions).

More frequent review is recommended for:

patients with risk factors for adverse outcomes (see Table 9.11) or for potentially fatal asthma (see Box 9.3)
patients with more severe asthma, even if well controlled (ie requiring high-intensity treatment; Step 4 in
Figure 9.4)—review every 3 months
pregnant women with asthma—review every 4 to 6 weeks.

Good communication is essential. All health professionals should ensure the patient understands the meaning of the
terms used. See failure to respond to adequate treatment, below, for definitions of severe and uncontrolled asthma.

The ‘Asthma cycle of care’ has been established in Australia to assist general practitioners in managing asthma; it
is a requirement of the Medicare Practice Incentive Program for asthma. For further information, see [URL].

Failure to respond to adequate treatment

Overview

Adults and adolescents may not respond to adequate asthma treatment due to incorrect diagnosis and/or a number
of other contributing factors including poor inhaler technique, poor adherence and comorbidities. Provided the
diagnosis is correct, addressing these contributing factors can vastly improve patients' asthma symptom control and
should be considered before stepping up treatment. However, it may not be possible to completely resolve
contributing factors and some patients may require a step-up in treatment to maintain good symptom control.

International guidelines for severe asthma define asthma as ‘severe’ when, to prevent asthma from becoming
uncontrolled, either:

Step 4 treatment (see Figure 9.4) has been required for the last year; or
oral corticosteroids have been required for at least 50% of the last year.

Guidelines also define asthma as severe if asthma remains uncontrolled despite either of the above treatments. This
also applies to patients in whom treatment of comorbidities remains incomplete.

Well-controlled asthma that worsens on tapering of high-dose ICS or systemic corticosteroid is also considered
severe.

‘Uncontrolled’ asthma is defined as at least one of:

poor symptom control

–
Asthma Control Questionnaire score consistently above 1.5 [Note 7]
 –
Asthma Control Test score consistently 15 or below [Note 8]
frequent flare-ups—2 or more flare-ups requiring courses of oral corticosteroids (each course lasting 3 days
or more) in the last 12 months
severe or life-threatening flare-up(s)—at least one flare-up requiring hospitalisation, intensive care unit
admission or mechanical ventilation in the last 12 months
airflow limitation—post-bronchodilator forced expiratory volume in 1 second (FEV1) less than 80%
predicted post-bronchodilator; consider coexisting chronic obstructive pulmonary disease in these patients
(see overlap of asthma and COPD).

Refer patients with severe asthma for specialist assessment and management.

Note 7: The Asthma Control Questionnaire is included in Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King
DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14(4):902–7.
[URL]

Note 8: The Asthma Control Test is available from the Australian Asthma Handbook website [URL]

Referral

Specialist consultation is recommended when there has been:

severe asthma as defined above

asthma in association with anaphylaxis
a life-threatening acute asthma flare-up requiring hospital admission and invasive ventilation
poor self-management (if referral to a practice nurse or asthma educator has not helped)
doubt about the diagnosis of asthma
suspected occupational asthma
suspected allergic bronchopulmonary aspergillosis
a concurrent condition complicating asthma management
frequent emergency department or urgent general practitioner visits for asthma.

Special categories of asthma in adults

Exercise-induced bronchoconstriction
Exercise-induced bronchoconstriction, commonly referred to as exercise-induced asthma, is bronchoconstriction
triggered by physical activity in people who already have a diagnosis of asthma. It may be the only, or
predominant, symptom of asthma. It is different from the bronchoconstriction that is induced by extreme physical
exertion in elite athletes who do not have classical asthma. Advice about the use of asthma drugs in sport is
available from the Australian Sports Anti-Doping Authority website [URL].

Regular physical exercise is recommended for both adults and children as part of asthma management for its
beneficial effect on cardiopulmonary fitness and quality of life. The amount of physical activity required to trigger
asthma symptoms depends on the level of fitness of the person. Ambient conditions can also influence the
likelihood of exercise-induced bronchoconstriction (more likely under cold and dry conditions). Symptoms such as
breathlessness triggered by exercise are not necessarily due to exercise-induced bronchoconstriction, but may be
due to lack of fitness or other causes.

Regular inhaled corticosteroid is the most effective strategy for preventing exercise-induced bronchoconstriction.

There are several strategies for preventing bronchoconstriction triggered by exercise. Regular inhaled
corticosteroid (ICS) therapy is the most effective. An adequate warm-up (short sprints separated by short breaks)
may help. If these measures are inadequate, a short-acting beta2 agonist (SABA), montelukast or a cromone may
prevent exercise-induced bronchoconstriction if used before the activity. For patients with persisting exercise-
induced bronchoconstriction, despite good adherence and good inhaler technique with ICS, use:

1 salbutamol 100 micrograms, 1 to 4 actuations by inhalation via pMDI, 15 minutes before

exercise

OR

1 terbutaline 500 micrograms, 1 to 2 actuations by inhalation via DPI, 15 minutes before

exercise.
Titrate dose to achieve optimal effect.

Alternative pre-exercise therapies include cromoglycate, nedocromil and montelukast [Note 9]. Treatment with a
SABA together with cromoglycate, nedocromil or montelukast may also be used.

Long-acting beta2 agonists are not recommended for the prevention of exercise-induced bronchoconstriction.

Note 9: At the time of writing, montelukast is not registered by the Therapeutic Goods Administration (TGA) for
as-needed use pre-exercise; see current information [URL]

Asthma and pregnancy

Fertility is not reduced in asthma. Asthma is the most common illness to complicate pregnancy. Asthma improves
in about one-third of pregnancies, and is the same or worsens in two-thirds.

Advise women that uncontrolled asthma is a greater risk to their baby than using asthma medications.

Many women stop asthma treatment when they become pregnant because of their concerns about perceived risks of
medications. However, evidence shows that the risk to their baby of uncontrolled maternal asthma is much greater
than the risk of taking asthma medications. Ninety-seven per cent to 99% of babies born to women with asthma
have no congenital birth defects. Babies born to women with asthma have a slightly greater risk of minor
congenital abnormalities compared with those born to women without asthma, but this risk is not influenced by
asthma medication.

If a switch of regular preventer therapy to an Australian Therapeutic Goods Administration Category A drug is
considered (see categorisation of drugs in pregnancy), it should be undertaken in the pre-conception period. Once a
woman with asthma is pregnant, maintain her current treatment as long as her asthma is well controlled.

Review asthma every 4 to 6 weeks during pregnancy because of the increased risk of flare-ups and the attendant
risk to the baby. Treat asthma flare-ups in pregnant women the same as flare-ups in nonpregnant women, ie oral
corticosteroids should not be avoided (see advice in management of acute asthma).

If regular preventer treatment is needed, budesonide and as-needed salbutamol or terbutaline are first choice,
advising the woman that these drugs have Category A ratings for pregnancy. Add other drugs such as long-acting
beta2 agonists (Category B3) if the benefits of preventing severe flare-ups outweigh potential harms.

Strongly advise women with asthma who are pregnant not to smoke, and to avoid exposure to tobacco smoke.
Update their asthma management plan and recommend vaccination according to the Australian Immunisation
Handbook [URL].

Asthma in adolescence
Adolescence is generally defined as 12 to 18 years of age. About one-third of adolescents will experience asthma
remission during puberty; the reason for this is unknown. However, asthma may improve or worsen in adolescence,
or it may be the time of first presentation. For females, flare-ups may be associated with their menstrual cycle.

Give adolescents the opportunity to be seen without parents/carers present. This allows discussion of sensitive
issues impacting on asthma management such as tobacco and drug use, adherence and their concerns about their
asthma. Assure them appropriate confidentiality will be maintained.

Assess health literacy and provide the appropriate level of verbal and written information.

Be aware of the increased prevalence of risk-taking behaviour in this age group.

Asthma in older people

Older people are generally defined as those older than 65 years. The prevalence of asthma in this age group is the
same as in the general adult population. Asthma first presenting in this age group is often called late-onset asthma.

Asthma may be harder to diagnose in older people due to under-reporting of symptoms that are assumed to be due
to ageing and the presence of concurrent conditions (eg chronic obstructive pulmonary disease [COPD], congestive
heart failure, deconditioning). The coexistence of increased airflow variability (asthma) and incompletely
reversible airflow limitation (COPD) is common in this age group (see overlap of asthma and COPD).

Consider the potential for drug interactions and aggravation of pre-existing conditions (eg tachyarrhythmias,
diabetes) when prescribing drugs for asthma.
Choose suitable inhaler devices and train patients in their use. Poor inhaler technique is common, and may be due
to mechanical difficulties (eg osteoarthritis), visual or cognitive impairment, and poor inspiratory flow. If possible,
avoid prescribing multiple different inhaler devices.

Occupational asthma
Occupational asthma is common, occurring in up to 20% of people with asthma, and is probably underdiagnosed.
Consider occupational asthma in all adult-onset asthma. Asthma may be induced de novo by occupational exposure
to a number of chemicals or allergens. For patients with pre-existing asthma, asthma symptom control may be
worsened by workplace exposures.

Ask patients whether asthma symptoms improve on days away from work or during holidays; if so, prioritise early
referral for further investigation.

The risk of developing occupational asthma may be reduced by avoiding workplace exposure to known sensitisers,
such as isocyanates in spray-painting workshops, laboratory animals, and latex gloves in healthcare facilities.

Further information about occupational asthma can be found in the National Asthma Council Australian Asthma
Handbook.

See also Table 9.15, for a list of some occupational triggers that may exacerbate existing asthma.

Allergic bronchopulmonary aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a condition in which a marked inflammatory reaction to the
Aspergillus fumigatus mould occurs in the airways. Most patients with ABPA have asthma, and the asthma is often
severe, so patients with severe asthma should be investigated for the presence of ABPA. It may require systemic
corticosteroid therapy and/or antifungal treatment.

To make a diagnosis, patients should have evidence of immunoglobulin E (IgE) antibodies to Aspergillus, an
elevated total serum IgE concentration (more than 1000 IU/mL), and at least two of the following features:

presence of precipitating or immunoglobulin G (IgG) antibodies against Aspergillus fumigatus in serum

radiographic pulmonary opacities consistent with ABPA [Note 10]
total blood eosinophil count more than 500 cells/microlitre in corticosteroid-naive patients (may be
historical).

If ABPA is suspected, refer to a specialist for diagnosis and management.

Note 10: The chest radiographic features consistent with ABPA may be transient (ie consolidation, nodules,
tram-track opacities, toothpaste/finger-in-glove opacities, fleeting opacities) or permanent (ie parallel line and
ring shadows, bronchiectasis and pleuropulmonary fibrosis); from Agarwal R, Chakrabarti A, Shah A, Gupta D,
Meis JF, Guleria R, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new
diagnostic and classification criteria. Clin Exp Allergy 2013;43(8):850–73. [URL]

Aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease is a specific asthma phenotype, which includes:

asthma
nasal polyposis
aspirin sensitivity (there may be coexisting nonsteroidal anti-inflammatory drug [NSAID] sensitivity)
chronic hyperplastic eosinophilic sinusitis.

Aspirin-exacerbated respiratory disease often starts with nasal symptoms. Asthma in this group is more likely to be
severe, and the onset is usually when patients are in their 20s or 30s. It is more common in females.

Specialist assessment is appropriate. Aspirin challenges are dangerous; desensitisation must only be done under
specialist supervision.

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Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute asthma in adults and adolescents
Introduction to acute asthma management in adults
This topic provides advice for managing acute asthma in adults and adolescents. For advice about managing acute asthma
in children 12 years and younger, see management of acute asthma in children.

In the event of an acute flare-up (exacerbation) of asthma, early intervention is the best strategy to prevent further
deterioration.

Educate all patients with asthma to recognise early symptoms of deterioration and to initiate the first steps of treatment
(see education and skills training and first aid).

Ongoing medical management is based on a rapid preliminary assessment with initiation of first-line treatment according
to severity. This is followed by a more detailed assessment to guide ongoing management (see secondary severity
assessment). The appropriate disposition (ie care environment) must be anticipated (see Figure 9.6) and follow-up
organised as appropriate.

Anaphylaxis is an important differential diagnosis for patients presenting with acute wheeze. Anaphylaxis is a life-
threatening condition; the patient can deteriorate exceedingly rapidly (ie within minutes). This diagnosis is likely if an
apparent asthma flare-up occurs with angioedema or rapid onset of a widespread rash. Also consider anaphylaxis if there
are marked abdominal symptoms or hypotension.

Intramuscular adrenaline is first-line treatment in suspected anaphylaxis.

Manage anaphylaxis according to appropriate national guidelines or local clinical protocols; see the Australian Prescriber
anaphylaxis wallchart. If anaphylaxis is suspected or cannot be excluded, intramuscular adrenaline should be given as a
priority.

First aid for acute asthma in adults

If symptoms are severe or life-threatening (see Table 9.16), urgently call an ambulance and advise that the patient is
having a ‘severe asthma attack’ (flare-up). Pending its arrival, administer high doses of inhaled short-acting beta2 agonist
(SABA) via pressurised metered dose inhaler (pMDI) with spacer (if available) or via nebuliser. Use:

1 salbutamol 100 micrograms, 6 to 12 separate actuations by inhalation via pMDI with spacer,
repeated every 20 minutes if indicated, or sooner if required

OR

1 salbutamol 5 mg by inhalation via nebuliser, repeated every 20 minutes if indicated, or sooner if

required.

If early signs of asthma deterioration are present, first-line treatment of an acute asthma flare-up should be initiated by
the patient or carer according to the patient's asthma plan. An ambulance should be called if there is not a rapid and
significant response to first-line home treatment, or if there are signs of a severe or life-threatening flare-up (see Table
9.16). Urgent medical review is also required if the patient initially responds but bronchodilator therapy is needed more
than 3 to 4 hourly.

Call an ambulance if there are signs of a severe or life-threatening flare-up or if the patient fails to respond rapidly and significantly to
first-line treatment.

There is a ‘first aid plan’ for acute asthma, used by many community and sports organisations, called ‘4×4×4’, which
recommends salbutamol pMDI; if available, use:

4 separate actuations, with spacer if available, one actuation at a time

take 4 breaths from the spacer after each actuation
wait 4 minutes and then give another 4 separate actuations
if the person still cannot breathe normally, call an ambulance and continue giving 4 separate actuations every 4
minutes until the ambulance arrives.

Corresponding first aid advice if using terbutaline or budesonide + eformoterol is available on the National Asthma
Council website [URL].
Overview of management of acute asthma in adults
When the patient arrives at the medical facility, perform a rapid assessment to evaluate the severity of the flare-up (see
Table 9.16), which determines initial management (see Figure 9.6).

After starting initial therapy, undertake a more detailed review to determine subsequent management (see Table 9.17).

The aim of management is to stabilise the patient with bronchodilators, administer corticosteroids, if indicated, within the
first hour, then attempt to lengthen the interval between salbutamol doses.

Patients with a mild-moderate flare-up may be managed in the primary care setting (see Figure 9.6), with ongoing
assessment of severity and response to treatment. If the patient's condition worsens, arrange urgent transfer to an acute
care facility.

Ongoing monitoring of the response to therapy is critical; the frequency of reassessment is determined by the severity of
the flare-up (see Figure 9.6). If the patient is not responding to treatment at the assessed level of severity, treat according to
the next level. Be aware that the patient may appear to respond initially and then relapse. This may be due to
bronchoconstriction; however, be alert to the possibility of complications such as pneumothorax. Salbutamol, although
relatively safe, is not without adverse effects, including paradoxical worsening of respiratory failure at very high doses;
see inhaled bronchodilators for further information.

Ongoing monitoring of treatment response is the key to successful management of acute asthma flare-ups.

Early anticipation of the required level of care is also important. This applies both on initial presentation and if the
condition either does not respond as expected or subsequently deteriorates. The need for escalation of level of care is
determined by limitations of the current care environment and skill levels of available staff, as well as other factors
including ease of access to more advanced assistance. In primary care an early decision must be made about the possible
need for transfer to hospital; this may be either due to the initial severity of the flare-up or the likely requirement for
ongoing monitoring and/or admission. In the emergency department, early involvement of senior staff is desirable for
sicker patients. If retrieval to a higher-level facility is anticipated, initiate discussions sooner rather than later.

In the post-acute phase of care, ongoing management must also be determined and instituted in an appropriate clinical
environment. Before discharge certain criteria must be fulfilled and appropriate follow-up arranged.

Assessment of acute asthma in adults

Initial rapid assessment

Perform an initial rapid assessment immediately on presentation to evaluate the severity of the flare-up (see Table 9.16).
This risk stratification determines the appropriate initial management (see Figure 9.6).

While clinical features can help identify severity of an acute asthma flare-up, they are not specific (either in isolation or in
combination); their absence does not exclude a severe or even life-threatening flare-up.

The degree of wheezing is an unreliable indicator of the severity of an acute asthma flare-up; in severe acute asthma it may
be essentially absent (ie ‘silent chest’). In these cases, the wheeze becomes apparent only as the airway obstruction is
relieved.

Wheezing may be absent in severe acute asthma (termed ‘silent chest’).

The severity category may also change with time either because more information is available (eg results of pulse
oximetry or spirometry) or because the situation itself has altered. The change may be either an increase or decrease in
severity, therefore ongoing observation is required as outlined in secondary severity assessment, below.

Initial rapid severity assessment of acute asthma in adults and adolescents (Table 9.16)

Life-threatening: Severe: Mild–moderate:

any of the following any of the following all of the following

increased work of breathing (eg
altered conscious level
accessory muscle use, tracheal
exhaustion
tug, subcostal recession or can walk and can speak whole
cyanosis
abdominal breathing) sentences in one breath
SpO2 less than 90%
unable to complete sentences in SpO2 more than 94%
poor respiratory effort one breath due to dyspnoea
soft or absent breath sounds SpO2 90 to 94%

Important additional information:

 The severity category may change when more information is available or over time. These changes may be in
either direction. Ongoing observation is required; see further assessment of acute asthma, below.
If oxygen therapy has already been started, it is not essential to stop oxygen to measure oximetry.
Oxygen saturation levels are a guide only and are not definitive; clinical judgment should be applied.
While clinical features can help identify severity of an acute asthma flare-up, they are not specific (either in
isolation or in combination); their absence does not exclude a severe or life-threatening flare-up. Of note:
wheezing may be absent in severe acute asthma (ie ‘silent chest’)
pulsus paradoxus is not a reliable indicator of the severity of acute asthma
life-threatening acute asthma can occur without cyanosis.

SpO2 = oxygen saturation measured by pulse oximetry

Source: National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia; 2014. [URL]

Secondary severity assessment

Following initial administration of salbutamol according to Figure 9.6, undertake a secondary severity assessment as
outlined in Table 9.17, and adjust management accordingly.

Assessment of response to treatment is an ongoing process; frequency of assessment should be tailored depending on the
result, and will change as the patient's condition changes. Repeat secondary severity assessment frequently within the first
hour (eg after each dose of salbutamol). In more severe cases, remain at the bedside until the patient is stabilised.

Secondary severity assessment of acute asthma in adults, adolescents and children 6 years or older
(Table 9.17) [NB1]

Note: If features of more than one severity level are present, treat according to the higher severity level.

Life-threatening: any of the Mild moderate: all of the

Severe: any of the following
following following
Consciousness drowsy or unconscious not applicable [NB2] alert
unable to vocalise due to can only speak a few words in can finish a sentence in one
Speech
dyspnoea one breath breath
unable to lie flat due to dyspnoea
Posture collapsed or exhausted sitting hunched forward can walk
(‘tripoding’)
paradoxical chest wall
movement: inward movement on
inspiration and outward
movement on expiration

severe respiratory distress or

Breathing or use of accessory muscles of neck respiratory distress is not severe

or intercostal muscles (‘tracheal
poor respiratory effort tug’)

or

subcostal recession (‘abdominal

breathing’)
Skin colour cyanosis not applicable [NB2] normal
adults: 25 breaths/min or more adults: less than 25 breaths/min
bradypnoea (indicates
Respiratory rate
respiratory exhaustion) [NB3] children and adolescents: children and adolescents: normal
tachypnoea [NB3] [NB3]
cardiac arrhythmia

or adults: 110 beats/min or more adults: less than 110 beats/min

Heart rate
children and adolescents: children and adolescents: normal
bradycardia (preterminal sign,
tachycardia [NB4] range [NB4]
may occur just before
respiratory arrest) [NB4]
‘silent chest’ wheeze

Chest auscultation or not applicable [NB2] or

reduced air entry normal lung sounds

SpO2 less than 90%

Pulse oximetry or SpO2 90 to 94% SpO2 more than 94%

clinical cyanosis
PaO2 lower than 60 mmHg

PaCO2 higher than 50 mmHg

[NB6]
may be indicated, eg if not
Arterial blood gas PaCO2 within normal range
responding to therapy or if there not indicated
analysis [NB5] despite normal or low PaO2 are other concerns
pH less than 7.35 [NB7]

raised lactate concentration

[NB8]
clinical indications include, but are not limited to:

life-threatening asthma
suspicion of pneumothorax
Chest X-ray
sudden deterioration
failure to respond to appropriate therapy
if signs remain focal

Asthma history assess risk factors for asthma-related death, see Box 9.3
Spirometry consider after 1 hour of management; see post-acute care for more information
PaCO2 = partial pressure of carbon dioxide; PaO2 = partial pressure of oxygen; SpO2 = oxygen saturation measured by pulse oximetry
NB1: Secondary severity assessment for children 5 years or younger is outlined in Table 9.7.
NB2: May be the same as mild–moderate and does not determine severity level.
NB3: Normal respiratory rate (breaths/min) for children and adolescents:6 to 12 years, 20 to 25; 12 to 18 years, 15 to 20.
NB4: Normal heart rate (beats/min) for children and adolescents:6 to 12 years, 80 to 120; 12 to 18 years, 60 to 100.
NB5: Perform blood gas analysis only if clinically indicated.
NB6: In moderate to severe asthma the patient is hyperventilating and therefore the PaCO2 should be low; anything other than this is a red flag for deterioration;
the presence of hypercapnia indicates that the patient is tiring and may need ventilatory support.
NB7: Metabolic acidosis (often associated with hypokalaemia) may occur with acute asthma and with high dose of salbutamol.
NB8: Lactic acidosis may occur with beta2 agonists as a result of the stimulation of anaerobic glycolysis.
Source: National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia; 2014. [URL]

Risk factors for potentially fatal asthma in adults and adolescents (Box 9.3)

Risk factors for potentially fatal asthma are any of the following:

previous ventilation or intensive care unit (ICU) admission due to asthma

hospital admission due to asthma in the last year
repeated emergency department attendances in the last year
requiring three or more classes of asthma maintenance medication
frequent short-acting beta2 agonist use (eg more than one canister used per month)
poor lung function
history of brittle asthma (ie sudden and severe flare-ups)
confirmed food allergy
current or recent oral corticosteroid use
rural or remote location.

The above factors often coexist with adverse psychosocial or behavioural factors, such as:

poor adherence, including with drugs and follow-up visits

depression and/or other psychiatric illness
substance misuse, including smoking
denial of seriousness of condition and need for regular treatment
social isolation
learning difficulties
financial, employment and/or domestic problems.

Sources: British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN). British guideline on the management of asthma: a national
clinical guideline (SIGN 141). Edinburgh: SIGN; 2014.

Goeman DP, Abramson MJ, McCarthy EA, Zubrinich CM, Douglass JA. Asthma mortality in Australia in the 21st century: a case series analysis. BMJ Open
2013;3(5). [URL]
Treatment of acute asthma in adults
Overview
This section provides a summary of the principles of drug treatment of acute asthma; see Figure 9.6 for further detail. For
dosing in adults and adolescents, see Table 9.18.

The early use of inhaled short-acting beta2 agonist therapy (such as salbutamol) is the cornerstone of successful
management of all patients with acute asthma, regardless of severity (see Table 9.16 and Table 9.17). Give oral
corticosteroids within the first hour of management to all patients with an acute asthma flare-up.

Patients with a life-threatening asthma flare-up usually require supplemental oxygen. Early initiation of ipratropium is
recommended.

In severe asthma flare-ups, supplemental oxygen is indicated if oxygen saturation is less than 95%. Early ipratropium
should be considered.

Depending on response to initial treatment, intravenous magnesium sulfate may be required in severe and life-threatening
acute asthma. Other bronchodilators that may be considered in life-threatening acute asthma are intravenous salbutamol
and intravenous aminophylline; see Figure 9.6 for further information.

Failure to respond to therapy should prompt reassessment. Review the diagnosis, including consideration of complications
such as pneumothorax or adverse effects of drug treatment.

Ventilatory support may need to be considered for patients with life-threatening flare-ups. Intubation and ventilation of
these patients is difficult and has significant associated risks. Ideally it should only be undertaken by an experienced
critical care practitioner. Noninvasive ventilation may be useful in selected patients but this is controversial and evidence
for its use is inconclusive.

Inhaled bronchodilators
Inhaled salbutamol is indicated for all episodes of acute asthma. Give salbutamol via pressurised metered dose inhaler
(pMDI) with spacer to those with mild–moderate acute asthma. For patients with severe acute asthma or those unable to
use a pMDI with spacer, administer salbutamol via intermittent nebulisation. For patients with life-threatening acute
asthma, administer salbutamol via continuous nebulisation.

Although relatively safe, salbutamol has a range of adverse effects. Hypokalaemia and hypomagnesaemia are expected
when repeated or high doses are given, and should be managed appropriately. The effects on the cardiovascular system
may lead to adverse consequences such as myocardial ischaemia or prolonged QT interval; the latter predisposes to
arrhythmias, especially in the context of electrolyte disturbances.

High doses of salbutamol may paradoxically worsen the respiratory compromise. This effect is thought to be
multifactorial; metabolic acidosis, rise in lactate levels and increased metabolic rate may all contribute. If suspected, the
patient should be closely observed and salbutamol treatment should be cautiously back-titrated; specialist input is
recommended.

If there is poor response to initial inhaled salbutamol, add inhaled ipratropium. Patients with more severe asthma benefit
the most from the addition of ipratropium.

Corticosteroids
Give oral prednis(ol)one within the first hour of management for all patients with an acute asthma flare-up. If the oral
route is not possible, intravenous hydrocortisone or methylprednisolone can be used.

Oxygen
If oxygen saturation measured by pulse oximetry (SpO2) is less than 95%, give supplemental oxygen and titrate to a target
SpO2 of 92 to 96%. For advice on supplemental oxygen administration, see acute oxygen therapy.

Intravenous magnesium sulfate

There is some evidence that magnesium sulfate may have bronchodilator effects. The sickest patients appear to be the
most likely to benefit from intravenous magnesium sulfate. Guidelines recommend considering intravenous magnesium
sulfate in severe and life-threatening acute asthma after first-line bronchodilator therapy (ie salbutamol and ipratropium)
has been initiated (see Figure 9.6). However, a recent randomised controlled trial (that excluded patients with acute severe
asthma) failed to demonstrate a clinically worthwhile benefit from intravenous or nebulised magnesium sulfate in adults.

Magnesium sulfate is administered as a single short intravenous infusion; the safety of repeated doses has not been
assessed. Hypermagnesaemia may cause loss of deep tendon reflexes and muscle weakness, including respiratory muscle
weakness. Comprehensive monitoring in a high-dependency–type environment is required.
Intravenous salbutamol
The potential harm versus benefit of intravenous salbutamol is not favourable compared to administration via nebulisation;
there is no evidence of increased efficacy. Intravenous salbutamol is therefore reserved for the sickest patients and/or when
nebulisation is impractical. Comprehensive monitoring in a critical care environment is required. See inhaled
bronchodilators, above, for information about salbutamol adverse effects.

Intravenous aminophylline
The potential harm versus benefit of intravenous aminophylline is considered unfavourable in the majority of situations. It
can cause vomiting, arrhythmias, convulsions and sudden death, and is rarely used.

The occasional patient with life-threatening acute asthma who is not improving with initial therapy, may respond
favourably to aminophylline. Comprehensive monitoring in a critical care environment is required.

Initial approach to managing an acute asthma flare-up in adults and adolescents (Figure 9.6) [NB1]

HDU = high-dependency unit; ICU = intensive care unit; IV = intravenous; pMDI = pressurised metered dose inhaler; SpO2 = oxygen saturation measured by
pulse oximetry

NB1: Doses for drugs used to manage acute asthma flare-ups in adults and adolescents are listed in Table 9.18.

NB2: In severe flare-ups, repeated secondary severity assessment should occur frequently within the first hour, eg after each dose of inhaled salbutamol. In
severe or life-threatening cases the clinician should remain at the bedside until the patient is stabilised.

Drug dosages for acute asthma in adults and adolescents (Table 9.18)

Drug [NB1] Delivery Dosage

pMDI with spacer 100 micrograms × 6 to 12 separate actuations
 intermittent nebulisation 5 mg
salbutamol
continuous nebulisation driven by
5 mg × 2 nebules
oxygen [NB2]
200 micrograms over 1 minute, then an initial
IV [NB3] infusion of 5 micrograms/minute adjusted according
to response; usual rate 10 to 20 micrograms/minute
pMDI with spacer 21 micrograms × 8 separate actuations
ipratropium
intermittent nebulisation 500 micrograms
prednis(ol)one 37.5 to 50 mg daily; continue for 5 to
oral
corticosteroids 10 days
IV [NB4] hydrocortisone 100 mg every 6 hours
start if SpO2 is less than 95% and titrate to target
oxygen [NB2] intranasal
SpO2 of 92 to 96%
10 mmol diluted in sodium chloride 0.9%, given over
magnesium sulfate [NB5] IV infusion
at least 20 minutes, as a single dose
IV loading dose [NB6]:

5 mg/kg (up to 500 mg)

FOLLOWED BY
IV loading dose [NB6],
aminophylline [NB3] IV infusion:
followed by IV infusion
0.5 mg/kg/hour

Target theophylline plasma concentration: 55 to 110

micromol/L (10 to 20 mg/L); measure daily
IV = intravenous; pMDI = pressurised metered dose inhaler; SpO2 = oxygen saturation measured by pulse oximetry
NB1: Drug, dose, frequency and delivery method depend on severity of acute asthma; see Table 9.16 for initial rapid severity assessment of acute asthma in adults
and adolescents and corresponding management in Figure 9.6.
NB2: Continuous nebulisation driven by oxygen is indicated in life-threatening acute asthma. Patients with severe acute asthma using intermittent nebulisation or
pMDI with spacer may require oxygen; administer oxygen separately.
NB3: Only indicated in life-threatening acute asthma (see Figure 9.6); comprehensive monitoring is required in a critical care environment.
NB4: Intravenous corticosteroids are only indicated if the oral route is not available. Change to oral corticosteroids as soon as possible.
NB5: Only indicated in severe and life-threatening acute asthma (see Figure 9.6); comprehensive monitoring is required in a high-dependency–type environment.
NB6: For patients already taking oral theophylline, omit the aminophylline loading dose.

Post-acute care of asthma in adults

Patients with any feature of acute life-threatening asthma require formal admission.

Patients with any feature of acute severe asthma persisting after initial treatment also require admission, which may be to a
ward or, in some cases, a short stay observation unit.

The extent of ongoing management of acute asthma, including decisions about admission and discharge, is also influenced
the patient's:

response to therapy
past history of flare-ups
current circumstances (eg time of day, distance from medical help, access to phone, home environment)
treatment adherence
comorbidities
risk factors for potentially fatal asthma (see Box 9.3).

There is no single physiological measurement that can define whether a patient is safe for discharge.

Note that there is no single physiological measurement that can define whether a patient is safe for discharge. In addition
to the above factors, spirometry after 1 hour of management, if performed, should be considered; low forced expiratory
volume in 1 second (FEV1) (eg less than 60% predicted) is likely to indicate need for hospital admission. Patients with
severe asthma and one or more adverse psychosocial factors are at risk of asthma-related death (see Box 9.3).

Patients with severe asthma and one or more adverse psychosocial factors are at risk of asthma-related death.

Before discharge, ensure the patient's medication can be continued at home (eg switch nebulised bronchodilators to pMDI
with spacer). Only discharge the patient if they require short-acting beta2 agonist (SABA) less frequently than every 4
hours; prescribe as-needed SABA on discharge. Continue oral corticosteroids for 5 to 10 days, including the doses
administered in the acute phase of management.
Any patient with a flare-up severe enough to require emergency department care, and who is not already using regular
inhaled corticosteroid (ICS) treatment (including combination inhaler therapy), should be started on regular ICS treatment
to reduce the risk of another flare-up.

A number of important reviews also need to be completed before discharge; see Box 9.4.

Reviews required before discharging an adult or adolescent after an acute asthma flare-up (Box 9.4)

Following the resolution of an acute asthma flare-up, review:

inhaler technique for all devices

adherence to prescribed drug regimen
triggers to identify the possible cause of this flare-up; discuss avoidance measures if necessary
inhaled corticosteroid dose; adjust the patient's maintenance therapy if necessary
written asthma action plan including documented advice about escalating treatment and when to seek medical
assistance; educate the patient about the action plan.

Follow-up after acute asthma attacks in adults

It is essential that a patient who suffers an acute asthma flare-up, of any severity, be followed up. The patient should visit
their general practitioner, preferably within 48 to 72 hours of discharge from the emergency department or the ward.
Provide a discharge summary to the patient's general practitioner in time for this review, including details of the:

severity of the flare-up

spirometry, if available
treatment administered
treatment prescribed at discharge
written asthma action plan provided to the patient.

Patients with near-fatal or brittle asthma (ie sudden and severe flare-ups) should have ongoing specialist review for life,
while those with a severe flare-up should receive specialist review for at least 1 year. Consider specialist referral for any
first presentations of asthma in adults and adolescents and for all asthma presentations requiring admission. Also consider
referral to a specialist for patients with ongoing poorly controlled asthma; see failure to respond to adequate treatment for
further information.

Key references
Management of acute asthma in adults and adolescents: overview

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Management of acute asthma in adults and adolescents: suspected anaphylaxis

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Management of acute asthma in adults and adolescents: first aid

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Medical management of acute asthma in adults and adolescents: overview and assessment

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Camargo CA, Jr., Rachelefsky G, Schatz M. Managing asthma exacerbations in the emergency department: summary of the
National Asthma Education And Prevention Program Expert Panel Report 3 guidelines for the management of asthma
exacerbations. Proc Am Thorac Soc 2009;6(4):357–66. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

Goeman DP, Abramson MJ, McCarthy EA, Zubrinich CM, Douglass JA. Asthma mortality in Australia in the 21st century: a
case series analysis. BMJ Open 2013;3(5):e002539. [ ]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic
Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical
asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180(1):59–99. [ ]

Treatment of acute asthma in adults and adolescents

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Camargo CA, Jr., Rachelefsky G, Schatz M. Managing asthma exacerbations in the emergency department: summary of the
National Asthma Education And Prevention Program Expert Panel Report 3 guidelines for the management of asthma
exacerbations. Proc Am Thorac Soc 2009;6(4):357–66. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

Goodacre S, Cohen J, Bradburn M, Stevens J, Gray A, Benger J, et al. The 3Mg trial: a randomised controlled trial of
intravenous or nebulised magnesium sulphate versus placebo in adults with acute severe asthma. Health Technol Assess
2014;18(22):1–168. [ ]

Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency
department. Cochrane Database Syst Rev 2014;(5):CD010909. [ ]

Lim WJ, Mohammed Akram R, Carson KV, Mysore S, Labiszewski NA, Wedzicha JA, et al. Non-invasive positive pressure
ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev
2012;(12):CD004360. [ ]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Powell CV. The role of magnesium sulfate in acute asthma: does route of administration make a difference? Curr Opin Pulm
Med 2014;20(1):103–8. [ ]

Powell C, Dwan K, Milan SJ, Beasley R, Hughes R, Knopp-Sihota JA, et al. Inhaled magnesium sulfate in the treatment of
acute asthma. Cochrane Database Syst Rev 2012;(12):CD003898. [ ]

Rice-McDonald G, Bowler S, Staines G, Mitchell C. Doubling daily inhaled corticosteroid dose is ineffective in mild to
moderately severe attacks of asthma in adults. Intern Med J 2005;35(12):693–8. [ ]

Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic
review with meta-analysis. Thorax 2005;60(9):740–6. [ ]
Tobin A. Intravenous salbutamol: too much of a good thing? Crit Care Resusc 2005;7(2):119–27. [ ]

Medical management of acute asthma in adults and adolescents: post-acute care and follow-up

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: quick reference guide [SIGN 141]. Edinburgh: SIGN; 2014.

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the management of
asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Camargo CA, Jr., Rachelefsky G, Schatz M. Managing asthma exacerbations in the emergency department: summary of the
National Asthma Education And Prevention Program Expert Panel Report 3 guidelines for the management of asthma
exacerbations. Proc Am Thorac Soc 2009;6(4):357–66. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

National Asthma Council Australia. Australian Asthma Handbook, Version 1.0. Melbourne: National Asthma Council Australia;
2014. [URL]

Osborne ML, Pedula KL, O'Hollaren M, Ettinger KM, Stibolt T, Buist AS, et al. Assessing future need for acute care in adult
asthmatics: the profile of asthma risk study: a prospective health maintenance organization-based study. Chest
2007;132(4):1151–61. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Rhinitis and rhinosinusitis
Overview of rhinitis
Rhinitis is inflammation of the mucosal lining of the nose causing symptoms including anterior and posterior
rhinorrhoea, sneezing, nasal blockage, itching of the nose and loss of the sense of smell. The commonest causes
are infections (see acute rhinosinusitis) and allergy (see allergic rhinitis).

Rhinitis and asthma commonly coexist, a concept sometimes referred to as ‘United Airway Disease’. Asthma
occurs in 30% of patients with allergic rhinitis, and allergic rhinitis occurs in more than 80% of patients with
allergic asthma. Chronic rhinosinusitis also occurs commonly in these patients. Always assess and manage both
upper and lower airway disease.

While most rhinitis is allergic, other categories of rhinitis exist including nonallergic rhinopathy (previously called
vasomotor rhinitis), infectious rhinitis, occupational rhinitis, rhinitis triggered by hormonal changes (including
during pregnancy), atrophic rhinitis, and drug-induced rhinitis.

Drugs can cause rhinitis by different pathological or pharmacological mechanisms. Aspirin, nonsteroidal anti-
inflammatory drugs (NSAIDs), vasodilator drugs (eg some antihypertensives), intranasal decongestants (causing
rhinitis medicamentosa) and oral contraceptives can all cause drug-induced rhinitis.

Management of nonallergic rhinitis involves minimising irritant exposure and stopping provocative drugs.

Allergic rhinitis and conjunctivitis

Clinical features and classification

Allergic rhinitis is the most common form of noninfectious rhinitis and is associated with an immunoglobulin E
(IgE)-mediated immune response. It is often associated with ocular symptoms and sinusitis (see rhinosinusitis).
The prevalence of allergic diseases, including allergic rhinitis, has increased in recent decades; they now affect 10
to 30% of the world's population. In Australia, up to 21% of the population is affected by allergic rhinitis, most
commonly between ages 25 and 44 years.

Allergic rhinitis is classified in terms of symptom duration (intermittent or persistent) and severity (mild or
moderate-to-severe), see Table 9.19. It was previously defined as seasonal allergic rhinitis (hay fever) or perennial
allergic rhinitis, according to the different allergic triggers implicated: seasonal allergens such as grass, weed and
tree pollens or perennial allergens such as dust mites, cat and dog dander. However, most patients are sensitised to
both seasonal and perennial allergens.

Allergic rhinitis and asthma often coexist; always assess and manage both upper and lower airway disease (see
diagnosis). Atopic dermatitis (eczema) is also commonly associated.

Allergic rhinitis is caused by environmental allergens (seasonal or perennial) and can be aggravated by chemical
irritants (eg active or second-hand smoking). If there is a clinically obvious allergen or irritant, it may be possible
to minimise exposure. Skin or blood testing for specific IgE levels is required if making recommendations
regarding allergen avoidance and suitability for specific allergen immunotherapy.

Check also for possible overuse of intranasal decongestants (rhinitis medicamentosa) (see decongestants).

Classification of allergic rhinitis by symptom duration and severity (Table 9.19)

Duration of symptoms
Intermittent Persistent
symptoms present: symptoms present:

on less than 4 days a week on more than 4 days a week

OR AND
for less than 4 consecutive weeks for more than 4 consecutive weeks

Severity of symptoms
Mild Moderate to severe
all of the following present:
 symptoms present but not troublesome one or more of the following present:
normal sleep
no impairment of daily activities, leisure troublesome symptoms
and/or sport sleep disturbance
no impairment of school or work impairment of daily activities, leisure and/or sport
performance impairment of school or work performance

Drug treatment of rhinitis

Overview

The drug treatment of allergic rhinitis is outlined in Figure 9.7 according to symptom duration and severity (see
Table 9.19). Drug doses are provided in the following text. Intranasal saline (sodium chloride solution) may be
useful as adjunctive therapy with any of the treatments.

In intermittent, or mild-to-moderate allergic rhinitis, drugs of different classes may be used in sequence, or in
combination from the start, according to the age of the patient, degree of disability and cost of therapy. Generally,
intranasal or oral antihistamines are used for mild, intermittent symptoms and oral antihistamines are especially
useful for associated ocular symptoms. Antihistamines are less effective for nasal obstruction, whereas intranasal
corticosteroids are more helpful for this symptom and for more severe disease. Antihistamines have a fast onset of
action making them a useful rescue medication; in contrast, intranasal corticosteroids have a slow onset of action.

For more severe symptoms occurring seasonally (eg in spring) and related to pollen exposure, starting an
intranasal corticosteroid at least 2 weeks before the onset of the relevant pollen season is recommended. This
avoids the priming effect of initial re-exposure to that allergen.

Undertake a full trial of drug treatment of at least 1 month (see Figure 9.7) and verify adherence. Adherence may
be poor due to cost of drug treatment or because the patient stops or reduces treatment when their symptoms
improve. If there is no response to treatment reconsider the patient's diagnosis.

Features such as unilateral symptoms, nasal obstruction without other symptoms, pain, purulent discharge,
recurrent epistaxis and anosmia suggest an alternative diagnosis. In these circumstances and while treatment is
continued, a computed tomography (CT) scan of the sinuses and/or referral to a specialist is appropriate. A CT
scan delivers significant local radiation; for sinus CT this includes to the lens of the eye, which is associated with
an increased risk of cataracts. For information on risk of malignancy associated with CT scans, see the X-ray risk
website [URL].

Treatment of allergic rhinitis (Figure 9.7) [NB1]

 NB1: The sequence and combination of drugs is decided by various factors. See drug treatment of allergic rhinitis for drug doses and further detail.

NB2: See Table 9.19 for explanation of symptom classification.

NB3: An intranasal antihistamine and corticosteroid combination spray is available.

NB4: In children with asthma and allergic rhinitis, montelukast may be selected ahead of an intranasal corticosteroid as it may be effective in both
conditions; administration of intranasal corticosteroids can be difficult in children with allergic rhinitis.

Oral antihistamines

For rapid relief of symptoms of allergic rhinitis such as sneezing and rhinorrhoea, the less-sedating oral
antihistamines can assist and ease both nasal and ocular symptoms. Use:

an antihistamine orally, see Table 9.20 for adults and Table 9.21 for children.

There is little difference in efficacy between any of the currently available antihistamines. If sedation is desirable, a
sedating antihistamine can be taken at night; however, international guidelines do not recommend their use for
rhinitis.

Oral antihistamine dosage regimens for adults (Table 9.20)

Drug [NB1] Dosage

cetirizine 10 mg once daily
desloratadine 5 mg once daily
fexofenadine 120 mg as a single or divided daily dose
loratadine 10 mg once daily
NB1: These are all less-sedating antihistamines, with cetirizine the most likely to cause sedation.

Oral antihistamine dosage regimens for children (Table 9.21)

Drug [NB1] Age (years) Dosage

1 to 2 0.25 mg/kg (up to 2.5 mg) twice daily
cetirizine 2 to 5 2.5 mg twice daily [NB2]
6 and older 5 mg twice daily [NB2]
1 to 5 1.25 mg once daily
desloratadine 6 to 11 2.5 mg once daily
12 and older 5 mg once daily
2 to 11 30 mg twice daily
fexofenadine
12 and older 120 mg as a single or divided daily dose
1 to 2 2.5 mg once daily
loratadine weight 30 kg or less: 5 mg once daily
2 and older
weight more than 30 kg: 10 mg once daily
NB1: These are all less-sedating antihistamines, with cetirizine the most likely to cause sedation.
NB2: Doses for children older than 2 years may be given once daily or in two divided doses. See product information for detail on paediatric dosing by
weight.

Intranasal antihistamines

Intranasal antihistamines are an equally effective alternative to oral antihistamines but have a faster onset of action.
If considered appropriate, use:

1 azelastine (adult and child 5 years and older) 1 mg/mL nasal spray, 1 spray into each
nostril, twice daily

OR

1 levocabastine (adult and child 6 years and older) 0.5 mg/mL nasal spray, 2 sprays into
each nostril, 2 to 4 times daily.

Instruct patients on how to administer nasal sprays correctly, see Box 9.5 for a patient handout.

Patient instructions for using a nasal spray (Box 9.5)

Print-friendly PDF

To use a nasal spray effectively and safely:

Clear the nasal passages first; using a saline nasal spray may be helpful.
Shake the bottle and follow the manufacturer's advice (package insert) about priming if needed.
Bend your neck forward and look down.
For intranasal corticosteroids, use your right hand for the left nostril and vice versa. Put the nozzle just
inside the nose aiming towards the outer wall.
Change hands and repeat for the other side.
Avoid sniffing too hard or the liquid is likely to go straight down the throat.

Intranasal corticosteroids

Intranasal corticosteroids are particularly useful for more severe allergic rhinitis. They are more effective than oral
antihistamines and are especially effective for congestive symptoms. Systematic analyses also indicate significant
reduction of ocular symptoms.

It is important to explain to patients that intranasal corticosteroids do not relieve symptoms at the time of use; their
role is to prevent symptoms. They usually start relieving symptoms within a few days but a minimum trial of a
month is needed to establish efficacy.
For both symptom relief and prevention with intranasal corticosteroids, the initial dose is used for 1 month then
reduced to a maintenance dose. Use:

an intranasal corticosteroid, see Table 9.22 for adults and Table 9.23 for children.

To reduce the likelihood of systemic adverse effects, use the minimum dose needed to control symptoms. Tailor
the duration of treatment to the patient's symptoms and any drug adverse effects. Intranasal corticosteroid
treatment may need to be continued for lengthy periods, even for many years.

Instruct patients on how to administer nasal sprays correctly, see Box 9.5 for a patient handout. Using a crossover
technique (right hand to left nostril, left hand to right nostril) reduces the deposition of a corticosteroid directly
onto the nasal septum, with less likelihood of causing nasal septal perforation. For videos demonstrating
administration, see the National Asthma Council website [URL].

Intranasal corticosteroid dosage regimens for adults (Table 9.22)

Drug Initial dosage [NB1] [NB2] Maintenance dosage [NB1]

beclomethasone 50 micrograms/spray 2 sprays twice daily 1 spray twice daily
4 sprays once daily

budesonide 32 micrograms/spray [NB3] OR 1 to 2 sprays once daily

2 sprays twice daily

2 sprays once daily

budesonide 64 micrograms/spray [NB3] OR 1 spray once daily

1 spray twice daily

ciclesonide 50 micrograms/spray 2 sprays once daily 2 sprays once daily [NB4]
fluticasone furoate 27.5 micrograms/spray 2 sprays once daily 1 spray once daily
fluticasone propionate 50 micrograms/spray 2 sprays once daily 1 spray once daily
mometasone 50 micrograms/spray 2 sprays once daily 1 spray once daily
triamcinolone 55 micrograms/spray 2 sprays once daily 1 spray once daily
NB1: Dose is the number of sprays into each nostril.
NB2: Use initial dose for 1 month then reduce to maintenance dose.
NB3: Budesonide is Australian Therapeutic Goods Administration pregnancy category A.
NB4: Based on lack of available clinical data, the manufacturer does not recommend decreasing the initial dose of ciclesonide.

Intranasal corticosteroid dosage regimens for children (Table 9.23)

Initial dosage [NB1] Maintenance dosage

Drug Age (years)
[NB2] [NB1]
beclomethasone 50 micrograms/spray 6 and older 1 to 2 sprays twice daily 1 spray twice daily
4 sprays once daily

budesonide 32 micrograms/spray 6 and older OR 1 to 2 sprays once daily

2 sprays twice daily

2 sprays once daily

budesonide 64 micrograms/spray 6 and older OR 1 spray once daily

1 spray twice daily

2 sprays once daily
ciclesonide 50 micrograms/spray 6 and older [NB3] 2 sprays once daily
[NB4]
fluticasone furoate 27.5 2 to 11 1 to 2 sprays once daily 1 spray once daily
micrograms/spray 12 and older 2 sprays once daily 1 spray once daily
fluticasone propionate 50
12 and older 2 sprays once daily 1 spray once daily
micrograms/spray
3 to 11 1 spray once daily 1 spray once daily
mometasone 50 micrograms/spray
12 and older 2 sprays once daily 1 spray once daily
2 to 5 1 spray once daily 1 spray once daily
triamcinolone 55 micrograms/spray
6 and older 1 to 2 sprays once daily 1 spray once daily
NB1: Dose is the number of sprays into each nostril.
NB2: Use initial dose for 1 month then reduce to maintenance dose.
 NB3: For children 6 to 12 years, ciclesonide is indicated for seasonal allergic rhinitis; in trials, use was for a total of 6 weeks.For children 12 years and
older, ciclesonide is indicated for seasonal or perennial allergic rhinitis; in trials, use was for up to 12 months.
NB4: Based on lack of available clinical data, the manufacturer does not recommend decreasing the initial dose of ciclesonide.

Intranasal antihistamine and corticosteroid combination

A combination intranasal formulation of antihistamine plus corticosteroid (azelastine + fluticasone propionate) is

available that offers the advantage of rapid relief of symptoms combined with an anti-inflammatory effect. Studies
have shown that the combination is effective for seasonal and perennial allergic rhinitis. If appropriate, for adults
and children 12 years and older, use:

azelastine+fluticasone propionate 125+50 micrograms/spray, 1 spray into each nostril,

twice daily.

Instruct patients on how to administer nasal sprays correctly, see Box 9.5 for a patient handout.

Montelukast

Guidelines [Note 1] conclude that leukotriene receptor antagonists such as montelukast are equivalent to oral
antihistamines but inferior to intranasal corticosteroids for treating intermittent (seasonal) allergic rhinitis.

In adults, if considered appropriate use:

montelukast 10 mg orally, once daily.

In children who also have asthma, montelukast may be first line before intranasal corticosteroids as it may be
beneficial for both conditions [Note 2]. If considered appropriate, use:

montelukast (child 2 to 5 years) 4 mg orally, once daily

or montelukast (child 6 to 14 years) 5 mg orally, once daily.

Note 1: Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic Rhinitis and its
Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and
AllerGen). Allergy 2008;63 Suppl 86:8–160. [URL]

Note 2: At the time of writing, montelukast is subsidised on the Pharmaceutical Benefits Scheme for children
with asthma; see current information [URL]

Ipratropium

Ipratropium intranasal spray (an antimuscarinic) has a rapid onset of action and a prolonged effect (4 to 12 hours).
If there is marked rhinorrhoea, it can be added to the intranasal corticosteroid and/or antihistamine.

If indicated, use:

ipratropium (adult and child 12 years and older) 22 micrograms/spray, 4 sprays into each
nostril, up to 3 times daily initially, reducing as rhinorrhoea improves

or ipratropium (adult and child 12 years and older) 44 micrograms/spray, 2 sprays into each nostril, up to 3 times
daily initially, reducing as rhinorrhoea improves.

Decongestants

If antihistamines and intranasal corticosteroids fail to relieve nasal congestion, an oral decongestant
(pseudoephedrine, phenylephrine) may provide rapid relief but care is needed if cardiovascular comorbidities exist.

Pseudoephedrine and phenylephrine are available as single-drug tablets [Note 3] and may be found as a component
of other multiple-ingredient preparations. Adverse effects of oral decongestants include increased blood pressure,
especially for patients with hypertension, and central nervous system effects such as insomnia, agitation and
anxiety.

Intranasal decongestants (eg oxymetazoline, tramazoline, xylometazoline) produce vasoconstriction in the nasal
mucosa, decreasing nasal blood flow and congestion. Consult the product information for directions on use.
Intranasal decongestants should not be used for more than 3 days because prolonged use causes rebound
congestion (rhinitis medicamentosa), which can be difficult to manage.

Intranasal or oral decongestants may be useful as short-term therapy in some cases of acute rhinosinusitis (see
acute rhinosinusitis) or when flying (see assessment of other respiratory conditions).

Decongestants are not recommended for use in children younger than 6 years because significant adverse effects
have been reported after use of both nasal and oral decongestants in this age group. Caution should be used in
children aged 6 to 12 years [Note 4]. In Australia, many paediatric oral formulations containing a decongestant
also contain a sedating antihistamine, and there are additional safety concerns for use of these combinations in
children.

Note 3: Because of the potential for illicit manufacture of methamphetamine from large quantities of
pseudoephedrine, many Australian states have restrictive scheduling for pseudoephedrine.

Note 4: See advice issued by the Australian Therapeutic Goods Administration in November 2012 [URL]

Treatment of allergic conjunctivitis

Allergic conjunctivitis can be the predominant symptom in some patients with allergic rhinitis (allergic
rhinoconjunctivitis). Oral antihistamines, intranasal corticosteroids and saline (sodium chloride solution) eye drops
may be adequate to reduce ocular symptoms; otherwise, use antihistamine or cromoglycate eye drops.

Use of eye drops containing preservatives is generally not recommended while wearing soft contact lenses.
Patients should seek advice if wearing contact lenses and needing to use any eye drops.

Anti-inflammatory eye drops, including ketorolac and corticosteroids, should not be used for allergic conjunctivitis
except under specialist advice.

Immunotherapy
When environmental measures and drug treatment do not control symptoms, documentation of specific allergen
sensitivities by in vivo skin testing or in vitro serum testing allows for targeted immunotherapy. If properly
performed, these tests provide useful confirmatory evidence for the diagnosis of a specific allergy. The tests need
to be carried out and interpreted by a skilled practitioner. Suitable patients can be offered desensitisation.

Immunotherapy in selected patients can be very effective in the management of allergic rhinitis. However, its use
is largely limited to patients with moderate-to-severe symptoms whose symptoms are incompletely or poorly
controlled with drug treatment and avoidance measures. It is most successful for patients who are mono-sensitised
rather than poly-sensitised. Immunotherapy is the only treatment that alters the course of the condition. Treatment
with either subcutaneous or sublingual immunotherapy continues for 3 years and relief of symptoms may be
delayed; however, reassess after 6 months if there is no improvement.

Subcutaneous immunotherapy is always given under medical supervision because there is a risk of immediate- or
slower-onset systemic reactions. These range from mild urticaria and rhinitis, through to angioedema, severe
asthma and anaphylactic shock. Systemic adverse effects affect 0.13% of patients and local adverse effects affect
50% of patients.

Sublingual immunotherapy is safer and effective in both adults and children with grass pollen and dust mite
allergy, but is more expensive than subcutaneous immunotherapy. Local adverse effects affect 20 to 30% of
patients and systemic adverse effects are rare. It remains to be established whether sublingual immunotherapy is as
effective against as wide a range of allergens as subcutaneous immunotherapy.

Chronic rhinosinusitis
Introduction
Rhinitis and sinusitis usually coexist and inflammation of the nasal mucosa and paranasal sinuses is concurrent in
most patients. Rhinosinusitis is classified as acute (symptoms lasting less than 4 weeks) or chronic (symptoms
lasting longer than 12 weeks).

Uncomplicated acute viral rhinosinusitis (common cold) is the commonest cause of rhinosinusitis. For information
on diagnosis and management of acute rhinosinusitis (including recurrent acute rhinosinusitis), see Acute
rhinosinusitis.

Chronic rhinosinusitis is a multifactorial disease, defined by symptoms lasting for longer than 12 weeks.
Contributing factors include bacterial infection, allergy, cystic fibrosis, physical obstruction (including nasal
polyps or anatomical variation), swelling of the mucosa for any other reason, mucociliary impairment, immune
deficiency or prolonged use of intranasal decongestant spray.

The diagnosis of chronic rhinosinusitis is primarily clinical and is characterised by two or more symptoms,
including nasal blockage/obstruction/congestion or nasal discharge (anterior or posterior). There may also be:

facial pain or pressure

reduced sense of smell and taste
cough
nausea.

Patients with coexisting allergic rhinitis may also have symptoms such as sneezing, watery rhinorrhoea, nasal
itching and itchy watery eyes.

Sinus X-rays are rarely helpful and computed tomography (CT) scans of the sinuses are only indicated for patients
failing medical therapy or those with atypical or severe disease (such as with unilateral symptoms, bloodstained
discharge, displacement of the eye or severe pain). A CT scan delivers significant local radiation; for sinus CT this
includes to the lens of the eye, which is associated with an increased risk of cataracts. For information on risk of
malignancy associated with CT scans, see the X-ray risk website [URL].

If a CT scan is performed, chronic rhinosinusitis will show mucosal changes in the osteomeatal complex or
sinuses. CT scans and endoscopic abnormalities should always be interpreted in the context of clinical symptoms
because there is a high false positive rate.

Nasal endoscopy of a patient with chronic rhinosinusitis will have at least one objective finding, such as:

polyps
mucopurulent discharge from the middle meatus
oedema or obstruction at the middle meatus.

There are two subtypes of chronic rhinosinusitis, which require different management approaches. They are:

chronic rhinosinusitis without nasal polyps, representing about two-thirds of cases

chronic rhinosinusitis with nasal polyps; a polyp appears macroscopically as a grape-like pearly or greyish-
yellow–coloured structure markedly different in colour from the nasal mucosa. It may be easily visible
inside the nasal cavity.

Chronic rhinosinusitis without nasal polyps

If allergy is suspected as an aetiological factor of chronic rhinosinusitis without nasal polyps, initial management is
as for allergic rhinitis. Additional therapies include isotonic or hypertonic saline nasal irrigation (sodium chloride
solution) and mucolytics. If there is inadequate response to at least 1 month of treatment or if there is an obvious
physical obstruction, refer for specialist management.

There are no data showing efficacy of oral corticosteroids in chronic rhinosinusitis without nasal polyps; however,
international guidelines suggest they may be used as short-term rescue medication for symptoms uncontrolled by
saline nasal irrigation, intranasal corticosteroids and short-term antibiotics [Note 5]. In this situation, for adults,
continue intranasal corticosteroids and add:

prednis(ol)one 25 mg orally, once daily in the morning for 5 to 10 days.

There is little evidence to support the use of antibiotics (including long-term, low-dose macrolide therapy) for
chronic rhinosinusitis but they are sometimes prescribed under expert guidance.

Surgery should be considered for patients with chronic rhinosinusitis unresponsive to the above measures, repeated
acute exacerbations, and/or complications of the condition.

Note 5: Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position
paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50(1):1–
12. [URL]

Chronic rhinosinusitis with nasal polyps

In children, the presence of nasal polyps should always prompt testing for cystic fibrosis. In adults, check for
coexisting asthma and aspirin sensitivity (see aspirin-exacerbated respiratory disease).

Saline nasal irrigations (sodium chloride solution) and intranasal corticosteroids are first-line treatment, see
chronic rhinosinusitis without nasal polyps above. If there is inadequate response to intranasal corticosteroids after
at least 1 month of treatment, or if the nose is too blocked to be able to use a nasal spray effectively, add a reducing
course of oral corticosteroids (‘medical polypectomy’). Use:

prednis(ol)one 25 mg orally, daily for 1 week, then 12.5 mg daily for 1 week, then 12.5
mg on alternate days for 1 week.

If a course of oral prednis(ol)one is ineffective or symptoms recur, consider specialist referral.

Surgery is indicated for those who fail medical treatment and remain symptomatic. Recurrence of nasal polyps
after surgery is usually less than 20%. It is important to continue intranasal corticosteroid therapy to delay or
prevent nasal polyp recurrence postsurgery, and this therapy may be needed long term.

Chronic rhinosinusitis with nasal polyps may have a fungal aetiology resulting in conditions such as allergic fungal
sinusitis and invasive fungal sinusitis. The fungal infection may need longer medical treatment and more
aggressive surgical approaches. Seek specialist review.

Sensitivity to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with chronic
rhinosinusitis with nasal polyps as well as with asthma; it is called aspirin-exacerbated respiratory disease.
Selected patients may benefit from aspirin desensitisation but aspirin challenges are dangerous; desensitisation
must only be done under specialist supervision.

Key references
Rhinitis

Australian Institute of Health and Welfare (AIHW). Allergic rhinitis (“hay fever”) in Australia. Canberra: AIHW; 2011.
[URL]

Berger WE, Nayak A, Lanier BQ, Kaiser HB, LaForce C, Darken P, et al. Efficacy and safety of once-daily ciclesonide
nasal spray in children with allergic rhinitis. Pediatr Allergy Immunol Pulmonol 2008;21(2):73–82.

Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic rhinitis and its impact on asthma
(ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 2008;63
Suppl 868–160. [ ]

Bousquet J, Reid J, van Weel C, Baena Cagnani C, Canonica GW, Demoly P, et al. Allergic rhinitis management
pocket reference 2008. Allergy 2008;63(8):990–6. [ ]

Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic rhinitis and its impact
on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126(3):466–76. [ ]

Chervinsky P, Kunjibettu S, Miller DL, Prenner BM, Raphael G, Hall N, et al. Long-term safety and efficacy of
intranasal ciclesonide in adult and adolescent patients with perennial allergic rhinitis. Ann Allergy Asthma Immunol
2007;99(1):69–76. [ ]

Ciprandi G, Cirillo I, Vizzaccaro A, Tosca M, Passalacqua G, Pallestrini E, et al. Seasonal and perennial allergic
rhinitis: is this classification adherent to real life? Allergy 2005;60(7):882–7. [ ]

Hermelingmeier KE, Weber RK, Hellmich M, Heubach CP, Mosges R. Nasal irrigation as an adjunctive treatment in
allergic rhinitis: a systematic review and meta-analysis. Am J Rhinol Allergy 2012;26(5):e119–25. [ ]

Kaliner MA. Classification of nonallergic rhinitis syndromes with a focus on vasomotor rhinitis, proposed to be known
henceforth as nonallergic rhinopathy. World Allergy Organ J 2009;2(6):98–101. [ ]

Kim K, Weiswasser M, Nave R, Ratner P, Nayak A, Herron J, et al. Safety of once-daily ciclesonide nasal spray in
children 2 to 5 years of age with perennial allergic rhinitis. Pediatr Allergy Immunol Pulmonol 2007;20(4):229–42.

Meltzer EO. The role of nasal corticosteroids in the treatment of rhinitis. Immunol Allergy Clin North Am
2011;31(3):545–60. [ ]

Meltzer EO, Kunjibettu S, Hall N, Wingertzahn MA, Murcia C, Berger W, et al. Efficacy and safety of ciclesonide, 200
microg once daily, for the treatment of perennial allergic rhinitis. Ann Allergy Asthma Immunol 2007;98(2):175–81. [
]

Meltzer EO, LaForce C, Ratner P, Price D, Ginsberg D, Carr W. MP29-02 (a novel intranasal formulation of azelastine
hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind,
placebo-controlled trial of efficacy and safety. Allergy Asthma Proc 2012;33(4):324–32. [ ]
Ratner PH, Wingertzahn MA, van Bavel JH, Hampel F, Darken PF, Shah T. Efficacy and safety of ciclesonide nasal
spray for the treatment of seasonal allergic rhinitis. J Allergy Clin Immunol 2006;118(5):1142–8. [ ]

Rimmer J. Allergic rhinoconjunctivitis returns. The new spring season 2013. Medicine Today 2013;14(10):18–28.

Yuan MK, Tsai DC, Chang SC, Yuan MC, Chang SJ, Chen HW, et al. The risk of cataract associated with repeated
head and neck CT studies: a nationwide population-based study. AJR Am J Roentgenol 2013;201(3):626–30. [
]

Rhinosinusitis

Desrosiers M, Evans GA, Keith PK, Wright ED, Kaplan A, Bouchard J, et al. Canadian clinical practice guidelines for
acute and chronic rhinosinusitis. Allergy Asthma Clin Immunol 2011;7(1):2. [ ]

Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on
rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50(1):1–12. [ ]

Legent F, Bordure P, Beauvillain C, Berche P. A double-blind comparison of ciprofloxacin and amoxycillin/clavulanic

acid in the treatment of chronic sinusitis. Chemotherapy 1994;40(Suppl 1):8–15. [ ]

Namyslowski G, Misiolek M, Czecior E, Malafiej E, Orecka B, Namyslowski P, et al. Comparison of the efficacy and
tolerability of amoxycillin/clavulanic acid 875 mg b.i.d. with cefuroxime 500 mg b.i.d. in the treatment of chronic and
acute exacerbation of chronic sinusitis in adults. J Chemother 2002;14(5):508–17. [ ]

Rimmer J. Allergic rhinoconjunctivitis returns. The new spring season 2013. Medicine Today 2013;14(10):18–28.

Sacks PL, Harvey RJ, Rimmer J, Gallagher RM, Sacks R. Topical and systemic antifungal therapy for the symptomatic
treatment of chronic rhinosinusitis. Cochrane Database Syst Rev 2011;(8):CD008263. [ ]

Scadding GK, Durham SR, Mirakian R, Jones NS, Drake-Lee AB, Ryan D, et al. BSACI guidelines for the
management of rhinosinusitis and nasal polyposis. Clin Exp Allergy 2008;38(2):260–75. [ ]

Yuan MK, Tsai DC, Chang SC, Yuan MC, Chang SJ, Chen HW, et al. The risk of cataract associated with repeated
head and neck CT studies: a nationwide population-based study. AJR Am J Roentgenol 2013;201(3):626–30. [
]

Published March 2015. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Chronic obstructive pulmonary disease
Diagnosis of COPD
Overview
Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow limitation due to varying
combinations of small airways disease and alveolar destruction. It is associated with an abnormal inflammatory
response of the lungs to noxious particles or gases, most commonly tobacco smoke, and is generally progressive.

Note that chronic bronchitis, defined as the presence of cough and sputum production for at least 3 months in each
of 2 consecutive years, is not necessarily associated with airflow limitation. Emphysema, defined as destruction of
the alveoli, is a pathological term often correlated with computed tomography (CT) findings, but it is often not an
accurate clinical descriptor.

It is possible for a patient to have expiratory airflow limitation in the absence of airway obstruction, because
airflow limitation may be due to other causes such as loss of tethering or emphysema. Airflow limitation in COPD
can be due to loss of supporting elastic recoil from the lung tissue and/or luminal narrowing as a result of airway
wall thickening. The term ‘limitation’ is used rather than ‘obstruction’, as obstruction may not always be present
(although inherent in the descriptor).

Cigarette smoking is the most important risk factor for COPD; clinically significant COPD is present in around
25% of smokers. However, not all patients with COPD have a history of smoking, especially in developing
countries where exposure to biomass smoke for heating and cooking is common. Other risk factors include
maternal smoking, long-standing asthma, respiratory symptoms in childhood, exposure to second-hand smoke,
occupational exposures to dusts and fumes, and genetic susceptibility.

Initial presentation
Chronic obstructive pulmonary disease (COPD) typically affects middle-aged and older people, with tobacco
smoke the major causative factor. Inherited conditions such as alpha1-antitrypsin deficiency render patients more
susceptible to the damaging effects of tobacco smoke, leading to early development of COPD. Figure 9.8
illustrates the accelerated decline in lung function caused by smoking.

Consider the possibility of COPD in all patients older than 35 years who are smokers, ex-smokers or have other
relevant exposures or predisposing factors, and who present with symptoms including:

breathlessness
cough
recurrent respiratory tract infection
sputum production
wheezing.

Breathlessness, which may be the patient's only symptom, typically occurs only on exertion initially, but worsens
insidiously over several years. While all these symptoms have some day-to-day variation, episodes of marked
deterioration in symptoms and functional capacity, known as exacerbations, occur periodically and more
frequently as COPD progresses.

Overlap of asthma and COPD

The overarching term chronic obstructive pulmonary disease (COPD) may include patients with a variety of
distinct clinical and other features who present differently and respond differently to treatment—these are referred
to as ‘clinical phenotypes’. Examples of phenotypes include patients with predominant breathlessness, those with
recurrent exacerbations and those with asthma ‘overlap’. Many patients with COPD report a history of asthma.

Clinical features favouring COPD include:

onset after age 40

symptoms persisting after several weeks or months of inhaled corticosteroid (ICS) treatment
persistent airflow limitation
heavier tobacco smoke exposure.

Clinical features favouring asthma include:

 onset before age 20
significant day-to-day variability in symptoms and airflow limitation
symptoms worse at night or in the early morning
normal lung function between symptoms
previous medical diagnosis of asthma
family history of asthma or atopy
seasonal variability in symptoms
spontaneous improvement in symptoms.

There is evidence that patients with overlap of COPD and asthma experience more rapid disease progression than
those with either disease alone. These patients have worse health-related quality of life, and experience more
frequent and severe respiratory exacerbations. This is despite younger age and reduced lifetime smoking exposure
when compared to those with COPD alone.

The evidence base for managing patients with overlap of COPD and asthma is limited because they are commonly
excluded from clinical trials. ICS have a key role in preventing asthma-related deaths in patients with asthma, and
long-acting bronchodilators have a significant role in COPD management; therefore, it would be expected that they
could be used in patients with overlap of asthma and COPD. Avoid monotherapy with either ICS or long-acting
bronchodilators in this group of patients.

The approach to using ICS in asthma is to establish the minimal effective dose; however, in COPD clinical trials
have used only medium to high doses and the effect of lower doses has not been adequately explored. See inhaled
corticosteroids for advice about use of ICS in COPD and stepwise approach to treatment in adults and adolescents
for advice about use of ICS in asthma.

Seek specialist advice for managing these patients as approaches differ.

Assessment of COPD
Overview
A medical history and clinical examination may suggest a diagnosis of chronic obstructive pulmonary disease
(COPD), but cannot reliably predict the presence of airflow limitation. Spirometry is essential to determine
whether COPD is the probable cause of respiratory symptoms. Consider the degree of breathlessness induced by
daily activities and frequency of exacerbations when evaluating overall disease severity. Also assess for the
presence of comorbidities and sequelae of COPD (eg cor pulmonale, hypoxaemia), which may require additional
treatment.

Measuring lung function

The spirometric abnormality required to diagnose COPD is a post-bronchodilator forced expiratory volume in 1
second (FEV1) to forced vital capacity (FVC) ratio less than 0.7 (ie an obstructive pattern). This definition is
widely accepted because of its practicality, although its use may lead to overdiagnosis in the older person (as FEV1
declines more rapidly with age than does FVC) and underdiagnosis in younger adults. Consequently, a lower limit
of normal (fifth percentile of the normal distribution range of FEV1/FVC values) is sometimes recommended.

More extensive lung function testing will often also show gas trapping (increased residual volume) and a diffusion
defect (decreased diffusing capacity for carbon monoxide [DLCO]). See guide to pulmonary function testing for
detail on the measurement and interpretation of pulmonary function tests.

Classifying severity

Typical symptoms and spirometry findings are used as criteria for assessing the severity of COPD in Australian
and New Zealand guidelines for the management of COPD, the COPD-X Plan [Note 1]. The severity guides
treatment, as outlined in Figure 9.9. Spirometric cut-points used in these and other guidelines are somewhat
arbitrary; note that those in COPD-X differ from those in the Global Initiative for Chronic Obstructive Lung
Disease (GOLD) report [Note 2].

Note 1: Abramson M, Crockett A, Dabscheck E, Frith P, George J, Glasgow N, et al. The COPD -X Plan:
Australian and New Zealand guidelines for the management of chronic obstructive pulmonary disease. Version
2.37. Milton, Qld: Lung Foundation Australia; April 2014. [URL]

Note 2: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis,
management, and prevention of chronic obstructive pulmonary disease. Bethesda, MD: GOLD; updated 2014.
[URL]
Other assessment tools
Validated questionnaires such as the COPD Assessment Test (CAT) are recommended for a comprehensive
assessment of symptoms [Note 3]. The modified British Medical Research Council (mMRC) scale is used to assess
breathlessness.

Note 3: The COPD Assessment Test is available at [URL]

Nondrug management of COPD

General principles

The goals of managing stable chronic obstructive pulmonary disease (COPD) are to:

reduce symptoms
reduce frequency and severity of exacerbations and consequent long-term decline in lung function
improve exercise tolerance
improve health-related quality of life
slow disease progression.

Guidelines for COPD management recommend a stepwise escalation of therapy based on disease severity. In
stable COPD, first give attention to:

smoking cessation
encouragement of physical activity
pulmonary rehabilitation
current Immunisation.

For patients with a low COPD Assessment Test (CAT) score (less than 10) and few symptoms, the above
interventions may be adequate initially.

Introduction of further therapy is guided by ongoing assessment and response to initial treatment. As the disease
progresses, introduce drug treatment to target day-to-day symptoms (primarily breathlessness) and to prevent
exacerbations. For symptom control there should be a stepwise approach to drug therapy until adequate control has
been achieved. This is summarised in Figure 9.9 and discussed in more detail with dosing regimens in drug
treatment.

Some drug treatments are also effective in preventing deterioration, either by decreasing exacerbations and
hospitalisations, attenuating decline in quality of life, or both. The effect of drug treatment on mortality remains
unclear.

Smoking cessation

When managing COPD, prioritise smoking cessation to prevent or limit lung damage. Tobacco smoking is the
main cause of COPD, and smoking cessation is the only intervention that has been shown to improve the natural
history of COPD (apart from oxygen therapy in those with severe hypoxaemia). Figure 9.8 is a graphical
representation of the natural history of airflow obstruction in relation to cessation of smoking. It is vital that all
patients with COPD stop smoking. See smoking cessation for strategies.

Smoking cessation is the only intervention shown to improve the natural history of COPD.

Smoking and loss of forced expiratory volume in 1 second (FEV1) with age (Figure 9.8)
 The differences between the lines illustrate effects that smoking, and stopping smoking, can have on the FEV1. This figure shows the rate of loss of
FEV1 for a ‘typical’ smoker, although susceptible smokers will have different rates of loss, thus reaching 'disability' at different ages. These curves are
simplified representations of cross-sectional and longitudinal data.

† = death, the underlying cause of which is irreversible chronic obstructive pulmonary disease, whether the immediate cause of death is respiratory
failure, pneumonia, cor pulmonale or aggravation of other heart disease by respiratory insufficiency.

Reproduced with permission from BMJ Publishing Group Ltd. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ
1977;1(6077):1645–8. © 1977

Physical activity

Many patients with COPD have a sedentary lifestyle and it is important to encourage an increase in regular
physical activity. Evidence suggests that performing some form of regular activity may lower the risk of
hospitalisation for patients with COPD. See also advice about pulmonary rehabilitation.

Pulmonary rehabilitation

Pulmonary rehabilitation is extremely effective therapy; it improves quality of life and exercise capacity in patients
at all stages of COPD severity. There is increasing evidence that it reduces frequency of admissions and length of
hospital stay.

Pulmonary rehabilitation should be made available to all patients whose activity is limited by COPD, provided
they are sufficiently motivated and do not have severe comorbidities that preclude participation.

Most pulmonary rehabilitation programs contain four elements:

exercise training
education
behaviour modification
outcome assessment.

The key components of exercise training are aerobic training and strength training of the upper and lower limbs.
Flexibility exercises are often included. Breathing techniques and positioning are taught, which assist patients to
recover from episodes of breathlessness. Targeted inspiratory muscle training may be used for some patients.

Supervision by a trained health professional is recommended to help build patient confidence, optimise training
intensity and outcomes, and encourage exercise maintenance. After a short pulmonary rehabilitation program
(ideally at least 8 weeks), patients are encouraged to continue regular exercise; 30 minutes per day is suggested.
Benefits can be sustained even after a single pulmonary rehabilitation program. The longer a program continues,
the more effective the results. Benefit wanes after a rehabilitation program ends, but if exercise training is
maintained at home the patient's health status remains above pre-rehabilitation levels.

Patient support organisations, such as Lungnet may help maintain the benefits of rehabilitation by providing
educational material for patients with COPD [Note 4]. Support organisations also provide an important social
contact for patients.

The Lung Foundation Australia Pulmonary Rehabilitation Toolkit [URL] is an online resource for health
professionals working in pulmonary rehabilitation. It may also assist patients who do not have access to a
pulmonary rehabilitation unit.

Note 4: Lungnet resources are available from the Lung Foundation Australia website [URL]

Immunisation
Patients with COPD should receive an influenza vaccine every year, which ideally should be given before the
influenza season begins. Influenza vaccination reduces exacerbations in COPD, although its effect on healthcare
use and mortality is unclear. Guidelines also recommend up-to-date pneumococcal vaccination for all people with
COPD [Note 5].

Note 5: For further information on immunisation and individual vaccines, see National Health and Medical
Research Council. The Australian immunisation handbook. 10th ed. Canberra: NHMRC; 2013. [URL]

Nutrition

Calculate the body mass index (BMI) of patients with COPD. If it is outside the healthy range, refer for nutritional
advice. Although the evidence for benefit of nutritional supplements in underweight patients with COPD is
limited, consider high-calorie supplements in malnourished patients.

For patients with COPD and coexisting obesity, as well as the expected metabolic consequences, there are a range
of adverse consequences in terms of impaired health-related quality of life, including increased dyspnoea and
fatigue. Nonetheless, the so-called ‘obesity paradox’ means that overweight people with COPD have a reduced
mortality risk, possibly due to decreases in static lung volumes or increased free fat mass. Thus, weight loss
strategies must be tailored to each patient and cautiously applied.

Stepwise management of stable COPD (Figure 9.9)

 COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; LABA = long-acting
beta2 agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting beta2 agonist; SAMA = short-acting muscarinic antagonist

NB1: Precautions:

– monotherapy with a LABA should not be used for patients with asthma or patients with overlap of asthma and COPD
– if starting a LAMA, discontinue ipratropium (a SAMA)
– if starting a fixed-dose LABA+LAMA combination inhaler, discontinue existing LABA and/or LAMA single-drug inhalers
– if starting a fixed-dose ICS+LABA combination inhaler, discontinue existing LABA single-drug inhaler.

Reproduced and modified with permission from Lung Foundation Australia. Stepwise Management of Stable COPD. ©2014.

Maintenance drug treatment of COPD

Overview
The aims of drug treatment in chronic obstructive pulmonary disease (COPD) are to relieve symptoms and to
prevent deterioration, either by reducing frequency of exacerbations or by reducing decline in quality of life, or
both. Figure 9.9 is a summary of a stepwise approach to managing COPD.

Bronchodilators include short-acting beta2 agonists (SABAs) and long-acting beta2 agonists (LABAs) as well as
short-acting muscarinic antagonists and long-acting muscarinic antagonists (LAMAs). Even in the absence of a
demonstrable improvement in forced expiratory volume in 1 second (FEV1) they can reduce the gas trapping that
is a feature of COPD, which may improve breathlessness and exercise capacity. As well as improving symptom
control, both LAMAs and LABAs have been shown to reduce exacerbations and hospitalisations.

Despite the relative insensitivity of the inflammatory response in COPD to corticosteroids, inhaled corticosteroids
(ICS) are recommended in addition to long-acting bronchodilators for patients with moderate to severe COPD,
especially in those with recurrent exacerbations. ICS give additional benefits of reduced exacerbations and
improved quality of life. However, these small additional benefits must be balanced against an increased risk of
pneumonia and local adverse effects (dysphonia, upper airway candidiasis).

When combining drug classes in the management of COPD, consider the aims of treatment and whether they can
be achieved with simpler regimens. Unfortunately there is little evidence to guide the best choice to benefit an
individual patient. Combination therapy generally has a greater risk of adverse effects, so the potential harm versus
benefit needs to be explored for each patient.

Various fixed-dose combination inhalers are becoming available in Australia; information about registered
indications is available on the Therapeutic Goods Administration website [Note 6], and information about
subsidised indications is available on the Pharmaceutical Benefits Scheme website [Note 7].

Regularly review the patient's medication and either continue or stop drugs based on treatment response and
tolerability. Check inhaler technique and adherence at each visit; up to 90% of patients use their devices
incorrectly. It is important that both the patient and treating doctor are clear about goals of treatment, ie symptom
control or longer-term outcomes (such as prevention of exacerbations and/or hospitalisations), or both.

Note 6: Information about registered indications for fixed-dose combination inhalers is available on the
Therapeutic Goods Administration (TGA) website [URL]

Note 7: See the Pharmaceutical Benefits Scheme website for subsidised indications for combination inhalers
[URL]

Inhaled bronchodilators

Introduction

For the long-term treatment of COPD, bronchodilators are recommended for symptom relief, to increase physical
capacity and to improve quality of life. Long-acting bronchodilators have also been shown to reduce
exacerbations.

The preferred route of administration is by inhalation, which requires correct delivery device technique. Inhaled
drugs can be administered by pressurised metered dose inhalers (pMDIs), dry powder inhalers (DPIs) or
nebulisers. Evidence suggests that a pMDI with spacer is as effective as a nebuliser; however, the appropriate
method of inhalation depends on the patient's therapeutic needs, characteristics and preference. For considerations
in device choice, see Table 9.39.
Many symptomatic patients get significant relief from bronchodilator therapy. Benefit can only be assessed by a
therapeutic trial with symptom control or quality of life as endpoints, which may take several weeks.

Short-term response to an inhaled bronchodilator in the setting of an exacerbation does not necessarily predict
response to regular long-term use. Conversely, some patients who do not have a short-term response may still
benefit from a long-term trial. This is because relief of gas trapping (not measured routinely), which correlates well
with relief of dyspnoea, may occur in the absence of a significant change in forced expiratory volume in 1 second
(FEV1). It is difficult to determine the length of time a long-acting bronchodilator should be trialled to assess its
impact on frequency of exacerbations; depending on the patient's usual frequency of exacerbations, the trial may
need to continue for months or up to a year.

Short-acting bronchodilator therapy

Short-acting bronchodilators including short-acting beta2 agonists (SABAs) (salbutamol, terbutaline) and the
short-acting muscarinic antagonist, ipratropium, are efficacious for patients with COPD. Although ipratropium is
marginally more effective, a SABA is recommended initially on the basis of more rapid onset of action, lower cost
and better risk profile. If patients do not respond adequately to an appropriate dose of SABA, a trial of ipratropium
is appropriate. Ipratropium is most commonly used for patients with adverse effects from SABAs.

There is no evidence to suggest that short-acting bronchodilator drugs reduce the rate of decline in lung function or
have any effect on survival. Although ipratropium relieves symptoms, there is evidence that it increases the risk of
cardiovascular death.

Patients with poor inhaler technique can use a pressurised metered dose inhaler (pMDI) with a spacer, or a breath-
actuated pMDI (see inhalational drug delivery devices). Using a pMDI with a spacer improves lung deposition of
the drug.

Use:

1 salbutamol 100 micrograms, 2 actuations by inhalation via pMDI (with or without

spacer), as needed

OR

1 terbutaline 500 micrograms, 1 actuation by inhalation via DPI, as needed

OR

2 ipratropium 21 micrograms, 2 actuations by inhalation via pMDI (with or without spacer),

as needed.

If the response to initial short-acting bronchodilator monotherapy is unsatisfactory, a combination of ipratropium

and either salbutamol or terbutaline at the doses recommended above can be used.

Generally, a nebuliser is only necessary for patients who are unable to use a pMDI (with or without a spacer) or a
DPI.

Long-acting bronchodilator therapy

Overview

Long-acting bronchodilators (listed in choice of long-acting bronchodilator) are indicated for patients who remain
symptomatic despite treatment with optimally used short-acting bronchodilator therapy at adequate doses. Long-
acting bronchodilators provide symptomatic relief of breathlessness and improve exercise capacity; they may also
reduce frequency and severity of exacerbations and improve quality of life. Short-acting bronchodilators as 'rescue'
medication are usually used in conjunction with long-acting bronchodilators.

Available long-acting inhaled bronchodilators are long-acting beta2 agonists (LABAs) and long-acting muscarinic
antagonists (LAMAs). LABAs induce bronchodilation directly by relaxing airway smooth muscle through
stimulation of beta2-adrenergic receptors; LAMAs prevent acetylcholine-induced bronchoconstriction by
competitive antagonism of muscarinic receptors.

Long-acting bronchodilators are recommended for patients with COPD who:

have moderate or severe COPD

experience frequent breathlessness requiring short-acting bronchodilator therapy
have mild COPD but experience breathlessness that is not adequately relieved by short-acting
 bronchodilator therapy.

LABAs and LAMAs can be used either separately as monotherapy, or in combination for patients experiencing
persistent breathlessness; see choice of long-acting bronchodilator.

If patients experience frequent exacerbations, consider adding an inhaled corticosteroid (ICS) to their treatment
regimen; see inhaled corticosteroids for further information.

Choice of long-acting bronchodilator

There are a number of different long-acting bronchodilators available.

Long-acting muscarinic antagonists (LAMAs), include tiotropium, glycopyrronium, aclidinium and umeclidinium.
Tiotropium taken once daily improves quality of life and reduces the frequency of exacerbations in comparison
with placebo and short-acting muscarinic antagonists. Glycopyrronium once daily and aclidinium twice daily have
been shown to provide similar efficacy and safety to tiotropium in trials of up to 12 months duration.

Long-acting beta2 agonists (LABAs) include:

eformoterol and salmeterol. When used twice daily in conjunction with a short-acting beta2 agonist (SABA)
they improve quality of life and reduce the use of rescue medications compared to using a short-acting
bronchodilator alone; they also reduce the frequency of exacerbations
indacaterol, olodaterol and vilanterol [Note 8] (ultra-long-acting beta2 agonists). Indacaterol taken once
daily has been demonstrated to improve symptoms and quality of life and to reduce use of rescue
medications compared to use of short-acting bronchodilators alone. Olodaterol taken once daily improves
lung function and reduces rescue inhaler use compared with placebo. It appears to have similar
bronchodilator effects to twice-daily eformoterol, and to be generally safe, although asymptomatic increases
in plasma creatine kinase have been reported.

There is individual variability in response to long-acting bronchodilators; an individual patient may respond to a
LAMA or a LABA. Symptomatic and functional benefits may be shown despite an absence of change in forced
expiratory volume in 1 second (FEV1), and should be seen within 6 to 12 weeks. Changes in quality of life,
breathlessness and/or functional limitation (measured with the CAT or mMRC dyspnoea scores), may be used to
quantify the patient's perception of benefit. If there is no improvement following a treatment trial, review inhaler
technique and exclude other causes of breathlessness. Consider specialist referral.

The combination of a LABA and a LAMA has shown additional benefit in lung function and quality of life
compared with a LAMA alone. Combination therapy with inhaled drugs is either via separate single-drug inhalers
or, if an appropriate combination is available, via fixed-dose combination inhalers.

Several new long-acting bronchodilators have become available for use in COPD. Evidence about long-term safety
and intraclass efficacy is lacking; therefore, drugs for which there is more clinical experience may be preferred
initially. Drug choice should also take into account patient preference (including dosage regimen and suitability of
device [see Table 9.39]), potential adverse effects, response to a trial of the drug and cost.

Acute changes in FEV1 are not a guide to long-term symptomatic benefit.

For treatment with a long-acting bronchodilator, use:

1 a LABA by inhalation, see Table 9.24

OR

1 a LAMA by inhalation, see Table 9.24.

Inhaled long-acting bronchodilator dosages for COPD (Table 9.24)

Drug [NB1] Delivery device [NB2] Dosage [NB3]

LABAs
eformoterol single-dose DPI [NB4] 12 micrograms, twice daily
indacaterol single-dose DPI 150 to 300 micrograms, once daily
olodaterol soft mist MDI [NB5] 5 micrograms, once daily
salmeterol multiple-dose DPI 50 micrograms, twice daily
LAMAs
aclidinium multiple-dose DPI 322 micrograms, twice daily
glycopyrronium single-dose DPI 50 micrograms, once daily
tiotropium single-dose DPI 18 micrograms, once daily
umeclidinium multiple-dose DPI 62.5 micrograms, once daily
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; LABA = long-acting beta2 agonist; LAMA = long-acting muscarinic
antagonist; MDI = metered dose inhaler
NB1: See choice of long-acting bronchodilator for further advice.
NB2: See inhalational drug delivery devices for advice about appropriate device choice.
NB3: Number of actuations to deliver a dose depends on the dose formulation available.
NB4: Eformoterol multiple-dose DPI preparation is not registered for use in COPD; see [URL] for current information.
NB5: Soft mist MDI device is not compatible with spacers.

Note 8: At the time of writing, vilanterol is only available in Australia as a fixed-dose combination inhaler with
a long-acting muscarinic antagonist or with an inhaled corticosteroid.

Long-acting beta2 agonist + long-acting muscarinic antagonist fixed-dose combination

If combination therapy with a long-acting beta2 agonist (LABA) and a long-acting muscarinic antagonist (LAMA)
is indicated, a fixed-dose combination inhaler may be more convenient for patients rather than separate single-drug
inhalers if a suitable combination is available. If indicated, use:

a LABA+LAMA by inhalation, see Table 9.25.

Inhaled long-acting beta2 agonist + long-acting muscarinic antagonist fixed-dose combination

dosages for COPD (Table 9.25)

Drug combination Delivery device [NB1] Dosage

indacaterol+glycopyrronium single-dose DPI 110+50 micrograms, once daily
vilanterol+umeclidinium multiple-dose DPI 25+62.5 micrograms, once daily
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler
NB1: See inhalational drug delivery devices for advice about appropriate device choice.

Inhaled corticosteroids
The aims of treatment with inhaled corticosteroids (ICS) in COPD are to reduce exacerbation rates and slow
decline in health status, not to improve lung function per se. The effect of ICS on mortality is uncertain. Response
to oral corticosteroids does not predict response to ICS; do not use oral corticosteroids to identify which patients
may benefit from ICS.

Clinical trials have observed an increased risk of pneumonia associated with ICS use in patients with COPD.
Although the risk appears higher with fluticasone than with budesonide, a recent systematic review concluded that
this finding should be interpreted with caution as much of the data came from a single study, and no trials directly
compared the two drugs. However, a similar pattern has been seen in case-control studies of community-based
patients, for more serious pneumonia. Further head-to-head clinical trial data are required to confirm whether or
not this is a class effect.

Smoking adversely affects response to ICS; advise patients who continue to smoke that the benefits of ICS
treatment is likely to be reduced.

ICS are indicated as add-on therapy for patients with both:

a forced expiratory volume in 1 second (FEV1) less than or equal to 50% predicted
two or more exacerbations requiring treatment with antibiotics or oral corticosteroids in a 12-month period.

ICS are also prescribed as add-on treatment for patients with documented evidence of responsiveness to ICS on the
grounds of spirometry or functional status. ICS may be indicated for patients with overlap of asthma and COPD.

Doses of ICS recommended in COPD reflect those used in clinical trials but are not therapeutic equivalents.
Emerging data indicate that moderate doses may be as effective as high doses, but head-to-head studies are
awaited.

If combination therapy with an ICS and a long-acting bronchodilator is indicated, a fixed-dose combination inhaler
may be more convenient for patients rather than separate single-drug inhalers if a suitable combination is available.

There is evidence combination therapy with an ICS and a long-acting beta2 agonist (LABA) provides greater
protection against exacerbations than ICS alone. If fixed-dose combination ICS+LABA is indicated, use:
 an ICS+LABA by inhalation, see Table 9.26.

At the time of writing, there are no fixed-dose combinations of ICS+LAMA available in Australia. If this
combination is indicated, separate single-drug inhalers should be used. ICS used in COPD that are available as
single-drug inhalers are budesonide and fluticasone propionate; note that COPD is not a registered indication for
these drugs in Australia [Note 9].

To minimise the risk of oropharyngeal candidiasis and systemic corticosteroid absorption, advise patients to rinse
their mouth with water and spit out straight after using ICS. Patients using a pressurised metered dose inhaler
(pMDI) should also be advised to use a spacer, which decreases oropharyngeal deposition of the inhaled
corticosteroid, thereby reducing systemic absorption, oropharyngeal candidiasis and dysphonia.

Oral corticosteroids should preferably not be used for maintenance therapy in COPD due to increased risk of
adverse effects, including weight gain and the development of diabetes, cataracts and osteoporosis.

Inhaled corticosteroid + long-acting beta2 agonist fixed-dose combination dosages for COPD
(Table 9.26)

Drug combination Delivery device [NB1] Dosage [NB2]

multiple-dose DPI

or

budesonide+eformoterol pMDI 400+12 micrograms, twice daily

or

pMDI
fluticasone furoate+vilanterol multiple-dose DPI 100+25 micrograms, once daily
multiple-dose DPI

or
250+50 to 500+50 micrograms, twice
fluticasone propionate+salmeterol pMDI
daily
or

pMDI
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; pMDI = pressurised metered dose inhaler
NB1: See inhalational drug delivery devices for advice about appropriate device choice.
NB2: Number of actuations to deliver a dose depends on the dose formulation available.

Note 9: Information about registered indications is available on the Therapeutic Goods Administration (TGA)
website [URL]

Oxygen
Patients with advanced COPD may develop significant hypoxaemia.

Measurement of arterial blood gases is recommended for patients with a forced expiratory volume in 1 second
(FEV1) of less than 1 litre or those whose arterial oxygen saturation measured by pulse oximetry (SpO2) is 92% or
less. Assessment for domiciliary oxygen therapy should be undertaken while COPD is stable, and more than 4
weeks after an exacerbation (when gas exchange may deteriorate). There is an increased risk of fire if patients
currently smoke; these patients should not be prescribed domiciliary oxygen.

Long-term continuous oxygen therapy, usually delivered by a concentrator, offers survival benefits for patients
with COPD and partial pressure of oxygen (PaO2) of 55 mmHg or less, or those with PaO2 55 to 59 mmHg with
cor pulmonale, pulmonary hypertension or polycythaemia. It should be used for at least 18 hours a day (see
domiciliary oxygen therapy) to maximise benefits.

The role of oxygen therapy for patients with isolated exertional or nocturnal hypoxaemia is unclear. Blinded trials
of oxygen may be of use in occasional patients with breathlessness and desaturation on exertion; however,
evidence showed little difference in breathlessness, exercise capacity or quality of life when exertional oxygen was
compared with exertional air. For further detail on oxygen therapy and access requirements throughout Australia,
see domiciliary oxygen therapy.

Theophylline
Theophylline may be helpful in some patients with COPD. However, at standard doses it has potential for
significant drug interactions and adverse effects. It should be considered only for patients in whom other treatment
has failed to control symptoms adequately, or for patients who are unable to use inhaled therapy.

Studies have suggested low-dose theophylline (eg 100 mg twice daily) may have anti-inflammatory effects and
may reduce exacerbation frequency. However, the role of theophylline for patients on maximal bronchodilator and
corticosteroid therapy is unclear. At these lower doses, plasma theophylline concentration would not normally
need to be monitored.

Mucolytics
Treating excess mucus in COPD should focus on treatment of the underlying disease. Although mucolytics may
have some benefit in reducing the frequency and severity of exacerbations, in patients on optimal recommended
therapy their role is uncertain.

Other drug treatment

For information on the harms and benefits of long-term macrolides as anti-inflammatory therapy for patients with
severe COPD and frequent exacerbations, see The role of long-term antibiotic therapy in COPD.

Comorbidities and complications of COPD

Introduction

A number of conditions that commonly coexist with chronic obstructive pulmonary disease (COPD) have
implications for diagnosis and/or management. COPD coexisting with asthma is discussed separately in overlap of
asthma and COPD.

Cardiovascular disease
Patients with COPD are at high risk of cardiovascular disease. Diagnosing cardiovascular disease in COPD is
made more difficult by similar presenting features, which in both cases may include breathlessness, fatigue and
even chest discomfort.

Managing cardiovascular disease coexisting with COPD can also be difficult; beta blockers have proven mortality
benefits in cardiovascular disease but their use remains low in patients with COPD because of the concern about
acute bronchospasm, particularly in those with overlap of asthma and COPD. Reviews suggest that cardioselective
beta blockers are generally safe and well tolerated for patients with COPD, but a cautious approach with low dose
initiation and gradual up-titration is recommended [Note 10].

Note 10: Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2005;(4):CD003566. [URL]

Anxiety and depression

Anxiety, including panic attacks, and depression occur frequently in patients with COPD and adversely affect
prognosis, particularly in those who are admitted to hospital. Comprehensive pulmonary rehabilitation can
significantly reduce symptoms of both anxiety and depression; there are also promising results with both cognitive
behavioural therapy and a collaborative care model. More severe symptoms may merit pharmacotherapy, for
management advice see depression and anxiety and associated disorders.

Osteoporosis
Patients with COPD have a higher than normal frequency of bone fracture, and their bone mineral density is on
average 10% lower than control patients. Identification and management of those at risk should be undertaken
using current guidelines for treatment of osteoporosis (see osteoporosis).

Diabetes

Patients with COPD are at increased risk of developing type 2 diabetes. Patients with COPD and comorbid
diabetes are also at increased risk of diabetes complications if using high-dose inhaled corticosteroids (ICS).
Review maintenance treatment for these patients regularly to ensure that minimally effective ICS doses are used
and blood glucose control is closely monitored.

Treatment with short courses of oral corticosteroids in these patients should be limited. It is important to optimise
the balance between benefits of treatment and potential short- and long-term adverse effects. Hypoglycaemic
therapy may need to be escalated during the corticosteroid course and subsequently de-escalated. For specific
advice about corticosteroid use in patients with diabetes, see glucocorticoid-induced hyperglycaemia.

Pulmonary hypertension and cor pulmonale

Mild-to-moderate pulmonary hypertension is a common complication of COPD that is associated with increased
risk of exacerbation, worsened quality of life and increased mortality. Pulmonary vascular remodelling is thought
to result from the combined effects of hypoxia, inflammation and loss of capillaries in severe emphysema. A small
proportion of COPD patients may present with ‘out-of-proportion’ pulmonary hypertension; this is defined as a
mean pulmonary artery pressure higher than 35 to 40 mmHg (normal is no higher than 20 mmHg) and relatively
well-preserved lung function that cannot explain prominent dyspnoea and fatigue.

Despite known benefits in idiopathic pulmonary hypertension, there is no evidence to date that pulmonary
vasodilator drugs (eg endothelin receptor antagonists, phosphodiesterase type-5 [PDE5] inhibitors) are beneficial
in pulmonary hypertension complicating COPD. These drugs potentially may even cause harm by worsening
ventilation perfusion mismatch and, consequently, hypoxaemia.

Cor pulmonale is defined as right ventricular hypertrophy and dilation secondary to lung disease; it should be
considered if a patient with COPD has:

peripheral oedema
raised jugular venous pressure
a systolic parasternal heave
a loud pulmonary secondary heart sound.

Assess patients with cor pulmonale for the need for long-term oxygen therapy. Oedema associated with cor
pulmonale can usually be controlled with diuretic therapy. Manage right heart failure associated with cor
pulmonale according to recommendations outlined in heart failure.

Self-management programs for COPD

Self-management programs aim to teach patients with chronic disease the skills needed to carry out medical
regimens specific to their condition. They also aim to guide behaviour change to help patients control their
condition and improve their wellbeing. Self-management programs involve a range of strategies such as avoiding
risk factors (eg smoking), maintaining adequate nutrition and physical activity, and adhering to drug regimens.

Assess and carefully select patients with chronic obstructive pulmonary disease (COPD) for self-management
programs, taking into consideration their likely ability to self-manage and initiate therapy using a self-management
plan.

Written COPD action plans are an important component of comprehensive self-management. However, they
should not be used in isolation because they have little beneficial effect unless accompanied by a self-management
program and case management.

If appropriate, a written COPD action plan should outline the initial measures for the patient to take following an
increase in symptoms, and may include:

adjusting bronchodilator therapy to control symptoms

commencing oral corticosteroid therapy (unless contraindicated) if breathlessness increases and interferes
with activities of daily living
commencing antibiotics if the patient has fever, increased sputum volume and sputum purulence or a change
in sputum colour (see Box 2.24).

Patients should keep a course of antibiotic and corticosteroid tablets at home for use as part of self-management.
Development, updates and review of the written COPD action plan must involve a partnership between the
healthcare team and the patient. A sample written COPD action plan is available from the Lung Foundation
Australia website [URL].

See Exacerbations of COPD for further information.

Prognosis, palliative care and advance care planning for COPD

Lung function impairment is a strong predictor of mortality; however, using lung function alone to classify disease
severity does not capture the multidimensional nature of chronic obstructive pulmonary disease (COPD). Severe
dyspnoea, cough, fatigue, social isolation, anxiety and depression are all features of late-stage COPD, which
adversely impact quality of life.
The course of COPD is often punctuated by recurrent exacerbations, which may require hospitalisation and
consideration of assisted ventilation. Hospitalisation for an exacerbation increases subsequent mortality risk. As
the disease progresses a palliative approach to care may be appropriate. Determining prognosis in end-stage COPD
is difficult; however, characteristics that should trigger discussions about a palliative approach to care, advance
care planning, and end-of-life issues include:

forced expiratory volume in 1 second (FEV1) less than 25% of predicted

oxygen dependence
respiratory failure
heart failure or other comorbidities
weight loss or cachexia
decreased functional status
increasing dependence on others
advanced age.

See advance care planning for further detail.

Ideally, end-of-life discussions, including resuscitation and intubation wishes and advance care planning, should
occur in an outpatient setting when the patient's condition is relatively stable. These discussions should include
consideration of the appointment of a Medical Enduring Power of Attorney.

Patients with severe COPD and their caregivers should be made aware of palliative care services, including carer
respite and admission to hospice. For further information, see the Respecting Patient Choices website [URL].

Patients with severe COPD may benefit from low-dose opioids, which reduce the sensation of breathlessness
without significantly depressing respiration. End-stage COPD gives further information on a palliative approach
for COPD.

Multidisciplinary management of COPD

Overview
Patients with chronic obstructive pulmonary disease (COPD) who have persistent dyspnoea despite optimised
therapy (including pulmonary rehabilitation) may require specialist referral. Specialist knowledge and
investigations can confirm the diagnosis of COPD and identify patients with either asthma or overlap of asthma
and COPD. In addition, specialist input assists in differentiating COPD from other airway diseases or occupational
exposures that may cause airway narrowing and/or airway hyperresponsiveness.

Box 9.6 lists indications for considering consultation with a respiratory specialist.

Palliative care and advance care planning are discussed in prognosis, palliative care and advance care planning.
Indication for referral to specialist respiratory services (Box 9.6)

For a patient with COPD, referral to a specialist respiratory service is recommended in the following situations:

Diagnostic uncertainty and exclusion of asthma—to establish diagnosis and optimise treatment, and check
degree of reversibility of airflow obstruction.
Unusual symptoms such as haemoptysis—to investigate cause including exclusion of malignancy.
Rapid decline in FEV1—to optimise management.
Moderate or severe COPD—to optimise management.
Onset of cor pulmonale—to confirm diagnosis and optimise treatment.
Assessment for domiciliary oxygen therapy (ambulatory or long term)—to optimise management, measure
blood gases and prescribe oxygen therapy.
Assessment of the need for pulmonary rehabilitation—to optimise management and refer to specialist or
community-based rehabilitation service.
Bullous lung disease—to confirm diagnosis and refer for bullectomy if appropriate.
Patient with COPD who is younger than 40 years—to establish diagnosis and exclude alpha1-antitrypsin
deficiency.
Frequent chest infections—to rule out coexisting bronchiectasis.
Dysfunctional breathing—to establish diagnosis and refer for management.
Assessment for lung transplantation or lung volume reduction procedures (see surgical procedures in
COPD, below)—to identify criteria for referral to a transplant centre.

COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second

Source: Abramson M, Crockett A, Dabscheck E, Frith P, George J, Glasgow N, et al. The COPD-X Plan: Australian and New Zealand guidelines
for the management of chronic obstructive pulmonary disease. Version 2.37. Milton, Qld: Lung Foundation Australia; April 2014

Surgical procedures in COPD

For patients with very severe chronic obstructive pulmonary disease (COPD) who remain incapacitated by
dyspnoea despite maximal therapy (including pulmonary rehabilitation), various surgical and nonsurgical
interventions have been trialled. Transplantation has become a treatment option for selected patients with end-
stage COPD, resulting in improved survival. However, transplantation is limited by donor availability, need for
lifelong immunosuppression, and the development of chronic allograft dysfunction. Younger patients with fewer
comorbidities may be suitable for consideration of lung transplantation.

Patients who have predominant upper lobe emphysema with marked hyperinflation or ‘gas trapping’ (which is
associated with inadequate lung emptying and thus mechanical disadvantage) may benefit from lung volume
reduction surgery. Alternative nonsurgical approaches include 'bronchoscopic lung volume reduction' employing
endobronchial valves or blockers, airway bypass, biologic sealants, airway implants and bronchoscopic thermal
vapour ablation.

Refer patients to a specialist centre for discussions about such highly specialised palliative approaches.

Multidisciplinary management

Ideally, many different service providers, including those from nursing and allied health professions, are involved
in managing patients with chronic obstructive pulmonary disease (COPD). The general practitioner is often best
suited to coordinate the different contributions to management.

The multidisciplinary team may be involved in:

checking inhalation device(s) technique

assessing adherence to treatment
performing spirometry to confirm the diagnosis or assess progress
determining ability to perform tasks of daily living
assessing the need for domicilliary oxygen use
managing symptoms (eg dyspnoea, cough, anxiety, panic, depression, aspiration)—management may
include physiotherapy (eg to teach techniques of sputum clearance), pulmonary rehabilitation, occupational
therapy and speech therapy (eg to assist with swallowing training to avoid aspiration)
educating patients—nutrition and exercise, self-management strategies, relaxation techniques
identifying patients at high risk of exacerbations (see Exacerbations of COPD)
organising additional home supports and community services during exacerbations and deteriorations—
 these allow alternatives to acute hospital-based treatment
providing alternative forms of management—hospital-in-the-home, early discharge schemes, palliative care
facilities.

Air travel

If patients who have a forced expiratory volume in 1 second (FEV1) less than 30% predicted or who are on long-
term oxygen therapy are planning air travel, they should be assessed for fitness to fly. For further information on
assessment, and in-flight oxygen supplementation, see fitness to fly.

Ongoing monitoring and review of COPD

Patients with chronic obstructive pulmonary disease (COPD) should be reviewed regularly; frequency of review
depends on various factors including patient symptoms and history of exacerbations. A summary of suggested
regular review for patients with COPD in primary care is outlined in Table 9.27.

Regular review of patients with COPD in primary care based on severity (Table 9.27)

Severity of COPD
Mild and moderate [NB1]
Minimum frequency
at least annual
of review [NB2]
smoking status and desire to quit
adequacy of symptom control:
breathlessness
exercise tolerance
exacerbation frequency
need for pulmonary rehabilitation
presence of complications
effects of each drug treatment
inhaler technique
Clinical assessment
adverse effects of treatment
adherence
use of written COPD action plan if
appropriate
presence of psychiatric comorbidities
(eg depression, anxiety)
need for referral to specialist physician
and therapy services
Severe [NB1]
at least twice per year
clinical assessment as for mild and moderate
COPD, plus:
presence of cor pulmonale
possible coexisting cardiovascular
disease (including heart failure, atrial
fibrillation, ischaemic heart disease),
particularly if there is evidence of
recent COPD deterioration
need for long-term oxygen therapy
patient's nutritional state
need for social services and
occupational therapy input
need for referral for specialist surgical
procedures
need for end-of-life discussion and
advance directives

measurements as for mild and moderate

FEV1 and FVC [NB3]
COPD, plus:
mMRC breathlessness score
Measurements CAT score arterial blood gases if SpO2 is less
BMI
than 92%

BMI = body mass index; CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; FEV1 = forced expiratory volume in 1 second;
FVC = forced vital capacity; mMRC = modified Medical Research Council; SpO2 = oxygen saturation measured by pulse oximetry
NB1: See Figure 9.9 for typical symptoms and FEV1.
NB2: More frequent opportunistic assessment of factors such as inhaler technique, smoking status, symptom control and adverse effects of treatment is
encouraged.
NB3: Perform spirometry annually in mild, moderate and severe COPD.
Source: National Institute for Clinical Excellence (NICE). Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary
disease in adults in primary and secondary care (CG101). Manchester: NICE; 2010. [URL]

Exacerbations of COPD
Introduction
An exacerbation of chronic obstructive pulmonary disease (COPD) is characterised by the following features,
beyond day-to-day variations:

increasing dyspnoea
reduced exercise tolerance
tachypnoea.
An exacerbation may also be associated with:

increasing cough frequency

increasing sputum volume and/or purulence, with or without fever
right heart failure, manifesting as ankle oedema.

The overlap between cardiac and pulmonary reasons for acute deterioration is common; diagnosis is made more
difficult by similar presenting features, which in both cases may include breathlessness, fatigue and even chest
discomfort.

Exacerbations are associated with considerable morbidity, mortality and healthcare costs; they are the second
leading cause of avoidable hospitalisations in Australia [Note 11]. Exacerbations become more frequent as the
severity of COPD worsens. Following hospitalisation for an exacerbation, quality of life and lung function decline
and patients are at risk for further serious exacerbations. Reducing exacerbations is therefore a primary goal of
treating COPD.

Triggers include viral and bacterial infections as well as environmental pollutants, heart failure and pulmonary
embolism. Prompt treatment with short-acting bronchodilators, antibiotics as appropriate (see Antibiotic therapy
for exacerbations of COPD) and corticosteroids hastens resolution and reduces need for hospitalisation.
Noninvasive ventilatory support is indicated for hypercapnic respiratory failure and is effective in avoiding
intubation and reducing risk of death. An admission to hospital with an exacerbation of COPD is a sentinel event
that should trigger review of current management, including preventive therapies and consideration of advance
care planning. Clarify patient wishes concerning use of noninvasive and invasive ventilation should the need arise.

Note 11: Page A, Ambrose S, Glover J, Hetzel D. Atlas of avoidable hospitalisations in Australia: ambulatory
care-sensitive conditions. Adelaide, S.A.: University of Adelaide, Public Health Information Development Unit;
2007. [URL]

Assessing severity
Objective assessment of the severity of a chronic obstructive pulmonary disease (COPD) exacerbation can be
difficult; it is based largely on the underlying severity of the patient's condition, in addition to other aspects of their
medical history, clinical signs and investigations (see Table 9.28). The combination of these factors determine
whether the exacerbation can be managed in an outpatient setting, or if the patient should be referred to hospital
for assessment with or without admission. Additional indicators are listed in Box 9.7.

Considerations in assessing severity of a COPD exacerbation (Table 9.28)

Assessment Details
severity of underlying COPD (see Figure 9.9)
duration of worsening or new symptoms
number of previous exacerbations (total; note how many required
hospitalisation)
comorbidities
Medical history
current treatment regimen
previous need for mechanical ventilation
recent increased oxygen requirements (if applicable)
recent degree of difficulty with activities of daily living

use of accessory respiratory muscles

paradoxical chest wall movements
worsening or new-onset central cyanosis
Signs of severity development of peripheral oedema
haemodynamic instability
deteriorated mental status

Clinical features suggestive of see Box 2.24

bacterial infection
Additional investigations, if
appropriate:
useful for tracking and/or adjusting supplemental oxygen therapy
pulse oximetry [NB1]

chest X-ray useful to exclude alternative diagnoses

may aid in diagnosis of coexisting cardiac problems

electrocardiogram
full blood count may identify polycythaemia, anaemia, leucocytosis
 not routinely recommended; see Is the COPD exacerbation caused by
sputum culture infection?

electrolyte disturbances and hyperglycaemia can be associated with

biochemical tests exacerbations; however, they can also be due to associated comorbidities

spirometry not recommended to assess an exacerbation [NB2]

COPD = chronic obstructive pulmonary disease

NB1: Measuring arterial blood gases is vital if coexistence of acute or acute-on-chronic respiratory failure is suspected. Assessing the acid–base status is
necessary before initiating ventilatory support.
NB2: Spirometry should ideally be performed during the hospital admission to confirm diagnosis and provide an estimate of disease severity.
Source: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic
obstructive pulmonary disease. Bethesda, MD: GOLD; updated 2014. [URL]

Possible indicators for hospital assessment or admission in COPD exacerbations (Box 9.7)

The following may be indicators for hospital assessment or admission of a patient with an exacerbation of COPD
[NB1]:

marked increase in intensity of symptoms, such as sudden development of resting dyspnoea

severe underlying COPD
onset of new physical signs (eg cyanosis, peripheral oedema)
failure of an exacerbation to respond to initial medical management
presence of serious comorbidities (eg heart failure, newly occurring arrhythmias)
history of frequent exacerbations
older age
insufficient home support.

COPD = chronic obstructive pulmonary disease

NB1: Local resources need to be considered.

Reproduced with permission from the Global Strategy for Diagnosis, Management and Prevention of COPD 2014, © Global Initiative for Chronic
Obstructive Lung Disease (GOLD), all rights reserved. Available from [URL]

Treatment

Inhaled bronchodilators

Treat patients with an exacerbation of chronic obstructive pulmonary disease (COPD) with a bronchodilator. Most
studies suggest that beta2 agonists (salbutamol, terbutaline) and the antimuscarinic drug ipratropium work equally
well, although the onset of effect of salbutamol is more rapid than that of ipratropium. Some patients may respond
better to one type of medication than the other; tailor treatment to individual response.

In all patients using a pressurised metered dose inhaler (pMDI), particularly those with poor inhaler technique,
using a spacer improves lung deposition of the aerosol. A pMDI with spacer is likely to be as effective as
nebulisation for patients with forced expiratory volume in 1 second (FEV1) greater than 30% predicted, although
evidence for this comes from studies in patients with asthma.

For initial treatment of an exacerbation of COPD, use:

1 salbutamol 100 micrograms, up to 10 separate actuations by inhalation via pMDI with

spacer, repeated as needed

OR

2 terbutaline 500 micrograms, 1 or 2 actuations by inhalation via DPI, repeated as needed

OR
 2 ipratropium 21 micrograms, up to 6 separate actuations by inhalation via pMDI with
spacer, repeated as needed.

If these do not control symptoms adequately, or if symptoms are severe, combine either salbutamol or terbutaline
with ipratropium at the doses given above.

If a nebuliser is used in COPD, it should be driven by compressed air, to avoid excessive and potentially
deleterious hyperoxygenation (see acute oxygen therapy). See also nebulisers for information. If appropriate, use:

1 salbutamol 2.5 to 5 mg by inhalation via nebuliser, as needed

OR

2 ipratropium 250 to 500 micrograms by inhalation via nebuliser, as needed.

If these do not control symptoms adequately, or if symptoms are severe, combining salbutamol and ipratropium at
the doses given above may provide added benefits without compounding adverse effects.

If these treatment regimens do not control symptoms, or if medication is required more frequently than 3-hourly,
the patient should seek medical attention and/or enact their written COPD action plan if they have one (see self-
management).

Systemic corticosteroids

A short course of systemic corticosteroids shortens the duration of hospital admission and hastens return to
previous lung function and stable symptom control. They should be used routinely for more severe exacerbations
of COPD (see assessing severity, above). A recent study has suggested that 5 days of corticosteroid therapy may be
adequate, and would reduce cumulative corticosteroid exposure compared with the longer treatment courses
commonly used [Note 12]. If the patient can take oral medication, use:

prednis(ol)one 30 to 50 mg orally, once daily in the morning for 5 days.

If oral medication cannot be tolerated, use:

hydrocortisone 100 mg IV, 6-hourly.

Conversion to oral corticosteroid should occur as soon as is practical. If the course of therapy has been shorter than
2 weeks, the prednis(ol)one may be stopped abruptly without the need for routine tapering.

Note 12: Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, et al. Short-term vs conventional
glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE
randomized clinical trial. JAMA 2013;309(21):2223–31. [URL]

Antibiotics

See Antibiotic therapy for exacerbations of COPD.

Oxygen therapy

If the patient is hypoxaemic, oxygen should be administered to maintain the arterial oxyhaemoglobin saturation at
88 to 92%. Patients with COPD are at risk of hypercapnic respiratory failure during an exacerbation; the principles
of oxygen therapy in such patients are discussed in detail in acute oxygen therapy.

Keep supplemental oxygen to the minimum consistent with adequate oxygen saturation (SaO2), adequate
peripheral oxygen delivery and stable partial pressure of carbon dioxide levels (PaCO2) and pH.

Ventilatory support

Noninvasive ventilation is considered the standard of care for patients with exacerbations of COPD associated
with hypercapnic respiratory failure and acidosis despite the following:

optimal drug therapy

treatment of other complications (eg pneumothorax)
attempts to minimise inspired oxygen while maintaining adequate oxygen saturation (SpO2) at 88 to 92% or
 more.

Noninvasive ventilatory support often avoids the need for intubation and has been shown to reduce mortality and
length of hospital stay. After an episode of acute hypercapnic respiratory failure treated with noninvasive
ventilation, patients are at high risk of readmission and life-threatening events during the following year.

If noninvasive ventilatory support is required, close monitoring on a specialist medical ward is necessary.
Management in an intensive care unit should be considered and is mandated if invasive ventilation is required.

Normally, noninvasive ventilation is used only during hospitalisation. Studies have examined its use in the home
for patients at risk of further hypercapnia, including those who exhibit persistent hypercapnia, but results are
mixed. A large study of patients who had persistent hypercapnia after acute noninvasive ventilation did not find
home use reduced readmission rates. However, another study suggested benefit from higher pressures than had
been used previously, with reductions in long-term mortality and improvements in quality of life. Further evidence
to support the use of noninvasive ventilation in a domiciliary setting as a treatment for COPD is awaited. It is not
routinely used at the time of writing.

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Published March 2015. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Cough
Causes and classification of cough
Cough is one of the most common reasons for presentation to healthcare providers. In children, cough is a
major source of parental anxiety. The scientific understanding of cough is evolving and several cough
guidelines have been published by specialist groups [Note 1] [Note 2].

Differential diagnosis to identify the underlying pathology is important. However, once the most common
causes have been eliminated, identifying an underlying condition can be difficult and complex.

Cough is generally classified according to its duration before presentation, because this assists in the
differential diagnosis. In children, an acute cough is one that has been present for up to 2 weeks; if it has
lasted for 2 to 4 weeks it is considered prolonged acute cough, and anything longer is considered chronic
cough. In adults, acute cough is one that has been present for up to 2 weeks; if it has lasted for more than 8
weeks it is considered chronic persistent cough. Australian cough guidelines do not include a descriptor for
cough present for 2 to 8 weeks in adults.

Any repetitive cough can cause laryngeal irritation and inflammation, leading to persistence of the urge to
cough.

A summary of common and/or important causes of cough are outlined in Table 9.29. For detailed advice on
diagnosis and assessment of cough in children and adults, see the CICADA guidelines [Note 1] .

Alarm symptoms and findings in cough are listed in Box 9.8. Cough can also affect the patient's quality of life
through the impact of adverse consequences of cough, such as urinary incontinence in women, headaches,
vomiting, rib fracture and sleep disturbance. Consider referral to a specialist if a patient's cough is proving
resistant to simple therapies, appears excessively prolonged or if the patient has any of the alarm symptoms
and findings listed in Box 9.8.

Summary of common and/or important causes of cough (Table 9.29)

Cause [NB1] Comments

Acute cough [NB2]
acute bronchitis
asthma and asthma-like syndromes
drug-induced cough
inhaled foreign body
Chronic cough [NB3] [NB4]
postviral cough
protracted bacterial bronchitis
pertussis
gastro-oesophageal reflux or
laryngopharyngeal reflux
upper airway cough syndrome
Productive or nonproductive cough in the presence of other signs of a
lower respiratory tract infection. It is the most common cause of cough
in the general practice setting. See Acute bronchitis.
Uncontrolled asthma is a common cause of cough, but it is unusual for
cough to be the sole symptom; see asthma in children and asthma in
adults and adolescents for advice about diagnosis and management.
Common precipitants include ACEIs and beta blockers; there is not
always a close temporal relationship between starting a drug and
development of cough.
Sudden onset of cough, particularly if cough started while eating or, in
a child, while playing with small objects.
Follows an acute viral respiratory tract infection such as acute
rhinosinusitis or acute bronchitis; may last up to 8 weeks.
Wet cough lasting for more than 4 weeks in children, particularly
children younger than 5 years of age. See Protracted bacterial
bronchitis in children.
Consider if cough is persistent and paroxysmal, and lasting for 2 to 6
weeks or more; see Pertussis for further information.
Consider if patient has symptoms such as heartburn or water brash, or
if cough is worse at night or after eating specific foods; diagnosis often
made clinically or following a response to empirical treatment.
May be associated with excessive mucus production (eg due to
allergic or nonallergic rhinopathy; see rhinitis and rhinosinusitis for
(previously called postnasal drip) treatment), or with increased perception of normal volumes of
postnasal mucus.
May be triggered by any other cause of cough and worsened by
upper airway dysfunction (vocal cord
irritants such as gastro-oesophageal reflux, exposure to smoke or
dysfunction)
fumes, or excessive use of the voice.
obstructive sleep apnoea Inflammation of the pharynx from snoring may contribute to cough.
psychogenic or habit cough Particularly in children; cough not present during the night.
Sudden onset of cough, particularly if cough started while eating or, in
retained inhaled foreign body
a child, while playing with small objects.
Can present with or without sputum, fever and/or weight loss;
tuberculosis consider in patients who were born in or have visited countries where
tuberculosis is endemic, or in patients with impaired immunity.
Consider in smokers older than 45 years with a new cough, altered
lung or laryngeal cancer
cough, or cough with voice disturbance.
Aspiration-prone people include patients with Parkinson disease,
stroke, dementia, COPD, impaired consciousness, or neuromuscular
recurrent aspiration disorders affecting bulbar muscles. For definitions of aspiration-
related terms, see Table 2.57. For prevention strategies, see
Management of recurrent aspiration.
Productive cough, occurring every day for at least 3 months, at least 2
chronic bronchitis years in a row; occurs in the majority of heavy smokers (more than 20
pack years [NB5]).
Productive cough and frequent chest infections; see bronchiectasis for
bronchiectasis
further information.
Dry cough, often associated with shortness of breath; see interstitial
interstitial lung disease
lung disease for further information.
Productive cough associated with gastrointestinal symptoms or failure
cystic fibrosis
to thrive; see cystic fibrosis for further information.
Common precipitants include ACEIs and beta blockers; there is not
drug-induced cough always a close temporal relationship between starting a drug and
development of cough.
ACEIs = angiotensin converting enzyme inhibitors; COPD = chronic obstructive pulmonary disease
NB1: For detailed advice on diagnosis and assessment of cough in children and adults, see the CICADA guidelines [URL].
NB2: Acute cough is present for up to 2 weeks in children and adults.
NB3: Chronic cough is present for more than 4 weeks in children and more than 8 weeks in adults.
NB4: Some of these diagnoses should also be considered as potential causes of acute cough, as the patient may present soon after onset of cough.
NB5: Pack years is calculated using the formula (years of smoking × cigarettes per day) / 20; see also [URL].
Alarm symptoms and findings in cough (Box 9.8)

The following are considered alarm symptoms and findings in cough.

In adults:

haemoptysis
smoker with greater than 20 pack-year smoking history
smoker older than 45 years with a new cough, altered cough, or cough with voice disturbance
prominent dyspnoea, especially at rest or at night
substantial sputum production
hoarseness
systemic symptoms (fever, weight loss)
complicated gastro-oesophageal reflux disease (GORD) associated with weight loss, anaemia, overt
gastrointestinal bleeding (haematemesis or melaena), dysphagia, odynophagia or empirical treatment
failure for GORD
feeding difficulties (including choking or vomiting)
recurrent pneumonia
abnormal clinical respiratory examination
abnormal chest x-ray

In children:

prominent dyspnoea, especially at rest or at night

recurrent episodes of chronic, wet or productive cough
systemic symptoms (fever, weight loss, failure to thrive)
feeding difficulties (including choking or vomiting)
recurrent pneumonia
stridor and other respiratory noises
abnormal clinical respiratory examination
abnormal chest x-ray

Reproduced with permission from Gibson PG, Chang AB, et al. CICADA: Cough in Children and Adults: Diagnosis and Assessment.
Australian Cough Guidelines summary statement. Med J Aust 2010; 192(5):265-271. © Copyright 2010 The Medical Journal of Australia.

Note 1: Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in
Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Med J
Aust 2010;192(5):265-71. [URL]

Note 2: Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and
management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest
2006;129(1 Suppl):1S-23S. [URL]

General principles for managing cough

The initial step in treating cough is identification and specific management of the cause(s) of cough. However,
persistent cough may become self-perpetuating because the mucosa of the upper airways becomes denuded
and inflamed due to the coughing. The damaged mucosa is more sensitive and any exposure to external
triggers may lead to renewed bouts of coughing. For many patients with chronic cough, nondrug interventions
are useful to break this self-perpetuating cycle. For patients with persistent productive cough, strategies to
facilitate mucus clearance may be useful. Few patients with either acute or chronic cough require antibiotic
treatment.

For patients with cough of any cause, nonspecific interventions can help to reduce symptoms and decrease
laryngeal irritation while any specific causes are being identified and (where relevant) treated. For patients
with a dry cough, these nonspecific interventions focus on reducing the urge to cough, whereas for patients
with a wet or productive cough, the focus is on facilitating sputum clearance.

For cough associated with self-limiting respiratory tract infections (eg acute bronchitis, acute rhinosinusitis),
many patients have an expectation of treatment with antibiotics. Effective communication with the patient or
carer about the role of antibiotics is essential. The discussion should address misconceptions about the
effectiveness of antibiotic therapy and the expectation of an antibiotic prescription. Shared decision making,
which involves a discussion of the evidence for the potential benefits and harms of therapy, provides a useful
template for these discussions. Resources for shared decision making are available for:

Acute bronchitis
Acute rhinosinusitis
exacerbations of chronic obstructive pulmonary disease (COPD) managed in the community (see
Antibiotic management of COPD)
Sore throat.

Providing a 'prescription' with advice about nonspecific strategies for dealing with acute respiratory tract
infection may also be useful to reduce patient expectation for antibiotics. NPS MedicineWise provides
handouts with advice about nondrug management; see [URL].

After a trial of any drug treatment for cough, assess the response and stop the treatment if it is not effective. In
severe or intractable cough, consider referral.

See cough in palliative care for management advice in palliative care situations.

Nondrug interventions for cough

Environmental factors
When relevant, advise patients to avoid exposure to environmental factors that may be contributing to or
worsening their cough. This includes exposure to environmental tobacco smoke and other inhaled irritants,
and to cold dry air.

Vocal hygiene
Vocal hygiene measures for patients with a dry cough are aimed at reducing further irritation to the larynx,
which may be perpetuating the urge to cough. These strategies include:

avoiding overuse of the voice

avoiding smoky or polluted environments
avoiding clearing the throat and minimising coughing; for example by taking sips of water with a hard
swallow
having a family member draw attention to unwitting habitual coughing or throat-clearing (not advised
for children because it tends to reinforce the habit)
referring to a speech pathologist for training in techniques to relieve glottal constriction during
inspiration and to recognise and alter the response to triggers [Note 3].

Note 3: This may be facilitated through a voice clinic.

Sputum clearance
For patients with a chronic productive cough, training in 'Active Cycle of Breathing' techniques can improve
the effectiveness of sputum clearance by moving secretions towards the mouth so they can be cleared. This
can reduce laryngeal trauma from repetitive coughing.

Patient information about airway clearance in the context of chronic obstructive pulmonary disease is
available from The Australian Lung Foundation [URL].

Drug treatment of cough

Caution for children
The Australian Therapeutic Goods Administration (TGA) has advised that cough and cold medicines,
including cough suppressants, antihistamines, decongestants and combination products, should not be given to
children younger than 6 years. Caution should be used when treating children aged 6 to 12 years; the TGA
advises cough and cold medicines should only be used in this age group on the advice of a doctor, pharmacist
or nurse practitioner.

For further information, see the TGA website [URL].

Cough suppressants
Treatment with opioid cough suppressants (codeine, dextromethorphan, dihydrocodeine, pholcodine) may be
considered in adults for a limited duration. However, cough suppressants have only marginal benefit over
placebo, and the potential for addiction with opioids should be considered. Cough suppressants are not
recommended for use in children.

If appropriate, use a cough suppressant for a limited duration in adults for short-term relief and to break the
cough cycle [Note 4].

Note 4: Codeine should not be used in breastfeeding women, patients known to be ultrarapid metabolisers,
in children younger than 12 years, and in children 12 to 18 years who have recently had a tonsillectomy
and/or adenoidectomy for obstructive sleep apnoea. For more information, see the TGA Medicines Safety
Update.

Antihistamines

Antihistamines have not been found to be more effective than placebo in relieving acute cough, although
some clinicians recommend using a sedating antihistamine at night if dry cough disturbs sleep.

Proton pump inhibitors

If gastro-oesophageal reflux disorder (GORD) is considered likely (eg symptoms of heartburn or water brash,
night-time choking without symptoms of obstructive sleep apnoea), an empirical trial of high-dose proton
pump inhibitors may be used. Review response after 8 to 12 weeks and stop if there is no response (see Table
6.1 for standard dosing of proton pump inhibitors). Also recommend lifestyle changes, such as avoiding
caffeine and meals late at night.

Corticosteroids

For patients with symptoms of allergic or nonallergic rhinopathy, an empirical trial of intranasal saline
(sodium chloride solution) and intranasal corticosteroids may be given for at least 1 month.

For patients with otherwise unexplained chronic cough, empirically trial low-dose inhaled corticosteroids and
review response after 2 to 4 weeks (see Table 9.5 and Table 9.12 for dosing). If the cough responds, this does
not necessarily indicate a diagnosis of asthma. Measurement of lung function before and after the trial of
inhaled corticosteroids will help to confirm a diagnosis of asthma (see children and adults and adolescents for
information). Cough due to eosinophilic bronchitis may also respond to inhaled corticosteroids.

Complementary medicines
There is minimal evidence for the effectiveness of the many complementary therapies sold over-the-counter
for treatment of cough. Some complementary therapies such as echinacea have been associated with severe
allergic reactions.

Key references
Cough

Gibson PG, Chang AB, Glasgow NJ, Holmes PW, Katelaris P, Kemp AS, et al. CICADA: Cough in children and
adults: diagnosis and assessment. Australian cough guidelines summary statement. Med J Aust
2010;192(5):265–71. [ ]

Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman SS, Brightling CE, et al. Diagnosis and management of
cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006;129(1 Suppl):1S–23S. [
]

Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in
ambulatory settings. Cochrane Database Syst Rev 2012;(8):CD001831. [ ]

Vertigan AE, Gibson PG. The role of speech pathology in the management of patients with chronic refractory
cough. Lung 2012;190(1):35–40. [ ]
Published March 2015. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute bronchiolitis
Management of acute bronchiolitis
Acute viral bronchiolitis is the most common lower respiratory tract infection in infants. It affects both the
upper and lower airways and has a peak prevalence and severity in infants younger than 6 months. The
diagnosis of bronchiolitis is clinical and based on a typical history of nasal discharge and fever, and
examination findings of tachypnoea, increased work of breathing, widespread inspiratory crackles and
expiratory wheeze. The diagnosis is usually limited to the first 12 months of life.

Babies born prematurely and children with congenital heart disease or undergoing treatment for
haematological malignancy are at particular risk for severe disease. There is an increased risk in infants of
parents who smoke and in male infants. Around 1% of infants are hospitalised for acute viral bronchiolitis.
Respiratory syncytial virus is the most common associated virus, although other respiratory viruses such as
rhinovirus, human metapneumovirus, parainfluenza and influenza may be involved.

Most children presenting to the general practitioner have mild bronchiolitis. The main issues in management
are parental reassurance and education about minimal handling and giving frequent feeds.

Clinical indications for admission to hospital are:

difficulty feeding
moderate to severe work of breathing
increased respiratory rate. Assessment varies with the age of the child; for normal values according to
age, see Table 1.26
oxygen saturation measured by pulse oximetry (SpO2) less than 94%.

Most children admitted to hospital require only symptomatic care with supplemental oxygen and minimal
handling. Nasogastric feeds may be preferable to intravenous fluids if normal feeding is not possible. A small
number of children with severe disease may require extra respiratory support with noninvasive ventilation (eg
high-flow heated humidified nasal cannula therapy or continuous positive airway pressure [CPAP]) or
invasive ventilation.

Corticosteroids have not shown benefit and are not indicated.

Bronchodilators have not been shown to provide benefit in reducing hospital length of stay or requirement for
supplemental oxygen.

There is some evidence that the use of inhaled 3% hypertonic saline (sodium chloride solution) may reduce
hospital length of stay and improve clinical severity score.

Antibiotics are not indicated in the outpatient management of acute bronchiolitis. However, they may be used
in very ill hospitalised infants, especially if there is associated consolidation on chest X-ray. This is because
secondary bacterial infection may complicate the illness, particularly in infants requiring ventilatory support.
For antibiotic treatment in this setting, see community-acquired pneumonia in children.

Nebulised ribavirin is not recommended without specialist consultation. It may be used in

immunocompromised patients, but provides at best marginal benefit for respiratory syncytial virus infection.
Ribavirin is expensive, potentially toxic and rarely indicated.

Key references
Acute bronchiolitis

Oakley E, Borland M, Neutze J, Acworth J, Krieser D, Dalziel S, et al. Nasogastric hydration versus intravenous
hydration for infants with bronchiolitis: a randomised trial. Lancet Respir Med 2013;1(2):113–20. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Croup
Introduction to croup
Croup (acute laryngotracheobronchitis) presents with a coryzal prodrome, hoarseness (or husky voice in those old
enough to speak), inspiratory stridor, a harsh barking ‘brassy’ cough, and variable airway obstruction due to
inflammatory oedema within the subglottis. It is most common in children aged 1 to 3 years and has a duration of 2
to 5 days; however, a postinfective cough may persist for many weeks. Parainfluenza viruses are the most common
cause of croup, and antibiotics are not indicated.

Spasmodic croup refers to typical croup symptoms that occur without acute viral infection, usually in the early
hours of the morning. Spasmodic croup usually has a shorter course than acute laryngotracheobronchitis, but is
often recurrent and occurs in older children. Affected children often have coexisting asthma. Treatment is the same
as for acute laryngotracheobronchitis.

Assessment of croup
Important points in early assessment of the child with suspected croup are:

Loudness of stridor is not a good guide to the severity of obstruction.

Avoid examination procedures that create anxiety, such as throat examination or physically separating the
child from the parent, as this exacerbates croup.
Blood tests, oxygen therapy, and nasopharyngeal aspirate are rarely indicated.

The severity of croup can be categorised as:

mild airway obstruction—mild chest wall retractions and tachycardia, but no stridor at rest
moderate airway obstruction—stridor at rest, chest wall retractions, use of accessory respiratory muscles,
and tachycardia
severe airway obstruction—persisting stridor at rest, increasing fatigue, markedly decreased air entry and
marked tachycardia.

Restlessness, decreased level of consciousness, hypotonia, cyanosis and pallor are signs of life-threatening airway
obstruction.

Restlessness, decreased level of consciousness, hypotonia, cyanosis and pallor are signs of life-threatening airway obstruction.

Management of croup
Initial treatment
There is good evidence to support the routine use of a single dose of corticosteroids in all children with croup,
whether mild, moderate or severe. This has been shown to reduce hospital admission rates and prevent re-
presentation.

In mild to moderate croup, use:

1 budesonide 2 mg by inhalation via nebuliser, as a single dose

OR

1 dexamethasone 0.15 mg/kg orally, as a single dose [Note 1]

OR

1 prednis(ol)one 1 mg/kg orally, as a single dose.

If there is persisting accessory muscle use, stridor at rest, or distress, treat the child as for severe croup (see below).

If the child settles initially after treatment for mild to moderate croup, but later in the day develops stridor at rest,
they should go to hospital and be managed as for severe croup.

For severe croup, use:

adrenaline 0.1% (1:1000, 1 mg/mL) solution 5 mL by inhalation via nebuliser, repeated

after 30 minutes if no improvement [Note 2] [Note 3]

PLUS EITHER

1 budesonide 2 mg by inhalation via nebuliser, as a single dose

OR

1 dexamethasone 0.15 to 0.3 mg/kg (maximum 12 mg) orally (or IM or IV if vomiting),

as a single dose [Note 1]

OR

1 prednis(ol)one 1 mg/kg orally, as a single dose.

Observe the child for a minimum of 4 hours after giving adrenaline. If there is no response or deterioration occurs,
immediately arrange urgent review by the intensive care unit (ICU). More detail on hospital management is given
in the Royal Children's Hospital clinical practice guidelines [URL]. Consider differential diagnoses such as
bacterial tracheitis or conditions associated with airway obstruction or deep neck space infection (see Table 2.7) in
children with a lack of response to therapy. Seek expert advice for management of bacterial tracheitis.

Hydrocortisone should not be used due to lack of evidence and short duration of action.

Inhalation of humidified air or steam provides no additional benefit.

Note 1: Oral dexamethasone solution is only available in Australia as an extemporaneous preparation from
specialised paediatric hospitals.

Note 2: Notify the intensive care unit about any child requiring more than one dose of nebulised adrenaline.

Note 3: The intravenous 1:1000 formulation of adrenaline is used for the nebuliser.

Hospital admission
The decision to admit to hospital is made after initial treatment and observation. In children with severe croup, if
there has been a good response to treatment with corticosteroids and/or nebulised adrenaline, observe the child for
4 hours or overnight before sending them home.

The presence of ongoing stridor at rest necessitates admission to the ICU. Notify the ICU if the child has needed
more than one dose of nebulised adrenaline in the emergency department.

Consider admission for children with mild to moderate croup if they have pre-existing narrowing of the upper
airways or Down syndrome, because they are prone to more severe croup.

When deciding whether to discharge or admit after initial assessment and treatment, take into account the usual
considerations such as time of day, social circumstances, parents' comprehension and adherence, and access to
rapid review.

Key references
Croup

Royal Children's Hospital (RCH). Croup (laryngotracheobronchitis). Melbourne: RCH; 2011. [URL]

Published March 2015. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Cystic fibrosis
Overview of cystic fibrosis
Cystic fibrosis (CF) is an inherited autosomal recessive condition, and is the most common cause of
bronchiectasis and chronic suppurative lung disease in Caucasian children. However, CF is a complex
multisystem disease, which affects not only the lungs, gastrointestinal tract and pancreas, but also the liver,
sinuses, sweat glands, bones and reproductive system.

The CF gene codes for a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR),
which functions as an epithelial cell ion channel. CF gene mutations cause a variety of defects in CFTR
production, location or function. Approximately 1800 mutations in the CF gene have been identified and can
be divided into several classes.

Most children with CF in Australia are diagnosed via the Newborn Screening Program, which involves
measurement of the pancreatic enzyme trypsinogen from a heel-prick blood sample taken on day 3 or 4 of
life. If the blood sample trypsinogen level is above the 99th percentile, it is analysed for the most common
CF mutations. Results are generally available when infants are approximately 6 to 8 weeks old. Infants with
two CF mutations are referred directly to a specialist CF centre; if only one mutation is identified, a sweat test
is obtained to determine whether the infant has CF or is merely a carrier.

The Newborn Screening Program may miss up to 5% of children affected with CF per year. Referral for a
sweat test should be considered in any child presenting with a persistent wet cough, particularly if there is
associated failure to thrive or frequent loose, oily bowel actions.

Extensive information on symptoms, screening, sweat testing and genetic mutation testing can be found in
the Cystic Fibrosis Standards of Care, Australia 2008 manual [Note 1]. Appendix 1 of the manual provides
basic advice for healthcare professionals involved in the management of patients with CF. The Cystic
Fibrosis Australia website ([URL]) also has information brochures for patients, parents and carers.

Although previously considered primarily a paediatric disease, many patients with CF are now surviving to
adulthood. In Australia in 2012, around 50% of patients with CF were older than 18 years. Improvements in
respiratory and nutritional management have increased median survival to over 35 years of age. In addition,
delivery of care in multidisciplinary specialist CF centres has been shown to improve clinical outcomes.
Therefore all patients with CF in Australia are managed by, or in consultation with, a specialist CF centre and
any changes in management are made after consultation with that centre.

Progressive lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF); aggressive
management of CF lung disease is vital. This progressive lung damage involves a predisposition to recurrent
bacterial infection and neutrophilic inflammation.

The lungs of infants with CF are histologically normal at birth; however, all patients with CF experience
worsening lung disease with advancing age. The aim of respiratory management is to limit the progression of
lung injury. There are a number of treatment modalities:

Early aggressive antibiotic therapy—bacteria exhibit a biofilm mode of growth in the CF lung, with
large numbers of organisms surrounded by a layer of ‘slime’ consisting of complex proteins and
polysaccharides. Established biofilms are resistant to antibiotic penetration, so treatment aims to
eradicate bacteria before the formation of biofilm.
Effective airway clearance, using both chest physiotherapy and mucolytic agents—lower airway
bacterial infection triggers a marked host inflammatory response. Lung damage is then caused by an
influx of circulating blood neutrophils into the airway and release of neutrophil products including
elastolytic enzymes. Neutrophil-derived DNA is also released, increasing sputum viscosity and
worsening airway obstruction.
Anti-inflammatory drugs—to reduce lung injury from neutrophil-derived products in
established CF lung disease.
Potentially, correction of cystic fibrosis transmembrane conductance regulator (CFTR) protein function
in patients with particular mutations of the CF gene, using drugs such as ivacaftor.

Note 1: Available from the Cystic Fibrosis Australia website [URL]

Lower airways infection in cystic fibrosis
Early cystic fibrosis (CF) lung disease is characterised by repeated episodes of endobronchial infection and
inflammation. The predominant initial bacterial pathogens include Staphylococcus aureus and Haemophilus
influenzae.

During adolescence and adulthood, Pseudomonas aeruginosa becomes the dominant organism cultured from
sputum. Early infecting strains of P. aeruginosa are of nonmucoid phenotype, are usually antibiotic-sensitive
and may be cleared from the airways with intensive antibiotic treatment. However, once P. aeruginosa
biofilm infection becomes established, the organism develops a mucoid phenotype and resistance to
antibiotics. Infection becomes chronic and antibiotic therapy can suppress, but not eradicate, P. aeruginosa
infection.

Burkholderia cepacia complex refers to a group of related environmental organisms that can cause chronic
lung infection in some patients with CF. These organisms are intrinsically antibiotic-resistant and often very
difficult to treat. Chronic infection with mucoid P. aeruginosa or B. cepacia complex is associated with
increased morbidity and mortality.

Many other organisms may be found in endobronchial secretions of patients with CF, including methicillin-
resistant Staphylococcus aureus (MRSA), other Gram-negative organisms such as Stenotrophomonas
maltophilia and Achromobacter xylosoxidans, nontuberculous mycobacteria and fungi.

Infection control

Strict infection control measures are needed for patients with CF because some respiratory pathogens are
potentially highly transmissible. Infection control guidelines for patients with CF, their carers and health
professionals can be found on the Cystic Fibrosis Australia website [URL].

Cross-infection refers to the transmission of an organism from an infected to a noninfected patient, and has
been shown to occur for certain strains (or genomovars) of B. cepacia. There is good evidence to support the
practice of separating all patients with CF who have B. cepacia complex infection from all other patients with
CF, and from each other; this includes providing single rooms during hospitalisations.

Initial infecting strains of P. aeruginosa are thought to be acquired from the environment, and most unrelated
patients with CF carry their own unique strain. The extent of the risk of cross-infection by P. aeruginosa is
controversial; however, all CF centres in Australia now separate patients with chronic P. aeruginosa from
patients who do not have chronic infection, both during clinics and hospitalisation. Some P. aeruginosa
strains in Australia may be highly transmissible, both to other patients with CF and also to patients with
bronchiectasis. Separation of these patients should be considered and discussed with treating specialists at a
CF centre.

Methicillin-resistant S. aureus (MRSA) and Mycobacterium abscessus can also be spread between patients
with CF; patients in whom these organisms have been isolated should also be separated from other patients
and cared for in a single room.

Exacerbations of cystic fibrosis lung disease

A persistent moist cough is the primary symptom of lower airway infection in CF, and must always be taken
seriously, even in the absence of abnormal respiratory signs such as tachypnoea, increased work of breathing,
crackles or wheeze.

An exacerbation is an increase in respiratory symptoms, often triggered by a viral upper respiratory tract
infection. Characteristic symptoms of an acute respiratory exacerbation in CF include increased cough
frequency or sputum production, increased dyspnoea, and decreased appetite, activity and energy levels.
Examination may reveal new crackles on chest auscultation. Pulmonary function may be reduced and new
infiltrates may be present on the chest X-ray. Management depends on severity and is usually undertaken in
consultation with a specialised CF centre.

Antibiotic therapy

General information

Antibiotic treatment of CF lung disease varies between different specialist CF centres and is based on general
principles and local experience, due to a lack of evidence-based recommendations. Both the dose and
duration of antibiotic therapy are different from those used for infections caused by the same pathogens in
patients without CF. For all antibiotic therapy, the choice, dose and duration must be decided in consultation
with the specialist CF centre.

Choice, dose and duration of antibiotic therapy must be decided in consultation with the specialist CF centre.

Ideally, the choice of drug is determined by the nature and antibiotic susceptibility of the infecting organism.
However, many patients with CF are not able to produce a sputum sample until the age of 6 to 7 years; in
younger patients the nature of the pathogen may be unknown. Some centres in Australia use bronchoalveolar
lavage to obtain bronchial secretions in young children. The use of throat swab cultures in infants with CF is
not ideal because this is likely to give a false positive result, although a negative result can help rule out
infection.

Current guidelines [Note 2] recommend obtaining respiratory cultures at least annually and during respiratory
exacerbations.

For an acute exacerbation of infection, if symptoms are relatively mild, treatment begins with a course of oral
antibiotics. If there is no improvement after 2 to 4 weeks, a course of intravenous antibiotic treatment is
given, either as an inpatient or by an outpatient parenteral antimicrobial therapy program.

Inhaled antibiotics may sometimes be used. They are administered through a suitable nebuliser delivery
system or podhaler, as recommended by the specialist CF centre. For nebulisation, a high-efficiency breathing
filter on the expiratory port is needed to reduce environmental contamination and exposure to others. To
maximise pulmonary deposition, a mouthpiece is preferable to a mask and can usually be used for children 4
years and older. When using a mask, it is important to wash the child's face after use. Careful daily
maintenance, cleaning, disinfection and drying of nebuliser equipment are essential.

When treating infection in CF, the following situations may be encountered. For further information on
bacteria involved, see background.

Note 2: Available from the Cystic Fibrosis Australia website [URL]

Infection before Pseudomonas aeruginosa becomes established

Before pseudomonas infection becomes established, the most common bacteria infecting the lower airway in
infants and young children are Staphylococcus aureus and Haemophilus influenzae.

Some Australian CF centres recommend prophylactic antistaphylococcal treatment for the first 2 years of life.
There is some evidence that this regimen is associated with an increased rate of pseudomonal infection. Other
centres recommend treatment only for respiratory exacerbations; the indication for antibiotics is the
development of a moist cough. This symptom should be treated promptly even though physical examination
of the chest is often normal.

Development of a moist cough should be treated promptly even if chest examination is normal.

Suitable oral antibiotics for episodes of moist cough in infants and young children include flucloxacillin,
cefalexin, clindamycin, trimethoprim+sulfamethoxazole or amoxicillin+clavulanate. Treatment is continued
for 2 to 4 weeks.

Initial infection with Pseudomonas aeruginosa

There is some evidence that intensive antibiotic treatment of initial Pseudomonas aeruginosa strains leads to
eradication of infection. Specialist CF centres offer such a regimen to all affected children. Eradication
treatment should also be considered for repeat infections until presence of chronic infection has been
established.

There is no current evidence to suggest the best treatment protocol for P. aeruginosa eradication; several
different protocols have been shown to be helpful. Treatment may involve a 2-week course of intravenous
antibiotics, most commonly a combination of an antipseudomonal penicillin or cephalosporin, with once-
daily tobramycin. In addition, many centres recommend a subsequent 2 to 3 month course of oral
ciprofloxacin with twice-daily inhaled tobramycin (either solution via nebuliser or powder via podhaler).
Nebulised colistimethate sodium is also commonly used, but is only available from hospital pharmacies.
 Oral and nebulised antibiotics for eradication of P. aeruginosa need to be given for 2 to 3 months.

Chronic Pseudomonas aeruginosa infection

Once chronic P. aeruginosa infection is established, antibiotic treatment aims to suppress infection and
reduce morbidity. At the time of writing there is little evidence to support one particular choice of treatment,
and antibiotic regimens vary. Many patients, both adults and children, with chronic P. aeruginosa are
managed with long-term inhaled antibiotics and may use a month-on/month-off regimen. In Australia, it is
usual to use inhaled tobramycin or colistimethate sodium, either continuously or alternating each drug
monthly. Continuous and intermittent regimens of these drugs have not been directly compared.

There is good evidence that patients with chronic pseudomonas infection show clinical improvement
following treatment with the macrolide antibiotic azithromycin. However, the improvement is due to
azithromycin's anti-inflammatory effect, rather than its antibiotic properties; for further information, see anti-
inflammatory treatment.

Burkholderia cepacia complex infection

The clinical course of patients with CF with Burkholderia cepacia complex infection is highly variable.
Many centres are now attempting eradication treatment for initial isolation of B. cepacia complex with some
success, although there are no data available from clinical trials. Eradication treatment includes up to three
antibiotics given intravenously, usually for at least 2 weeks, followed in some cases by oral ciprofloxacin and
inhaled tobramycin for up to 2 months.

Other respiratory pathogens

Some patients with CF have chronic infection with organisms such as Staphylococcus aureus (methicillin
sensitive or resistant), Haemophilus influenzae or Stenotrophomonas maltophilia. There is little evidence to
guide antibiotic recommendations, but most specialist CF centres recommend attempting to eradicate these
infections, particularly if respiratory symptoms are present. Treatment protocols are determined by the
specialist CF centre. Failure of 2 to 4 weeks of outpatient therapy usually indicates the need for intravenous
antibiotic treatment.

Other respiratory pathogens, including Achromobacter xylosoxidans, nontuberculous mycobacteria and fungi,
may be cultured either intermittently or chronically from sputum. Treatment decisions are determined by the
specialist CF centre.

Chest physiotherapy for cystic fibrosis

Chest physiotherapy for cystic fibrosis (CF) aims to clear infected secretions from the bronchi, thus relieving
airway obstruction and preventing progressive lung injury. An active lifestyle is encouraged, and standard
physiotherapy combined with an exercise program results in a greater increase in lung function compared
with physiotherapy alone.

An effective cough is the most successful method of clearing bronchial secretions, and teaching this should
be the basis of any physiotherapy program for patients with CF. This is particularly relevant in young
children.

There are many different chest physiotherapy techniques available; choice depends on the age of the patient.
Daily physiotherapy is recommended for patients with CF. In general, physiotherapy is performed once daily
in those with mild lung disease when asymptomatic, and twice daily during any pulmonary exacerbation.

Aerosolised mucolytics for cystic fibrosis

Dornase alfa
Patients with cystic fibrosis (CF) (even infants) have a high concentration of neutrophil-derived DNA within
the lower airways, which causes increased sputum viscosity. Dornase alfa is recombinant human DNase,
which cleaves extracellular DNA reducing the viscosity of CF sputum. Aerosolised DNase facilitates sputum
clearance and improves lung function in CF. The initial phase of therapy consists of a 4-week trial using:
 dornase alfa 2.5 mg by inhalation via nebuliser, once daily.

There is evidence that use of dornase alfa over 2 years reduces exacerbations and loss of lung function, even
in patients with normal lung function at the start of treatment.

Hypertonic saline

Nebulised hypertonic saline (sodium chloride 3 to 7% solution) improves lung function, reduces acute
infective exacerbations and is safe. There have not been any long-term studies of a direct comparison with
dornase alfa.

Nebulised hypertonic saline may cause bronchospasm in susceptible patients; pretreatment with
bronchodilators may be required.

Mannitol

Inhaled dry powder mannitol in a dose of 400 mg (ten 40 mg capsules) twice daily improves mucociliary
clearance and lung function over a 6-month period, and is used in Australia in adults and children 6 years or
older with CF.

Inhaled mannitol may cause bronchospasm; therefore for safety, all patients must undergo a Mannitol
Tolerance Test before it is prescribed as a regular treatment. The test involves giving increasing doses of
mannitol and repeated measures of pulmonary function to ensure that forced expiratory volume in 1 second
(FEV1) does not fall by more than 17% from baseline.

Anti-inflammatory treatment for cystic fibrosis

There is consensus among CF physicians that the host inflammatory response plays a role in lung injury in
CF.

The macrolide antibiotic azithromycin has been shown to be effective in the treatment of chronic
Pseudomonas aeruginosa infection. Azithromycin has an anti-inflammatory as well as antibiotic effect by
penetrating P. aeruginosa biofilms and augmenting neutrophil function.

Patients aged 6 years or older with chronic P. aeruginosa infection who use regular azithromycin may
experience fewer exacerbations, have a reduced fall in lung function, and have better quality of life scores
over time. Azithromycin is usually given orally three times weekly.

Although long-term anti-inflammatory therapy with oral corticosteroids can slow the progression of CF lung
disease, their use is controversial because it is associated with severe adverse effects, including growth
suppression and the development of diabetes, cataracts and osteoporosis.

Inhaled corticosteroids are used in 30 to 40% of children and adults with CF in Australia, but at the time of
writing there is insufficient evidence to determine whether this is beneficial or harmful in CF lung disease.

Treatment of coexisting asthma and cystic fibrosis

There is evidence that inhaled corticosteroids and other asthma treatments are overprescribed in CF. Beta2
agonists, such as salbutamol or terbutaline, should only be used if there is evidence of associated asthma or if
there has been a significant improvement of forced expiratory volume in 1 second (FEV1) with these drugs on
repeated testing.

Although beta2 agonists can be delivered by nebuliser, an equivalent bronchodilator effect can be achieved by
using a spacer to deliver 4 to 12 separate actuations from a standard pressurised metered dose inhaler. Using
an inhaler with a spacer offers considerable advantages in terms of cost, ease of use, convenience and
portability. The spacer is easily cleaned, thus reducing the risk of fomite infection.

Potentiator therapy for cystic fibrosis

Ivacaftor, a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, is the first
drug to target the abnormal CFTR protein. It is only effective for patients with the gene mutation G551D,
which is present in approximately 8% of patients with CF in Australia.

Clinical trials of ivacaftor in patients with CF and the G551D gene mutation have shown improvements in
lung function and nutritional status, and reductions in sweat chloride levels. Ivacaftor is taken orally twice
daily and is only available through specialist CF centres [Note 3].

Drugs targeting other gene mutations of the CFTR protein are in development.

Note 3: See the Pharmaceutical Benefits Scheme website for subsidised indications for ivacaftor [URL]

Allergic bronchopulmonary aspergillosis in cystic fibrosis

Allergic bronchopulmonary aspergillosis (ABPA) refers to an immunologically mediated response to lung
colonisation by the common environmental fungus Aspergillus fumigatus. It affects approximately 10% of
people with CF. Culture of A. fumigatus from the sputum is common and is not necessarily associated with
clinical disease.

Patients with ABPA usually present with wheezing, decreased exercise tolerance and reduced lung function.
It may be difficult to differentiate between an exacerbation of CF and ABPA; if the diagnosis of ABPA is
suspected, discuss this with the patient's CF physician. Diagnosis is based on clinical findings and
immunological investigations.

Treatment of ABPA is with high-dose corticosteroids. At the time of writing there is some, but not good,
evidence indicating that the addition of an azole antifungal (such as itraconazole) for patients with CF and
ABPA is beneficial. Moreover, extrapolation from management of ABPA in patients without CF would
support the use of antifungals. Itraconazole should be used under advice from a specialist centre because the
pharmacokinetics in patients with CF are different to patients without CF. Itraconazole serum concentrations
must be monitored to avoid toxicity or subtherapeutic doses.

Severe advanced lung disease in cystic fibrosis

Severe advanced lung disease in CF occurs when progressive lung injury leads to a reduction in forced
expiratory volume in 1 second (FEV1) below 30%. This is often associated with dyspnoea and hypoxaemia at
rest, with frequent cough and copious sputum production. Therapeutic options include supplemental oxygen,
noninvasive ventilation and lung transplantation.

Nonrespiratory aspects of cystic fibrosis

Gastrointestinal aspects

Most patients with cystic fibrosis (CF) have exocrine pancreatic insufficiency, and pancreatic enzyme
supplementation and a high-calorie diet are important to optimise nutritional status. See management of
pancreatic insufficiency for further information.

Bowel problems are very common and include abdominal bloating and pain, diarrhoea, constipation and
bowel obstruction. These problems are best addressed by CF centres with a multidisciplinary team including
dieticians and gastroenterologists with experience in CF.

Mild increases in liver enzymes (particularly alkaline phosphatase) are common in patients with CF but liver
disease is uncommon. Biliary cirrhosis can occur but liver failure is uncommon. Rarely, and mainly in
children, biliary cirrhosis may result in portal hypertension, oesophageal varices, and hypersplenism.
Cholelithiasis may also occur and ursodeoxycholic acid is used to rebalance the constituents of the bile salts.

Cystic fibrosis–related diabetes

Occurrence of cystic fibrosis–related diabetes (CFRD) increases with increasing age; it affects approximately
10% of adolescents and over 40% of adults older than 40 years. The classical symptoms of hyperglycaemia,
such as polyuria and polydipsia, are uncommon at the time of diagnosis; some patients with CFRD present
only with an unexplained fall of lung function and/or weight loss. CFRD is usually treated with insulin and/or
oral hypoglycaemic drugs. Diabetic ketoacidosis is rare.

CFRD dietary requirements are unlike normal diabetic dietary restrictions. Patients are encouraged to
maintain high-calorie diets (including fats and carbohydrates) with appropriate blood glucose control using
insulin and/or oral hypoglycaemics.

Fertility
There are increasing numbers of pregnancies successfully completed in women with CF. The management of
the pregnancy requires close multidisciplinary specialist management, but in general it is not associated with
a worsening of respiratory status. However, there is some risk to the fetus (increased risk of premature birth).
Collaboration is essential between the obstetric service and the specialist CF centre in the management of the
pregnancy.

Although over 95% of males with CF have azoospermia, recovery of sperm from the testis can be achieved in
up to 70% of cases. Pregnancy rates of up to 50% have been reported with in-vitro fertilisation and
intracytoplasmic sperm injection.

Bone health

Osteoporosis or osteopenia occurs in up to 75% of adults with CF. Inadequate bone mass accrual during
childhood and adolescence contributes to the low bone mass in adults with CF, but the cause is multifactorial.

Treatment includes optimising nutritional status, regular exercise and limiting the progression of chronic
suppurative lung disease. It may also require vitamin D, vitamin K and calcium supplementation, and
recognition and treatment of delayed puberty. Bisphosphonates may be helpful to reduce bone resorption, but
osteoporosis therapy should be initiated by the specialist CF centre.

Psychosocial aspects

CF is a chronic disease with multiple associated problems. As a group, the patients cope remarkably well.
Management of psychosocial needs is important to overall health and outcomes, and professional
psychological and social support should be made available when required.

Adherence to cystic fibrosis treatment

There are many barriers to adhering to all the treatments necessary to maintain good health in patients with
cystic fibrosis (CF). CF treatment is often complex and time-consuming. Patients find it difficult to fit
treatments into busy daily schedules. Keep every aspect of management as simple as possible, and regularly
review it with input from the patient. Where possible keep time-consuming treatments, in particular nebulised
drugs, to a minimum.

Cost of drugs may be a barrier. Patients may be discouraged following an acute exacerbation or declining
lung function despite good adherence.

Adherence may be a particular problem in adolescents and young adults. Give adolescents the opportunity to
be seen without their parents present, and encourage them to ask questions about their disease and its
management. Allow them as much input as possible into treatment decisions. Negotiate management plans,
rather than imposing plans without adequate explanation.

Key references
Cystic fibrosis: overview

Bell S, Robinson P. Cystic fibrosis standards of care, Australia. North Ryde: Cystic Fibrosis Australia; 2008.
[URL]

Cystic Fibrosis Australia. Cystic fibrosis in Australia 2012. 15th annual report from the Australian Cystic Fibrosis
Data Registry. Baulkham Hills, NSW: Cystic Fibrosis Australia; 2013. [URL]

Mahadeva R, Webb K, Westerbeek RC, Carroll NR, Dodd ME, Bilton D, et al. Clinical outcome in relation to care
in centres specialising in cystic fibrosis: cross sectional study. BMJ 1998;316(7147):1771–5. [ ]

Massie RJ, Curnow L, Glazner J, Armstrong DS, Francis I. Lessons learned from 20 years of newborn screening
for cystic fibrosis. Med J Aust 2012;196(1):67–70. [ ]

Cystic fibrosis: management of respiratory manifestations

Aitken ML, Bellon G, De Boeck K, Flume PA, Fox HG, Geller DE, et al. Long-term inhaled dry powder mannitol in
cystic fibrosis: an international randomized study. Am J Respir Crit Care Med 2012;185(6):645–52. [ ]

Armstrong D, Grimwood K. Infection control guidelines for cystic fibrosis patients and carers: Cystic Fibrosis
Australia; 2012. [URL]

Balfour-Lynn IM, Welch K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev 2012;
(11):CD001915. [ ]

Bell S, Robinson P. Cystic fibrosis standards of care, Australia. North Ryde: Cystic Fibrosis Australia; 2008.
[URL]

Bilton D, Bellon G, Charlton B, Cooper P, De Boeck K, Flume PA, et al. Pooled analysis of two large randomised
phase III inhaled mannitol studies in cystic fibrosis. J Cyst Fibros 2013;12(4):367–76. [ ]

Bilton D, Robinson P, Cooper P, Gallagher CG, Kolbe J, Fox H, et al. Inhaled dry powder mannitol in cystic
fibrosis: an efficacy and safety study. Eur Respir J 2011;38(5):1071–80. [ ]

Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, et al. A controlled trial of long-term
inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354(3):229–40. [ ]

Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ, et al. A two-year randomized,
placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities.
J Pediatr 2001;139(6):813–20. [ ]

Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, et al. Intermittent administration
of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J
Med 1999;340(1):23–30. [ ]

Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, et al. Azithromycin in patients
with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA
2003;290(13):1749–56. [ ]

Southern KW, Barker PM, Solis-Moya A, Patel L. Macrolide antibiotics for cystic fibrosis. Cochrane Database
Syst Rev 2012;(11):CD002203. [ ]

Cystic fibrosis: nonrespiratory aspects

Ahluwalia M, Hoag JB, Hadeh A, Ferrin M, Hadjiliadis D. Cystic fibrosis and pregnancy in the modern era: a case
control study. J Cyst Fibros 2014;13(1):69–73. [ ]

Bell S, Robinson P. Cystic fibrosis standards of care, Australia. North Ryde: Cystic Fibrosis Australia; 2008.
[URL]

Lau EM, Barnes DJ, Moriarty C, Ogle R, Dentice R, Civitico J, et al. Pregnancy outcomes in the current era of
cystic fibrosis care: a 15-year experience. Aust N Z J Obstet Gynaecol 2011;51(3):220–4. [ ]

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis-
related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of
the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 2010;33(12):2697–
708. [ ]

Patel EM, Swamy GK, Heine RP, Kuller JA, James AH, Grotegut CA. Medical and obstetric complications among
pregnant women with cystic fibrosis. Am J Obstet Gynecol 2014;212(1):98.e1-9. [ ]

Tonelli MR, Aitken ML. Pregnancy in cystic fibrosis. Curr Opin Pulm Med 2007;13(6):537–40. [ ]

Cystic fibrosis: adherence to treatment

Bell S, Robinson P. Cystic fibrosis standards of care, Australia. North Ryde: Cystic Fibrosis Australia; 2008.
[URL]
Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Bronchiectasis
Definition of bronchiectasis
Bronchiectasis is a disease characterised morphologically by the permanent dilatation of bronchi and
bronchioles, and clinically by recurrent or persistent bronchial infection, cough and often sputum. The
pathogenesis is related to chronic airway infection and inflammation resulting in airway damage.

Bronchiectasis may be classified under the chronic suppurative lung disease spectrum.

Causes of bronchiectasis
Bronchiectasis may be localised to one lobe or segment, or generalised in both lungs. Pneumonia, often in
childhood, is the most commonly recognised cause of bronchiectasis. However, in one series, no definite
cause could be established in 51% of patients. When focal disease is present, the cause may be an
intraluminal obstruction (eg an unsuspected foreign body or endobronchial tumour), or extrinsic compression
of the airway by enlarged lymph nodes.

Other less common causes or conditions found to be associated with bronchiectasis include:

congenital abnormalities of large airways and congenital forms of bronchiectasis

yellow nail syndrome
inherited immune deficiencies in children and adults, particularly deficiencies of immunoglobulin G
(IgG) and immunoglobulin M (IgM)
cystic fibrosis in both children and adults
primary ciliary dyskinesia
autoimmune diseases including rheumatoid arthritis and inflammatory bowel disease
acquired immunodeficiencies and recurrent pneumonia
panbronchiolitis
Aspergillus fumigatus causing proximal airway bronchiectasis in patients with asthma
Mycobacterium avium complex infection, particularly in women older than 60 years
recurrent sepsis in patients with sinus disease and suppurative otitis media
recurrent aspiration where there are neurological or anatomical disorders affecting oropharyngeal
muscle coordination and swallowing
lung irradiation
fibrotic lung diseases such as idiopathic pulmonary fibrosis, causing traction bronchiectasis.

Bronchiectasis may coexist with asthma or chronic obstructive pulmonary disease (COPD).

Clinical features and diagnosis of bronchiectasis

Most adult patients with bronchiectasis have a chronic cough with sputum production. Children may present
with a persistent wet cough, as they are unable to expectorate sputum (see bronchiectasis in children). The
sputum is usually purulent and may be intermittently bloodstained. Consider bronchiectasis in patients who
have persistent symptoms not responding to standard treatment and/or in whom a Gram-negative organism,
such as Pseudomonas aeruginosa, is found on sputum culture. Patients may present with life-threatening
haemoptysis requiring urgent hospitalisation.

Wheezing and shortness of breath are common during exacerbations, and pleurisy may occur if distal
pneumonia is present. Crackles and wheeze are commonly heard, although chest examination in children may
be normal. A small proportion of patients (less than 5%) have clubbing of the fingers.

High-resolution computed tomography (HRCT) scan of the chest is the preferred test to confirm the diagnosis
of bronchiectasis because it allows clear visualisation of the severity and distribution of the disease.
Pulmonary function testing often reveals associated airflow limitation. Diagnostic testing for some of the
specific conditions associated with bronchiectasis (see list in causes) is mandatory in children and may be
appropriate in adults, depending on the clinical setting and/or radiological appearances.

Patient history and physical examination should direct investigations. If there is no obvious clue, basic
investigations would include immunoglobulin concentrations (including IgG subtypes) an autoimmune screen
(rheumatoid factor [RF], antinuclear antibodies [ANA]), and cystic fibrosis sweat chloride and mutation
testing.

Nonantibiotic management of bronchiectasis

Overview
The basic aims in bronchiectasis management are to keep the airways as free of secretions as possible (see
general measures), the background microbiological load low and the number of infective exacerbations to a
minimum. This involves treating all acute respiratory tract infections and managing any underlying
conditions. Rarely, removing a severely damaged section of lung may be helpful.

Baseline management is outlined in general measures below. The following are suggested indications for
seeking respiratory physician opinion:

rapid progression of disease or symptoms

disease requiring hospitalisation
severe respiratory symptoms or lack of response to current treatment
frequent need for antibiotics, such as more than 3 to 4 courses of antibiotics within 12 months
resistant or unusual organisms isolated in sputum
haemoptysis
clinical deterioration indicated by
–
inability to maintain weight
–
declining lung function.

For management of exacerbations of bronchiectasis, see Antibiotic management of bronchiectasis.

General measures
Keeping the airways as free of secretions as possible is an important part of the management of
bronchiectasis. Modern methods of airway clearance, including physical techniques and drug treatment,
allow greater patient independence.

Physical methods include various breathing and coughing techniques and the use of aids, such as mechanical
devices, for sputum mobilisation. Tipping with postural drainage is no longer the preferred method of airway
clearance. Refer patients to an experienced respiratory physiotherapist to develop an individualised sputum-
clearing program.

Nebulised agents that may assist with airway clearance include bronchodilators and normal and hypertonic
saline (sodium chloride solution). Dry powder mannitol has also been shown to have some efficacy. Treat any
reversible component of airflow limitation with bronchodilators and inhaled corticosteroids.

It is important for patients to maintain weight, muscle strength and mass through good nutrition and exercise.
Exercise may be useful in promoting respiratory secretion clearance.

Lung function testing should be performed initially to assess lung function. Spirometry should be done when
clinically indicated to monitor airflow limitation. Patients may benefit from pulmonary rehabilitation.

To avoid cross-infection, advise patients about standard infection control measures, including covering the
mouth when coughing, attention to hand hygiene, and not sharing utensils. Patients with bronchiectasis
requiring hospital treatment should be separated from patients with chronic suppurative lung diseases or with
respiratory viral infections.

Immunisation with pneumococcal vaccine and annual influenza vaccine is recommended [Note 1].

Note 1: For details see National Health and Medical Research Council. The Australian immunisation
handbook. 10th ed. Canberra: NHMRC; 2013. [URL]

Antibiotic therapy
For assessment and management of exacerbations of bronchiectasis and information about the role of long-
term antibiotic therapy for patients with frequent exacerbations, see Antibiotic management of bronchiectasis.

Management of haemorrhage

In adults with bronchiectasis, minor haemoptysis may be an indication of infection but does not necessarily
require further investigation. Assess the patient for signs of a bacterial infection—see Assessment of
exacerbations of bronchiectasis. If possible, stop any drugs that may promote haemorrhage (eg nonsteroidal
anti-inflammatory drugs [NSAIDs], anticoagulants). Refer patients with recurrent small haemoptyses for
assessment by a specialist.

Massive haemoptysis (more than 250 mL in 24 hours) can occur with bronchiectasis. If this happens,
immediately send the patient to a hospital where appropriate specialist services are available. Investigations
are generally aimed at localising the site of haemorrhage, and may include computed tomography (CT) scan
of the chest with angiography, selective bronchial artery angiography, and bronchoscopy. Treatment options
include bronchial artery embolisation and lobectomy.

Bronchiectasis in children
Bronchiectasis not associated with cystic fibrosis may occur in children and has been recognised as a more
common problem in Indigenous children. Appropriate investigation of potential causes and intensive
treatment (including airway clearance, preventive immunisations, antibiotic therapy, and optimisation of
nutrition and growth) are key to reducing long-term lung damage and maintaining lung function. Children
should be managed by a specialist respiratory clinic.

Key references
Bronchiectasis

Chang AB, Bell SC, Byrnes CA, Grimwood K, Holmes PW, King PT, et al. Chronic suppurative lung disease and
bronchiectasis in children and adults in Australia and New Zealand. Med J Aust 2010;193(6):356–65. [ ]

Crosbie PA, Woodhead MA. Long-term macrolide therapy in chronic inflammatory airway diseases. Eur Respir J
2009;33(1):171–81. [ ]

McCool FD, Rosen MJ. Nonpharmacologic airway clearance therapies: ACCP evidence-based clinical practice
guidelines. Chest 2006;129(1 Suppl):250S–9S. [ ]

Pasteur MC, Bilton D, Hill AT, British Thoracic Society Bronchiectasis non CFGG. British Thoracic Society
guideline for non-CF bronchiectasis. Thorax 2010;65 Suppl 1i1–58. [ ]

Published March 2015. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Pleural disease
Pleuritic pain
Pleuritic pain may be associated with:

inflammation of the pleura caused by viral or bacterial pneumonia

pulmonary infarction caused by pulmonary embolism
pneumothorax
connective tissue disease
trauma
benign asbestos pleurisy.

An accurate diagnosis is important. Provide sufficient analgesia during investigations to allow adequate respiratory
movements and so decrease the risk of atelectasis and pneumonia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be appropriate initially; however, opioids may be needed.
The cough suppressant and respiratory depressant actions of opioids should be considered before use. If opioids
are required for patients with chronic obstructive pulmonary disease or patients thought to be hypoxaemic,
admission to hospital for monitoring is advised. For information on analgesia, see acute pain in adults and acute
pain in children.

Pneumothorax
Introduction
Pneumothorax is the presence of air between the parietal and visceral pleura, and can be classified as spontaneous,
traumatic or iatrogenic.

Spontaneous pneumothoraces are subdivided into:

primary—where there is no evidence of underlying lung disease

secondary—where lung disease is present, most commonly chronic obstructive pulmonary disease (COPD)
but also asthma, interstitial lung disease, cystic fibrosis or HIV-associated infection.

Spontaneous pneumothorax usually presents with sudden onset of pleuritic chest pain and breathlessness, and is
diagnosed primarily on history and chest X-ray, preferably taken with the patient erect. Pneumothoraces may be
difficult to see on plain films taken in the supine position, and computed tomography (CT) scan may be required.

Specific chest signs depend on the size of the pneumothorax and may be difficult to detect. In a large
pneumothorax, physical signs include absent breath sounds, tachypnoea, decreased chest wall movement,
hyperresonance to percussion, decreased vocal resonance and tracheal deviation to the opposite side.

For a summary of the approach to management of spontaneous pneumothorax, see Figure 9.10.

Management of spontaneous pneumothorax (Figure 9.10)

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Decompensated pneumothorax

Decompensated pneumothorax (also known as tension pneumothorax) is a medical emergency and requires urgent
decompression. The rapid development of a large pneumothorax, particularly if there is underlying lung disease or
trauma, may result in severe breathlessness, hypoxaemia, hypotension and cardiovascular collapse.

The diagnosis is clinical not radiological. Mediastinal shift is seen in many large pneumothoraces and does not of
itself indicate a need for decompression.

The concept that the effects of a decompensated pneumothorax relate to supra-atmospheric intrapleural pressure
has been questioned, and the term decompensated pneumothorax is preferred to tension pneumothorax. However,
patients on positive pressure ventilation, including continuous positive airway pressure (CPAP), may develop
intrathoracic pressures exceeding atmospheric pressure and deteriorate rapidly.

Decompensated pneumothorax is extremely rare in primary spontaneous pneumothorax.

Primary spontaneous pneumothorax

Conservative management versus intervention procedures

Primary spontaneous pneumothorax is usually a nuisance rather than a dangerous condition. Symptoms commonly
resolve within 24 to 48 hours without treatment.

Conservative management of even large, primary spontaneous pneumothoraces was usual in the past with
excellent results, and is increasingly being used. Drainage of pneumothorax is often painful and carries risks
(including damage to internal organs, bleeding and infection) and should not be attempted by inexperienced
practitioners. A large multicentre randomised controlled trial is in progress comparing conservative management
with active intervention [Note 1].

If an intervention procedure for pneumothorax is performed, there is good evidence that aspiration is preferable to
insertion of an intercostal drain. Earlier and more vigorous intervention is associated with increased complications.

Existing guidelines [Note 2] advise that patients with small (less than 2 cm) pneumothoraces who are stable may
be observed. Patients can be considered clinically stable if they:

are not short of breath

are able to speak in sentences
have a respiratory rate less than 24 breaths/minute
 have a pulse rate between 60 and 120 beats/minute
have a blood pressure that is normal for them.

The objectives of treatment are to relieve symptoms, minimise hospital admission and prevent recurrence.

Adequate analgesia is important and often substantially improves breathlessness, which may be largely related to
the pain of breathing. For information on analgesia, see acute pain in adults and acute pain in children.

If the patient is in hospital, oxygen may be given not only to maintain oxygenation but also to increase the rate of
resorption of the intrapleural air. Use:

oxygen 10 L/minute via face mask.

Note 1: A study to investigate the treatment of pneumothorax (collapsed lung) registered with Australian New
Zealand Clinical Trials Registry (ANZCTR) on 16/2/2011 (Trial ID: ACTRN12611000184976) [URL]

Note 2: Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J, et al. Management of spontaneous
pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001;119(2):590-
602. [URL]
and MacDuff A, Arnold A, Harvey J, Group BTSPDG. Management of spontaneous pneumothorax: British
Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2:ii18-31. [URL]

Persistent air leak

A persistent air leak (bronchopleural fistula) develops in about one-third of cases of pneumothorax treated with
intercostal drains. It is more common in secondary spontaneous pneumothorax. One study has shown that all
persistent air leaks in primary pneumothorax resolved in 15 days and up to 80% of persistent air leaks in secondary
spontaneous pneumothorax resolved in 14 days [Note 3]. Early surgical intervention is sometimes advised but
there is no evidence to support this. An alternative is insertion of a small catheter attached to a lightweight one-
way valve (Heimlich valve), which allows outpatient ambulatory management.

Note 3: Chee CB, Abisheganaden J, Yeo JK, Lee P, Huan PY, Poh SC, et al. Persistent air-leak in spontaneous
pneumothorax: clinical course and outcome. Respir Med 1998;92(5):757-61. [URL]

Recurrence

The risk of a recurrence of spontaneous pneumothorax is estimated to be 30 to 50%; continuing smokers have
higher risk. If there has been one recurrence on the same side, the risk of further recurrences rises sharply and
referral for pleurodesis is recommended. Pleurodesis techniques include medical thoracoscopy with talc
insufflation, surgical video-assisted thoracoscopy with pleural abrasion, and injection of talc slurry through an
intercostal catheter.

Secondary spontaneous pneumothorax

Patients with secondary spontaneous pneumothorax generally require early active intervention and hospitalisation
for observation. Existing guidelines [Note 4] recommend intercostal drainage except for patients who are not
breathless and have a very small or apical pneumothorax. Simple aspiration is less likely to be successful and is
only recommended as initial treatment in small pneumothoraces in patients with minimal symptoms and who are
younger than 50 years.

Note 4: Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J, et al. Management of spontaneous
pneumothorax: an American College of Chest Physicians Delphi consensus statement. Chest 2001;119(2):590-
602. [URL]
and MacDuff A, Arnold A, Harvey J, Group BTSPDG. Management of spontaneous pneumothorax: British
Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2:ii18-31. [URL]

Iatrogenic pneumothorax
Iatrogenic pneumothorax may occur following pleural aspiration, or transbronchial or percutaneous lung biopsy.
They are usually small and resolve spontaneously, but aspiration may be considered.

Pneumothorax decompression methods

Urgent needle decompression

If the patient is in extremis, do not delay decompression while arranging for sterile procedures and local
anaesthetic (although these are desirable).

For urgent needle decompression of a pneumothorax:

Insert a cannula above the third rib in the mid-clavicular line.

Remove the needle from the cannula.
A gush of air confirms the diagnosis.
Once complete, insert a thoracostomy tube expeditiously.

Catheter aspiration

For catheter aspiration of a pneumothorax (sometimes termed thoracocentesis), see Box 9.9.

Catheter aspiration of a pneumothorax (Box 9.9)

For catheter aspiration of a pneumothorax:

Use a small-bore catheter, such as a venous catheter with a 3-way valve or a pigtail catheter, or a catheter
such as a single-lumen central line.
Using an aseptic technique, identify the third rib in the mid-clavicular line.
At this surface landmark, infiltrate local anaesthetic (5 to 10 mL of 1% lidocaine) subcutaneously and
deeper until reaching the pleural space; this must be confirmed by aspiration of air into the syringe.
Insert the catheter above the third rib in the mid-clavicular line, unless the pneumothorax is elsewhere.
Aspirate until no more air is returned.
Leave the catheter in situ and immediately repeat the chest X-ray.
Repeat the chest X-ray again in 2 to 4 hours.
If the pneumothorax has not reaccumulated, remove the catheter.
If the pneumothorax has reaccumulated, connect the catheter to a continuous drainage underwater
seal or Heimlich valve.
If there is no reaccumulation, discharge the patient with advice to return if symptoms recur, or every 2
weeks until the pneumothorax has resolved.

Intercostal tube drainage

Intercostal tube drainage (tube thoracostomy) is indicated in the following circumstances:

if simple aspiration fails in primary spontaneous pneumothorax

in secondary spontaneous pneumothorax unless the patient is asymptomatic and the pneumothorax is very
small
in most cases of traumatic pneumothorax
in decompensated (tension) pneumothorax.

For simple pneumothorax, preferably connect a small-bore catheter (10 to 14 Fr gauge) either to a Heimlich valve
or to an underwater seal. There is no evidence that insertion using a Seldinger technique reduces complications.
Suction is not indicated. Large-bore catheters are used in traumatic pneumothorax to allow for drainage of blood.

Intercostal tube drainage is a specialised procedure; for further information see British Thoracic Society guidelines
[Note 5].

Note 5: Havelock T, Teoh R, Laws D, Gleeson F, Group BTSPDG. Pleural procedures and thoracic ultrasound:
British Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2:ii61-76. [URL]
and MacDuff A, Arnold A, Harvey J, Group BTSPDG. Management of spontaneous pneumothorax: British
Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2:ii18-31. [URL]

Pleural effusion
Introduction
The appropriate management of pleural effusion depends on an accurate diagnosis. Effusions can be either
transudates or exudates. Most transudates occur in clinically obvious situations of heart failure, liver cirrhosis,
nephrotic syndrome, or in patients receiving peritoneal dialysis.
 Use direct ultrasound guidance to sample pleural fluid by aspiration.

Use direct ultrasound guidance to sample pleural fluid by aspiration. This can be safely undertaken at the bedside,
sampling with a 21 G (green) needle and a syringe. Obtain as large a sample as possible to analyse for
biochemistry (which may include pH, lactate dehydrogenase [LDH], protein and glucose), cytology and culture
(including for mycobacteria). Note the gross appearance of the fluid. If clinical suspicion of tuberculosis is high,
consider a pleural biopsy.

Management of parapneumonic effusion and empyema

Introduction

Pleural effusion complicates up to 50% of cases of pneumonia; it is then called a parapneumonic effusion. This is
sterile initially, but if not detected and managed appropriately may develop into a thoracic empyema. Any
clinically significant parapneumonic effusion confirmed on chest X-ray requires diagnostic sampling and culture of
the fluid sample.

Empyemas, as with any collection of pus, always require adequate drainage and antibiotic therapy. For antibiotic
management, see parapneumonic effusion and empyema.

Drainage

Indications for drainage of parapneumonic effusion are:

continued fever and sepsis despite adequate antibiotic therapy

large size (more than one-third of the hemithorax)
loculated pleural effusions
evidence of continued pleural infection, such as
–
frankly purulent or turbid fluid on sampling
–
presence of bacteria on Gram stain or culture of pleural fluid
–
pleural fluid pH less than 7.2
–
pleural fluid LDH concentration more than 1000 units/L.

Intrapleural enzyme therapy

Recombinant human DNase (dornase alfa) has been shown to reduce intrapleural pus viscosity. A randomised
controlled study in adults has shown DNase combined with a fibrinolytic (recombinant tissue plasminogen
activator [alteplase]), significantly reduces length of hospital stay and the need for surgery, and improves
radiographic appearance [Note 6]. Although neither drug is registered by the Therapeutic Goods Administration
(TGA) for this indication, at the time of writing alteplase plus dornase alfa is regarded as the international and
Australian standard of care for treatment of empyema.

For adults, use a combination of:

alteplase 10 mg

PLUS

dornase alfa 5 mg.

Combine both drugs in 50 mL sodium chloride 0.9% and inject via intercostal tube. Give
this dose twice daily for 3 days. Clamp the tube for 2 hours after each instillation then
flush it and put it onto suction at 20 cm H2O.

If alteplase is unavailable, an alternative would be urokinase (100 000 units twice daily) [Note 7] combined with
dornase alfa in the same manner.

Intrapleural fibrinolytic enzymes were previously recommended as monotherapy to treat empyema. However, a
randomised multicentre study of intrapleural administration of streptokinase has shown that its use does not
improve mortality, need for surgery, final radiographic appearance or length of hospital stay, and fibrinolytics alone
are no longer recommended [Note 8].
For intrapleural enzyme treatment of empyema in children, seek specialist advice.

Note 6: Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, et al. Intrapleural use of tissue
plasminogen activator and DNase in pleural infection. N Engl J Med 2011;365(6):518-26. [URL] ​

Note 7: Urokinase is not registered for use in Australia; available via Special Access Scheme

Note 8: Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, et al. U.K. Controlled trial of
intrapleural streptokinase for pleural infection. N Engl J Med 2005;352(9):865-74. [URL]

Surgery

For patients in whom sepsis continues despite adequate antibiotic therapy and tube drainage (including the
placement of additional catheters under imaging into the other loculations if necessary), consult a thoracic surgeon
to consider thoracoscopy, including video-assisted thoracoscopic surgery, or thoracotomy and open drainage.

Persisting chest X-ray abnormalities in a well patient are not an indication for surgery and are likely to improve
over time.

Management of malignant pleural effusions

The presence of pleural effusion in malignancy is an adverse prognostic factor. Symptomatic malignant pleural
effusions may require drainage. Reaccumulation of fluid after drainage is very common. More definitive treatment
with pleurodesis depends on individual patient circumstances and preferences.

Pleurodesis is normally carried out under direct specialist supervision. It can be performed as dry talc poudrage at
thoracoscopy, or by instillation of a sclerosant (eg talc slurry) through an intercostal catheter. The latter entails
drainage of the fluid from the pleural space, then instillation of a talc slurry or other sclerosing agent under local
anaesthesia. The tube remains in place until the daily fluid drainage is less than 150 mL. Graded talc with a large
particle size reduces the risk of acquired respiratory distress syndrome (ARDS), which has been reported with
ungraded talc.

Instillation of talc and other sclerosing agents into the pleural space can cause considerable pain, although this is
less common with malignant effusions. As well as lidocaine before instillation of the sclerosant, parenteral
morphine is required for premedication and for treatment of pain following the procedure.

Some centres use sclerosants other than talc (including minocycline, bleomycin and mustine hydrochloride) with
limited success.

An alternative to pleurodesis in cases where the lung fails to re-expand (trapped lung) or in the case of patient
preference, is the placement of a permanent indwelling tunnelled pleural catheter. This is performed in a specialist
centre.

Malignant mesothelioma
Pleural malignant mesothelioma is usually associated with asbestos exposure, which may have taken place decades
earlier. Presenting symptoms are usually breathlessness caused by pleural effusion or chest wall pain. No curative
treatment exists and most patients can only be offered palliative therapy.

If patients have localised tumours (which are rare), surgical treatment by extrapleural pneumonectomy may be
suitable.

The most important palliation is effective pleurodesis, usually using talc. Tumours may invade along needle or
intercostal tube tracks and form subcutaneous masses. These are usually asymptomatic and do not require
treatment. If they cause discomfort, local radiotherapy may help.

Patients should be advised to seek legal advice; compensation may be available if there has been asbestos
exposure.

Key references
Pneumothorax

Andrivet P, Djedaini K, Teboul JL, Brochard L, Dreyfuss D. Spontaneous pneumothorax. Comparison of thoracic
drainage vs immediate or delayed needle aspiration. Chest 1995;108(2):335–9. [ ]
Baumann MH. Management of spontaneous pneumothorax. Clin Chest Med 2006;27(2):369–81. [ ]

Baumann MH, Strange C, Heffner JE, Light R, Kirby TJ, Klein J, et al. Management of spontaneous pneumothorax: an
American College of Chest Physicians Delphi consensus statement. Chest 2001;119(2):590–602. [ ]

Chee CB, Abisheganaden J, Yeo JK, Lee P, Huan PY, Poh SC, et al. Persistent air-leak in spontaneous
pneumothorax: clinical course and outcome. Respir Med 1998;92(5):757–61. [ ]

Harriss DR, Graham TR. Management of intercostal drains. Br J Hosp Med 1991;45(6):383–6. [ ]

Harvey J, Prescott RJ. Simple aspiration versus intercostal tube drainage for spontaneous pneumothorax in patients
with normal lungs. British Thoracic Society Research Committee. BMJ 1994;309(6965):1338–9. [ ]

Havelock T, Teoh R, Laws D, Gleeson F, Group BTSPDG. Pleural procedures and thoracic ultrasound: British Thoracic
Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2ii61–76. [ ]

Laws D, Neville E, Duffy J. BTS guidelines for the insertion of a chest drain. Thorax 2003;58 Suppl 2ii53–9. [ ]

MacDuff A, Arnold A, Harvey J, Group BTSPDG. Management of spontaneous pneumothorax: British Thoracic
Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2ii18–31. [ ]

Maskell NA, Medford A, Gleeson FV. Seldinger chest drain insertion: simpler but not necessarily safer. Thorax
2010;65(1):5–6. [ ]

Noppen M, Alexander P, Driesen P, Slabbynck H, Verstraeten A. Manual aspiration versus chest tube drainage in first
episodes of primary spontaneous pneumothorax: a multicenter, prospective, randomized pilot study. Am J Respir Crit
Care Med 2002;165(9):1240–4. [ ]

Noppen M, Baumann MH. Pathogenesis and treatment of primary spontaneous pneumothorax: an overview.
Respiration 2003;70(4):431–8. [ ]

Northfield TC. Oxygen therapy for spontaneous pneumothorax. Br Med J 1971;4(5779):86–8. [ ]

Sadikot RT, Greene T, Meadows K, Arnold AG. Recurrence of primary spontaneous pneumothorax. Thorax
1997;52(9):805–9. [ ]

Sahn SA, Heffner JE. Spontaneous pneumothorax. N Engl J Med 2000;342(12):868–74. [ ]

Simpson G. Spontaneous pneumothorax: time for some fresh air. Intern Med J 2010;40(3):231–4. [ ]

Simpson G, Vincent S, Ferns J. Spontaneous tension pneumothorax: what is it and does it exist? Intern Med J
2012;42(10):1157–60. [ ]

Stradling P, Poole G. Conservative management of spontaneous pneumothorax. Thorax 1966;21(2):145–9. [

]

Tschopp JM, Boutin C, Astoul P, Janssen JP, Grandin S, Bolliger CT, et al. Talcage by medical thoracoscopy for
primary spontaneous pneumothorax is more cost-effective than drainage: a randomised study. Eur Respir J
2002;20(4):1003–9. [ ]

Waller DA. Video-assisted thoracoscopic surgery (VATS) in the management of spontaneous pneumothorax. Thorax
1997;52(4):307–8. [ ]

Pleural effusion

Balfour-Lynn IM, Abrahamson E, Cohen G, Hartley J, King S, Parikh D, et al. BTS guidelines for the management of
pleural infection in children. Thorax 2005;60 Suppl 1i1–21. [ ]

Davies HE, Davies RJ, Davies CW, Group BTSPDG. Management of pleural infection in adults: British Thoracic
Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2ii41–53. [ ]

Maskell NA, Davies CW, Nunn AJ, Hedley EL, Gleeson FV, Miller R, et al. U.K. Controlled trial of intrapleural
streptokinase for pleural infection. N Engl J Med 2005;352(9):865–74. [ ]
Rahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, et al. Intrapleural use of tissue plasminogen
activator and DNase in pleural infection. N Engl J Med 2011;365(6):518–26. [ ]

Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ, Group BTSPDG. Management of a malignant pleural
effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax 2010;65 Suppl 2ii32–40. [ ]

Simpson G, Roomes D, Heron M. Effects of streptokinase and deoxyribonuclease on viscosity of human surgical and
empyema pus. Chest 2000;117(6):1728–33. [ ]

Simpson G, Roomes D, Reeves B. Successful treatment of empyema thoracis with human recombinant
deoxyribonuclease. Thorax 2003;58(4):365–6. [ ]

Malignant mesothelioma

Organising Committee. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. Sydney:
Asbestos Diseases Research Institute; 2013. [URL]

Vogelzang N, Pass HI. Newer issues in mesothelioma chemotherapy. J Thorac Oncol 2006;1(2):177–9. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Interstitial lung disease
Introduction to interstitial lung disease
The interstitial lung diseases (ILDs) are a diverse group of largely unrelated conditions. They are classified
together because of a shared pathology centred on the interstitial compartment or parenchyma of the lung.
They share varying degrees of inflammation and/or fibrosis of the interstitium or lung parenchyma. The terms
ILD and lung fibrosis are used interchangeably.

Many of the ILDs are of unknown aetiology; the commonest are idiopathic pulmonary fibrosis (IPF) in older
people and pulmonary sarcoidosis in younger adults. Additionally, there are a number of environmental
exposures and other systemic diseases that can result in and be accompanied by lung fibrosis. A classification
of the major interstitial lung diseases is shown in Box 9.10.

For information about ILD in children, see childhood interstitial lung disease.

Achieving a definitive diagnosis is important because the management, treatment choices and prognosis differ
among the various ILDs. If an ILD is suspected, refer the patient to a specialist for a definitive diagnosis.

If ILD is suspected, refer the patient to a specialist for a definitive diagnosis.

The diagnosis of many ILDs, and in particular IPF, is ideally performed in a multidisciplinary setting, with
input from experienced clinicians, radiologists and pathologists. Discussion between the various disciplines
has been shown to improve agreement regarding the correct ILD diagnosis, and recent position papers
strongly recommend this in the evaluation of IPF. Early referral to a specialist for management may also result
in enrolment in a clinical trial and/or timely referral to a lung transplant service.

Patterns of disease behaviour, prognosis and response to therapies vary between the different ILDs. The rate
of clinical progression from initial symptoms to end-stage disease can extend from a few months to many
years. A classification of the ILDs based on expected clinical course has recently been suggested, and may be
useful in deciding which patients will benefit from drug treatment, see Table 9.30.
Classification of major interstitial lung diseases (Box 9.10)

Idiopathic interstitial pneumonias

idiopathic pulmonary fibrosis

nonspecific interstitial pneumonia
desquamative interstitial pneumonia
respiratory bronchiolitis-interstitial lung disease
cryptogenic organising pneumonia

Multisystem disorders

connective tissue disease

sarcoidosis
inflammatory bowel disease

Environmental exposures

hypersensitivity pneumonitis
pneumoconiosis
drug-induced interstitial lung disease
radiation-induced interstitial lung disease

Genetic

familial idiopathic pulmonary fibrosis

short telomeres

Miscellaneous

histiocytosis
lymphangioleiomyomatosis
pulmonary alveolar proteinosis
eosinophilic pneumonia

Clinical course of some interstitial lung diseases (Table 9.30)

Examples of ILD Expected clinical course

RB–ILD
reversible and self-limited disease
hypersensitivity pneumonitis
cellular NSIP

histiocytosis reversible disease with risk of progression

pulmonary sarcoidosis
may be stable with residual disease, or
fibrotic NSIP may be progressive irreversible disease with potential for
some stabilisation
IPF progressive irreversible disease despite therapy
ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; RB-ILD = respiratory bronchiolitis-
interstitial lung disease

Presentation of interstitial lung diease

Patients with interstitial lung disease (ILD) typically present with progressive dyspnoea, dry cough and/or
incidental findings of crackles on auscultation. The latter are often associated with an initial misdiagnosis of
pulmonary oedema. Advanced disease presents with tachypnoea, tachycardia and low oxygen saturation
measured by pulse oximetry (SpO2). Clubbing may be present. Early in the onset of ILD, there may be
clinical signs (such as crackles) similar to those seen with pneumonia.
If ILD is suspected, take a detailed clinical history consisting of the following:

age—median age of diagnosis of idiopathic pulmonary fibrosis (IPF) is 67 years; younger patients
presenting with IPF may have familial IPF
sex—pulmonary lymphangioleiomyomatosis only occurs in females
drug history—over 350 drugs have been associated with lung fibrosis, such as amiodarone, leflunomide,
methotrexate, nitrofurantoin and some oncology drugs and biological disease-modifying drugs. A
comprehensive list is available on the Drug-induced Respiratory Disease website [URL]
occupational history—especially exposure to dusts including coal, asbestos and silica
environment—possible exposure to birds, compost, manure, spas, and other antigens associated with
hypersensitivity pneumonitis
smoking history—eosinophilic pneumonia, respiratory bronchiolitis-ILD and IPF are more common in
smokers
presence of connective tissue disease—eg rheumatoid arthritis, scleroderma, polymyositis
presence of rashes
history of receiving radiotherapy
history of gastro-oesophageal reflux—may cause lung fibrosis, as well as acute exacerbations of
established fibrotic lung diseases
family history—eg short telomere–associated IPF.

Investigations for interstitial lung disease

Initial investigations
If interstitial lung disease (ILD) is suspected, a general practitioner could consider investigations to exclude
other causes of dyspnoea and crackles. For example, full blood count (FBC), chest X-ray and echocardiogram
to exclude anaemia, pneumonia or heart failure. A detailed history (see presentation above) may assist in
determining the likely cause of the ILD (eg drug-induced, occupational exposure, concomitant autoimmune
disease). An oximetry reading, basic spirometry and a computed tomography (CT) scan may also assist in
determining the urgency of the referral to a specialist. However, consider the dose of radiation exposure to the
patient from high-resolution CT, especially as the specialist may need to repeat the scan for additional clarity
(see CT of the chest for further information).

Blood tests
Blood tests can help to determine the underlying cause of lung fibrosis, see Box 9.11. Specialty ILD clinics
will generally consider ordering some or all of the blood tests, depending on the clinical scenario.

Some blood tests used in diagnosing interstitial lung disease (Box 9.11)

Depending on the clinical scenario, interstitial lung disease specialists could order some or all of the
following blood tests to help to determine the underlying cause of lung fibrosis:

full blood count (FBC) with eosinophil count

antinuclear antibodies (ANA)
extractable nuclear antigens (ENA)
double-stranded DNA (dsDNA)
serum angiotensin converting enzyme (sACE)
serum calcium
rheumatoid factor (RF)
anticyclic citrullinated peptide (ACCP)
creatine kinase (CK)
cytoplasmic antineutrophil cytoplasmic antibodies (cANCA)
perinuclear antineutrophil cytoplasmic antibodies (pANCA)
myeloperoxidase (MPO)
proteinase 3 antibody (PR3Ab)
mould precipitins
avian precipitins.

Respiratory function testing

Patients with ILD develop a restrictive defect in pulmonary function. This is characterised by reduced forced
vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). Static lung volumes are typically
reduced, although total lung capacity may be preserved in smokers who also have evidence of emphysema in
addition to lung fibrosis. Gas exchange is typically impaired with a reduced diffusing capacity for carbon
monoxide (DLCO).

The physiological impairments in patients with ILD become more pronounced during exercise.
Cardiopulmonary exercise testing can be used to assess severity of disease and to exclude an alternative
diagnosis, such as heart failure. Cardiopulmonary exercise testing involves incremental work load on a
stationary bicycle or treadmill with measurement of ventilation, oxygenation, oxygen uptake, carbon dioxide
production, heart rate and blood pressure. Characteristically, patients with ILD have a reduced exercise
capacity, oxyhaemoglobin desaturation and a ventilatory limitation to exercise. Peak ventilation is diminished
in ILD due to abnormal ventilatory mechanics and an exaggerated resting minute ventilation. Healthy subjects
and patients with heart disease do not desaturate during exercise and have cardiac limitation to exercise.

Changes in pulmonary function tests over time are used to follow disease progression. Either a 10% decline in
FVC or a 15% drop in DLCO is defined as being significant.

Imaging

Lung fibrosis is typically first suspected on chest X-ray, although a high-resolution computed tomography
(HRCT) scan is required to clarify the diagnosis.

The most common chest X-ray abnormality is a reticular pattern, although alveolar ground glass and more
nodular appearances may be seen. Idiopathic pulmonary fibrosis (IPF) is suggested by basal reticular changes,
and the presence of small cystic changes (honeycombing) in more advanced cases. Occasionally, the chest X-
ray may appear normal. Sometimes a supine and prone HRCT will help confirm heart failure if it is a possible
differential diagnosis of ILD.

HRCT is the pivotal diagnostic test in ILD. The pattern of distribution can help to distinguish the different
ILDs. Peripheral ILDs include eosinophilic pneumonia and cryptogenic organising pneumonia. Upper zone
predominant diseases include granulomatous disorders (sarcoidosis, chronic hypersensitivity pneumonitis),
while lower zone distribution diseases include IPF and nonspecific interstitial pneumonitis. Examples of some
patterns seen on HRCT are described in Table 9.31. IPF, the commonest ILD in older people, has a
characteristic HRCT pattern of:

subpleural, basal predominance

reticular abnormalities
honeycombing with or without traction bronchiectasis.

Examples of radiographic patterns of interstitial lung disease on HRCT scan (Table 9.31)

HRCT pattern Interstitial lung disease

cryptogenic organising pneumonia

airspace (alveolar) pattern—consolidation chronic eosinophilic pneumonia

(dense) bronchoalveolar cell carcinoma

lymphoma
pulmonary alveolar proteinosis

nonspecific interstitial pneumonia

airspace (alveolar) pattern—ground glass (less
respiratory bronchiolitis–interstitial lung disease
dense)
desquamative interstitial pneumonia

Pneumocystis jirovecii pneumonia

sarcoidosis

silicosis
nodular pattern
histiocytosis

subacute hypersensitivity pneumonitis

 idiopathic pulmonary fibrosis

asbestosis
reticular pattern
collagen vascular disease

chronic hypersensitivity pneumonitis

nonspecific interstitial pneumonitis (fibrosing form)

possible asbestosis

pleural involvement collagen vascular disease

some drug-induced interstitial lung disease

HRCT = high-resolution computed tomography

Pathological diagnosis
Bronchoalveolar lavage (BAL) fluid analysis should be performed if an infective aetiology is suspected, or to
confirm a diagnosis of chronic hypersensitivity pneumonitis (BAL lymphocyte count greater than 40%) or
chronic eosinophilic pneumonia (BAL eosinophil count greater than 15%). Bronchoscopy and cellular
analysis of BAL fluid is not routinely recommended for patients with features on high-resolution computed
tomography (HRCT) that suggest a diagnosis of IPF.

Bronchoscopy is indicated for patients presenting with haemoptysis or acute onset ILD with rapidly
progressing symptoms and radiographic infiltrates. A BAL with a lymphocyte count greater than 25%
indicates a granulomatous disease (eg sarcoidosis or hypersensitivity pneumonitis). A transbronchial biopsy is
appropriate in suspected granulomatous ILD and is useful to culture if an infective (eg tuberculosis) or
malignant (eg lymphangitis) cause is suspected.

Endoscopic bronchial ultrasound (EBUS)-guided transbronchial biopsy can also be used to make a
histological diagnosis from mediastinal lymph nodes (eg sarcoidosis, lymphoma) or a peripheral lung
consolidation (eg eosinophilic pneumonia, bronchoalveolar cell carcinoma).

The need for a video-assisted thoracoscopic surgery (VATS) biopsy should be assessed on a case-by-case
basis, and may be considered for patients with ILD whose clinical presentation or HRCT changes are atypical
for IPF or the other common ILDs. The decision to biopsy must include consideration of the patient's other
comorbidities, the morbidity associated with surgery, and the likely diagnos​tic yield of the procedure. The
diagnosis of classical IPF does not require a surgical biopsy.

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) (previously termed cryptogenic fibrosing alveolitis) is typically a disease
of older people, with a median age of onset of 67 years. It is slightly more common in males and smokers.
The cause is unknown. A family history will be present in 10% of patients.

The diagnosis of IPF requires:

exclusion of other known causes of interstitial lung disease (ILD), eg environmental exposures, drug
toxicity, connective tissue disease
typical high-resolution computed tomography (HRCT) pattern (see description in imaging) if patients
are not undergoing surgical lung biopsy.

HRCT has a high specificity for diagnosing IPF. Surgical lung biopsy is not required in most cases; it is
reserved for patients with either an atypical history or nonclassical radiology.

The histological features of IPF are termed ‘usual interstitial pneumonia’ and include:

marked fibrosis and honeycombing in a subpleural distribution

patchy involvement of lung parenchyma with fibrosis
presence of fibroblastic foci.

The natural history of IPF is variable and unpredictable. It is characterised by a gradual worsening of lung
function over years and in most cases is fatal 3 to 5 years from diagnosis. Disease progression is demonstrated
by increasing respiratory symptoms, deteriorating pulmonary function tests and worsening appearance of
fibrosis on HRCT.
Recommended therapies for IPF include:

pulmonary rehabilitation
drugs for symptom control, such as drugs for gastro-oesophageal reflux, opioids for dyspnoea and short
courses of corticosteroids for acute exacerbations
long-term oxygen therapy for patients with resting hypoxaemia; although oxygen may not improve
symptoms.

Early lung transplant assessment is recommended for appropriate patients.

While commonly prescribed, there is no evidence to support the use of prolonged duration corticosteroid
monotherapy, although acute exacerbations can be treated with short courses of prednis(ol)one. At the time of
writing, pirfenidone and nintedanib have recently been approved by the US Food and Drug Administration for
the treatment of IPF.

For patients with refractory symptoms, referral to a palliative care service is recommended.

Nonspecific interstitial pneumonia

Nonspecific interstitial pneumonia is commonly seen in association with connective tissue diseases (eg
scleroderma, rheumatoid arthritis, polymyositis) but can be idiopathic. The clinical course is highly
heterogeneous, with an accelerated course seen in patients with greater amounts of fibrosis. Overall, survival
is significantly better than that seen with IPF.

Nonspecific interstitial pneumonia HRCT patterns (seen in 75% of patients) include bilateral lower-zone
ground glass opacities with reticular changes and traction bronchiectasis. Histology reveals varying amounts
of interstitial inflammation and fibrosis.

Treatment is reserved for patients with severe or progressive disease. For patients with connective tissue
disease, therapy that is already prescribed for the underlying disease (eg cyclophosphamide, azathioprine,
methotrexate) may positively influence the natural history of the ILD. Otherwise, first-line therapy includes
corticosteroids given for 3 months with or without corticosteroid-sparing drugs, such as cyclophosphamide or
azathioprine. Total duration and intensity of therapy is tailored to clinical, physiological and radiological
response.

Smoking-related interstitial lung disease

Respiratory bronchiolitis–interstitial lung disease, Langerhan cell histiocytosis and desquamative interstitial
pneumonia have characteristic radiological and histological patterns. All three are strongly associated with
smoking, but complete resolution can be seen if patients stop smoking. Refractory cases can be treated with
corticosteroids.

Many patients with IPF have a history of smoking and a significant proportion also have evidence of upper
zone emphysema. Patients with combined pulmonary fibrosis and emphysema have a high incidence of
associated pulmonary hypertension and a poor prognosis.

Pulmonary sarcoidosis
Sarcoidosis is a chronic, multiorgan granulomatous disorder of unknown aetiology. It may present as
asymptomatic hilar lymphadenopathy, which may be found incidentally, and has a self-limiting disease
course. Mediastinal lymphadenopathy is seen in 90% of cases. Symptoms related to lung disease include
dyspnoea on exertion, and cough.

Signs in pulmonary sarcoidosis are few, and clubbing is not a feature. Pulmonary infiltration is usually
bilateral with nodular shadowing typically in the mid-zones. More dense infiltration leading to reticulonodular
shadowing and fibrosis of the upper lobes is seen in advanced cases. Nodules may be present along the pleural
surfaces, but pleural effusion is rare.

Considerable debate continues on the role of corticosteroids in pulmonary sarcoidosis. Many patients
demonstrate spontaneous resolution of both clinical and radiological features without treatment. To ascertain
disease trajectory, patients are typically observed for a period before starting therapy. Oral corticosteroids are
indicated in dyspnoeic patients with pulmonary infiltrates and worsening pulmonary function tests. The dose
used would be:
 prednis(ol)one 0.5 mg/kg (up to 50 mg) orally, daily for 4 weeks, with subsequent
duration and intensity of therapy tailored to clinical, physiological and radiological
response.

Other therapy may be primarily targeted to extrathoracic disease, which is common and may involve the skin
(see skin lesions of sarcoidosis), eyes, nervous system, heart, kidneys and gastrointestinal system. MRI scan
may be required to identify cardiac sarcoidosis. Hypercalcaemia and hypercalciuria may occur.
Ophthalmological assessment should also be considered.

Hypersensitivity pneumonitis
Hypersensitivity pneumonitis (previously termed extrinsic allergic alveolitis) is a granulomatous condition
whose chronic form can be associated with lung fibrosis. Pathology is linked to repeated inhaled exposure to a
sensitising antigen. A detailed history to identify potential exposures in both the work and home environment
is mandatory and measurement of specific circulating immunoglobulin G (IgG) antibodies is recommended.
However, in 30% of cases the causative exposure will not be identified.

Common forms of chronic hypersensitivity pneumonitis include bird fancier's lung (exposure to proteins
found in feathers or droppings) and hot tub lung (exposure to Mycobacterium avium complex). The key to
management is avoidance of the inciting environmental exposure because continued antigen exposure is
associated with chronic disease and progression to lung fibrosis. Corticosteroids are recommended in acute,
severe and progressive disease. The dose used would be:

prednis(ol)one 0.5 mg/kg (up to 50 mg) orally, daily for 4 weeks, with subsequent
duration and intensity of therapy tailored to clinical, physiological and radiological
response.

Childhood interstitial lung disease

The published prevalence of childhood interstitial lung disease (ChILD) (0.36 per 100 000) is much lower
than in adults (approximately 65 to 80 per 100 000 in adult females and males respectively). However, with
advances in classification and identification the estimated prevalence of ChILD may increase.

The characteristic clinical features on presentation are tachypnoea, crackles, hypoxaemia and/or diffuse
infiltrates on chest X-ray. If ChILD is suspected, refer to a paediatric respiratory physician.

As in adult ILD, some forms of ChILD respond to corticosteroids. The response to therapy and overall
prognosis is better than in most adult forms of ILD. The majority of children recover and most can lead
normal lives. However, some subgroups of ChILD, particularly those with genetic abnormalities of surfactant
function, have a poor prognosis.

Key references
Interstitial lung disease: introduction and assessment

American Thoracic Society. Guidelines for the diagnosis and management of idiopathic pulmonary fibrosis.
Pocket publication: American Thoracic Society; 2013. [URL]

Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, et al. An official American Thoracic
Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung
disease. Am J Respir Crit Care Med 2012;185(9):1004–14. [ ]

National Institute for Health and Care Excellence (NICE). Idiopathic pulmonary fibrosis [CG163]. London: NICE;
2013. [URL]

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement:
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care
Med 2011;183(6):788–824. [ ]

Specific adult interstitial lung diseases

American Thoracic Society. Guidelines for the diagnosis and management of idiopathic pulmonary fibrosis.
Pocket publication: American Thoracic Society; 2013. [URL]
Holland AE, Hill CJ, Conron M, Munro P, McDonald CF. Short term improvement in exercise capacity and
symptoms following exercise training in interstitial lung disease. Thorax 2008;63(6):549–54. [ ]

King TE, Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. A phase 3 trial of
pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370(22):2083–92. [ ]

National Institute for Health and Care Excellence (NICE). Idiopathic pulmonary fibrosis [CG163]. London: NICE;
2013. [URL]

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement:
idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care
Med 2011;183(6):788–824. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Sleep-disordered breathing in adults
Introduction
Sleep-disordered breathing refers to a variety of problems with breathing during sleep, including obstructive
sleep apnoea (OSA), OSA coexisting with chronic lung disorder, central sleep apnoea and obesity
hypoventilation.

Management of sleep-disordered breathing in children differs from management in adults.

Obstructive sleep apnoea

Overview
Obstructive sleep apnoea is the most common form of sleep-disordered breathing. The obstructive sleep
apnoea syndrome (also called obstructive sleep apnoea–hypopnoea syndrome) refers to the presence of
apnoeas and hypopnoeas during sleep together with daytime dysfunction, predominantly excessive daytime
sleepiness.

The typical patient with sleep apnoea is overweight, middle-aged, male and often has a short thick neck, and a
history of alcohol and tobacco consumption. However, women and thin young people can also develop sleep
apnoea, especially those with a narrow anteroposterior diameter to their pharynx (which may occur in people
of Asian origin) or those with a high arched palate (which may occur in Marfan syndrome).

Increasing evidence suggests that untreated obstructive sleep apnoea is associated with:

hypertension
arrhythmias such as paroxysmal atrial fibrillation
cardiovascular mortality
cerebrovascular mortality
motor vehicle accidents, especially single-vehicle accidents at night
pregnancy-related hypertension and pre-eclampsia.

In view of the potential for impaired driving, patients with severe obstructive sleep apnoea are advised to stop
driving vehicles and operating machinery until their condition has been adequately stabilised on treatment.
However, it is not possible to accurately predict individual driving risk, even for patients with severe sleep
apnoea, as other factors are also important, such as acute sleep deprivation, circadian misalignment (eg shift
work and jet lag), narcolepsy), alcohol, comorbidities and other drugs (see Austroads [URL]).

Patients may benefit from general advice on good sleep practices, see Box 8.2.

Clinical assessment
The symptoms and possible associated diseases suggestive of obstructive sleep apnoea are listed in Box 9.12.

The Berlin questionnaire [Note 1] is a validated checklist that can be used to identify patients who may have
sleep apnoea.

The Epworth Sleepiness Scale [Note 2] can be completed by the patient to give an indication of daytime
sleepiness, but it needs to be used with caution because patients may deny or be unaware of the severity of
their sleepiness. Patients do not always recognise significant daytime dysfunction despite severe disturbance
of their nocturnal breathing; their partner may give a better indication of their daytime sleepiness.

Restless legs syndrome is a separate entity, but it may coexist with obstructive sleep apnoea and worsen sleep
independently of the sleep-disordered breathing.
History-taking in suspected obstructive sleep apnoea (Box 9.12)

Print-friendly PDF

Check for the following symptoms (with both the patient and their partner):

snoring—frequency, loudness, and whether the partner needs to leave the bedroom
waking through the night with a sensation of choking
nocturnal interruption to breathing recognised by the partner, termed ‘witnessed apnoeas’
nocturia
nocturnal sweating
daytime sleepiness and irritability
poor concentration or attention span
morning headache
gastro-oesophageal reflux
erectile dysfunction.

Ask about possible coexisting disease:

hypertension, especially in younger patients

cardiovascular disease, especially atrial fibrillation and heart failure
cerebrovascular disease
diabetes mellitus
thyroid disease
family history of sleep apnoea or continuous positive airway pressure (CPAP) use.

Note 1: Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin questionnaire to identify
patients at risk for the sleep apnea syndrome. Ann Intern Med 1999;131(7):485-91. [URL]

Note 2: Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep
1991;14(6):540-5. [URL]. A copy of the scale is available on many websites.

Diagnostic tests
The standard diagnostic test for obstructive sleep apnoea is the overnight in-laboratory polysomnogram. This
allows detailed monitoring of body position and sleep stage, the two most important variables influencing
sleep-disordered breathing.

Simplified home-based assessments vary greatly in complexity from simple oximetry screening to almost a
full polysomnogram. To help prioritise and reduce waiting lists, home-based tests may be appropriate in some
settings as a screening tool for patients with high pre-test probability of obstructive sleep apnoea (eg sleepy
obese patients who snore and take antihypertensive drugs). Home-based tests can be useful to rule in
obstructive sleep apnoea in these patients, but not to rule out obstructive sleep apnoea; the tests have high
specificity and low sensitivity. Therefore, if there is a strong clinical suspicion of obstructive sleep apnoea, the
diagnosis should not be excluded without an in-laboratory sleep study and specialist review.

Prioritisation of sleep testing with polysomnogram is important in busy centres; patients who require urgent
assessment are those with:

unstable cardiovascular status, eg nocturnal angina or recurring cardiogenic pulmonary oedema

hypercapnic respiratory failure
high pre-test probability of obstructive sleep apnoea who are about to undergo major surgery
history of significant drowsiness while driving.

A polysomnogram calculates the number and severity of obstructive apnoeas and hypopnoeas with
desaturation and arousal. Severity is defined by the apnoea–hypopnoea index provided by the laboratory.
Significant sleep apnoea is indicated by an apnoea–hypopnoea index of more than five events per hour, and is
severe with more than thirty events per hour.

Treatment

General measures
Many patients with obstructive sleep apnoea may need treatment with continuous positive airway pressure.
However, address the following measures where possible, especially in mild disease with no daytime
sleepiness, no impairment to daytime functioning, and no intercurrent hypertension or other cardiovascular
disease. These measures can be implemented before testing for sleep apnoea.

Consider the following:

Weight reduction—as many patients with obstructive sleep apnoea are overweight, weight reduction is
generally recommended. Gastric banding or gastric–small intestine bypass operations are generally
associated with better weight loss in the long term. However, if the weight loss is not maintained, the
sleep apnoea will return and the benefit of bariatric surgery will be lost.
Avoidance of alcohol and drugs that affect sleep.
Increased time in bed—sleep deprivation together with mild sleep apnoea increases the risk of daytime
dysfunction.
Positional therapy—if the patient has predominantly supine obstructive sleep apnoea, studies have
shown that sleeping on their side can improve nocturnal sleep and lessen daytime dysfunction.
Preventive measures may include tennis balls attached to the middle of the back of a pyjama shirt, foam
blocks to prevent the patient sleeping in the supine position, or alarms that sound if the patient adopts
the supine position. Standard pillows behind the back in bed are generally insufficient. Raising the head
of the bed (by 5 to 8 cm) so that the bed is angled up may help by reducing ‘rostral fluid shift’, a
phenomenon in which extravascular fluid shifts from lower limbs and abdomen to the thorax, head and
neck while the patient is supine overnight.
Reduced nasal resistance—with smoking cessation and using intranasal corticosteroid spray.

Many complementary treatments (eg nasal strips, nasal dilators, snore-stop drops, snore-easy pillows and
other devices) have been marketed to improve or ‘cure’ snoring and mild sleep apnoea, but they have little
supporting scientific data. Nasal expiratory valves have proven benefit, but in general are poorly tolerated.

Continuous positive airway pressure

The most effective therapy for obstructive sleep apnoea is continuous positive airway pressure (CPAP).
Consider CPAP for:

any patient with severe obstructive sleep apnoea (apnoea–hypopnoea index greater than 30)
patients with mild to moderate obstructive sleep apnoea who have any symptoms of daytime
dysfunction
patients with mild to moderate obstructive sleep apnoea with hypertension or other cardiovascular
disease.

CPAP works by splinting the upper airway open. The pressure required to prevent the obstructive apnoea and
hypopnoea is individually titrated during a second polysomnogram, the CPAP determination study.

Alternatively, automatic titrating CPAP machines can be used in motivated capable patients to initiate CPAP
over 1 to 4 weeks and determine the ideal CPAP pressure. These automatic titrating machines have been
designed to monitor airflow during inspiration and adjust the pressure applied. However, there is little
evidence to suggest any clinical benefit of autotitrating over standard fixed-pressure machines in the long
term.

Given the complexity of optimising the mask interface, controlling leaks and fitting chin straps, it is
recommended that CPAP be started with backup support from a specialist clinic. Patient information
brochures about CPAP are available from the Sleep Health Foundation website [URL].

Table 9.32 summarises some common problems that occur with CPAP. Experienced staff from the sleep clinic
can assess and rectify problems to improve patient comfort and acceptability of CPAP.

A repeat sleep study in patients who do not show adequate symptomatic improvement following CPAP
treatment may show that a leak is still not controlled, that pressure requirements have changed, or it may
reveal the presence of other disorders requiring independent treatment (eg restless legs syndrome).

Common problems with long-term CPAP (Table 9.32)

Problem Possible solution

nasal symptoms due to relatively dry Use intranasal corticosteroid spray, pressure reduction and in-built or
air of CPAP machine add-on humidifiers to CPAP machine.
mouth leak Use chin straps [NB1].
Usually indicates significant mouth leak; trial chin straps.
dry mouth Humidification of the CPAP machine will not relieve the dry mouth
while a mouth leak exists. Consider reduction in CPAP pressure.
Suggests the mask is not fitted properly or is applied too tightly. The
skin ulceration over the nasal bridge
CPAP therapist can refit the mask or arrange a trial of a new mask.
ear discomfort Use intranasal corticosteroid spray.
Ensure:

mask is comfortable
humidification is operational
there is no anatomic obstruction (eg chronic nasal injury,
secondary obstruction) requiring surgical intervention.

Exclude coexisting lifestyle, medical and psychological factors that

prevent sleep.
adherence
Provide encouragement.

Consider:

using CPAP while distracted (eg while watching TV)

using CPAP on alternate nights
a short nocturnal course of anxiolytic drugs at initiation (eg for
1 week).

CPAP = continuous positive airway pressure

NB1: Chin straps are especially important when starting CPAP. In the long term, chin straps are important for those patients who have undergone
uvulopalatal pharyngoplasty because the normal sealing of the soft palate against the tongue is not possible, increasing the problem of mouth leak.

Other interventions

Mandibular advancement splints

Mandibular splinting devices are an alternative to continuous positive airway pressure (CPAP), but are
effective only in mild to moderate obstructive sleep apnoea. These splints can be used to either advance the
mandible forward or to widen the maxilla.

Mandibular advancement splints must be professionally fitted and patients need to be under long-term review
by a dentist. In the long term, the splints may cause temporomandibular joint pain, changes to the bite, and
excessive salivation. Simple mouth guards purchased without dental guidance may damage the teeth and often
do not work.

A mandibular advancement splint may have a role for patients who have ‘simple’ snoring, that is snoring with
minimal apnoea or hypopnoea on polysomnogram.

Surgery

Maxillary and mandibular reconstructive surgery is undertaken in patients with a significant craniofacial
abnormality, and it may also alleviate underlying obstructive sleep apnoea.

Tonsillectomy and adenoidectomy and/or nasal decongestive surgery may be helpful if anatomical
abnormalities contribute to the patient's snoring. In addition to alleviating snoring, these types of surgery may
also improve adherence to other forms of treatment such as CPAP or a mandibular advancement splint.

Removal of the soft palate (uvulopalatal pharyngoplasty) was used more commonly in the past to treat
obstructive sleep apnoea but the results were unpredictable. Surgery to reduce the tongue base was also
undertaken. Formal studies have shown minimal reduction in the apnoea–hypopnoea index with these
surgeries, though often there is a transient reduction in snoring measures. Palatal surgery is now only
considered in highly selected cases.

Oral pressure therapy

Oral pressure therapy devices are designed to ‘suck’ the tongue forward and thereby prevent oropharyngeal
collapse and snoring. They are worn inside the mouth and connected by a narrow tube to a negative pressure
pump. Although preliminary studies are promising, larger clinical trials are awaited.
Upper airway pacemaker

Over the past 20 years, there have been small short-term trials of upper airway muscle stimulating pacemakers
for sleep apnoea in patients resistant to other forms of treatment. The results have not shown consistent benefit
and long-term adverse effects are not well described. At the time of writing, this remains a research tool.

Obstructive sleep apnoea with other coexisting respiratory disorders

Obstructive sleep apnoea may be associated with chronic obstructive pulmonary disease (COPD), asthma or
other significant respiratory disorders.

Patients with severe COPD can develop nocturnal hypoventilation due to a combination of their airway
disorder and episodes of apnoea and hypopnoea. It is important to clarify the presence of COPD or other
respiratory disorder. To achieve the best outcome for the sleep disorder, it is imperative to optimise daytime
respiratory function through weight loss, smoking cessation and appropriate treatment of any underlying
respiratory disorder.

A full polysomnogram with measurement of transcutaneous carbon dioxide and arterial blood gases is needed
to assess these patients.

Central sleep apnoea

Central sleep apnoea occurs when there is either brief periodic or prolonged loss of respiratory effort during
sleep.

Brief periodic loss of respiratory drive is common in:

heart failure (known as Cheyne-Stokes respiration)

regular opioid users
premature infants
healthy people sleeping at high altitude (higher than 2500 metres).

Central sleep apnoea in these patients is generally associated with a low partial pressure of carbon dioxide
(PaCO2).

Prolonged loss of respiratory drive usually indicates a neuromuscular disorder (eg motor neurone disease)
or chest wall disorder (eg kyphoscoliosis), or severe obesity (see obesity hypoventilation syndrome, below).
Central sleep apnoea in these disorders is usually associated with elevated PaCO2 or a PaCO2 rise of more
than 5 mmHg from the beginning to the end of sleep.

Diagnosis and management of central sleep apnoea requires specialist referral, with full polysomnogram
assessment.

Obesity hypoventilation syndrome

Obesity hypoventilation syndrome refers to sleep-related nonobstructive hypoventilation with hypercapnia
(partial pressure of carbon dioxide [PaCO2] higher than 45 mmHg) in higher classes of obesity (body mass
index [BMI] more than 35 kg/m2) for which no other cause of hypoventilation can be identified (such as
kyphoscoliosis, drugs or neuromuscular disease).

A typical patient with obesity hypoventilation syndrome has the following characteristics:

marked obesity
cyanosis or plethora
right heart failure or biventricular heart failure
excessive daytime sleepiness.

Many patients exhibit features of both obesity hypoventilation syndrome and obstructive sleep apnoea, with a
combination of obstructive apnoeas and progressive hypoxaemia/hypercapnia through the night.

Diagnosis of obesity hypoventilation syndrome requires a polysomnogram, usually with a transcutaneous

carbon dioxide monitor and, often, arterial blood gases taken in the evening and morning. In the absence of
arterial or transcutaneous carbon dioxide levels, serum bicarbonate concentration can be used as a marker of
prevailing carbon dioxide levels, except in patients with disorders affecting bicarbonate concentration (eg due
to kidney failure).

Treatment for obesity hypoventilation syndrome involves weight loss, together with either continuous positive
airway pressure (CPAP) or bi-level ventilation with high expiratory pressures. Rarely, in patients with
persistent hypoxaemia despite positive airway pressure to assist ventilation, supplemental oxygen may be
needed at low-flow rates. Use care to prevent oxygen-induced hypercapnia. Although respiratory stimulants
have been used in clinical trials to increase the sensitivity of the ventilatory chemoreceptors, long-term studies
to support this therapy are not yet available.

Key references
Sleep-disordered breathing in adults

American Academy of Sleep Medicine. The international classification of sleep disorders: diagnostic & coding
manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Aurora RN, Casey KR, Kristo D, Auerbach S, Bista SR, Chowdhuri S, et al. Practice parameters for the surgical
modifications of the upper airway for obstructive sleep apnea in adults. Sleep 2010;33(10):1408–13. [ ]

Aurora RN, Chowdhuri S, Ramar K, Bista SR, Casey KR, Lamm CI, et al. The treatment of central sleep apnea
syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses. Sleep
2012;35(1):17–40. [ ]

Caples SM, Rowley JA, Prinsell JR, Pallanch JF, Elamin MB, Katz SG, et al. Surgical modifications of the upper
airway for obstructive sleep apnea in adults: a systematic review and meta-analysis. Sleep 2010;33(10):1396–
407. [ ]

Cartwright RD, Lloyd S, Lilie J, Kravitz H. Sleep position training as treatment for sleep apnea syndrome: a
preliminary study. Sleep 1985;8(2):87–94. [ ]

Desai AV, Marks GB, Jankelson D, Grunstein RR. Do sleep deprivation and time of day interact with mild
obstructive sleep apnea to worsen performance and neurobehavioral function? J Clin Sleep Med 2006;2(1):63–70.
[ ]

Edwards N, Middleton PG, Blyton DM, Sullivan CE. Sleep disordered breathing and pregnancy. Thorax
2002;57(6):555–8. [ ]

Epstein LJ, Kristo D, Strollo PJ, Jr., Friedman N, Malhotra A, Patil SP, et al. Clinical guideline for the evaluation,
management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5(3):263–76. [
]

Farid-Moayer M, Siegel LC, Black J. A feasibility evaluation of oral pressure therapy for the treatment of
obstructive sleep apnea. Ther Adv Respir Dis 2013;7(1):3–12. [ ]

Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term opioid
therapy. Chest 2003;123(2):632–9. [ ]

Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep
1991;14(6):540–5. [ ]

National Institute for Health and Care Excellence (NICE). Continuous positive airway pressure for the treatment of
obstructive sleep apnoea/hypopnoea syndrome [TA139]. London: NICE; 2010. [URL]

Netzer NC, Stoohs RA, Netzer CM, Clark K, Strohl KP. Using the Berlin questionnaire to identify patients at risk
for the sleep apnea syndrome. Ann Intern Med 1999;131(7):485–91. [ ]

Parati G, Lombardi C, Hedner J, Bonsignore MR, Grote L, Tkacova R, et al. Recommendations for the
management of patients with obstructive sleep apnoea and hypertension. Eur Respir J 2013;41(3):523–38. [
]

Randerath WJ, Verbraecken J, Andreas S, Bettega G, Boudewyns A, Hamans E, et al. Non-CPAP therapies in
obstructive sleep apnoea. Eur Respir J 2011;37(5):1000–28. [ ]
 Schwab RJ, Kim C, Siegel LC, Black J, Farid-Moayer M, Podmore JL, et al. Mechanism of action of a novel
device using oral pressure therapy (OPT) for the treatment of OSA. Am J Respir Crit Care Med 2012;185A6811
(abstract).

Wang D, Teichtahl H, Drummer O, Goodman C, Cherry G, Cunnington D, et al. Central sleep apnea in stable
methadone maintenance treatment patients. Chest 2005;128(3):1348–56. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Sleep-disordered breathing in children
Causes of sleep-disordered breathing in children
As in adults, sleep-disordered breathing in children may be obstructive sleep apnoea or central sleep apnoea.

Obstructive sleep apnoea occurs in 1 to 4% of children. In most children it is due to adenotonsillar

hypertrophy. Other possible causes are listed in Table 9.33.

Central sleep apnoea in children is uncommon and is managed in specialist centres. See investigation and
treatment for more information.

Causes of obstructive sleep apnoea in children (Table 9.33)

Cause Comment or examples

adenotonsillar hypertrophy most common cause
macroglossia of Down syndrome [NB1]
craniofacial abnormalities, eg Robin sequence,
anatomical abnormalities
Crouzon syndrome

hypotonia of neuromuscular disorders leading to

collapse of upper airway during inspiration [NB1]
functional abnormalities hypertonia, commonly seen in cerebral palsy, causing
functional narrowing

may be associated with simple obstructive sleep

apnoea, with or without tonsillar enlargement
obesity severely obese children may need to be treated as for
adults with obesity hypoventilation syndrome

NB1: In Down syndrome, there may be both anatomical narrowing (due to macroglossia) and functional obstruction (due to hypotonia). It is
estimated that 40% of children with Down syndrome have obstructive sleep apnoea.

Clinical assessment of obstructive sleep apnoea in children

Obstructive sleep apnoea reaches a peak incidence between the ages of 2 to 7 years; it is rare in the first 6
months of life.

The diagnosis is suggested in a child with habitual snoring and observed apnoea during sleep. Box 9.13 lists
other common nocturnal and daytime features of childhood obstructive sleep apnoea. In contrast to adults,
children frequently present with hyperactivity, behavioural problems and poor school performance. Tiredness
may or may not be present.

Examination usually reveals tonsillar enlargement and mouth breathing. Children with obstructive sleep
apnoea may also present with poor weight gain, which is thought to be related to increased work of breathing
during sleep.

A careful history of symptoms of sleep-disordered breathing is warranted in those with predisposing genetic,
anatomical or developmental conditions (see Table 9.33).

Acute life-threatening events (ALTEs) occur predominantly in infants younger than 6 months. The typical
history is of the infant being found pale, limp and not breathing, often during sleep. Vigorous stimulation or
active resuscitation has usually been required, and parental anxiety is (not surprisingly) often extremely high.
Although acute life-threatening events are thought to have multiple causes, they may be the presenting
symptom of sleep-disordered breathing and can occur with obstructive or central sleep apnoea. Refer all
infants who have a significant acute life-threatening event requiring resuscitation for an urgent paediatric
assessment to determine if an aetiology can be found. Some infants may require a sleep study.
Clinical features of obstructive sleep apnoea in children (Box 9.13)

Snoring and/or witnessed apnoeas plus any of the following clinical features may be indicative of
obstructive sleep apnoea in a child.

Nocturnal symptoms or signs:

gasps
increased work of breathing
restlessness
sweating
night waking
enuresis
mouth breathing
neck extension

Daytime symptoms:

hyperactivity
poor attention
behavioural problems
poor school performance
morning hypersomnolence
tiredness

Management of obstructive sleep apnoea in children

Most children with a history suggesting obstructive sleep apnoea (see Box 9.13, above) and marked tonsillar
hypertrophy are referred directly for adenotonsillectomy without further investigation.

If there is doubt about the diagnosis of obstructive sleep apnoea or the recommended treatment, a sleep study
may be necessary. Home overnight oximetry showing multiple clusters of desaturation is a specific but not
sensitive test for obstructive sleep apnoea; it can obviate the need for a full sleep study in up to 25% of
preschool children with a suggestive history. However, a full sleep study is required in children with normal
overnight oximetry.

Adenotonsillectomy is curative in up to 90% of children with obstructive sleep apnoea in the absence of
underlying medical problems. Other treatment strategies, which may be required in the remaining group,
include noninvasive ventilation (usually continuous positive airway pressure [CPAP]) or craniofacial surgery.
Refer all children with persisting obstructive sleep apnoea following adenotonsillectomy to a specialist
paediatric sleep service.

Central sleep apnoea can occur in children, but is far less common than obstructive sleep apnoea. It can only
be diagnosed by polysomnography.

Overnight polysomnography in children is performed in the same way as for adults. Developmental and
maturational changes occur throughout childhood, including alterations in sleep structure, respiratory rate and
breathing patterns. As a result, separate scoring criteria have been developed for infants and children, and
paediatric polysomnography is best performed in a specialised paediatric sleep laboratory.

Treatment of children with disordered central control of breathing is usually by ventilatory support,
supervised by a specialist paediatric sleep service. Ventilatory support may be provided invasively or
noninvasively. It is often used long term, but usually restricted to use during sleep. In babies, who may spend
up to 18 hours a day asleep, the mask used to deliver noninvasive ventilation can lead to complications such
as pressure sores or interference with development of the facial bones if used for long periods. There is no
place for CPAP in central sleep apnoea. Respiratory stimulants such as caffeine are commonly used in apnoea
of prematurity.

Key references
Sleep-disordered breathing in children

Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, et al. A randomized trial of
adenotonsillectomy for childhood sleep apnea. N Engl J Med 2013;368(25):2366–76. [ ]

Nixon GM, Kermack AS, Davis GM, Manoukian JJ, Brown KA, Brouillette RT. Planning adenotonsillectomy in
children with obstructive sleep apnea: the role of overnight oximetry. Pediatrics 2004;113(1 Pt 1):e19–25. [
]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Acute oxygen therapy
Principles of oxygen use
Oxygen is a therapeutic agent that may be lifesaving. However, it is not without adverse effects; these include
the risk of hypercapnia and adverse consequences related to hyperoxaemia (see potential harms of oxygen
use, below).

Prescribe oxygen on a medication chart or an oxygen prescription form, specifying an appropriate delivery
method and flow rates to ensure safe delivery of therapy (see indications, below). The desired outcome is the
patient-specific target oxygen saturation range, which must be stated on the prescription. Most oxygenation
systems, unlike ventilation systems, do not deliver a precise dose of oxygen at a particular flow rate, with the
relative exception of the Venturi mask system and high-flow nasal cannula therapy [Note 1].

Monitor the patient to check the target oxygen saturation is achieved, and to detect adverse effects such as
hypercapnia or hyperoxaemia (see monitoring, below); if needed, adjust the oxygen prescription
appropriately.

Prioritise management of the underlying cause of hypoxaemia.

Investigate to determine the cause of hypoxaemia, and treat the cause. Recognise that when oxygen is
prescribed it is merely treating a result of underlying pathology (ie hypoxaemia) and any need for increased
oxygen should prompt a vigorous search for new or worsening pathology.

Note 1: High-flow nasal cannula oxygen therapy uses heated humidified gases, and the fractional inspired
oxygen can be altered independently of the overall flow rate.

Potential harms of oxygen use

Possible harms of oxygen use include the risk of potentially fatal hypercapnia and adverse consequences
related to hyperoxaemia.

Supplemental oxygen therapy may lead to potentially fatal hypercapnia.

Apart from caution in those at risk of carbon dioxide retention and in premature neonates, avoidance of
hypoxaemia and ischaemia has traditionally been emphasised, with little attention focused on the
consequences of unrestricted acute supplemental oxygen. Until recently, it was common practice to use
oxygen in the clinic, ambulance or emergency department for any patient who appeared breathless or even
just acutely unwell.

While there are many beneficial physiological and pharmacological effects of hyperoxia, there is also
potential for oxygen toxicity. Reviews have drawn attention to the lack of evidence for improved clinical
outcomes with routine use of oxygen in patients who are not actually hypoxaemic. Several clinical studies
have provided evidence that supplemental oxygen causes adverse effects in some settings; these include acute
myocardial infarction without hypoxaemia or heart failure, acute stroke, and resuscitation of the newborn. A
paradigm shift in practice has occurred in response, as outlined in Indications.

Indications for oxygen

High levels of oxygen are currently recommended for some critical illnesses, including cardiac arrest, shock,
major trauma, sepsis, anaphylaxis, status epilepticus, near-drowning, scuba diving accidents (see
decompression sickness), or carbon monoxide poisoning. Patients with these illnesses should be given high-
flow oxygen through a reservoir mask at 15 L per minute. Once the patient is stable, oxygen should be
administered to maintain a target oxygen saturation of 92 to 96%.
Guidelines vary slightly, but there is generally no indication for oxygen therapy in other patients with a pre-
treatment oxygen saturation by pulse oximetry of greater than 92 to 96%. In particular, in the absence of
hypoxaemia, supplemental oxygen is no longer recommended for acute coronary syndromes, stroke, or
obstetric emergencies. Neonatal resuscitation guidelines target much lower oxygen saturations for much
longer than previously recommended before advising a switch from room air to supplemental oxygen. One
caveat is that pulse oximetry readings may be misleading in some situations (see monitoring, below).

Other acutely unwell patients, many of whom will have an underlying respiratory cause, need moderate
levels of supplemental oxygen if the patient is hypoxaemic on pulse oximetry. Oxygen may initially be
administered by nasal cannulae at 2 to 4 L per minute or a simple face mask at 5 to 10 L per minute.
However, if the oxygen saturation is less than 85% and the patient is not at risk of hypercapnic respiratory
failure (see patient groups at risk of hypercapnia, below), oxygen should be started and titrated to effect as the
situation stabilises.

Patient groups at risk of hypercapnia

Identify patients at risk for hypercapnic respiratory failure if oxygen therapy is being considered; these
patients may hypoventilate and develop a rise in carbon dioxide levels. To mitigate this potentially fatal risk,
use lower target oxygen saturation with appropriate monitoring. Recognise that adequate oxygenation is not
the same as adequate ventilation, and that pulse oximetry does not detect hypercapnia.

The following conditions or situations may put patients at risk of hypercapnia:

chronic obstructive pulmonary disease (COPD) or bronchiectasis

history of heavy smoking
severe obstructive sleep apnoea
morbid obesity
severe kyphoscoliosis or ankylosing spondylitis
neuromuscular disorders with respiratory muscle weakness, especially if using home ventilation
use of respiratory depressant drugs such as opioids and benzodiazepines
acute asthma in some patients.

Note that the above list is not exhaustive.

Except for patients with recurrent hypercapnic respiratory failure, it is not possible to predict if an individual
patient with COPD will develop hypercapnia during an acute exacerbation; therefore, consider all patients
with moderate to severe COPD at risk of hypercapnia. Once identified, patients who have developed
hypercapnic respiratory failure with oxygen should be given some form of documentation such as a medical
alert bracelet. Notify the regional ambulance service of the patient's details for inclusion on the relevant
registry. See oxygen therapy in COPD exacerbations for further details.

Target oxygen saturation

The target oxygen saturation is generally 92 to 96% unless the patient has an underlying condition that results
in chronically lower values or risk of hypercapnic respiratory failure. For the latter group, oxygen should be
given to achieve a target oxygen saturation of 88 to 92%; however, in critical illness, the standard target
oxygen saturations (92 to 96%) may initially be used pending the results of early arterial blood gas analysis.

Monitoring of oxygen use

With acute oxygen therapy, monitor pulse oximetry continuously. Alter the flow administered to keep the
oxygen saturation within the target range.

Be aware of the limitations of pulse oximetry. It measures only haemoglobin saturation, not oxygenation or
ventilation. Readings may also be misleading, for example they will be misleadingly low with hypoperfusion
and methaemoglobinaemia but conversely falsely reassuring in carbon monoxide poisoning, cyanide
poisoning and severe anaemia. In particular, pulse oximetry does not measure carbon dioxide levels; arterial
blood gases must be performed in patients thought to be at risk of hypercapnia [Note 2]. See further
information in tests of gas exchange and gas transfer.

Arterial blood gas analysis is needed to quantify hypercapnia; it is not detected by pulse oximetry.
Monitoring of oxygen therapy is an ongoing process. Repeat arterial blood gases are needed if the patient's
condition changes (for example drowsiness suggesting hypoventilation) or about 30 to 60 minutes after
oxygen flow rates have been increased.

In addition, serial blood gases may be indicated at routine intervals to track the patient's progress in those
who are critically unwell. If blood gas values for oxygen and carbon dioxide cannot be corrected
satisfactorily with oxygen therapy, ventilatory support may be indicated.

Note 2: Venous carbon dioxide values do not correlate directly with arterial carbon dioxide values; their
use to exclude clinically significant carbon dioxide retention is controversial.

Key references
Acute oxygen therapy

Austin MA, Wills KE, Blizzard L, Walters EH, Wood-Baker R. Effect of high flow oxygen on mortality in chronic
obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 2010;341c5462. [
]

Beasley R, Aldington S, Robinson G. Is it time to change the approach to oxygen therapy in the breathless
patient? Thorax 2007;62(10):840–1. [ ]

Beasley R, McNaughton A, Robinson G. New look at the oxyhaemoglobin dissociation curve. Lancet
2006;367(9517):1124–6. [ ]

Bloom BM, Grundlingh J, Bestwick JP, Harris T. The role of venous blood gas in the emergency department: a
systematic review and meta-analysis. Eur J Emerg Med 2014;21(2):81–8. [ ]

Byrne AL, Bennett M, Chatterji R, Symons R, Pace NL, Thomas PS. Peripheral venous and arterial blood gas
analysis in adults: are they comparable? A systematic review and meta-analysis. Respirology 2014;19(2):168–75.
[ ]

Lim BL, Kelly AM. A meta-analysis on the utility of peripheral venous blood gas analyses in exacerbations of
chronic obstructive pulmonary disease in the emergency department. Eur J Emerg Med 2010;17(5):246–8. [
]

MacIntyre NR. Supporting oxygenation in acute respiratory failure. Respir Care 2013;58(1):142–50. [ ]

Martin DS, Grocott MP. Oxygen therapy in critical illness: precise control of arterial oxygenation and permissive
hypoxemia. Crit Care Med 2013;41(2):423–32. [ ]

Perrin K, Wijesinghe M, Healy B, Wadsworth K, Bowditch R, Bibby S, et al. Randomised controlled trial of high
concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax 2011;66(11):937–41. [
]

Pretto JJ, Roebuck T, Beckert L, Hamilton G. Clinical use of pulse oximetry: official guidelines from the Thoracic
Society of Australia and New Zealand. Respirology 2014;19(1):38–46. [ ]

Ridler N, Plumb J, Grocott MP. Oxygen therapy in critical illness: Friend or foe? a review of oxygen therapy in
selected acute illnesses 1A01, 1A03. J Intensive Care Soc 2014;15(3):190–8. [URL]

Rodrigo GJ, Rodriquez Verde M, Peregalli V, Rodrigo C. Effects of short-term 28% and 100% oxygen on PaCO2
and peak expiratory flow rate in acute asthma: a randomized trial. Chest 2003;124(4):1312–7. [ ]

Sjoberg F, Singer M. The medical use of oxygen: a time for critical reappraisal. J Intern Med 2013;274(6):505–
28. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Domiciliary oxygen therapy
Indications for domiciliary oxygen therapy
Domiciliary oxygen therapy is prescribed for patients with chronic hypoxaemia, with the most common cause
being chronic obstructive pulmonary disease (COPD) in adults, and chronic neonatal lung disease in children.

Domiciliary oxygen is not prescribed to treat the symptom of breathlessness without hypoxaemia. The
purpose of domiciliary oxygen therapy is to prolong life. The Thoracic Society of Australia and New Zealand
(TSANZ) gives recommendations for when to prescribe domiciliary oxygen based on the patient's clinical
criteria [Note 1]. These guidelines should be adhered to because prescribing long-term oxygen therapy for
normoxaemic patients can cause harm (see also acute oxygen therapy).

Note 1: McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P, Pretto JJ. Position statement: adult
domiciliary oxygen therapy. Sydney: The Thoracic Society of Australia and New Zealand; 2014. [URL]

Domiciliary oxygen therapy for children

Domiciliary oxygen therapy is indicated for children with severe chronic hypoxaemia (unable to maintain
oxygen saturation measured by pulse oximetry [SpO2] greater than 94% in room air). The largest group of
children with severe chronic hypoxaemia are infants with chronic lung disease of prematurity, which is a
sequela to severe hyaline membrane disease (caused by deficiency of pulmonary surfactant). Domiciliary
oxygen is used in these children to maintain SpO2 above 92% during sleep, which minimises pulmonary
vascular resistance thus reducing the risk of increased right ventricular afterload.

Most infants needing domiciliary oxygen therapy need a low flow of oxygen, between 0.125 and 0.5 L per
minute. Oxygen is usually delivered through an oxygen concentrator via a low-flow meter, lightweight plastic
tubing and nasal cannulae. Small cylinders can be used for portability.

All infants born prematurely with oxygen-dependent chronic lung disease should be monitored by respiratory
paediatricians every 4 to 6 weeks following discharge from the neonatal unit. Feeding, weight gain and SpO2
(measured at the time of clinic visits) are used to determine the rate of weaning from oxygen treatment.

Oxygen desaturation during sleep continues for longer than daytime desaturation in these infants, particularly
during rapid eye movement sleep. Therefore, overnight pulse oximetry without supplemental oxygen showing
SpO2 is maintained above 92% throughout the night is essential before stopping domiciliary oxygen.
Respiratory illness in the months following discontinuation of oxygen may require temporary reintroduction
of low-flow oxygen.

Domiciliary oxygen therapy for adults

Long-term continuous therapy
Long-term continuous oxygen therapy has been shown to prolong survival in patients with:

stable chronic obstructive pulmonary disease (COPD) who, when breathing air at rest and awake, have
a consistent partial pressure of oxygen (PaO2) of 55 mmHg or less
stable COPD with evidence of complications of hypoxaemia, such as polycythaemia, pulmonary
hypertension or right-sided heart failure, and a PaO2 of 59 mmHg or less.

The goal of oxygen therapy is to maintain a resting oxygen saturation measured by pulse oximetry (SpO2)
greater than 90% during periods of wakefulness. This is usually achieved at an oxygen flow of 2 L per minute.
The TSANZ suggest following the traditional recommendation that patients increase the flow rate empirically
by 1 Litre per minute nocturnally and during activity or exercise (including for everyday physical activities
such as showering) [Note 2]. There is no documented evidence for or against any adverse effects with this
approach.
Patients needing continuous domiciliary oxygen should use oxygen supplementation for as close as possible
to 24 hours per day, ideally a minimum of 18 hours per day; this includes hours asleep. Oxygen use must be
balanced with the patient's need to exercise and to pursue activities to maintain a satisfactory quality of life,
which may not be attainable with a fixed oxygen supply. Patients can use portable oxygen devices (oxygen
cylinders and portable concentrators) to maximise the amount of time they are using oxygen.

Domiciliary oxygen supplementation should be supplied from oxygen concentrators, with cylinders for
portable use (see delivery systems and devices). Portable oxygen may be useful for patients who demonstrate
an objective improvement in exercise endurance, for example measured using a treadmill, cycle ergometer, 6-
minute walk test, or shuttle walk test.

Regularly reassess patients receiving long-term oxygen therapy (see assessment and reassessment).

Note 2: McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P, Pretto JJ. Position statement: adult
domiciliary oxygen therapy. Sydney: The Thoracic Society of Australia and New Zealand; 2014. [URL]

Intermittent therapy
There is equivocal evidence for benefit of intermittent oxygen therapy. It may be indicated for patients who
have obstructive or fibrotic lung diseases who do not meet the criteria for long-term continuous oxygen
therapy and whose ability to exercise is limited by hypoxaemia.

To establish the benefit of intermittent oxygen for these patients, measure gas exchange at rest and while
exercising, together with the patient's exercise endurance using pulse oximetry and a treadmill exercise
assessment, cycle ergometer, 6-minute walk test or incremental shuttle walk test.

Intermittent oxygen may be prescribed for some patients with severe asthma who live in isolated areas for use
during acute flare-ups while awaiting medical attention.

Intermittent oxygen therapy may be used for palliative relief of dyspnoea due to hypoxaemia for patients with
pulmonary vascular, interstitial or neoplastic lung disease. Intermittent oxygen therapy is also effective for
acute cluster headache; see cluster headache for dosing information.

Although domiciliary oxygen therapy is often prescribed for patients with chronic heart failure with
intractable breathlessness, there is no supporting evidence that it reduces breathlessness or hospitalisation, or
improves survival. Only a small proportion of patients with chronic heart failure experience daytime
hypoxaemia. Sleep-disordered breathing may coexist with chronic heart failure in up to one-third of patients;
in this setting there is weak evidence that nocturnal oxygen may provide some symptomatic benefit.

Nocturnal therapy
A formal sleep study is needed to assess the need for nocturnal oxygen therapy in patients who do not meet
the criteria for long-term therapy. Local requirements to obtain funding support vary.

Hypoxaemia at night may be related to sleep apnoea and may require use of continuous positive airway
pressure (CPAP).

Assessment and reassessment

Perform initial assessment for domiciliary oxygen therapy when patients are clinically stable, have had their
treatment optimised and have stopped smoking for at least 1 month.

Patients are often prescribed domiciliary oxygen therapy on discharge from hospital; however, there is no
evidence to support this practice. If prescribed on discharge, clinicians must emphasise that it is short-term
therapy and timely reassessment is especially important. A study found 38% of patients who met the criteria
for domiciliary oxygen therapy at discharge no longer had a clinical requirement for domiciliary oxygen at
follow-up 4 to 8 weeks later. If oxygen is no longer needed at follow-up, convey this information positively to
patients. Explain that due to improved response oxygen is no longer needed, rather than saying that the patient
is not eligible for funding.

Ongoing reassessment is vital for all patients prescribed oxygen therapy.

Reassessment is vital for all patients prescribed oxygen therapy to ensure the treatment:
 has been appropriately prescribed
is still indicated
is being effectively adhered to.

Reassess patients within 1 to 2 months of starting therapy. Assess partial pressure of oxygen (PaO2), partial
pressure of carbon dioxide (PaCO2) and smoking status, as well as the impact the oxygen therapy is having on
the patient's quality of life. Ongoing reassessment should be performed annually thereafter, or more frequently
if the patient's condition warrants it. It is important to reassess the need for long-term oxygen therapy when
patients are stable. Reassessment in an unstable state may suggest a need for ongoing therapy when there is
none.

Incorporate regular patient education into assessments to help maximise the patient's understanding and
adherence, and the effectiveness of treatment. The Lung Foundation of Australia ([URL]) publishes
comprehensive patient education material for starting and continuing domiciliary oxygen therapy.

Eligible patients may qualify for subsidised oxygen through government schemes, which vary throughout
Australia, see access to domiciliary oxygen throughout Australia for further information.

Contraindications to domiciliary oxygen therapy

Long-term and intermittent domiciliary oxygen are not indicated for patients:

whose main complaint is dyspnoea but who maintain PaO2 higher than 60 mmHg
who continue to smoke (because of the risk of causing fire)
who have not received adequate therapy for their underlying disease.

Delivery systems and devices

Overview

Oxygen is usually delivered by oxygen concentrators or cylinders. Choice of delivery system depends on cost
and the number of hours per day that oxygen is needed, see Table 9.34.

For domiciliary oxygen therapy, low-flow devices are usually prescribed. The first-line choice is the standard
nasal cannula; however, consider the patient's clinical condition, PaO2, PaCO2 and comfort when choosing the
device.

Oxygen concentrators

Oxygen concentrators are a cost-effective means of delivering oxygen to patients needing continuous therapy.

They are mobile, floor-standing electrically driven machines that extract nitrogen from room air in molecular
sieves. They deliver 90 to 95% oxygen to the machine outlet. These machines do not store oxygen; they must
be turned on continuously when delivering oxygen. They do not produce the pressure needed to drive jet
nebulisers and cannot be used with Venturi masks. They can be used with up to 30 metres of tubing to allow
mobility within the home. Portable, rechargeable, battery-driven concentrators are available.

Check with the local administering authority whether a rebate for electricity use is available.

Oxygen cylinders

Oxygen cylinders are used to maximise delivery of oxygen over a 24-hour period. Additionally, cylinders are
used when:

ambulatory patients need oxygen away from the home

patients are receiving intermittent oxygen therapy
the supply of electricity is too unreliable for concentrator use, or backup is needed for possible
electricity supply failure.

Cylinders come in a range of sizes, see Table 9.34.

Oxygen conservation devices (eg Oxymizer, Oximatic) increase the life of cylinders substantially by enabling
a pulse of oxygen to be delivered on inspiration only; however, there is limited available evidence of their
effectiveness in correcting hypoxaemia.
Oxygen supply companies can arrange oxygen at travel destinations. For information about oxygen supply on
aircraft, see in-flight oxygen therapy.

Oxygen cylinder size and capacity (Table 9.34)

Duration of oxygen supply at flow rate 2 L per

Size Volume (m3) minute
G 7.6 to 8.8 hospital use only
E 3.8 to 5.2 about 30 hours
D 1.5 about 11 hours
C 0.55 about 3 hours
Traveller 0.257 to 0.682 depends on size
1 m3 = 1000 Litres
Modified with permission from McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P, Pretto JJ. Position statement: adult domiciliary oxygen
therapy. Sydney: The Thoracic Society of Australia and New Zealand; 2014.

Adverse effects of oxygen delivery

Nasal symptoms from oxygen delivery, such as nasal stuffiness, dryness or bleeding, are common and may be
alleviated by the use of saline nasal sprays (sodium chloride solution) or water-based lubricant, or by placing
the cannulae in the mouth, which may be practical at night. Nasal cannulae may cause pressure area marks
behind the ears or on the cheeks, which can be avoided and alleviated by the use of soft foam pads, cotton
wool or gauze.

The equipment supplier may be able to advise on the availability of extra devices or attachments that would
help to solve some of these problems.

Access to domiciliary oxygen in Australia

In Australia, funding for domiciliary oxygen therapy varies between states and territories and, in some cases,
from region to region within a state or territory. Obtain details from the relevant state or territory Health
Department.

Clinical criteria may be specific to a jurisdiction. However, unless otherwise stated, the 2014 position
statement of the Thoracic Society of Australia and New Zealand [Note 3] provides the clinical criteria on
which an application would be based.

Once a patient is admitted to a high-level residential care facility, oxygen supply is federally subsidised. The
medical criteria are still the same, but the funding package needs to be reassessed and a social worker may
need to organise this.

For people who receive a Department of Veterans' Affairs pension, oxygen is subsidised through the
Department of Veterans' Affairs ([URL]); the clinical criteria of the TSANZ position paper apply [Note 3].

To obtain subsidised oxygen therapy, prescription by a medical specialist is needed, usually a thoracic
physician, palliative care physician, specialist general physician, cardiologist, oncologist, neurologist or the
relevant paediatric specialist. For patients in remote areas in some jurisdictions, annual renewal prescriptions
may be written by a general practitioner with the endorsement of a designated specialist.

For patients who pay for their own oxygen therapy, any registered medical practitioner can prescribe
treatment.

Note 3: McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P, Pretto JJ. Position statement: adult
domiciliary oxygen therapy. Sydney: The Thoracic Society of Australia and New Zealand; 2014. [URL]

Key references
Domiciliary oxygen therapy

Abramson M, Crockett A, Dabscheck E, Frith P, George J, Glasgow N, et al. The COPD-X Plan: Australian and
New Zealand guidelines for the management of chronic obstructive pulmonary disease. Version 2.37. Milton, Qld:
Lung Foundation Australia; April 2014. [URL]
 Abramson MJ, Crockett AJ, Frith PA, McDonald CF. COPDX: an update of guidelines for the management of
chronic obstructive pulmonary disease with a review of recent evidence. Med J Aust 2006;184(7):342–5. [
]

Australian Institute of Health and Welfare (AIHW), Marks G, Reddel H, Guevara-Rattray E, Poulos L, Ampon R.
Monitoring pulmonary rehabilitation and long-term oxygen therapy for people with chronic obstructive pulmonary
disease (COPD) in Australia: a discussion paper. Cat. no. ACM 29. Canberra: AIHW; 2013. [URL]

Balfour-Lynn IM, Field DJ, Gringras P, Hicks B, Jardine E, Jones RC, et al. BTS guidelines for home oxygen in
children. Thorax 2009;64 Suppl 2ii1–26. [ ]

Boyle M, Wong J. Prescribing oxygen therapy. An audit of oxygen prescribing practices on medical wards at
North Shore Hospital, Auckland, New Zealand. N Z Med J 2006;119(1238):U2080. [ ]

Clark AL, Johnson MJ, Squire I. Does home oxygen benefit people with chronic heart failure? BMJ
2011;342d234. [ ]

Eaton TE, Grey C, Garrett JE. An evaluation of short-term oxygen therapy: the prescription of oxygen to patients
with chronic lung disease hypoxic at discharge from hospital. Respir Med 2001;95(7):582–7. [ ]

Lewis CA, Fergusson W, Eaton T, Zeng I, Kolbe J. Isolated nocturnal desaturation in COPD: prevalence and
impact on quality of life and sleep. Thorax 2009;64(2):133–8. [ ]

McDonald CF, Crockett AJ. Optimising the therapeutic use of oxygen in Australia. Med J Aust 2009;191(10):526–
7. [ ]

McDonald CF, Whyte K, Jenkins S, Serginson J, Frith P, Pretto JJ. Position statement: adult domiciliary oxygen
therapy. Sydney: The Thoracic Society of Australia and New Zealand; 2014. [URL]

Moore RP, Berlowitz DJ, Denehy L, Pretto JJ, Brazzale DJ, Sharpe K, et al. A randomised trial of domiciliary,
ambulatory oxygen in patients with COPD and dyspnoea but without resting hypoxaemia. Thorax 2011;66(1):32–
7. [ ]

Nixon GM, Edwards EA, Cooper DM, Fitzgerald DA, Harris M, Martin J, et al. Ventilatory support at home for
children. A consensus statement from the Australasian Paediatric Respiratory Group. Clayton, VIC: The Thoracic
Society of Australia and New Zealand; 2008. [URL]

Petersen AS, Barloese MC, Jensen RH. Oxygen treatment of cluster headache: A review. Cephalalgia
2014;34(13):1079–87. [ ]

Serginson JG, Yang IA, Armstrong JG, Cooper DM, Matthiesson AM, Morrison SC, et al. Variability in the rate of
prescription and cost of domiciliary oxygen therapy in Australia. Med J Aust 2009;191(10):549–53. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Noninvasive ventilation
Introduction to noninvasive ventilation
Noninvasive ventilation (NIV), also known as noninvasive positive pressure ventilation (NIPPV), is
ventilatory support given by a face mask rather than by endotracheal intubation. It is an effective means of
treating patients with acute respiratory failure, particularly in exacerbations of chronic obstructive pulmonary
disease (COPD).

Noninvasive ventilation may consist of continuous positive airway pressure (CPAP) or bi-level therapy
(BiPAP), where a higher pressure is given during inspiration and lower during expiration.

Noninvasive ventilation is supportive therapy to be used only in addition to first-line therapy directed at the
underlying disease.

Sufficient adequately trained staff are needed to give and monitor noninvasive ventilation, usually in a critical
care environment or a high-dependency unit. Arterial blood gases should be measured.

Indications for acute noninvasive ventilation

Acute exacerbations of COPD

Patients particularly suitable for noninvasive ventilation are those with exacerbations of chronic obstructive
pulmonary disease (COPD) with carbon dioxide retention, respiratory acidosis with a pH in the range 7.25 to
7.35, and tachypnoea. In this group, it reduces the need for intensive care admission as well as length of
hospital stay and mortality. It is also useful for relieving their dyspnoea.

Noninvasive ventilation should also be trialled in patients with more severe acidosis; however, if it fails they
may need tracheal intubation and invasive mechanical ventilation. Usually in these more severely acidotic
patients, the trial is best done in a critical care environment, except if noninvasive ventilation is the agreed
ceiling of care. Before instituting any form of ventilatory support, a decision should be made as to what the
ceiling of care is and whether intensive care unit (ICU) admission is contemplated.

Acute cardiogenic pulmonary oedema

Continuous positive airway pressure (CPAP) (at a pressure of 5 to 10 cm H2O) is useful in acute cardiogenic
pulmonary oedema. Noninvasive ventilation has been shown to produce more rapid improvement in
respiratory distress and metabolic disturbance than standard therapy, but has no effect on short-term
mortality. Bi-level ventilation should be reserved for patients failing to improve on CPAP, particularly if there
is carbon dioxide retention.

Hypoxaemic respiratory failure

Noninvasive ventilation may be beneficial for patients with hypoxaemic respiratory failure caused by
conditions other than COPD or acute pulmonary oedema, particularly for immunocompromised patients (eg
neutropenic patients with pulmonary infiltrates). Classically, these patients are already taking several
antimicrobials, are tachypnoeic and have radiological changes suggestive of either widespread pulmonary
infection and/or noncardiogenic pulmonary oedema.

Weaning from invasive ventilation

Weaning with noninvasive ventilation should be beneficial for intubated and mechanically ventilated ICU
patients in whom the risk of post-extubation respiratory failure is high. These patients often have pre-existing
respiratory or cardiac disease, or have been in ICU for long periods of time (more than 10 days), often
recuperating following a sudden medical or surgical event.

Acute asthma
Noninvasive ventilation may be used in acute asthma, but caution is needed and close observation in a high-
dependency or intensive care unit is recommended.

Indications for long-term noninvasive ventilation

Long-term nocturnal continuous positive airway pressure (CPAP) is indicated for patients with significant
obstructive sleep apnoea.

Long-term bi-level ventilation may be used for patients with neuromuscular disease (eg motor neurone
disease) or a chest wall disorder (eg kyphoscoliosis).

Occasionally patients with end-stage airway disease (eg COPD, cystic fibrosis) who are hypercapnic may
benefit from long-term noninvasive ventilation. These patients generally have demonstrated nocturnal
hypoventilation associated with a rise in partial pressure of carbon dioxide (PaCO2) of more than 5 mmHg.
They tolerate and have demonstrated a physiological benefit with noninvasive ventilation.

Contraindications to noninvasive ventilation

Use of noninvasive ventilation is contraindicated in the following situations:

immediate need for tracheal intubation

cardiorespiratory arrest
haemodynamic instability
impaired consciousness with inability to protect the airway
fixed upper airway obstruction
copious secretions or vomiting
pneumothorax
facial injuries
recent upper gastrointestinal surgery
uncooperative patient or patient intolerant of the mask
insufficient trained staff to give and monitor noninvasive ventilation.

Using noninvasive ventilation

Before using noninvasive ventilation
Measure arterial blood gases, where possible, before commencing noninvasive ventilation.

Obtain informed consent and discuss whether noninvasive ventilation is the ceiling of care or whether
intubation will be undertaken if noninvasive ventilation fails.

Set up and check the appropriate ventilator mask and circuit, which must include a carbon dioxide exhalation
port.

A carbon dioxide exhalation port must be present in the ventilation circuit.

Equipment settings and monitoring

Equipment settings and monitoring for noninvasive ventilation are listed in Box 9.14. Either a full-face or
nasal mask can be used.

Once the machine is attached and switched on, hold the mask to the patient's face to familiarise them with it.
After a few minutes the headgear can be secured. Do not overtighten the headgear because severe ulceration
of the bridge of the nose can occur very rapidly (see also management of problems).

Show the patient how to remove the mask and how to summon help if needed.
Equipment settings and monitoring for noninvasive ventilation (Box 9.14)

Suggested settings for noninvasive ventilation:

Initial settings for bi-level noninvasive ventilation in COPD are inspiratory positive airway pressure
(IPAP) 10 to 12 cm H2O and expiratory positive airway pressure (EPAP) 4 to 6 cm H2O.
If a spontaneous/time mode ventilator is used, set this with a backup rate of 15 breaths per minute
and inspiratory to expiratory (I:E) ratio of 1:3.
Set triggers at maximum sensitivity.
Initial settings for CPAP in acute pulmonary oedema are 5 to 15 cm H2O (approximately 10% of
body weight in kg).

Suggested monitoring for noninvasive ventilation:

Monitor pulse oximetry continuously.

Reassess the patient within a few minutes and adjust ventilator settings and supplemental oxygen to
optimal levels, see ventilator adjustment and supplemental oxygen.
Repeat clinical assessment and arterial blood gases in 1 hour and thereafter as clinically indicated.

COPD = chronic obstructive pulmonary disease; CPAP = continuous positive airway pressure

Ventilator adjustment and supplemental oxygen

Expiratory positive airway pressure (EPAP) improves aeration of the lungs and, in chronic obstructive
pulmonary disease (COPD), overcomes intrinsic positive end expiratory pressure (PEEPi). The main
indication for increasing EPAP is persistent hypoxaemia despite a satisfactory fall in partial pressure of
carbon dioxide (PaCO2). Inspiratory positive airway pressure (IPAP) provides pressure support for
inspiration, which increases alveolar ventilation and assists in reducing carbon dioxide.

For patients receiving noninvasive ventilation, adequacy of ventilation is assessed clinically by assessing
chest expansion, and biochemically by repeat arterial blood gases and/or the device's measurements. There
should always be a difference of at least 6 cm H2O between IPAP and EPAP. Supplemental oxygen should be
given after optimising ventilator settings to maintain the oxygen saturation measured by pulse oximetry
(SpO2) between 88 to 92% for patients with COPD and 92 to 96% for patients with acute pulmonary oedema.

In some patients with mainly hypoxaemic respiratory failure, high-flow oxygen therapy can be considered
because it provides heated and humidified oxygen blends (21 to 100%) with 2 to 3 cm H2O continuous
positive airway pressure (CPAP) via loose-fitting nasal prongs.

Management of problems

Treatment failure

Treatment failure with noninvasive ventilation may be indicated by clinical deterioration, increasing distress
or deteriorating arterial blood gas results.

If treatment failure occurs:

ensure the medical treatment has been optimised (bronchodilators, corticosteroids, antibiotics) and
ensure it has actually been given
consider chest X-ray to exclude pneumothorax or aspiration pneumonia
consider ventilation perfusion isotope (V/Q) lung scan or computed tomography pulmonary
angiography (CTPA) to exclude pulmonary embolus
consider physiotherapy for sputum retention.

If there is persistent elevation of the PaCO2 and continued acidosis:

check inspired oxygen concentration and pulse oximetry and reduce oxygen if necessary. Target
oxygen saturation measured by pulse oximetry (SpO2) is 88 to 92% for patients with chronic
obstructive pulmonary disease (COPD)
check the circuit for leaks, including mask leaks, and check that the circuit includes a carbon dioxide
expiration port
 consider increasing expiratory positive airway pressure (EPAP) to reduce the possibility of rebreathing
check the patient's synchronisation with the ventilator and adjust the backup rate
check the ventilator trigger is set for maximum sensitivity
observe chest expansion and, if inadequate, consider increasing inspiratory positive airway pressure
(IPAP). If this is not tolerated or chest expansion is adequate, consider increasing respiratory rate or
inspiratory to expiratory (I:E) ratio to increase expiratory time.

If there is persisting hypoxaemia despite improvement in PaCO2, consider increasing EPAP (maintain the
difference between IPAP and EPAP) or increasing supplemental oxygen, and review the need for intubation
and mechanical ventilation.

Miscellaneous problems

Some miscellaneous problems associated with noninvasive ventilation are:

nasal bridge ulceration, which should not occur with appropriate mask fitting. A prophylactic
hydrocolloid dressing may be used
rhinorrhoea, which may be reduced by the use of ipratropium nasal spray and by incorporating a heated
humidifier in the circuit
retention of secretions, which may be overcome by humidification, bronchodilators and regular
physiotherapy
gastric distension, which may cause discomfort. Consider lowering both IPAP and EPAP.

Stopping noninvasive ventilation

In the acute setting, noninvasive ventilation usually produces rapid improvement. In exacerbations of chronic
obstructive pulmonary disease (COPD) it is usually applied throughout the first 24 hours (with breaks for
meals) and then overnight for 1 to 2 nights. For patients with cardiogenic pulmonary oedema, continuous
positive airway pressure (CPAP) is usually only required for approximately 6 to 12 hours.

Patients can usually be weaned from noninvasive ventilation once dyspnoea has resolved and arterial blood
gases have normalised. Following acute noninvasive ventilation, consider assessing ventilation during sleep
(eg by pulse oximetry) to guide whether overnight noninvasive ventilation should be continued for a few
extra nights to allow restoration of quality sleep. Most patients admitted to hospital with acute-on-chronic
respiratory failure have arrived severely sleep deprived.

Key references
Noninvasive ventilation

Burns KE, Adhikari NK, Keenan SP, Meade M. Use of non-invasive ventilation to wean critically ill adults off
invasive ventilation: meta-analysis and systematic review. BMJ 2009;338b1574. [ ]

Crummy F, Naughton MT. Non-invasive positive pressure ventilation for acute respiratory failure: justified or just
hot air? Intern Med J 2007;37(2):112–8. [ ]

Ferrer M, Esquinas A, Leon M, Gonzalez G, Alarcon A, Torres A. Noninvasive ventilation in severe hypoxemic
respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med 2003;168(12):1438–44. [ ]

Li H, Hu C, Xia J, Li X, Wei H, Zeng X, et al. A comparison of bilevel and continuous positive airway pressure
noninvasive ventilation in acute cardiogenic pulmonary edema. Am J Emerg Med 2013;31(9):1322–7. [ ]

Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary
disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010;182(3):325–31. [
]

Pallin M, Naughton MT. Noninvasive ventilation in acute asthma. J Crit Care 2014;29(4):586–93. [ ]

Peter JV, Moran JL, Phillips-Hughes J, Graham P, Bersten AD. Effect of non-invasive positive pressure
ventilation (NIPPV) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-analysis. Lancet
2006;367(9517):1155–63. [ ]

Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of
respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev
2004;(3):CD004104. [ ]

Soroksky A, Klinowski E, Ilgyev E, Mizrachi A, Miller A, Ben Yehuda TM, et al. Noninvasive positive pressure
ventilation in acute asthmatic attack. Eur Respir Rev 2010;19(115):39–45. [ ]

Squadrone V, Massaia M, Bruno B, Marmont F, Falda M, Bagna C, et al. Early CPAP prevents evolution of acute
lung injury in patients with hematologic malignancy. Intensive Care Med 2010;36(10):1666–74. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Fitness for surgery
Impact of respiratory impairment on surgery
Patients who have respiratory impairment due to respiratory disease need proper assessment before surgery.
They may require specific interventions or precautions before and after the operation.

In general, deficiencies of the respiratory system can be overcome during surgery by using assisted
ventilation, high concentrations of supplemental oxygen and effective intra-airway suction to remove
secretions. However, the postoperative period is a time of major morbidity and mortality for patients with
respiratory disease. This is due to increased demands on, and reduced capacity of, the respiratory system.

Increased demands on the respiratory system, such as fever, sepsis and tissue repair, cause the basal metabolic
rate to increase two- to three-fold postoperatively. This increases oxygen consumption and carbon dioxide
production, and hence the requirement for increased ventilation.

Reduced ventilatory capacity of the respiratory system postoperatively can be due to pain from abdominal
and thoracic wounds, the need to lie supine and the use of sedatives and analgesics. It can also be due to
atelectasis, sputum retention, pneumonia and fluid overload adversely affecting both gas-exchange and
ventilatory capacity.

Respiratory disease risk groups for surgery

The risk of perioperative complications depends on the type of procedure and the nature of the respiratory
disease.

Procedures that put patients with respiratory disease at most risk are:

coronary artery bypass grafts and procedures involving the thorax and upper abdomen
procedures with long operating duration
procedures requiring high levels of postoperative analgesia.

People with respiratory disease at most risk of postoperative complications are those:

who smoke
with poorly controlled asthma and/or a history of severe flare-ups (exacerbations)
taking long-term systemic or high-dose inhaled corticosteroids; a brief course of supplementary
corticosteroids may be needed perioperatively
with limited mechanical ventilatory reserve, eg due to
–
severe airway obstruction
–
interstitial lung disease
–
obesity
–
disease associated with weak respiratory muscles
with mucus hypersecretion, eg due to
–
chronic bronchitis
–
bronchiectasis
–
cystic fibrosis
with a chest wall disorder causing a rigid chest, eg kyphoscoliosis
with reduced ability to protect the upper airway or to clear secretions from the lungs, eg due to
neuromuscular disorders affecting the bulbar muscles and cough mechanism
with uncontrolled reflux
prone to pulmonary oedema because of coexisting cardiac disease
with significant sleep apnoea
 prone to respiratory centre depression, eg due to chronic carbon dioxide retention
who have difficulty cooperating with instructions, eg with physical or mental disability.

In addition, some patients are deemed by anaesthetists to have an airway that is difficult to intubate. These
patients often have significant craniofacial abnormalities such as a small mouth opening or significant
retrognathia. They are more likely to develop postoperative respiratory complications and are more prone to
obstructive sleep apnoea. The STOPBang questionnaire [Note 1] may help to identify obstructive sleep
apnoea; these patients may benefit from continuous positive airway pressure (CPAP) or noninvasive
ventilation postoperatively.

Acute viral and bacterial infections can temporarily affect mucociliary function and increase mucus
production. This can increase the risk of postoperative complications. In otherwise healthy people, this risk is
relatively low but elective surgery may need to be postponed.

Children who have had a viral respiratory tract infection in the preceding 4 weeks are at increased risk of
intraoperative respiratory events (coughing, laryngospasm, oxygen desaturation), but there is no evidence of
increased postoperative morbidity or mortality. It is unnecessary and impractical to cancel surgery for
children with a history of a recent respiratory tract infection. However, elective surgery should be delayed for
2 to 4 weeks if a child is acutely viraemic (eg has fever, malaise, lack of appetite, rhinorrhoea).

Note 1: STOPBang questionnaire is available from the British Snoring and Sleep Apnoea Association
website [URL]

Assessment of patients with respiratory disease before surgery

The assessment of fitness for an anaesthetic in individual patients with an acute illness rests with the
anaesthetist.

Clinical assessment

Clinical assessment of a patient before surgery should include relevant assessment of:

smoking—use a multifaceted approach to quitting and, if practical, postpone surgery until the patient
has not smoked for 6 weeks. See smoking cessation for suggested strategies.
chronic bronchitis and bronchiectasis—take measures to improve mucus clearance (see bronchiectasis)
unstable asthma—take measures to control (see control-based management)
respiratory impairment—usually identified because of breathlessness and reduced exercise capacity.
This may be due to asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis,
pulmonary vascular disease or respiratory muscle weakness.

Respiratory function tests

All patients with clinical evidence of respiratory impairment, should have respiratory function tests (such as
spirometry and measurement of diffusing capacity, see pulmonary function tests). If such patients are unable
to perform respiratory function testing due to physical or mental disability, in addition to careful
postoperative monitoring, it may be necessary to use surrogates such as thorough clinical examination, chest
X-ray, pulse oximetry and blood tests to assess for hypercapnia (or serum bicarbonate concentration) and
polycythaemia.

If oxygen therapy is provided, it is as important to monitor for and prevent hyperoxaemia as it is to treat
hypoxaemia.

No further respiratory assessment is needed for patients with both a forced expiratory volume in 1 second
(FEV1) and a diffusing capacity for carbon monoxide (DLCO) of greater than 60% of predicted because they
have a low risk of postoperative complications (even following major operations such as pneumonectomy).

Lobectomy is associated with a low risk of postoperative complications if FEV1 is greater than 40% of
predicted and DLCO is greater than 60% of predicted. This probably also applies to other relatively high-risk
operations such as chest or upper abdominal surgery.

The lower limit of respiratory function needed for medium- or low-impact surgery (ie not interfering with
respiratory muscles or cough) is not known. However, an individual with any of the following has a very
limited respiratory reserve and needs expert preoperative assessment:
 FEV1 less than 60% of predicted
DLCO less than 60% of predicted
partial pressure of carbon dioxide (PaCO2) higher than 45 mmHg
moderate or severe pulmonary hypertension
oxygen saturation measured by pulse oximetry (SpO2) 90% or less when breathing room air
receiving long-term domiciliary oxygen.

In some cases, additional physiological investigations, including cardiopulmonary cycle exercise testing
(VO2 max) and electrocardiogram (ECG), are performed before surgery involving general anaesthesia.
Postoperative complication risk from major surgery is usually considered high if VO2 max is less than 15
mL/min/kg.

Postoperative management of patients with respiratory disease

The key requirements in the early postoperative period for patients with respiratory impairment are:

good pain control (epidural analgesia may be indicated). Care should be taken in patients with asthma;
aspirin-sensitive patients should not be given nonsteroidal anti-inflammatory drugs (NSAIDs). See
postoperative analgesia for further information and precautions
supplemental oxygen, humidified for ‘mouth breathers’. Ensure supplemental oxygen is titrated to
oxygen saturation measured by pulse oximetry (SpO2), eg 92 to 96% in otherwise healthy patients, 88
to 92% in patients prone to hypercapnia such as patients with chronic obstructive pulmonary disease
(COPD)
nebulised bronchodilators. Take care to avoid excessive dosing, eg more frequently than 4 hourly
prevention of atelectasis by effective deep breathing and coughing, and prophylactic continuous
positive airway pressure (CPAP) or bi-level support in some instances, eg after cardiac surgery or in
children with neuromuscular disorders or restrictive lung disease such as kyphoscoliosis
airway clearance techniques, eg bubble positive airway pressure (PEP)
early ambulation
increased corticosteroid dosage in appropriate situations, eg patients with asthma.

Necessary prevention or early identification of potential complications involves:

frequent clinical examination to detect fever, inspiratory crackles, disorientation

continuous or regular monitoring of SpO2 and partial pressure of carbon dioxide (PaCO2) if indicated.
Ensure avoidance of excessive oxygen, thus keeping SpO2 at 92 to 96% in otherwise healthy patients,
or at 88 to 92% if patients are prone to hypercapnia, eg patients with COPD
staff being alert to the dangers of oversedation, vomiting and aspiration, reflux, fluid overload and
cardiac arrhythmias
formal monitoring of pain control and the patient's ability to cough effectively
monitoring sputum volume and purulence
monitoring forced expiratory volume in 1 second (FEV1) and/or peak expiratory flow when
appropriate.

Abnormal chest findings, fever or hypoxaemia warrant investigation, including a chest X-ray.

Key references
Fitness for surgery

Bapoje SR, Whitaker JF, Schulz T, Chu ES, Albert RK. Preoperative evaluation of the patient with pulmonary
disease. Chest 2007;132(5):1637–45. [ ]

Hwang D, Shakir N, Limann B, Sison C, Kalra S, Shulman L, et al. Association of sleep-disordered breathing with
postoperative complications. Chest 2008;133(5):1128–34. [ ]

Krage R, van Rijn C, van Groeningen D, Loer SA, Schwarte LA, Schober P. Cormack-Lehane classification
revisited. Br J Anaesth 2010;105(2):220–7. [ ]

Rachel Homer J, Elwood T, Peterson D, Rampersad S. Risk factors for adverse events in children with colds
emerging from anesthesia: a logistic regression. Paediatr Anaesth 2007;17(2):154–61. [ ]

Tait AR, Malviya S, Voepel-Lewis T, Munro HM, Seiwert M, Pandit UA. Risk factors for perioperative adverse
respiratory events in children with upper respiratory tract infections. Anesthesiology 2001;95(2):299–306. [
]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Fitness to fly
Respiratory disease and fitness to fly
Air travel is safe for the vast majority of the two billion or so passengers who fly each year. It can pose
significant risks to people with respiratory disease, although most tolerate flight well. Approximately 12% of
acute in-flight medical episodes are respiratory in nature, and it is likely that respiratory disease and
hypoxaemia contribute to other episodes including cardiac or neurological events.

No further investigation is needed for patients whose respiratory disease is stable when assessed, who have
not had a previous in-flight problem, and whose resting arterial blood oxygen saturation is 95% or greater.
For other patients with respiratory disease, spirometry, arterial blood gas and haemoglobin oxygen saturation
levels do not reliably predict in-flight complications, so further assessment is necessary.

Effect of cabin environment on respiratory disease

Commercial aircraft usually cruise at altitudes between 10 000 and 13 500 metres (32 800 and 44 300 feet).
Pressurisation of the cabin ensures that the pressure corresponds to an altitude much lower than that at which
the aircraft is flying. However, for reasons of aircraft weight and fuel economy, the cabin is not fully
pressurised to sea level.

The maximum allowable cabin altitude by international regulation is 2438 metres (8000 feet), generating a
cabin air pressure of 565 mmHg. At this pressure, the partial pressure of inspired oxygen (PiO2) in
humidified air falls to 108 mmHg (normally about 148 mmHg at sea level), which is equivalent to breathing
15.1% oxygen at sea level (normally 20.8%). The low PiO2 causes a reduction in arterial oxygen partial
pressure (PaO2). In people with normal lung function, the PaO2 is likely to fall to between 53 and 64 mmHg
with haemoglobin oxygen saturation (SaO2) falling to 85 to 92% (normally greater than 95%). Healthy
people do not notice this change.

In people with chronic respiratory disease who already have a reduced PaO2 and SaO2 at sea level, the
reduced PiO2 may cause significant hypoxaemia and reduced tissue oxygenation.

In addition, the reduced cabin pressure causes expansion of gas by about one-third. This can be important if
there is trapped gas in closed body spaces such as the sinuses, middle ear, pleural cavity or pulmonary bullae.

Other features of commercial air travel, which might cause problems, are:

dryness of the air

reduced mobility of travellers, causing potential for venous thromboembolism (see long-distance
travel)
close proximity to other people and consequent risk of respiratory tract infections
disturbance of circadian rhythms on longer flights (see jet lag).

Assessing the need for in-flight supplemental oxygen

Patients needing assessment
Patient groups needing assessment for in-flight supplemental oxygen include those:

with a history of respiratory problems during air travel, such as breathlessness, chest pain, confusion or
syncope
with severe asthma or severe chronic obstructive pulmonary disease (COPD) (forced expiratory
volume in 1 second [FEV1] less than 30% predicted)
with severe restrictive lung disease (forced vital capacity [FVC] less than 1 Litre)
with arterial oxygen saturation measured by pulse oximetry (SpO2) of less than 95%
within 6 weeks of hospital discharge for acute severe or acute-on-chronic respiratory illness
with a comorbidity that is worsened by hypoxaemia, such as cerebrovascular disease, coronary artery
 disease or heart failure
with a pre-existing requirement for supplemental oxygen or ventilator support, including noninvasive
ventilation.

Clinical assessment

Clinical assessment includes cardiorespiratory history and examination, spirometry, pulse oximetry and
review of previous air travel experience.

Hypoxic challenge test

The hypoxic challenge test (HCT), also known as the high altitude simulation test (HAST), simulates the
reduced inspired oxygen partial pressure (PiO2) at 2438 metres (8000 feet) by exposing the person to air
containing a reduced concentration of oxygen at sea level. The test is performed in a respiratory function
laboratory over a 20- to 30-minute period, either with special low-oxygen gas cylinders or with the person
breathing air while wearing a 40% Venturi mask with nitrogen as the driving gas.

Arterial oxygenation is assessed by continuous measurement of oxygen saturation by a pulse oximeter

(SpO2). If SpO2 falls below 85% or the patient becomes distressed during HCT, in-flight oxygen is indicated.

The HCT has been validated and has the advantage that the effects of any hypoxaemia, such as respiratory
distress or angina, can be observed. However, it is too complicated to use as a screening test in large
populations.

Walk tests

Walk tests are no longer recommended unless hypoxic challenge testing is unavailable. Patients unable to
walk 50 metres on level ground should be considered unfit to fly.

Assessment of other respiratory conditions before flying

Doctors in primary care are often asked whether a child or adult with an acute respiratory tract infection is fit
to fly. Upper airway infections can impair the ability to equalise pressures between the middle ear and
oropharynx via the eustachian tube. This can result in barotrauma to the tympanic membrane, particularly at
the time of descent. If travel is necessary, and the patient has lost their usual ability to equalise the pressure
with the Valsalva manoeuvre at sea level, nasal or oral decongestants may be used at a suitable time before
ascent and/or descent. Anecdotal evidence suggests that semi-permeable earplugs (eg Ear Planes, Alpine
FlyFit) may be helpful.

Flying with an upper respiratory tract infection rarely causes permanent damage to the tympanic membrane.
However, patients who experience deafness, vertigo, or bleeding from the external auditory meatus after air
travel must be examined by their doctor.

As with any infection, patients with an acute respiratory tract infection should be cautioned about the risk of
spreading the infection to others.

Subject to specialist advice, patients with pulmonary tuberculosis must not travel by air until they are
noninfectious (usually after at least 2 weeks of effective treatment).

The volume of air in the pleural space expands by about one-third at cabin altitude, so patients who have a
pneumothorax should not travel by air unless they have an intercostal drain with a one-way valve (Heimlich
valve) in place. Air travel should be delayed for 1 week after radiological resolution of spontaneous
pneumothorax or by 2 weeks following pneumothorax after thoracic surgery or trauma.

Reports of problems during air travel in patients with large lung bullae are rare. Pressure changes during
commercial flights happen slowly, allowing time for equilibration, so the presence of bullae is not a
contraindication to air travel.

Infants and young children who have had chronic neonatal lung disease require specialist assessment before
air travel, even if they no longer require supplemental oxygen.

In-flight oxygen therapy

The usual flow rate for in-flight oxygen is 2 L per minute via nasal cannulae. Patients already using
supplemental oxygen should have their normal flow rate increased. Those needing oxygen at flow rates of 4 L
per minute or more at sea level are not fit to fly.

The requirement for in-flight oxygen must be communicated to the airline well in advance of travel, often by
completion of a medical information form, which details the patient's condition and oxygen requirements (eg
British Airways MEDIF Medical Information Sheet, QANTAS Travel Clearance Form).

Most airlines provide in-flight oxygen on request and may charge for this service. Consider the need for
oxygen at the airport (including for stopovers) because most airlines only provide in-flight oxygen. Some
airlines allow passengers to carry and use their own small oxygen cylinders on board.

In-flight continuous positive airway pressure

For the majority of people with obstructive sleep apnoea, it is not essential to use continuous positive airway
pressure (CPAP) every time they sleep. However, CPAP may be required by some patients with severe
obstructive sleep apnoea on long-haul flights.

If CPAP is necessary, the airline should be consulted before making the travel booking. A doctor's letter
outlining the diagnosis and necessary equipment is needed. It should state the CPAP machine should travel in
the cabin as extra hand luggage. Dry cell battery–powered CPAP can be used during the flight but must be
switched off before landing.

During the flight, all patients with obstructive sleep apnoea should avoid factors that worsen their apnoea,
such as alcohol or sedatives.

Key references
Fitness to fly

Ahmedzai S, Balfour-Lynn IM, Bewick T, Buchdahl R, Coker RK, Cummin AR, et al. Managing passengers with
stable respiratory disease planning air travel: British Thoracic Society recommendations. Thorax 2011;66 Suppl
1i1–30. [ ]

Akero A, Christensen CC, Edvardsen A, Ryg M, Skjonsberg OH. Pulse oximetry in the preflight evaluation of
patients with chronic obstructive pulmonary disease. Aviat Space Environ Med 2008;79(5):518–24. [ ]

Chetta A, Castagnetti C, Aiello M, Sergio F, Fabiano N, Tzani P, et al. Walking capacity and fitness to fly in
patients with chronic respiratory disease. Aviat Space Environ Med 2007;78(8):789–92. [ ]

Coker RK, Shiner RJ, Partridge MR. Is air travel safe for those with lung disease? Eur Respir J 2007;30(6):1057–
63. [ ]

Kelly PT, Swanney MP, Seccombe LM, Frampton C, Peters MJ, Beckert L. Air travel hypoxemia vs. the hypoxia
inhalation test in passengers with COPD. Chest 2008;133(4):920–6. [ ]

Martin AC, Verheggen M, Stick SM, Stavreska V, Oostryck J, Wilson AC, et al. Definition of cutoff values for the
hypoxia test used for preflight testing in young children with neonatal chronic lung disease. Chest
2008;133(4):914–9. [ ]

Peckham D, Watson A, Pollard K, Etherington C, Conway SP. Predictors of desaturation during formal hypoxic
challenge in adult patients with cystic fibrosis. J Cyst Fibros 2002;1(4):281–6. [ ]

Peterson DC, Martin-Gill C, Guyette FX, Tobias AZ, McCarthy CE, Harrington ST, et al. Outcomes of medical
emergencies on commercial airline flights. N Engl J Med 2013;368(22):2075–83. [ ]

Resnick SM, Hall GL, Simmer KN, Stick SM, Sharp MJ. The hypoxia challenge test does not accurately predict
hypoxia in flight in ex-preterm neonates. Chest 2008;133(5):1161–6. [ ]

Robson AG, Lenney J, Innes JA. Using laboratory measurements to predict in-flight desaturation in respiratory
patients: are current guidelines appropriate? Respir Med 2008;102(11):1592–7. [ ]
Vohra KP, Klocke RA. Detection and correction of hypoxemia associated with air travel. Am Rev Respir Dis
1993;148(5):1215–9. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Fitness to scuba dive
Overview of respiratory disease and fitness to scuba dive
All professional scuba divers in Australia are required to undergo regular examinations for medical fitness;
these are described in the Australian Standard AS/NZS 2299 [Note 1]. Most diving organisations require
trainee recreational scuba divers to undergo a medical examination or declare any relevant medical
conditions. The standards suggested by the South Pacific Underwater Medicine Society (SPUMS) have been
adopted as the Australian Standard AS 4005.1 [Note 1]. There is evidence that, in practice, these standards
are not always applied.

Introductory or ‘resort’ dives can be performed without a medical examination. Divers are required to fill in a
questionnaire and to declare any relevant conditions. If there is any doubt, divers should be referred for full
assessment.

Any doctor who performs pre-diving medical examinations must have completed an approved training course
in underwater medicine. Details of approved courses can be obtained from SPUMS [URL].

Pulmonary barotrauma is the most common cause of severe diving accidents, and most of the decisions
regarding fitness to scuba dive involve assessment of the respiratory system. While scuba diving, the diver
breathes air at the same pressure as the surrounding water. As the diver ascends, the air in the lungs expands
(in accordance with Boyle's law) and, unless it can escape from the air spaces easily, there is the potential for
barotrauma (pneumothorax, pneumomediastinum and arterial gas embolism).

Pressure changes on ascent are proportionally greater at shallower depths. Consequently, with respect to
altered respiratory structure or function, there is never an indication to pass divers as fit with the proviso that
they do not exceed a certain depth.

A reasonable overall level of cardiorespiratory fitness is required for safe scuba diving. Even if candidates
meet other more specific criteria, if general physical fitness and cardiorespiratory reserve seem inadequate to
cope with potential emergencies, they should be advised against diving.

Analyses of scuba diving fatalities show that medical conditions are rarely implicated, with the exception of
sudden cardiac deaths. Most accidents are caused by poor training and unsafe diving practices, not by illness.

Note 1: Information available from the Standards Australia website [URL]

Asthma or other obstructive airway disease and scuba diving

Assess carefully people with significant obstructive airway disease because there is a theoretical risk of
localised gas trapping due to airway narrowing or the presence of bullae, resulting in an increased risk of
barotrauma. Most of these patients are disqualified on spirometric criteria (see assessment). However, those
who meet the criteria should be further assessed with regard to exercise tolerance and the presence of other
smoking-associated diseases that may render them unfit to dive.

The most contentious decisions regarding fitness to dive relate to the presence or absence of asthma. A
diagnosis of asthma has been an automatic disqualification in the past, but attitudes have changed and well-
controlled asthma is now regarded as compatible with diving (as it always has been in countries other than
Australia).

People with asthma who are asymptomatic and who have normal lung function, even if on regular treatment,
may be fit to dive. However, consider that many people are given asthma medication for uncertain indications
and they may not have asthma.

For patients with a history of asthma but no current medication use, the standards state that further
investigation is needed, including bronchial provocation testing with exercise, hypertonic saline (sodium
chloride solution), histamine, methacholine or mannitol. Bronchial provocation testing is also recommended
if the patient has had asthma symptoms within the last 10 years. Those who fail bronchial provocation testing
may be retested after asthma therapy has been optimised. Annual retesting is advised.
There is no evidence of a statistically significant risk of cerebral gas embolism or other diving accidents in
people with asthma who scuba dive. Rather than harm from barotrauma, the major risk of harm is probably
related to the development of a flare-up of asthma triggered by exercise, inhalation of cold dry air or
aspiration of sea water, resulting in diminished exercise capacity and a higher risk of drowning. Swimmers,
surfers and snorkellers may be at similar risk. People with wheeze precipitated by exercise or cold should be
advised not to dive.

The use of a scuba regulator during exercise in people with asthma is associated with significant decreases in
forced expiratory volume in 1 second (FEV1).

The widely held belief that diving regulators can develop faults and produce a stream of respirable-sized
particles of salt water, and hence precipitate bronchospasm, is almost certainly untrue.

Pneumothorax and scuba diving

Any history of spontaneous pneumothorax precludes scuba diving because of the almost certain presence of
bullae or blebs on the visceral pleura. Lung bullae increase the risk of barotrauma and are a contraindication
to diving.

Although there is no evidence of increased risk, the standards also state that previous perforating chest
injuries or open chest surgery are automatic disqualifications. Chest surgery (such as coronary artery surgery)
where the pleural cavities are not entered is not specifically a disqualification.

Patients with a history of traumatic pneumothorax not involving chest wall perforation are also not
specifically excluded from diving by the standards, but could be at increased risk because of local lung
scarring. Some authorities recommend expiratory chest X-rays or high-resolution computed tomography
(HRCT) scans of the lung in such cases, but there is no sound basis to this. If there are residual abnormalities
on the plain chest X-ray, the patient should be declared unfit to dive.

Upper respiratory tract problems and scuba diving

The most common upper respiratory tract problems in scuba divers are infection, allergic rhinitis and sinus
disease. On descent and ascent, pressure of air in the middle ear and in the sinuses has to equalise with the
ambient pressure; failure of pressure to equalise leads to pain (squeeze) and, potentially, to barotrauma of the
ear. If a diver has upper respiratory tract inflammation related to infection or allergy, which can interfere with
pressure equalisation, they should not dive until their symptoms resolve. It is common practice among divers
to take decongestants such as pseudoephedrine in such situations, but this should be discouraged.

Other respiratory conditions that affect scuba diving

The standards state that any chronic lung disease or fibrotic lesion of the lung that may cause altered
compliance in lung tissue, including cystic fibrosis, should disqualify the person from diving. This lacks any
supportive evidence and is based on theoretical considerations.

There is a single case report of decompression illness related to asymptomatic sarcoidosis.

Patients with active pulmonary tuberculosis should not dive.

Assessment of respiratory fitness to scuba dive

Pre-diving medical assessment must be performed by a doctor who has completed an approved training
course in underwater medicine.

The patient history should include details of exercise tolerance, smoking history, current symptoms,
childhood symptoms that may suggest asthma, upper airway problems and any episodes that could indicate
previous pneumothorax. For specific information on assessment of people with asthma, see asthma and other
obstructive airway disease.

Spirometry, including a flow–volume loop, must be performed on all prospective scuba divers. Both the
forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) should be at least 80% of
predicted values and there should be no significant improvement (12% or more) with bronchodilators. An
FEV1/FVC ratio of less than 0.75 requires specialist opinion; however, the majority of people meeting these
criteria simply have large vital capacities and are fit to dive.
Routine bronchial provocation testing is not needed. Exercise testing with spirometry up to 30 minutes after
exercise should be performed if there is a history of exercise-induced wheeze.

Chest X-rays are not required for recreational scuba divers, but should be performed in occupational divers
and if there is any history of significant respiratory illness or any abnormal physical findings in recreational
divers.

If there is doubt as to fitness to scuba dive, the standards require referral for specialist opinion.

Key references
Fitness to scuba dive

Training and certification of recreational divers Part 1: Minimum entry-level SCUBA diving. AS 4005.1. Strathfield:
Standards Australia International Ltd; 2000.

Anderson SD, Wong R, Bennett M, Beckert L. Summary of knowledge and thinking about asthma and diving
since 1993. Discussion paper for the Thoracic Society of Australia and New Zealand. Camperdown, NSW:
Thoracic Society of Australia and New Zealand; 2004. [URL]

British Thoracic Society Fitness to Dive Group SotBTSSoCC. British Thoracic Society guidelines on respiratory
aspects of fitness for diving. Thorax 2003;58(1):3–13. [ ]

Cumming B. NDC Diving incidents report: The British Sub-Aqua Club; 1998.

Divers Alert Network (DAN). Report on decompression illness and diving fatalities. In: DAN's annual review of
recreational scuba diving injuries and deaths. Durham; 1999.

Edmonds CW, Walker DG. Snorkelling deaths in Australia, 1987-1996. Med J Aust 1999;171(11-12):591–4. [
]

Glanvill P, St Leger Dowse M, Bryson P. A longitudinal cohort study of UK divers with asthma: diving habits and
asthma health issues. Spums J 2005; 35(1):18–22.

Gottshall RW, Fedorczak LJ, Rasmussen JJ. Severity of exercise-induced bronchoconstricition during
compressed-air breathing via scuba. Spums J 2004;34(4):178–82.

McClelland A. Diving-related deaths in New Zealand 2000-2006. Diving and Hyperbaric Medicine
2007;37(4):174–88.

Simpson G. Primary lung bullae and scuba diving. Spums J 1998;28(1):10–2.

Simpson G, Roomes D. Scuba diving medical examinations in practice: a postal survey. Med J Aust
1999;171(11-12):595–8. [ ]

South Pacific Underwater Medicine Society (SPUMS) Inc. In Victoria SPUMS Policy on asthma and fitness for
diving. Melbourne: SPUMS; 2009.

Walker D. Report on Australian diving deaths 1972-1993. Melbourne: J.L. Publications [in conjunction with Divers
Alert Network SE Asia-Pacific]; 1998.

Walker D. Provisional report on diving-related fatalities in Australian waters 2002. Diving and Hyperbaric
Medicine 2008;38(1):8–28.

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Guide to pulmonary function testing and thoracic
imaging
Introduction to pulmonary function tests
Standard tests of pulmonary function include spirometry, bronchial provocation testing and static lung
volumes. Tests of gas exchange and gas transfer include analysis of arterial blood gases, pulse oximetry and
diffusing capacity for carbon monoxide (DLCO).

Pulmonary function tests are useful for:

assessing causes of breathlessness

diagnosing respiratory conditions including
–
airway obstruction
–
interstitial lung disease
–
pulmonary vascular disorders
–
respiratory muscle weakness
–
disorders of ventilatory control
assessing and monitoring asthma and other chronic chest disorders
monitoring response to treatment
assessing fitness to undergo surgery, to fly, to scuba dive and to enter certain occupations (eg the
defence forces).

Contraindications to performing lung function testing include [Note 1]:

recent cardiothoracic, intracranial, ear, nose, throat or ophthalmic surgery

recent myocardial infarction, stroke, untreated pulmonary embolism, vascular aneurysm
current pneumothorax or chest wall injury (with uncontrolled pain).

The patient must have good comprehension, the ability to cooperate with the testing, and be able to maintain a
good lip seal around a mouthpiece for spirometry.

Note 1: See also Cooper BG. An update on contraindications for lung function testing. Thorax
2011;66(8):714-23. [URL]

Spirometry and flow–volume loops

Overview
Spirometry is the most commonly performed lung function test and perhaps the most useful. The testing
equipment is relatively inexpensive, can be portable and is suitable to be used in a physician's office. Capacity
for accurate and reproducible results depends on:

quality equipment that can be calibrated and is well maintained

operator technique
the ability of the patient to follow instructions and give consistent effort; the test requires considerable
physical effort and sick patients cannot perform it well.

Not all children can adequately perform lung function tests; success and reliability depends on various factors,
including the child's age, the equipment and the operator. Extra time is generally needed to gain the
confidence of younger children, and patience is required to obtain reliable results.

Equipment calibration, infection control and quality control are addressed in detail in a guide to spirometry
commissioned by the Thoracic Society of Australia and New Zealand (TSANZ), available from the National
Asthma Council website [URL]. A video demonstrating correct technique is available from the National
Asthma Council website [URL].

Spirometry is used to measure flow and volume during a forced expiratory manoeuvre, in which the patient
first inhales to total lung capacity (TLC) and then exhales with maximum effort to residual volume (RV).
Airflow measured at the mouth during this manoeuvre depends on lung elastic recoil, respiratory muscle
strength and airway calibre, as well as patient cooperation in performing the test.

In the past, lung function equipment measured expired volume against time (a spirogram; see Figure 9.12).
Most equipment now directly measures airflow as a function of volume and records this in a flow-volume loop
(see Figure 9.11). It can also express the data as volume versus time. A maximum inspiratory flow volume
manoeuvre is usually only performed in a specialist laboratory or if upper airway obstruction is suspected.

The common parameters measured with spirometry are:

forced vital capacity (FVC)—the total volume exhaled

forced expiratory volume in 1 second (FEV1)—the volume exhaled in the first second
FEV1/FVC—expressed as a percentage or ratio (eg 70% or 0.7); may be referred to as forced expiratory
ratio (FER).

Interpretation of spirometry

Overview

Spirometry results for an individual are compared with reference values matched for age, sex, height and
ethnicity.

In the flow–volume loop of a healthy person, expiration results in a straight-sided triangle in the upper half of
the loop, and inspiration produces a semicircle in the lower half (see the normal curve in Figure 9.11).

The reference range for lung function values is approximately 80 to 120% of predicted. Tables of reference
values can be found in the TSANZ document on the National Asthma Council website [URL]. However, in
this reference document, increasing values for children to adults are not a continuum; a different set starts at
age 18 requiring different interpretation.

Some laboratories are now using lower limits of normal as a reference value. The severity of any abnormality
is determined by referring to the mean predicted value.

Spirometry is a robust test when done in accordance with established standards. There will be some individual
variability on a day-to-day basis, but this is generally less than 10% (occasionally higher).

Useful spirometry resources available on the National Asthma Council website include:

Spirometry: The Measurement & Interpretation of Ventilatory Function in Clinical Practice [URL]
Spirometry Users' and Buyers' Guide [URL].

The Pocket Guide to Spirometry is another useful and comprehensive resource with detailed advice about
performing and interpreting spirometry [Note 2].

Flow-volume loops showing normal, obstructive and restrictive patterns (Figure 9.11)
Note 2: Johns DP, Pierce R. Pocket guide to spirometry. 3rd ed. North Ryde: McGraw-Hill Medical
Australia; 2011.

Reduced FEV1 with FEV1/FVC below the predicted range

A reduced forced expiratory volume in 1 second (FEV1) with FEV1/ forced vital capacity (FVC) below the
predicted range indicates an obstructive ventilatory defect. Conditions causing airway obstruction include
asthma and chronic obstructive pulmonary disease (COPD). FEV1 is reduced but FVC is usually reduced to a
lesser extent and, as a result, the ratio of FEV1 to FVC is also reduced; see Table 9.35 and Figure 9.12 for
diagrammatic representation.

Reversible airflow limitation (bronchodilator response) is demonstrated by performing spirometry before and
about 15 minutes after giving a bronchodilator (at least 200 micrograms of salbutamol). Current guidelines
define a positive bronchodilator response as an increase above pre-bronchodilator baseline in FEV1 and/or an
increase in FVC of at least 12% and 200 mL [Note 3]. An increase of more than 12% and 400 mL is
suggestive of asthma; other important factors in diagnosing asthma are detailed in children, and adults and
adolescents.

Note 3: British Thoracic Society, Scottish Intercollegiate Guidelines Network. British Guideline on the
Management of Asthma: a national clinical guideline. Scottish Intercollegiate Guidelines Network; 2014
Global Initiative for Asthma. Global strategy for asthma management and prevention; 2014. [URL]​
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung
function tests. Eur Respir J 2005;26(5):948-68 [URL]

Reduced FEV1 with normal or increased FEV1/FVC

A reduced FEV1 with normal or increased FEV1/FVC indicates a restrictive ventilatory defect. Conditions
causing a restrictive ventilatory defect include interstitial lung disease, respiratory muscle weakness and
restrictive chest wall disease such as kyphoscoliosis. Both FEV1 and FVC are reduced and the FEV1/FVC
remains normal. See Table 9.35 and Figure 9.12 for diagrammatic representation.

Classification of ventilatory defects by spirometry (Table 9.35)

Obstructive Restrictive
FEV1 decreased decreased
normal (or decreased if very
FVC decreased
severe)
FEV1/FVC decreased normal
FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity

Spirograms showing normal, obstructive and restrictive patterns (Figure 9.12)

 FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity

Peak expiratory flow

Peak expiratory flow (PEF) measurements are useful in monitoring airway obstruction. PEF meters are
usually small handheld devices for personal use. PEF measurements should always be performed on the same
meter, as there is substantial variability in the results from different PEF meters.

PEF monitoring can be valuable in assessing the diurnal variability of airway obstruction (a characteristic
feature of asthma), as well as the response to therapy. Measuring PEF may also be useful in the diagnosis and
evaluation of occupational asthma.

The PEF technique is simple, with flow measured in Litres per minute (L/min). However, as an isolated
measurement it is not a sensitive diagnostic tool and is less sensitive than forced expiratory volume in 1
second (FEV1) when airway obstruction becomes severe. In general, PEF measurements are unreliable in
children.

Bronchial provocation testing

Bronchial provocation testing identifies airway hyperresponsiveness, which is an exaggerated response to a
bronchoconstrictor stimulus and is characteristic of asthma. The presence and severity of bronchial
hyperresponsiveness may be used to assist in diagnosis or to follow the response to treatment.

Bronchial provocation tests should only be performed by experienced operators using standard laboratory
protocols, ideally in an accredited respiratory laboratory. The stimuli used include histamine and methacholine
(direct tests), and cold dry air, nonisotonic aerosols and mannitol (indirect tests). For safety reasons, bronchial
challenge is not performed on patients with a very low forced expiratory volume in 1 second (FEV1)
(laboratory dependent, but usually FEV1 less than 1 Litre). Once a child is able to perform reliable spirometry,
bronchial provocation testing is possible.

Various drugs can interfere with provocation tests (eg beta agonists, antimuscarinic and antihistaminic drugs).
Consult the laboratory about which drugs the patient should avoid before testing. Advise patients to withhold
their usual short-acting bronchodilator for 6 hours before the test and withhold long-acting bronchodilators for
24 hours beforehand. Interpreting the results can be difficult if inhaled corticosteroids (ICS) have been started,
stopped or changed in dose in the previous 4 weeks. Whether treatment with ICS should continue in the lead
up to testing depends on the objective of the test; seek expert advice.

Viral respiratory tract infections may result in transient bronchial hyperresponsiveness, so bronchial
provocation testing should be delayed until 6 weeks after recovery.

Static lung volumes

Static lung volume measurements and the subdivisions are useful in diagnosis of lung disease, eg emphysema
and restrictive lung disease. The test is also useful to assess respiratory disability and for preoperative
evaluation (particularly before lung resection surgery).

Arterial blood gas analysis

Arterial blood gas analysis provides information to assess the blood oxygenation, acid–base balance and
adequacy of ventilation by measuring:

partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2)

pH
values for bicarbonate concentration and base excess in a blood sample.

In adults, an arterial sample is usually taken from the radial or brachial artery, preferably under local
anaesthetic. Collect the sample in a heparinised syringe, put on ice immediately, and analyse within 10
minutes.

Arterial blood gas analysis is indicated in:

management of acute respiratory disorders requiring admission to hospital

assessment of disorders associated with chronic ventilatory failure (ie with elevated PaCO2 levels)
assessment for long-term domiciliary oxygen therapy.

Normal values for the parameters measured in arterial blood gas analysis are given in Table 9.36. A guide to
acid–base changes due to different pathophysiological states is provided in Table 9.37.

Normal values for arterial blood gas analysis (Table 9.36)

Parameter Normal value

pH 7.40 plus or minus 0.04
higher than 85 mmHg breathing air
PaO2
values reduce with age; normal PaO2 = 100 minus (0.2 ×
age)
PaCO2 40 plus or minus 4 mmHg
PaCO2 = partial pressure of carbon dioxide; PaO2 = partial pressure of oxygen

Guide to interpreting acid–base status from arterial blood gas analysis (Table 9.37)

Bicarbonate
Clinical state Example pH PaCO2
concentration
7.4 plus or minus 40 plus or minus 4
normal — 22 to 28 mmol/L
0.04 mmHg
slight decrease: 1
acute respiratory mmol/L for every 10
hypercapnic COPD decreased increased mmHg increase in
acidosis
PaCO2
chronic respiratory lower limit of
COPD increased increased
acidosis normal
acute respiratory
hyperventilation increased decreased slightly decreased
alkalosis
chronic respiratory upper limit of
heart failure decreased decreased
alkalosis normal
acute metabolic
DKA decreased decreased decreased
acidosis
chronic metabolic chronic kidney
mildly decreased decreased decreased
acidosis failure
acute metabolic drug-induced,
increased increased increased
alkalosis nasogastric tube
chronic vomiting
chronic metabolic and/or chronic mildly increased increased increased
alkalosis diarrhoea
 COPD = chronic obstructive pulmonary disease; DKA = diabetic ketoacidosis; PaCO2 = partial pressure of carbon dioxide

Venous blood gas analysis

The use of venous blood gas samples to measure and follow partial pressure of carbon dioxide (PaCO2), pH
and bicarbonate concentration values has been promoted as an alternative to arterial blood gas samples. This
has mainly come from emergency department and critical care literature.

Because venous blood gas values do not correlate directly with arterial blood gas values, there is considerable
controversy as to whether venous blood gas analysis is clinically useful.

Pulse oximetry
Oxyhaemoglobin saturation (SaO2) can be measured in clinical practice with a pulse oximeter (referred to as
SpO2). Pulse oximetry involves applying a close-fitting cap or clip containing light-emitting diodes to the
finger or earlobe, which compare light absorption by oxyhaemoglobin and reduced haemoglobin. The method
is noninvasive and inexpensive. It has become widely used in the care of patients with unstable respiratory
disease or when close monitoring of oxygenation is needed.

Factors that can affect the accuracy of pulse oximetry include:

poor circulation due to reduced cardiac output or peripheral vasoconstriction

carboxyhaemoglobin or methaemoglobin—most available pulse oximeters overestimate the SaO2 in the
presence of even quite high concentrations of carboxyhaemoglobin or methaemoglobin. Causes of
carboxyhaemoglobin include smoking, smoke inhalation, haemolysis, large haematoma; causes of
methaemoglobin include dapsone, nitroprusside
poor technique in the application of the monitoring device to the finger or earlobe
faulty equipment
some nail polish colours—placing the pulse oximeter sideways on the finger may improve accuracy
dark skin.

In patients receiving supplemental oxygen, a normal SpO2 may be maintained despite worsening lung
function and the development of hypercapnia and respiratory acidosis (see Table 9.37). If there is concern
about the patient's condition (eg reduced level of consciousness), obtain arterial blood gas analysis with direct
measurement of pH, partial pressure of oxygen (PaO2) and partial pressure of carbon dioxide (PaCO2).

Diffusing capacity for carbon monoxide

The diffusing capacity for carbon monoxide (DLCO) is a measure of the capacity of the lung to transfer gas
from alveolar spaces into pulmonary capillary blood, ie the gas exchanging capability of the lung.

DLCO may be reduced in:

interstitial lung disease

emphysema
pulmonary vascular disease
anaemia (corrected for haemoglobin in most laboratories)
drug-induced pulmonary toxicity.

It is recommended that a baseline DLCO be measured before, or soon after, initiating drug treatment that
carries an increased risk of pulmonary toxicity (eg amiodarone, leflunomide, methotrexate, some oncology
drugs, some biological disease-modifying drugs). A comprehensive list of drugs causing pulmonary toxicity is
available on the Drug-induced Respiratory Disease Website [URL].

DLCO may be useful in diagnosing underlying lung disease; for example, differentiating between airflow
limitation of asthma and emphysema (in which DLCO may be decreased).

Given the variability in test results of up to 10%, it is difficult to interpret results obtained at different times or
in different laboratories. The choice of reference values for each laboratory depends on the type of equipment
used.

Exercise testing
Exercise testing is performed in specialist centres and is usually organised after a specialist physician
consultation. Incremental exercise testing to symptom-limited maximum on a cycle ergometer or treadmill
may be used for:

investigating breathlessness of unknown cause when there is no apparent lung or cardiac disease found
after routine investigations
quantifying exercise impairment due to known respiratory disease
assessing response to therapy or progression of underlying disease
assessing fitness for surgery, especially lung resection.

Exercise-induced bronchoconstriction (exercise-induced asthma) may be investigated using specific treadmill

protocols; this should be specifically requested.

Introduction to thoracic imaging

The diagnosis of most respiratory problems can be clarified using spirometry and plain chest X-ray imaging.
If further imaging is required specialist referral should be considered.

The effective dose referred to in this topic is a radiation protection quantity defined by the International
Commission on Radiological Protection and measured in the unit sievert (Sv) or millisievert (mSv). It is
useful for comparing relative risk of exposures to different parts of the body, or from different sources of
exposure (eg computed tomography [CT], nuclear medicine). The risk of cancer in an individual organ or
tissue is determined from the mean absorbed dose, which is measured in milligray (mGy).

Natural background radiation arises from various sources including cosmic and terrestrial. The average annual
natural background radiation in Australia is approximately 2 mSv.

Chest X-ray
Chest X-ray is a useful investigation when lung pathology is suspected, and should be performed before
requesting other imaging. The dose of radiation involved is very low—0.02 to 0.1 mSv depending on the
number of views taken (eg just posterior–anterior [PA] or also with a lateral view). This dose is equivalent to
4 to 18 days of background radiation.

For assessment in primary care, a chest X-ray can:

distinguish pneumonia from bronchitis

diagnose important causes of breathlessness such as pneumothorax, pleural effusion, pneumonia,
interstitial lung disease or cardiac failure
identify lung mass(es) in a patient presenting with symptoms suggesting malignancy.

Compare chest X-rays to the patient's previous X-rays when possible. In some situations a follow-up chest X-
ray should be done at an appropriate interval (eg to follow pneumonia to resolution, particularly in a smoker),
which depends on the possible pathology.

Computed tomography of the chest

General considerations
Computed tomography (CT) of the chest is the key to diagnosis of many lung diseases; however, many
requests for CT of the chest, both in general and hospital practice, lack clinical justification and are therefore
inappropriate.

CT of the chest is expensive and results in high radiation exposure. The effective dose is typically around 8
mSv [Note 4], which is equivalent to 4 years of background radiation or 400 chest X-rays. The dose to the
breast may be as high as 10 to 33 mSv. The International Commission on Radiological Protection estimates
that this dose will cause a fatal cancer in 1 in 2500 people exposed overall; the risk is higher in younger
people and females. The X-ray risk website ([URL]) has further information on risk of malignancy associated
with CT scans.

To avoid extra radiation exposure from an unnecessary repeat scan, the appropriate CT scan and its timing in
relation to the specialist appointment should be discussed with the thoracic specialist.

CT scanning of the chest can be performed as conventional CT chest with contrast injection, high-resolution
CT (HRCT) scanning or CT pulmonary angiography (CTPA).

Note 4: The dose per CT scan is variable and depends on the type of scanner and dose reduction
technology available, as well as the patient's size.

Conventional CT chest with contrast injection

Conventional CT chest with contrast injection is the modality of choice to image the chest wall, mediastinum
and pleura, and for evaluation of lung masses. It is usually the first staging investigation for lung cancer, when
it is combined with upper abdomen CT to detect liver and adrenal metastases. However, if there is a clinically
obvious pulmonary mass or pleural effusion, the first step should be a specialist referral for definitive
histological diagnosis before CT is requested. The effective dose from a chest CT scan is about 5 to 10 mSv.

High-resolution CT
In high-resolution CT (HRCT) scanning, 1 mm cuts of the lungs are examined at intervals of 7 to 10 mm. It is
used in the diagnosis and assessment of bronchiectasis and interstitial lung diseases. Only a small fraction of
the lung volume is examined by the radiologist and small focal lung lesions can be missed. The effective dose
from an HRCT scan is about 2 to 8 mSv depending on the technique used.

CT pulmonary angiography
CT pulmonary angiography (CTPA) has become the most common investigation for suspected pulmonary
embolism. A drawback is the high radiation exposure, especially to the breast. In children and females of
reproductive age, caution is needed and alternative investigations should be considered (eg ventilation
perfusion isotope lung scans).

CTPA should not be used to screen for pulmonary embolism when clinical probability of pulmonary
embolism is low; D-dimer is preferred in this group. If screening investigations are positive or clinical
suspicion is high, CTPA may be appropriate.

CTPA may be contraindicated for patients with allergies to contrast media, kidney disease or diabetic
nephropathy. The effective dose from a CTPA scan is about 7 to 10 mSv.

Ventilation perfusion isotope lung scans

Ventilation perfusion isotope (V/Q) lung scan is useful for patients who have severe reactions to contrast
agents, or if radiation exposure needs to be minimised. V/Q lung scan is the preferred modality for
investigating suspected thromboembolic pulmonary hypertension. It is also preferred over CT pulmonary
angiography, above, for investigating pulmonary embolism when minimal radiation exposure is desired. It is
of limited use in patients with known obstructive lung disease. The effective dose for a V/Q lung scan is 2 to 3
mSv.

Ultrasound of the thorax

Ultrasound of the thorax is the most sensitive method for detecting pleural effusions and for demonstrating
loculations in pleural effusions. Ultrasound should be used at the bedside for guiding diagnostic aspiration or
insertion of intercostal catheters.

Key references
Pulmonary function tests

British Thoracic Society (BTS), Scottish Intercollegiate Guidelines Network (SIGN) British guideline on the
management of asthma: a national clinical guideline [SIGN 141]. Edinburgh: SIGN; 2014.

Burton D, Johns DP, Swanney MP. Spirometer users' and buyers' guide. Melbourne: National Asthma Council
Australia; 2013. [URL]

Byrne AL, Bennett M, Chatterji R, Symons R, Pace NL, Thomas PS. Peripheral venous and arterial blood gas
analysis in adults: are they comparable? A systematic review and meta-analysis. Respirology 2014;19(2):168–75.
[ ]
Cooper BG. An update on contraindications for lung function testing. Thorax 2011;66(8):714–23. [ ]

Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention; 2014. [URL]

Johns DP, Pierce R. Spirometry: the measurement and interpretation of ventilatory function in clinical practice.
South Melbourne: National Asthma Council Ltd Australia; 2008. [URL]

Johns DP, Pierce R. Pocket guide to spirometry. 3rd ed. North Ryde: McGraw-Hill Medical Australia; 2011.

McCanny P, Bennett K, Staunton P, McMahon G. Venous vs arterial blood gases in the assessment of patients
presenting with an exacerbation of chronic obstructive pulmonary disease. Am J Emerg Med 2012;30(6):896–900.
[ ]

Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung
function tests. Eur Respir J 2005;26(5):948–68. [ ]

Pretto JJ, Roebuck T, Beckert L, Hamilton G. Clinical use of pulse oximetry: official guidelines from the Thoracic
Society of Australia and New Zealand. Respirology 2014;19(1):38–46. [ ]

Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry
for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40(6):1324–43. [ ]

Thoracic imaging

Australian Radiation Protection and Nuclear Safety Agency [website]. Australian Government; 2014. [URL]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Inhalational drug delivery devices
Overview of inhalational drug delivery devices
Introduction
Many respiratory drugs are delivered directly to the airway by inhalational devices. This achieves a higher
drug concentration at the receptors and a more rapid onset of action than systemic delivery, resulting in fewer
systemic adverse effects.

There are a growing number of different inhalational delivery devices available, which can cause confusion
for both patients and practitioners. At the time of writing, inhalational delivery devices available in Australia
for managing asthma and chronic obstructive pulmonary disease (COPD) can be categorised as:

pressurised metered dose inhalers (pMDIs) [Note 1]

multiple-dose dry powder inhalers (DPIs)
single-dose dry powder inhalers (DPIs)
nebulisers.

Table 9.38 lists the dose forms of inhaled respiratory drugs used in asthma and COPD available in Australia.

Note 1: The term pressurised metered dose inhaler (pMDI) is used rather than metered dose inhaler (MDI);
a dry powder inhaler also delivers a metered dose of drug.

Device choice
Once the drug or drug class has been chosen, an appropriate inhalational delivery device is important to
effectively deliver the drug to the airway. Table 9.38 lists dose forms of inhaled respiratory drugs, sorted by
drug type.

Patient preference and ability to use a device correctly are key considerations when selecting a suitable
device. Patient characteristics that can impact preference and ability to use a device include:

age
lung function
cognition
dexterity (may be impaired due to conditions such as arthritis)
general health status.

Also consider the patient's risk of adverse effects, as some delivery devices minimise oropharyngeal drug
deposition; this is particularly important when inhaled corticosteroids are being used.

A pressurised metered dose inhaler (pMDI) with spacer is the preferred delivery device in children younger
than 8 years. All children using a pMDI should use a small-volume spacer (see also practical points for
children with asthma). The addition of a mask is useful in children younger than 2 years of age and those
unable to form a lip seal around the mouthpiece of the spacer. Dry powder inhalers are inappropriate for
children younger than 5 years; preferably only use in children 8 years and older who can use them correctly
after training. Nebulisers can be used in any age group.

Table 9.39 lists potential advantages and precautions for the various types of inhalational drug delivery
devices available.

Whenever possible, minimise the number of different types of devices a patient is using. If a patient is unable
to use their device correctly despite repeated instruction, use an alternative device.

Inhaler technique
Repeated assessment and demonstration of correct inhaler technique are essential. Up to 90% of patients use
an incorrect technique with their device, resulting in inadequate drug delivery to the lungs. Check patient
technique and demonstrate the correct technique, if necessary, at every opportunity. This is important because
patients are often unaware they are using the devices incorrectly, and their technique can deteriorate over time.

Check inhaler technique at each review, and demonstrate correct technique if required.

Advice on device-specific technique, including instructions, videos and patient printouts, is available on the
National Asthma Council and NPS MedicineWise websites [URL] and [URL]. An inhaler technique checklist
for patients is also available [URL].

Pressurised metered dose inhalers

Pressurised metered dose inhalers (pMDIs) are multiple-dose drug delivery devices, usually containing a
propellant system such as hydrofluoroalkane [Note 2].

The closed-mouth technique is the only approved method for use of a pMDI without a spacer. The lips are
sealed around the mouthpiece of the pMDI after exhalation and before the inhaler is actuated. The open-
mouth technique, where the inhaler is actuated when held up to 6 cm away from the open mouth, is no longer
recommended.

Patients with arthritis or weakened hand muscles may have difficulty pressing down on the pMDI canister.
Using two hands to actuate the inhaler may be easier. A plastic lever device (Haleraid) can be attached to
some pMDIs to increase pressure. They are available from pharmacies or the inhaler manufacturer.

For some pMDIs correct cleaning is particularly important to prevent blockage and to ensure delivery of the
intended dose. Cleaning instructions vary for the different devices; consult product information. However, in
general:

corticosteroid-containing inhalers—never wash

cromones—wash and dry mouthpiece every night and allow to dry for 24 hours before re-using. This
prevents blockages from build-up of excess powder; additional mouthpieces may be supplied with the
device (see product information for further details)
other pMDIs—wash weekly.

Advice on technique for pMDIs, including instructions, videos and patient printouts, is available on the
National Asthma Council and NPS MedicineWise websites [URL] and [URL].

Note 2: The Respimat device does not contain a propellant; the drug is aerosolised by physical means.

Spacer devices
Using a spacer device with pressurised metered dose inhalers (pMDIs) is essential for children, and for adults
using corticosteroid-containing inhalers.

Spacers hold the aerosol cloud from the pMDI in a confined space sealed with a valve system. This allows
subsequent inhalation, which is easier for patients with poor hand-breath coordination.

In the spacer, evaporation of some of the propellant produces particles of smaller size, which may increase
endobronchial drug deposition and decrease oropharyngeal drug deposition. For inhaled corticosteroids, this
reduces oropharyngeal candidiasis, dysphonia and systemic absorption.

In most circumstances, a pMDI with spacer should be used instead of a nebuliser. This includes in first aid for
asthma flare-ups, and in other emergency situations; see management of acute asthma in children and in
adults. However, for treatment of life-threatening asthma, or if forced expiratory volume in 1 second (FEV1)
is less than 30% predicted, use of a nebuliser is recommended.

Spacer devices may be small volume, large volume, or cardboard, which is only recommended for single-
patient short-term use (ie up to 7 days). Examples of large-volume and small-volume spacer device products
are listed in Table 9.39. Smaller spacers are now available for adults.

Different spacers have different priming and cleaning requirements, depending on the material they are made
from and its propensity for forming electrostatic surface charge. Unlike the plastic spacers commonly used in
the past (eg Volumatic), polyurethane spacers (eg E-Chamber, AeroChamber Plus) may not require washing
or priming before first use. Disposable cardboard spacers do not require priming or washing.
It is best to wash a new plastic spacer before first use to reduce electrostatic charges. If it must be used
immediately, the static charge may be reduced by actuating the inhaler multiple times into the spacer.
However, the optimal number of actuations for priming is unknown; the findings from in vitro studies vary
widely.

Plastic and polyurethane spacers require regular washing with water and mild detergent (without rinsing). Air
dry the spacer; do not use a cloth to dry it. See the manufacturers' instructions for further details, including
when to replace the spacer.

Most spacers have pliable fittings, so they are compatible with all pMDIs. Adapters may be needed for spacers
with fixed fittings; these are available from pharmacies or the inhaler manufacturer.

A face mask adapter (available from pharmacies) may be used with some spacers for infants, young children,
and patients unable to form a lip seal around the spacer mouthpiece (eg people with cognitive impairment or
disabilities).

Spacers should not be used by multiple patients except in emergencies or if the manufacturer specifies they
can be autoclaved.

Advice on technique for using a spacer, including instructions, videos and patient printouts, is available on the
National Asthma Council and NPS MedicineWise websites [URL] and [URL].

Breath-actuated pressurised metered dose inhalers

A few drugs are available in breath-actuated pressurised metered dose inhalers (pMDIs), which are spring-
loaded and actuated when inhalation through the mouthpiece begins. These are useful for patients with poor
hand–breath coordination who cannot use a regular pMDI. However, when using a breath-actuated pMDI the
patient still needs to inhale slowly through the mouth and hold the breath for about 5 seconds, or as long as
possible, then breathe out gently. Breath-actuated pMDIs are not compatible with spacers.

Advice on technique for breath-actuated pMDIs, including instructions, videos and patient printouts, is
available on the National Asthma Council and NPS MedicineWise websites [URL] and [URL].

Dry powder inhalers

Dry powder inhalers (DPIs) are breath-actuated, but are not conventionally referred to as such. Good
inspiratory flow is needed to allow rapid inspiration to break up powdered drug agglomerates into respirable-
sized particles. Hence, DPIs may not be suitable during flare-ups or severe exacerbations, or for people with
severe airflow limitation, and some older people. They are unsuitable for children younger than 5 years and
preferably should only be used for children 8 years and older who can use them correctly after training.

DPIs are available in multiple-dose devices and single-dose capsule devices; some formulations contain
lactose filler.

Advice on technique for DPIs, including instructions, videos and patient printouts, is available on the National
Asthma Council and NPS MedicineWise websites [URL] and [URL].

Nebulisers
Use of nebulisers is decreasing because an equivalent bronchodilator effect can be achieved by inhalation via
a spacer using a short-acting beta2 agonist pressurised metered dose inhaler (pMDI). However, for life-
threatening asthma, or if forced expiratory volume in 1 second (FEV1) is less than 30% predicted, use of a
nebuliser is recommended.

Nebulisers produce a respirable aerosol from a drug solution. Jet nebulisation can use compressed air or
oxygen to drive the system. Oxygen is only used to drive nebulisation for patients with acute life-threatening
asthma flare-ups (see Figure 9.2 for children and Figure 9.6 for adults and adolescents). Oxygen should not be
used to drive nebulisation for patients with acute exacerbations of chronic obstructive pulmonary disease
(COPD); see also acute oxygen therapy.

Ultrasonic nebulisers use an electronic source to create droplet aerosols from the surface of the liquid. The
rate of nebulisation is usually faster than from jet nebulisers, but the nebulisers are usually more expensive
and less robust than jet nebulisers and air pumps.
Inhaled respiratory drugs and available devices
Dose forms of inhaled respiratory drugs used in asthma and COPD (Table 9.38) [NB1]

Delivery device available

Drug
pMDI multiple-dose DPI single-dose DPI nebules
Short-acting beta2 agonist (SABA)
salbutamol yes [NB2] yes yes
terbutaline yes
Inhaled corticosteroid (ICS)
beclomethasone yes [NB2]
budesonide yes yes
ciclesonide yes
fluticasone propionate yes yes yes
Short-acting muscarinic antagonist (SAMA)
ipratropium yes yes
Long-acting muscarinic antagonist (LAMA)
aclidinium yes
glycopyrronium yes
tiotropium yes [NB3] yes
umeclidinium yes
Long-acting beta2 agonist (LABA)
eformoterol yes yes
indacaterol yes
olodaterol yes [NB3]
salmeterol yes
ICS+LABA fixed-dose combination
budesonide +
yes yes
eformoterol
fluticasone furoate +
yes
vilanterol
fluticasone propionate +
yes
eformoterol
fluticasone propionate +
yes yes
salmeterol
LAMA+LABA fixed-dose combination
glycopyrronium +
yes
indacaterol
umeclidinium +
yes
vilanterol
Cromone
cromoglycate yes yes yes
nedocromil yes
COPD = chronic obstructive pulmonary disease; DPI = dry powder inhaler; pMDI = pressurised metered dose inhaler
NB1: Current at the time of writing.
NB2: Available as both a regular and breath-actuated pMDI.
NB3: Soft mist inhaler; not compatible with spacers.

Advantages and precautions of inhalational drug delivery devices

Inhalational drug delivery devices and device-specific considerations (Table 9.39) [NB1]
[NB2]

Device type Examples Advantages Precautions

Drug delivery devices
require good hand–breath coordination,
 especially if not used with a spacer
require sufficient hand strength to actuate—
compatible with a plastic lever device (Haleraid) is available
generic pMDIs spacers to for some pMDIs to assist; for other pMDIs,
pressurised suggest using two hands to actuate
metered dose Rapihaler improve lung
deposition of unsuitable for use without a spacer in
inhaler children younger than 8 years old
Respimat [NB3] drug [NB3]
not all products have dose counters
some devices need to be primed before first
use or if not used for several days (see
product information for details)

breath-actuated useful for people

pressurised with poor hand– not compatible with spacers
Autohaler breath no dose counter
metered dose
inhaler coordination

unsuitable for children younger than 5

years; preferably only use in children 8
years and older who can use it correctly
after training
require good inspiratory flow; may not be
Accuhaler suitable during flare-ups or severe
useful for people
exacerbations and in some older people
multiple-dose with poor hand–
Ellipta may not be suitable for people with severe
breath
dry powder airflow limitation
inhaler Genuair coordination
some devices need to be held in a specific
dose counter
orientation when loading drug into device
Turbuhaler (see product information for details)
clogging and dispersion of drug can occur if
the patient breathes into the device
Turbuhaler device requires extra twists for
priming before first use

Aerolizer require good inspiratory flow; may not be

suitable during flare-ups or severe
Breezhaler useful for people
exacerbations and in some older people
with poor hand–
single-dose dry may not be suitable for people with severe
Handihaler breath
powder inhaler airflow limitation
coordination
Rotacaps good dexterity required to insert capsule
into device
Spinhaler
higher doses of drug delivered, so systemic
adverse effects may be greater
expensive
longer time required to deliver equivalent
useful in some dose compared to other devices
acute situations, regular device servicing needed
eg FEV1 less not suitable for use in patients with acute
nebuliser infection due to potential to spread infective
than 30% organisms
predicted risk of acute angle glaucoma if using
antimuscarinic drugs
risk of local adverse effects (eg to face) if
using mask rather than mouthpiece when
nebulising corticosteroids

Spacer devices
Able Spacer

AeroChamber recommended for

use with pMDI
AeroChamber containing ICS or
device must be compatible with the spacer;
Plus ICS+LABA, and
spacers either have an oval or round fitting
any pMDI used
 Breath-a-Tech by children for plastic spacers, washing with detergent
reduced required before first use (without rinsing) to
Compact Space oropharyngeal reduce electrostatic adhesion; see spacer
Chamber Plus deposition— devices for more information
small volume reduction in local cleaning required weekly to monthly
E-Chamber La adverse effects depending on device (see product
Petite increased lung information), and after the resolution of a
deposition respiratory tract infection. Cleaning plastic
E-Chamber useful for people spacers too frequently can increase
Turbo with poor hand– electrostatic charge
breath
Funhaler
coordination
MEDI-spacer

Spacer Chamber
Volumatic

E-Chamber
large volume
E-Chamber La
Grande
collapsible;
to be used by one patient for up to 7 days
disposable Lite-Air useful when
only
travelling

useful for
small
children
people
with
cognitive
impairment
face mask (with people
spacer) with
disabilities
people
unable to
form a lip
seal with a
spacer

FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroids; LABA = long-acting beta2 agonist; pMDI = pressurised metered dose
inhaler
NB1: Devices listed are for delivery of drugs used in asthma and/or chronic obstructive pulmonary disease; the list of examples is current at the
time of writing.
NB2: The device and regimen depends firstly on the drug that meets the patient's clinical needs; appropriate device choice is then based on patient
preference and capabilities.
NB3: Respimat is a soft mist spray; device is not compatible with spacers.

Key references
Inhalational drug delivery devices

Basheti IA, Bosnic-Anticevich SZ, Armour CL, Reddel HK. Checklists for powder inhaler technique: a review and
recommendations. Respir Care 2014;59(7):1140–54. [ ]

Basheti IA, Qunaibi EA, Hamadi SA, Reddel HK. Inhaler technique training and health-care professionals:
effective long-term solution for a current problem. Respir Care 2014;59(11):1716–25. [ ]

Basheti IA, Reddel HK, Armour CL, Bosnic-Anticevich SZ. Improved asthma outcomes with a simple inhaler
technique intervention by community pharmacists. J Allergy Clin Immunol 2007;119(6):1537–8. [ ]

Berg E. In vitro properties of pressurized metered dose inhalers with and without spacer devices. J Aerosol Med
1995;8 Suppl 3S3–10; discussion S1. [ ]
Bosnic-Anticevich SZ, Sinha H, So S, Reddel HK. Metered-dose inhaler technique: the effect of two educational
interventions delivered in community pharmacy over time. J Asthma 2010;47(3):251–6. [ ]

Dompeling E, Oudesluys-Murphy AM, Janssens HM, Hop W, Brinkman JG, Sukhai RN, et al. Randomised
controlled study of clinical efficacy of spacer therapy in asthma with regard to electrostatic charge. Arch Dis Child
2001;84(2):178–82. [ ]

Melani AS, Bonavia M, Cilenti V, Cinti C, Lodi M, Martucci P, et al. Inhaler mishandling remains common in real
life and is associated with reduced disease control. Respir Med 2011;105(6):930–8. [ ]

National Asthma Council Australia. Using your inhaler: National Asthma Council; 2008. [URL]

Selroos O. Dry-powder inhalers in acute asthma. Ther Deliv 2014;5(1):69–81. [ ]

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Respiratory drug use in pregnancy and
breastfeeding
General information on respiratory drug use in pregnancy
There is no convincing evidence that any of the drugs commonly used to treat respiratory disorders cause
particular problems during pregnancy. As a general principle, the lowest dose achieving best control should
be used. Inhalation has particular advantages as a means of drug administration during pregnancy. The
therapeutic effect may be achieved without reaching plasma concentrations likely to have a pharmacological
effect on the fetus.

See asthma (including drug treatment) during pregnancy for a discussion of management.

The major period of danger for teratogenic effects of any drug is the first trimester of pregnancy, although
some drugs can interfere with functional development of organ systems and the central nervous system in the
second and third trimesters.

These tables provide advice on the safety of individual drugs used in respiratory disorders in pregnant
women.

General information on respiratory drug use in breastfeeding

The benefits of breastfeeding are sufficiently important to recommend that breastfeeding should be continued
unless there is substantial evidence that the drug taken by the mother will be harmful to the infant and that no
therapeutic equivalent can be given.

Most drugs are excreted only to a minimal extent in breastmilk and in most cases the dosage to which the
infant is ultimately exposed is very low and is well below the therapeutic dose level for infants. In most
situations, drugs cross the placenta more efficiently than they pass into breastmilk.

Inhalation has particular advantages as a means of maternal drug administration during breastfeeding because
the therapeutic effect may be achieved without reaching plasma concentrations that may contribute to the
drug entering breastmilk.

These tables provide advice on the safety of individual drugs used in respiratory disorders in breastfeeding
women.

Published March 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Assessing peripheral musculoskeletal symptoms in
adults
Clinically assessing peripheral musculoskeletal symptoms in adults
Approach to clinical assessment
Peripheral musculoskeletal problems are commonly encountered in primary care, contributing to about one in
five patient encounters with general practitioners in Australia. The majority of these encounters are for
longstanding complaints, particularly osteoarthritis; however, a proportion of encounters involve symptoms of
recent onset. Early diagnosis and prompt treatment may avert or minimise permanent joint damage and
disability, and are crucial if a serious pathology is suggested (see Box 12.1).

A thorough history and comprehensive physical examination are central to the initial assessment of a patient
with a peripheral musculoskeletal problem. Investigations, including imaging, play a limited role, because
they are often not necessary to make a diagnosis and rarely definitively confirm a diagnosis that could not be
made on the basis of history and physical examination alone (see Investigations for peripheral
musculoskeletal symptoms in adults and Imaging for peripheral musculoskeletal symptoms in adults for
further detail). Most problems are diagnosed by recognising a pattern of musculoskeletal involvement, extra-
articular features and risk factors for specific rheumatological conditions. For example, one or two inflamed
joints in the lower limbs after a diarrhoeal illness in a returned traveller suggests reactive arthritis; gradual
onset of pain in the knee(s) after activity in a retiree suggests osteoarthritis; bilateral symmetrical pain and
swelling in the hands and feet in a woman with no recent fever or rash suggests rheumatoid arthritis.

Consider risk factors for specific rheumatological conditions, including the patient's age, gender, family
history, ethnicity, and any relevant exposures (eg cigarette smoke, infection [including sexually acquired],
medications [including aromatase inhibitors and statins]). Assess all body systems for extra-articular features
of rheumatological disease, particularly the skin and nails, eyes, respiratory tract, nervous system,
gastrointestinal tract, cardiovascular system and genitourinary tract. Ask about any prodromal symptoms,
fatigue, night sweats, weight loss and myalgia.

Patients with apparently minor peripheral musculoskeletal symptoms must still be carefully evaluated because
their symptoms may signal a more serious condition. Clinical features that suggest a pathology requiring
urgent management are outlined in Box 12.1. Seek urgent specialist advice if any of these conditions are
likely.

Alerting features suggestive of a serious pathology requiring urgent management (Box

12.1)

Some clinical features, which may be present in a patient with peripheral musculoskeletal symptoms,
suggest a serious pathology that requires urgent management. Urgently refer the patient to a specialist or an
emergency department if a serious pathology is suggested by:

acute swelling, erythema and marked reduction in range of motion of a joint (suggestive of septic
arthritis)
unilateral headache and acute onset of visual or auditory disturbance with systemic features
(suggestive of giant cell arteritis or other vasculitis)
acute painful red eye (suggestive of uveitis, a complication of spondyloarthritides and vasculitides)
mononeuritis (suggestive of vasculitis)
digital ischaemia (suggestive of systemic sclerosis)
long-tract neurological signs (suggestive of myelopathy, for example due to atlanto-axial subluxation
in rheumatoid arthritis) or altered bladder and/or bowel function and reduced perianal sensation
(suggestive of cauda equina compression)—see Alerting features (‘red flags’) of serious pathologies
in patients with spinal pain (Table 12.20).

For information on assessing patients with spinal pain, see Assessment of low back pain, Assessment of
thoracic spine pain and Assessment of neck pain. For information on assessing patients with noninflammatory
peri-articular pain or impaired function, see Limb conditions.

For assessment of patients who are achey and tired, see The achey, tired patient.

Pattern of musculoskeletal involvement

Initial assessment of patients with peripheral musculoskeletal symptoms should focus on determining whether
the problem is:

articular, peri-articular or nonarticular in origin

monoarticular, oligoarticular (up to 5 joints), polyarticular (more than 5 joints) and/or axial
(spinal and sacroiliac joints)
inflammatory or noninflammatory in nature
acute (days to weeks) or chronic (months).

A thorough history may be required to distinguish between pain or impaired function arising from articular,
peri-articular and nonarticular structures, because the symptoms may not be experienced at the site of origin.
Articular (joint) involvement is indicated by joint-line tenderness, joint effusion or swelling with loss of
normal joint skin creases and pain on passive joint movement. Peri-articular pain may be experienced in
muscles, bones, ligaments, tendons, entheses (sites of tendon and ligament attachment to bone) and bursae.
For example, knee pain (at rest or during activity) can be related to inflammation of bursae of the knee. A
peri-articular source of nociception (eg a gluteal tendon) might be experienced as articular pain (eg in the hip
joint). Nonarticular sources of nociception (eg cervical nerve root, diaphragm, pulmonary embolus) may be
perceived as pain in the joints (eg shoulder) or peri-articular structures (ie referred pain). For example, an
expanding or dissecting aorta may be experienced as back pain.

Inflammatory pain and the resulting stiffness and restricted range of joint movement usually originates in the
synovial membrane (synovitis) or peri-articular structures such as tendon sheaths (tenosynovitis) and entheses
(enthesitis). Synovitis presents with boggy swelling, warmth and erythema of the joint, effusions, and pain
and stiffness that is relieved by activity and nonsteroidal anti-inflammatory drugs (NSAIDs). The stiffness is
more pronounced after inactivity (especially in the morning and often lasting longer than 1 hour). Associated
symptoms of fatigue, weight loss, fever and night sweats suggest the inflammation is systemic. Enthesitis
(inflammation at the sites of tendon and ligament attachment to bone) is characteristic of the
spondyloarthritides; examples include plantar fasciitis, insertional Achilles tendinitis and costochondritis.
Noninflammatory causes of joint pain, stiffness, restricted movement or impaired function are typically due
to structural changes in the joint, for example subchondral bone changes associated with articular cartilage
breakdown. Noninflammatory pain tends to be exacerbated by activity and relieved by rest. Stiffness in the
mornings or after prolonged sitting or rest is usually short-lived. The symptoms of osteoarthritis are
predominantly noninflammatory, although its pathogenesis is now recognised to have an important
inflammatory component. Joint pain and tenderness, in the absence of other abnormalities, may be due to
syndromes of altered sensation such as fibromyalgia.

The duration of a patient's symptoms influences the likelihood of a specific diagnosis. For example, an acute
presentation is likely in patients with an infection, whereas a more insidious onset of symptoms and a chronic
presentation may be seen in patients with an autoimmune disease.

Recognising the pattern of a patient's musculoskeletal symptoms—ie their origin, nature, duration, and extent
or distribution—can assist diagnosis; see Figure 12.1 for presentations with an articular origin and Figure
12.2 for presentations with a peri-articular origin. The likely diagnosis is influenced by the presence of extra-
articular features associated with, and risk factors for, specific rheumatological conditions.

Pattern recognition in musculoskeletal presentations with an articular origin (Figure 12.1)

 CPPD = calcium pyrophosphate deposition

NB1: The likely diagnosis is influenced by the presence of extra-articular features associated with, and risk factors for, specific rheumatological
conditions.

NB2: The symptoms of osteoarthritis are predominantly noninflammatory, although its pathogenesis is now recognised to have an important
inflammatory component.

Pattern recognition in musculoskeletal presentations with a peri-articular origin (Figure 12.2)

 NB1: The likely diagnosis is influenced by the presence of extra-articular features associated with, and risk factors for, specific rheumatological
conditions.

Investigations for peripheral musculoskeletal symptoms in adults

The role of investigations
Only a limited number of rheumatological conditions can be confirmed definitively by a specific investigation.
Examples include:

septic arthritis—Gram stain and culture of synovial fluid

gout or calcium pyrophosphate deposition—polarised light microscopy of synovial fluid
inflammatory myopathies or giant cell arteritis—tissue biopsy.

Although confirmation of an infection is rarely needed for the diagnosis of viral or reactive arthritis, preceding
infection can be confirmed by specific microbiological tests. For example, viral serology on paired sera,
antistreptolysin-O titre, stool culture, or urethral swabs or urine nucleic acid amplification testing (NAAT) (eg
polymerase chain reaction [PCR]) for Chlamydia trachomatis or Neisseria gonorrhoeae. See Viral
arthritis and Reactive arthritis for further detail.

Certain test results are key to the diagnosis of other rheumatological conditions. However, these conditions
are not definitively confirmed by a positive test result because results can also be positive in healthy
individuals:

systemic lupus erythematosus (SLE)—the antinuclear antibody (ANA) is positive in more than 90% of
patients with SLE, as well as up to 5% of healthy individuals
Sjögren syndrome—positive Ro (SS-A) and/or La (SS-B) antibodies on enzyme-linked immunosorbent
assay (ELISA) for antibodies to extractable nuclear antigens (ENA).

In most instances, investigations can be corroborative; however, they can also be misleading if used out of
context. Importantly, pathology testing should only be undertaken in patients with signs or symptoms
suggestive of a specific diagnosis.

Confirming inflammation
Elevation of the acute phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) can
help confirm the inflammatory nature of a disorder because they are surrogate markers of inflammation.
Although nonspecific, these markers are the most commonly used indicators of the acute phase response.
Unlike ESR, CRP concentration is not affected by age or hyperviscosity (eg hypergammaglobulinaemia). CRP
also responds more rapidly than ESR to changes in disease activity. Consider the possibility of infection in
patients with an elevated CRP concentration but a normal ESR; this is particularly relevant in patients with
established connective tissue disease. Importantly, a normal ESR or CRP concentration does not exclude an
inflammatory pathology.

A mild normochromic, normocytic anaemia with raised serum ferritin and low serum iron suggests an
anaemia of chronic disease due to systemic inflammation. Other indirect indicators of systemic inflammation
include thrombocytosis and hypergammaglobulinaemia. An elevated white cell count suggests infection rather
than inflammation.

Evidence of autoimmunity

The presence of autoantibodies can provide evidence of autoimmunity.

Antinuclear antibody (ANA) testing should only be requested if systemic lupus erythematosus (SLE) or
another connective tissue disease is suspected. A positive ANA, particularly in low titre, can occur in a
healthy individual, and a negative ANA does not exclude an autoimmune disease (although SLE would be
unlikely). The need for further testing for specific autoantibodies should be guided by the result of the ANA
test (ie testing should occur in a two-step process) (see Antinuclear antibody testing for inflammatory
connective tissue diseases for more information).

Rheumatoid factor (RF) is an autoantibody against the Fc component of immunoglobulin G (IgG). RF is

positive in approximately 75% of patients with rheumatoid arthritis, but is also found in a range of chronic
inflammatory diseases including infection, connective tissue disease and malignancy.

Antibodies to cyclic citrullinated peptides (CCP) may have a pathogenic role in rheumatoid arthritis. They are
a more specific marker of rheumatoid arthritis than RF, although the test is somewhat less sensitive. They are
present early, sometimes years before disease manifests, and are associated with poorer outcomes. Antibodies
to CCP are particularly helpful for the diagnosis of rheumatoid arthritis in a patient with a negative RF.

Antineutrophil cytoplasmic antibodies (ANCA) are found in some of the systemic vasculitides. Testing should
only be performed if the patient's clinical presentation suggests a vasculitic syndrome for which serological
confirmation is needed. Initial screening by immunofluorescence can be nonspecific. Cytoplasmic staining
(cANCA) is typically associated with granulomatosis with polyangiitis (formerly known as Wegener
granulomatosis) and peripheral staining (pANCA) with microscopic polyangiitis.

Genetic testing

Genetic testing has a limited role in confirming rheumatological diagnoses, even though genetic
predisposition is relevant to almost all rheumatological conditions. Human leucocyte antigen B27 (HLA-B27)
is associated with spondyloarthritides (more than 90% of patients with ankylosing spondylitis have HLA-B27
compared with 10% of the normal population); testing should only be performed if the patient has
inflammatory back pain and there is a strong clinical suspicion of a spondyloarthritis.

Imaging for peripheral musculoskeletal symptoms in adults

Imaging has a limited role in the diagnosis of rheumatological conditions and should not be performed if the
diagnosis can be confirmed with history and physical examination. Furthermore, because imaging often
identifies abnormalities unrelated to the patient's symptoms, it should only be used when the suspected
diagnosis can be corroborated by imaging.

Imaging is important in the diagnosis of:

fracture—plain X-ray
avascular necrosis—magnetic resonance imaging (MRI)
anterior cruciate ligament damage (eg knee pain following acute trauma in a young person)—MRI
septic discitis or osteomyelitis—MRI or computed tomography (CT).

Perform imaging only if the diagnosis cannot be confirmed with history and physical examination.

Imaging may have a role in the investigation of:

enthesitis or synovitis (for early diagnosis)—power Doppler ultrasound or MRI

 hand or knee osteoarthritis—plain X-ray
rheumatoid arthritis—sequential, yearly plain X-ray of the hands and feet
Paget disease or malignancy—radionuclide bone scan
spondyloarthritis and sacroiliitis—MRI.

The following examples of commonly requested diagnostic imaging are no more useful than comprehensive
history and physical examination and should not be used:

MRI for investigation of knee pain in the absence of trauma

ultrasound for investigation of lateral thigh pain
ultrasound for investigation of nonspecific shoulder pain suggestive of rotator cuff pathology
imaging, including CT, for investigation of nonspecific low back pain; for more information, see
Assessment of low back pain.

If initial imaging is normal but the suspicion of a fracture or acute internal derangement remains, more
specialised imaging may be warranted.

Joint aspiration in adults

General considerations
Joint aspiration (arthrocentesis) is the most important initial investigation in monoarthritis. Complications are
rare and adverse effects (eg pain, infection, bleeding) are likely outweighed by the benefits resulting from a
prompt and accurate diagnosis. Joint aspiration should be performed by experienced clinicians, using an
aseptic technique under local anaesthetic. Refer to a rheumatologist or other specialist if local expertise is
lacking. Key points on joint aspiration are shown in Box 12.2 and key points on collection and analysis of
synovial fluid are shown in Box 12.3.

The potential harms and benefits of joint aspiration should be carefully considered in the following
circumstances because the risk of complications is increased:

infection overlying a joint targeted for aspiration—the joint should be imaged to see if there is an
associated effusion. Seek urgent specialist advice if an effusion is present
extensive psoriasis over a joint targeted for aspiration—risk of iatrogenic infection is increased when
placing a needle through plaques, which may be colonised with Staphylococcus aureus. Seek specialist
advice
a prosthetic joint—refer the patient for an orthopaedic opinion. Seek urgent specialist advice if there is
concern regarding infection in a prosthetic joint.

Key points on joint aspiration in rheumatological patients (Box 12.2)

Joint aspiration enables diagnosis of infection, crystal deposition disease, and haemarthrosis.
The complication rate is low.
Ultrasound- (or computed tomography [CT]-) guided aspiration is recommended for deeper joints,
such as the hip, and for other joints that are difficult to access, such as the metatarsophalangeal joints.
When performing diagnostic aspiration, aspirating the bulk of the effusion can offer therapeutic
benefits. Aspiration should be as complete as possible without compromising patient comfort or
causing damage to the joint.
If infection, crystal deposition or haemarthrosis is suspected, use of larger bore needles (eg 19 gauge)
is recommended.
If a fracture is suspected, perform imaging of the joint because there is an increased risk of
osteomyelitis with aspiration of a fractured joint.
Therapeutic anticoagulation is not a contraindication to joint aspiration.
Key points on synovial fluid collection and analysis (Box 12.3)

2 mL or more of synovial fluid in a plain sterile tube is desirable for Gram stain, culture and polarised
microscopy. However, even a few drops of fluid may allow diagnosis. An additional 1 mL of synovial
fluid should be placed in a non-sterile anticoagulated tube (such as a full blood count tube) for
accurate cell count and differential.
All aspirated fluid should be sent for examination.
Ideally, the synovial fluid should be analysed within a few hours because, over time, changes can
occur ex vivo (eg a drop in white cell count, reduction in the number of calcium pyrophosphate
crystals, difficulty detecting monosodium urate crystals).
Direct inoculation of a blood culture bottle with synovial fluid increases the chance of a positive
synovial fluid culture result, particularly if the fluid will not be analysed immediately.

Examination of synovial fluid

Macroscopic examination of synovial fluid

Macroscopic examination of the synovial fluid may aid diagnosis. The following findings can suggest specific
conditions:

uniformly bloody fluid, which can have a yellow-brown supernatant (xanthochromia)—indicates

haemarthrosis. This contrasts with a traumatic aspirate, which usually contains streaks of blood
fat droplets—raises the suspicion of a fracture
grossly cloudy synovial fluid—consistent with infection but can also occur in crystal deposition disease,
psoriatic arthritis and other inflammatory arthritis.

Microscopic examination of synovial fluid

All synovial fluid should be examined using polarised microscopy for monosodium urate crystals and calcium
pyrophosphate crystals.

A negative result does not exclude the diagnosis of crystal deposition disease. Both the concentration of
crystals in the fluid and the experience of the observer are important factors in making a correct diagnosis.
Consultation with the laboratory, and repeated examination of the fluid or repeat aspiration of the joint, may
be appropriate if the clinician is reasonably certain of the diagnosis, especially for suspected calcium
pyrophosphate deposition.

It is important to remember that gout and calcium pyrophosphate deposition can coexist with infection.

The number of white cells and percentage of polymorphs in the synovial fluid help to differentiate between
inflammatory and noninflammatory joint conditions. Table 12.1 summarises the typical findings associated
with various diagnoses; however, there is considerable overlap so it provides a guide only. In particular,
calcium pyrophosphate deposition or severe rheumatoid arthritis may be associated with very high white cell
counts that may be mistaken for infection. Furthermore, in septic arthritis caused by a bacterial pathogen, 10
to 20% of clinically diagnosed cases are not confirmed on synovial fluid analysis. Whenever possible, a
synovial fluid (or blood, if necessary) sample should be taken for culture before starting antibiotic therapy.

Nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) of synovial fluid can
identify microorganisms not detected by synovial fluid cultures and should be performed in any patient with a
history suggestive of reactive arthritis (eg recent diarrhoea, sexually transmitted infection). NAAT should also
be considered if synovial fluid examination reveals inflammation but the results of Gram stain and culture are
negative.

Analysis of synovial fluid (Table 12.1)

Findings
Diagnosis
Macroscopic appearance WCC (106/L) % PMN
normal clear, viscous, pale yellow 0 to 200 less than 10%
noninflammatory clear to slightly turbid 200 to 2000 less than 20%
noninfective inflammatory slightly turbid 2000 to 50 000 20 to 70%
septic turbid to purulent greater than 50 000 [NB1] greater than 70%
 PMN = polymorphonuclear leucocyte / neutrophil; WCC = white cell count
NB1: Crystal deposition disease or severe rheumatoid arthritis may be associated with very high white cell counts that may be mistaken for
infection.

The achey, tired patient

Diffuse arthralgia and myalgia, often with fatigue, in the absence of joint inflammation on examination, is a
common clinical presentation. Physical examination should be combined with a thorough history (including a
comprehensive sleep history) in the initial assessment of patients who are achey and tired.

Noninflammatory causes of diffuse arthralgia and myalgia include fibromyalgia, benign hypermobility
syndrome, osteoarthritis, hypothyroidism, osteomalacia and multiple myeloma. Inflammatory causes include
polymyalgia rheumatica, giant cell arteritis, systemic lupus erythematosus (SLE), Sjögren syndrome and
polymyositis. Serious conditions such as malignancy and sepsis are infrequent causes. Frequently, chronic
diffuse musculoskeletal pain without evidence of inflammation is consistent with a diagnosis of fibromyalgia
(see Fibromyalgia), or does not fit into any diagnostic category.

Investigations are rarely helpful, but can be considered to confirm or exclude the most common differential
diagnoses. They should only be performed if the patient's signs and symptoms suggest a specific diagnosis
that cannot be made on the basis of clinical presentation alone. If indicated by the patient's presentation, the
following investigations may be useful: full blood count, erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP), creatine kinase, thyroid function, serum electrolytes (including calcium) and creatinine, serum
ferritin, blood glucose concentration, and liver biochemistry.

For more information on the role of investigations in a patient with fatigue, see Fatigue: diagnostic process.

The patient with arthralgia, myalgia and a positive antinuclear antibody (ANA) result is a common clinical
dilemma. If extra-articular features of a connective tissue disease are absent, a connective tissue disease such
as SLE is unlikely.

If a diagnosis cannot be found despite the above investigations, further investigations should not be pursued;
rather, the patient should be monitored for any changes in their condition. Reassure the patient that a
nonprogressive course suggests a benign underlying cause.

If the patient's symptoms are thought to be related to insomnia, provide advice on good sleep practices.

Nonarticular and noninflammatory disorders are discussed elsewhere—see Inflammatory connective tissue
diseases, Systemic vasculitides, Miscellaneous inflammatory syndromes, Fibromyalgia and Immune-mediated
myopathies.

Key references
Britt H, Miller GC, Henderson J, Bayram C, Valenti L, Harrison C, et al. A decade of Australian general practice
activity 2005–06 to 2014–15. Sydney: Sydney University Press; 2015. http://hdl.handle.net/2123/13974

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Undifferentiated arthritis in adults
Undifferentiated polyarthritis in adults
Assessing undifferentiated polyarthritis
The principal differential diagnoses in patients with recent-onset inflammatory polyarthritis are rheumatoid
arthritis and a self-limiting arthritis, which is often due to viral infection. The clinical features of viral arthritis
may be indistinguishable from early rheumatoid arthritis. For patients whose arthritis remits, a definitive diagnosis
is not always achieved and, often, their arthritis is presumed to have a viral cause. Most cases of viral arthritis
resolve spontaneously within 12 weeks; follow-up from recent-onset polyarthritis clinics shows that a significant
proportion of episodes of recent-onset polyarthritis resolve within 12 months.

If rheumatoid arthritis is suspected, prompt action is critical so that diagnosis and disease-modifying therapy are
not delayed; early suppression of inflammation can prevent irreversible joint damage and impact long-term
prognosis.

Urgently refer any patient with suspected rheumatoid arthritis to a specialist.

Urgently refer any patient with suspected rheumatoid arthritis to a specialist (see also Diagnosis of rheumatoid
arthritis). Rheumatologists often have fast-track triage systems for these patients and strongly encourage direct
contact by general practitioners to expedite referral or to obtain advice on treatment (eg before starting
prednisolone).

Helpful tests for recent-onset polyarthritis include:

full blood count

erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)
rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (CCP) (see Diagnosis of rheumatoid
arthritis)
antinuclear antibodies (ANA) (see Antinuclear antibody testing for inflammatory connective tissue diseases)
serum uric acid, liver biochemistry, serum creatinine and urinalysis
viral serology (see Viral arthritis).

If symptoms are of acute onset, consider tests for infection (eg blood cultures).

Iron studies and chest X-ray may be considered in some circumstances.

Managing undifferentiated polyarthritis

Specific treatment of polyarthritis depends on the diagnosis. If a specific diagnosis is suspected, treatment should
be tailored accordingly. The management of various types of polyarthritis is discussed in Rheumatoid arthritis,
Viral arthritis, Osteoarthritis, Spondyloarthritides, including psoriatic arthritis and Inflammatory connective tissue
diseases.

While awaiting diagnostic confirmation (eg through the results of investigations, disease evolution or specialist
consultation), undifferentiated polyarthritis is treated according to the severity of symptoms. Advise patients with
undifferentiated polyarthritis to stop smoking. Stopping smoking can improve response to therapy and may
attenuate disease progression. See Smoking cessation for more information on assessment of patients' smoking and
advice on smoking cessation.

For mild to moderate inflammatory joint pain, nonsteroidal anti-inflammatory drugs (NSAIDs) are most
commonly used because of their known efficacy in treating pain, stiffness and swelling associated with established
inflammatory rheumatological disease. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults).

Although paracetamol is generally less effective than NSAIDs for moderate to severe pain, its more favourable
safety profile justifies recommending it as a first-line analgesic for mild to moderate musculoskeletal pain.
Paracetamol has little, if any, anti-inflammatory effect. Paracetamol may be used in combination with an NSAID,
or instead of an NSAID if an NSAID is contraindicated or not tolerated. Use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

There is evidence to suggest that fish oil has a mild anti-inflammatory effect. However, it may take up to 3 months
for maximal effectiveness, so it may be necessary to co-prescribe fish oil with an NSAID and/or paracetamol
initially. Use:

fish oil at least 2.7 g (omega-3) orally, daily (see Table 12.8 for preparations).

See Principles of fish oil use for musculoskeletal conditions in adults for more information.

For patients with severe symptoms and associated impaired function, low-dose prednis(ol)one may be required.
However, starting prednis(ol)one before specialist review may delay subsequent diagnosis. There should always be
a plan for early withdrawal because long-term use is not justified in this setting. If considered essential for rapid
symptom relief, use:

prednis(ol)one 5 to 15 mg orally, daily.

Early specialist review is crucial if prednis(ol)one is ineffective at a dose at the upper end of the range.

Intramuscular administration of corticosteroids is sometimes used, based on a theoretical reduction in overall

corticosteroid exposure compared to oral therapy. A single dose of intramuscular corticosteroid has a prolonged
effect (up to 8 weeks) and repeat doses are often unnecessary.

If intramuscular therapy is indicated, the usual dosage is:

methylprednisolone acetate 120 mg intramuscularly, as a single dose.

Although NSAIDs and prednis(ol)one can rapidly control inflammation, they are inadequate to prevent joint
damage and achieve disease control. Seek urgent specialist advice if joint inflammation is still present at 12 weeks,
because treatment with a disease-modifying antirheumatic drug (DMARD) should be considered.

Seek urgent specialist advice if joint inflammation is still present at 12 weeks.

Methotrexate (in combination with folic acid) can be given in the setting of early undifferentiated polyarthritis that
is not controlled with the above regimens or that recurs on withdrawal of prednis(ol)one. It should be dosed once
weekly at the dose used for rheumatoid arthritis (see Conventional synthetic disease-modifying antirheumatic
drugs for dosage). Methotrexate appears to be particularly beneficial for preventing progression to erosive
definitive rheumatoid arthritis in the presence of antibodies to cyclic citrullinated peptides (CCP). The immediate
or subsequent initiation of one or more DMARDs would generally be on the advice of a specialist, who would also
facilitate the withdrawal of prednis(ol)one. NSAIDs are often continued even after a DMARD is started, but the
aim is to reduce or withdraw both NSAIDs and prednis(ol)one.

Undifferentiated monoarthritis in adults

Assessing undifferentiated monoarthritis
Common causes of monoarthritis include infection (ie septic arthritis), trauma and crystal deposition disease (see
Gout and Calcium pyrophosphate deposition). Septic arthritis is a rheumatological emergency that requires
immediate referral. Conditions that usually involve multiple joints, such as reactive arthritis (eg following
Chlamydia trachomatis or Neisseria gonorrhoeae infection), can also initially present as a monoarthritis. Other
less common noninflammatory causes of pain in a single joint include haemarthrosis, juxta-articular fracture and
osteonecrosis.

Joint aspiration is the most critical diagnostic procedure and can exclude significant joint inflammation. Consider
also nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]) of urine samples if sexually
transmitted infection is possible. Cultures of other sites (blood, cervix, urethra, pharynx) may also be indicated if
gonococcal infection is possible, and susceptibility testing should be performed because of regional differences in
the susceptibility of N. gonorrhoeae and emerging resistance to ceftriaxone.

Plain X-ray is indicated if the monoarthritis is associated with trauma. If initial imaging is normal but the suspicion
of a fracture or acute internal derangement remains, more specialised imaging may be warranted.

In the setting of suspected acute septic arthritis, plain X-ray is rarely useful because it generally shows only soft-
tissue swelling; the destructive changes of septic arthritis usually take 10 to 14 days to become apparent. If a
swollen joint does not settle with treatment with an anti-inflammatory drug (eg an NSAID or prednisolone), then
plain X-ray may be considered to detect unsuspected underlying pathology, including fracture, osteomyelitis,
avascular necrosis, chondrocalcinosis or a tumour.

In undifferentiated monoarthritis, blood tests are usually nonspecific. However, an elevated erythrocyte
sedimentation rate (ESR) and/or C-reactive protein (CRP) concentration supports the diagnosis of an infective or
inflammatory condition. There are several traps in interpreting blood tests:

A normal white cell count does not exclude infection, especially in old or immunosuppressed patients.
Blood cultures are only positive in about 50% of cases of nongonococcal septic arthritis.
Serum uric acid concentration may be normal in patients with acute gout. Conversely, hyperuricaemia alone
is insufficient to diagnose gout.
Testing for autoantibodies such as rheumatoid factor (RF) and antinuclear antibody (ANA) is rarely helpful
in an acute monoarthritis.

Diagnostic clues and potential pitfalls with monoarthritis are shown in Box 12.4.

Diagnostic clues and potential pitfalls with monoarthritis (Box 12.4)

Haemarthrosis

Suspect haemarthrosis in anticoagulated patients with acute monoarthritis, particularly in the

weightbearing or glenohumeral joints. Haemarthrosis can occur even when the international normalised
ratio (INR) is in the therapeutic range.
For patients with recurrent haemarthrosis due to haemophilia, expert advice should be sought from a
haematologist before joint aspiration because the patient will need coagulation factors.
Haemarthrosis in an elderly patient may be associated with acute synovitis secondary to calcium
pyrophosphate deposition.

Trauma

Even minimal trauma can cause an articular fracture in an osteoporotic patient.

Trauma can precipitate flares of crystal deposition disease.

Fever

Temperature can be normal in patients with septic arthritis (20% are afebrile) or increased in patients with
crystal deposition disease or other inflammatory processes.

Septic arthritis

Immunosuppressed patients may have a more indolent presentation of septic arthritis, with only mild pain
or swelling.
Septic arthritis is not necessarily excluded by finding two or three involved joints; 10 to 20% of patients
have an oligoarticular presentation.
Presence of crystals in synovial fluid does not exclude sepsis.
Infection in people who inject drugs often occurs in atypical sites, such as the sternoclavicular,
costochondral, shoulder, vertebral or sacroiliac joints.
False-negative synovial fluid culture results can be seen in patients previously treated with antibiotic
therapy.

If a chronic inflammatory monoarthritis remains undiagnosed after 8 weeks, refer the patient to a specialist to
determine whether synovial biopsy is indicated to exclude rare causes, such as malignancy or chronic fungal or
mycobacterial infections.

Managing undifferentiated monoarthritis

In general, therapeutic aspiration of large tense joint effusions will provide pain relief and reduce potential damage
from increased pressure within the joint capsule (see also Joint aspiration in adults). If symptoms persist and the
diagnosis remains unclear, re-aspiration after 1 or 2 days is reasonable.

Specific treatment of monoarthritis depends on the diagnosis. If a specific diagnosis is suspected, treatment should
be tailored accordingly.

Septic arthritis, even if the diagnosis is only suspected, requires urgent hospital referral. See Septic arthritis for a
discussion of management (including antibiotic regimens).

For management of monoarthritis associated with crystal deposition disease, see Gout or Calcium pyrophosphate
deposition.

Traumatic (nonfracture) monoarthritis will be helped by rest, the application of ice, simple analgesia and gentle
mobilisation.

Inflammatory monoarthritis where sepsis is not suspected can be treated with intra-articular corticosteroids and
nonsteroidal anti-inflammatory drugs (NSAIDs) (see Principles of analgesic and anti-inflammatory drug use for
musculoskeletal conditions in adults).

Undifferentiated oligoarthritis in adults

An oligoarticular presentation is most suggestive of a spondyloarthritis (including ankylosing spondylitis, psoriatic
arthritis, reactive arthritis and enteropathic arthritis) or seronegative arthritis. However, conditions that usually
present as single-joint arthritis (infection, gout) can also cause oligoarthritis, as can still-evolving polyarthritis.

Key references
Wevers-de Boer KV, Heimans L, Huizinga TW, Allaart CF. Drug therapy in undifferentiated arthritis: a systematic
literature review. Ann Rheum Dis 2013;72(9):1436–44.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Assessing musculoskeletal symptoms in children
and adolescents
Introduction to assessing musculoskeletal symptoms in children and
adolescents
Musculoskeletal symptoms are common in children and adolescents. In the majority of cases, they are
noninflammatory in nature and management is centred on providing reassurance and education regarding
their cause (see Noninflammatory musculoskeletal pain in children and adolescents). The challenge for
general practitioners is to distinguish between noninflammatory conditions and a systemic inflammatory
disease or other serious pathology (eg malignancy, infection, fracture). See Pattern of musculoskeletal
involvement for general advice on distinguishing between inflammatory and noninflammatory symptoms;
additional detail on making this distinction in children and adolescents is included in history,
examination and investigations.

Inflammatory rheumatological diseases in children and adolescents include:

juvenile idiopathic arthritis (JIA), including enthesitis-related arthritis and psoriatic arthritis
connective tissue diseases, such as juvenile dermatomyositis and systemic lupus erythematosus (SLE)
systemic vasculitides and other inflammatory syndromes, such as immunoglobulin A
vasculitis (formerly known as Henoch–Schönlein purpura), Kawasaki disease, periodic fever
syndromes and acute rheumatic fever.

Accurate diagnosis is aided by careful attention to particular features on history and examination, and
judicious subsequent investigations, if necessary. Early diagnosis and prompt treatment may avert or
minimise permanent joint damage and disability, and are crucial if a significant pathology is suggested.

Assessing musculoskeletal symptoms in children and adolescents:

history
A thorough history can help determine whether the problem is articular or nonarticular in origin;
inflammatory or noninflammatory in nature; acute (days to weeks) or chronic (months); oligoarticular
(up to 4 joints) or polyarticular (more than 4 joints) and/or axial (spinal and sacroiliac joints). In children
and adolescents with musculoskeletal symptoms, important aspects of history include:

site of pain—articular pain is common in juvenile idiopathic arthritis (JIA), while nonarticular pain
may occur in a wide range of conditions, including pain amplification syndromes, fracture and
malignancy
duration of symptoms—in a child or adolescent with arthritis, longstanding symptoms are more likely
to be due to JIA than acute symptoms. Acute symptoms are more likely to be caused by reactive
arthritis, subacute osteomyelitis with joint involvement, or septic arthritis
variation in symptoms over the day—stiffness after inactivity (especially in the morning) suggests an
inflammatory pathology, whereas pain after activity suggests a noninflammatory cause. In toddlers,
morning stiffness may manifest as wanting to be carried on waking or crying with morning nappy
changes
degree of interference with daily activities—symptoms that interfere with daily activities strongly
suggest a significant underlying pathology. Such interference may manifest as withdrawal from play,
sporting or hobby activities; apparent loss of motor skills (eg a toddler stopping walking); or absence
from school
change in pattern of sleep—night pain that wakes the child suggests a serious underlying pathology
presence of systemic features—fever, malaise, fatigue, weight loss, skin rash or persistent diarrhoea are
alerting features of a systemic pathology
recent history of infection or antibiotic use—reactive arthritis is a differential diagnosis
history of infectious contacts—a history of tuberculosis infection or environmental exposure may be
relevant in a child or adolescent with arthritis in a single joint; tuberculous arthritis is a differential
diagnosis
family history of rheumatological disease—particularly relevant with the spondyloarthritides, but may
 also be a clue to pain ‘role models’ in pain amplification syndromes.

Assessing musculoskeletal symptoms in children and adolescents:

examination
In combination with a thorough history, a comprehensive examination can help determine the origin, nature,
duration and distribution of musculoskeletal symptoms. In children and adolescents with musculoskeletal
symptoms, important aspects of examination include:

examination of joints for swelling or, in the absence of swelling, two of the following:
pain at the extremes of joint range of movement (‘stress pain’)
loss of range of motion
joint-line tenderness.
These are the cardinal clinical features of an inflammatory arthritis and their absence excludes
inflammatory joint disease as the basis for joint symptoms. Joints affected by inflammatory arthritis
may not always be symptomatic, so it is important to examine all joints
detection of signs of chronicity—localised muscle wasting, leg length inequality or fixed flexion
deformity suggest longstanding joint inflammation
detection of extra-articular features—specific patterns of extra-articular features are associated with
some inflammatory rheumatological diseases; for example, psoriatic rash and nail pitting with psoriatic
arthritis; synechiae secondary to uveitis with juvenile idiopathic arthritis (JIA), particularly the
oligoarticular form; pallor, mouth ulcers, rash, alopecia or muscle weakness with connective tissue
diseases
examination of growth parameters such as weight, height and body mass index (considered in the
context of pubertal status)—significant deviations from normal percentiles are an alerting feature of a
systemic pathology
elicitation of features suggestive of a pain amplification syndrome—multiple tender points, extreme
hyperaesthesia and bizarre gait patterns are characteristic of a pain amplification syndrome.

Assessing musculoskeletal symptoms in children and adolescents:

investigations
Only a limited number of rheumatological conditions can be confirmed definitively by a specific
investigation. In most instances, investigations can be corroborative; however, they can also be misleading if
used out of context. Importantly, pathology testing or imaging should only be undertaken in patients with
signs or symptoms suggestive of a specific diagnosis.

Useful investigations in the assessment of children and adolescents with a suspected inflammatory
rheumatological disease include:

erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) concentration, full blood count
(FBC)—elevation of the acute phase reactants CRP and ESR can help confirm inflammation; however,
it is possible to have an inflammatory rheumatological disease without abnormalities in these tests.
FBC may identify differential diagnoses such as leukaemia (suggested by the presence of peripheral
blasts or cytopenias). An elevated white cell count suggests infection rather than inflammation
tests for evidence of preceding streptococcal infection, such as antistreptolysin-O titre (ASOT)—
indicated in children or adolescents with migratory polyarthritis, in whom rheumatic fever is a possible
diagnosis (see Acute rheumatic fever for more information on diagnosis)
serum ferritin concentration—often markedly elevated (greater than 1000 micrograms/L) in systemic
arthritis, out of proportion to its role as an acute phase reactant
other biochemical assessments (eg muscle enzyme levels, liver biochemistry, kidney function tests)
and/or serological testing for connective tissue disease (eg antinuclear antibodies [ANA], antibodies to
double-stranded DNA [dsDNA], antibodies to extractable nuclear antigens [ENA])—indicated if there
are features of multisystem disease on history or examination
urinalysis—checking for proteinuria and/or haematuria is useful for evaluating possible vasculitis or
connective tissue disease; checking for sterile pyuria is useful for evaluating possible reactive arthritis
plain X-ray—may be indicated for conditions where bone changes are expected (eg fracture, the
osteochondritides [including Perthes disease], osteomyelitis, tarsal coalition), but is usually not helpful
in the initial assessment of a synovitis
ultrasound—can be useful for differentiating tendon sheath from joint inflammation and also in
synovitis of the hip
radionuclide bone scan and magnetic resonance imaging (MRI)—may be indicated in specific
situations, particularly in differentiating the mimics of juvenile idiopathic arthritis (JIA) and/or bone
 inflammation
synovial fluid aspiration—detection of a microbial pathogen on nucleic acid amplification testing
(NAAT) (eg polymerase chain reaction [PCR]) or culture of synovial fluid is diagnostic of infection,
and synovial fluid aspiration should be performed in children or adolescents with suspected septic
arthritis as part of acute management in hospital. Local or general anaesthesia may be required,
depending on the affected joint and the patient's age. Crystal deposition disease is extremely rare in
childhood; therefore, aspiration for microscopy alone is not usually helpful in the differential diagnosis
of an inflammatory arthritis in children.

Key references
McGhee JL, Kickingbird LM, Jarvis JN. Clinical utility of antinuclear antibody tests in children. BMC Pediatr
2004;4:13.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Principles of immunomodulatory drug use for
rheumatological diseases in adults
Introduction to immunomodulatory drug use for rheumatological
diseases in adults
The goal of immunomodulatory therapy in inflammatory rheumatological diseases is sustained remission;
cure is usually not possible and patients generally require ongoing immunomodulatory therapy. The
immunomodulatory drugs used in rheumatology are systemic corticosteroids, conventional synthetic disease-
modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs)
and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Regular monitoring of disease
activity and adjustment of immunomodulatory therapy is required to achieve disease targets; where
appropriate, specific advice is included in the clinical topics.

The management of patients with inflammatory rheumatological disease is complex and an integrated
multidisciplinary approach is often required. The general practitioner can support the interventions of the
rheumatologist (eg by monitoring adherence and managing residual symptoms), as well as proactively
prevent, screen for and manage comorbidities (eg cardiovascular disease, depression) and adverse effects (eg
infections) associated with inflammatory rheumatological disease and its treatment.

When an immunomodulatory drug is prescribed, the patient or the patient's carer should be provided with
information about the goals of treatment, potential adverse effects and how to minimise them, screening
requirements before and during treatment, and the importance of monitoring. This topic includes practical
information on using these drugs for rheumatological diseases in adults. For comprehensive drug information,
including precautions, contraindications, adverse effects and drug interactions, consult an appropriate drug
information resource. Patient medicine information sheets for many of the drugs used in rheumatology can be
accessed from the Australian Rheumatology Association website [URL].

General approach to immunomodulatory drug use for

rheumatological diseases in adults
Untreated active systemic inflammatory disease is associated with an increased risk of infection, as is
treatment with immunomodulatory therapy. The relative risk of infection varies between individual
immunomodulatory drugs and is greatest in patients treated with high-dose corticosteroids, biological disease-
modifying antirheumatic drugs (bDMARDs), targeted synthetic disease-modifying antirheumatic drugs
(tsDMARDs) and combination therapy. Clinicians must always be alert to the possibility of infection
(including opportunistic infection), particularly because the usual symptoms and signs of infection (eg fever)
are often absent in patients treated with immunomodulatory drugs. If a patient develops symptoms or signs of
infection, withhold disease-modifying antirheumatic drug (DMARD) therapy until a thorough assessment is
completed. The DMARD is usually restarted once the infection has resolved. In contrast, corticosteroids
should not be withheld, even if infection is confirmed. If the patient has severe infection and hypothalamic–
pituitary–adrenal axis suppression, the corticosteroid dose may need to be increased; see Glucocorticoid-
induced hyperglycaemia. Discuss any serious infection with the treating specialist.

DMARD therapy should be withheld in patients who are acutely unwell (eg dehydration, renal impairment)
and specialist advice should be sought.

Considerations before starting immunomodulatory therapy

Before starting immunomodulatory therapy, it is important to:

screen the patient for active infection (see Screening for infection and vaccination for further details)
check for history of tuberculosis infection and environmental exposure (see Screening for infection and
vaccination for details on tuberculosis testing and treatment)
assess vaccination status (see Screening for infection and vaccination for further details)
assess the patient's serology and, as appropriate, consider vaccination, treatment or prophylaxis (see
Screening for infection and vaccination for recommendations)
 perform investigations to determine kidney, liver and bone marrow function, as well as chest X-ray. The
results of these investigations may influence the choice of immunomodulatory drug and its dosing
regimen, and provide a baseline measurement against which future results can be compared
check for history of malignancy, including melanoma [Note 1]
discuss reproductive health, including contraception, with patients of childbearing potential (see also
Immunomodulatory drug use and reproductive health)
perform a medication review and, if necessary, consult an appropriate drug interactions resource
determine the frequency of monitoring required, and communicate this to the patient and other
healthcare practitioners involved in their care. The specialist will determine the appropriate monitoring
regimen based on the adverse effect profile of the immunomodulatory drug(s) used and patient factors
(eg disease activity, comorbidities). Monitoring is most frequent in the first 3 to 6 months of therapy and
after dose increases because adverse effects are more likely. Once the patient's drug regimen and disease
activity are stable, the frequency of monitoring can be reduced, but should not stop completely.

For further detail, see systemic corticosteroids (Table 12.3), conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs) (Table 12.4), biological disease-modifying antirheumatic drugs
(bDMARDs) (Table 12.5) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (Table
12.6).

Note 1: Data on the risk of malignancy with immunomodulatory therapy are conflicting and incomplete.
While malignancy risk is known to be drug specific, the particular risk posed by individual
immunomodulatory drugs has not been elucidated. For example, Australian data suggest an increased risk of
melanoma in patients with rheumatoid arthritis treated with methotrexate. However, it is not clear whether
the increased risk relates to treatment with methotrexate or the disease process, and international studies
have not replicated these findings. The choice of immunomodulatory drug in a patient with a history of
malignancy requires shared decision-making between the patient and their specialists, and should be
informed by the benefit–harm profile of the treatment options in the individual patient.

Considerations throughout immunomodulatory therapy

When reviewing the patient after immunomodulatory therapy has started, it is important to:

ask about adherence to immunomodulatory therapy

assess disease activity to determine whether the immunomodulatory therapy is effective—where
appropriate, advice on specific disease targets is included in the clinical topics; the general practitioner
should refer the patient back to the rheumatologist if these targets are not met
assess for adverse effects
monitor kidney, liver and bone marrow function according to the schedule determined. This is not
required for patients treated with corticosteroid or hydroxychloroquine monotherapy
ensure that vaccinations remain up to date (see Screening for infection and vaccination)
assess patients who present with fever, cough, systemic symptoms or unexplained illness for
opportunistic infection, including tuberculosis or fungal infection
continue to screen for and optimise the management of osteoporosis, residual pain and other common
comorbidities (eg cardiovascular disease, diabetes, depression)
maintain vigilance for malignancy and ensure that malignancy screening that is appropriate for the
patient's age and gender remains up to date; this might include skin checks every 6 to 12 months
(depending on skin type and sun exposure) to detect early skin cancer. Encourage patients to monitor
their skin for new or changing lesions. If malignancy is detected, immunomodulatory therapy may need
to be interrupted—seek specialist advice
for patients planning travel, refer to an infectious diseases or travel medicine specialist for travel advice
(vaccination, prevention and treatment of infection).

For further detail, see systemic corticosteroids (Table 12.3), conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs) (Table 12.4), biological disease-modifying antirheumatic drugs
(bDMARDs) (Table 12.5) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) (Table
12.6).

Screening for infection and vaccination in adults with

rheumatological diseases
The optimal approach to screening, vaccination and antimicrobial prophylaxis to minimise the risk of
infection in patients with inflammatory rheumatological diseases is not known; the following
recommendations offer a practical approach based on expert consensus. For guidance on when to give
antimicrobial prophylaxis (eg Pneumocystis jirovecii pneumonia [PJP] prophylaxis) for patients taking
corticosteroids or immunomodulatory drugs, see Assessing the need for antimicrobial prophylaxis in
immunocompromised adults without HIV infection.

Screen patients for infection before starting immunomodulatory therapy. Take a detailed infection history,
considering potential bacterial (including latent or active tuberculosis), fungal, viral (including herpes
simplex, varicella-zoster, hepatitis B and C, and HIV), and parasitic infections. Consider the environmental
risk of tuberculosis (eg contact with tuberculosis patients, at-risk country of origin, prolonged stay in or plans
to travel to an endemic area) or other infections (eg history of prolonged stay in or plans to travel to the
tropics or areas where Strongyloides stercoralis or Burkholderia pseudomallei are endemic). Perform a
thorough physical examination, looking for signs of active infection. Treat any active infection identified
before starting immunomodulatory therapy. In patients treated with immunomodulatory therapy, clinicians
should remain alert to the possibility of infection (including opportunistic infection)—see General approach to
immunomodulatory drug use for advice on managing immunomodulatory therapy in patients who develop
infection.

Assess the patient's vaccination history (including Bacille Calmette-Guérin [BCG]) and serology. In
particular, perform hepatitis B and C virus serology in all patients [Note 2]; perform HIV serology if the
patient's history suggests they are at risk of HIV infection; and consider varicella-zoster serology, particularly
in patients planned for treatment with tofacitinib.

Perform a tuberculin skin test (Mantoux) or tuberculosis-specific interferon gamma release assay (IGRA) for
all patients who are likely to be treated with a biological disease-modifying antirheumatic drug (bDMARD) or
targeted synthetic disease-modifying antirheumatic drug (tsDMARD) (with the exception of apremilast) [Note
3].

Patients with latent tuberculosis (TB) are at increased risk of reactivated infection when they are treated with
immunomodulatory drugs. For patients found to have latent TB infection, seek expert advice. Similarly,
patients with hepatitis B are at increased risk of reactivated infection when they are treated with
immunomodulatory drugs. For information about hepatitis B prophylaxis in patients taking
immunomodulatory drugs, see Patients undergoing cancer chemotherapy or immunosuppression.

To minimise the risk of vaccine-preventable infections, ensure all patients with inflammatory
rheumatological disease are kept up to date with recommended vaccines (including influenza and
pneumococcal vaccines) [Note 4]. If vaccination is necessary, it is ideally performed before starting
immunomodulatory therapy because the safety of live vaccines, and immunological response to both live and
inactivated vaccines, may be reduced in immunosuppressed patients. However, if immediate treatment of
rheumatological disease is required, immunomodulatory therapy should not be delayed so that vaccination can
be completed. Nor should inactivated vaccines be withheld after immunomodulatory (including bDMARD)
therapy is started, even though immunological response may be reduced. If there is uncertainty about the level
of immunosuppression or when vaccine administration may be safe, seek specialist advice.

The patient's risk of exposure to vaccine-preventable infections can be further reduced by ensuring their
household contacts are kept up to date with recommended vaccines.

Live vaccines (measles, mumps, rubella, varicella, zoster, yellow fever, Japanese encephalitis, Bacille
Calmette-Guérin [BCG], oral typhoid) should not be given to patients already taking an immunomodulatory
drug; they should be given at least 4 weeks before starting therapy to minimise the risk of adverse effects and
vaccine-related disease. The exceptions are varicella and zoster vaccines, which can be given to patients
treated with low-level immunosuppression but should not be administered to highly immunosuppressed
patients [Note 5] [Note 6].

Inactivated vaccines should ideally be given at least 2 weeks before starting immunomodulatory therapy for
maximal immunogenicity. When inactivated vaccines are given to patients treated with immunomodulatory
therapy, larger or repeat doses are sometimes required. Alternatively, revaccination can be considered (usually
after 3 months) for patients who have achieved only a low antibody titre—seek specialist advice.

For more information, see ‘Vaccination for people who are immunocompromised’ in the Australian
Immunisation Handbook [URL].

For detailed advice about vaccination of patients with inflammatory rheumatological diseases, see the
Australian recommendations [Note 7].

For patients planning travel, refer to an infectious diseases or travel medicine specialist for travel advice
(vaccination, prevention and treatment of infection).

Note 2: Detailed information about testing for hepatitis B virus is provided in the National HBV testing
policy [URL].
Note 3: False-negative results can occur in patients who have an acute systemic illness or are
immunosuppressed. If the patient has risk factors for latent tuberculosis infection or there is clinical
suspicion of tuberculosis, consider repeating the screening test after 1 to 3 weeks.

Note 4: For recommended vaccinations, see the Australian Immunisation Handbook [URL].

Note 5: Low-level immunosuppression is defined as prednis(ol)one less than 20 mg/day or equivalent;

methotrexate up to 0.4 mg/kg/week; azathioprine up to 3 mg/kg/day.

Note 6: See the Australian Immunisation Handbook [URL] for recommendations for the use of varicella and
zoster vaccines. For seronegative patients without reliable history of chickenpox or shingles, give varicella
vaccine; for seropositive patients, consider zoster vaccine.

Note 7: Wong PKK, Bagga H, Barrett C, Hanrahan P, Johnson D, Katrib A, et al. A practical approach to
vaccination of patients with autoimmune inflammatory rheumatic diseases in Australia. Internal Medicine
Journal 2017;47(5):491-500. [URL]

Immunomodulatory drug use and reproductive health in adults with

rheumatological diseases
The choice of immunomodulatory therapy in patients of childbearing potential needs to be carefully
considered—seek specialist advice. For many immunomodulatory drugs there is a paucity of data to inform
treatment decisions. Collaborative decision-making involving the patient, rheumatologist, general practitioner
and, as necessary, other specialists (eg obstetric drug information service providers [Note 8]) is crucial.

When immunomodulatory therapy is initiated in men or women of childbearing potential, consider the
effect of the drug on long-term fertility (such as premature gonadal failure with cyclophosphamide), as well as
the need for effective contraception (such as when a teratogenic drug is used).

In men and women who are planning pregnancy, choice of therapy should take into account the impact of
the drug on fertility. In women who are planning pregnancy or pregnant, choice of therapy should also take
into account the safety of the drug in pregnancy, as well as the need to implement measures that may reduce
the risk of harms (such as folic acid supplementation for patients treated with sulfasalazine or therapeutic drug
monitoring for patients treated with cyclosporin). The risks of immunomodulatory therapy to the fetus or
infant must be balanced against the risks associated with poor disease control if therapy is discontinued.
Ideally, these factors should be considered before pregnancy is planned, to ensure that drug therapy can be
continued throughout the perinatal period.

For women who are breastfeeding, consideration should be given to the compatibility of the drug with
breastfeeding. Ideally, this should be considered before pregnancy is planned, to ensure that therapy can be
continued throughout the perinatal period.

There are some data to suggest that the following drugs may, with appropriate precautions, be safely used in
pregnancy: azathioprine, cyclosporin, hydroxychloroquine, prednis(ol)one, sulfasalazine and tumour necrosis
factor (TNF) inhibitors. Specific information on the use of these and other immunomodulatory drugs in
patients of childbearing potential (including males) or pregnant or breastfeeding women, is available from the
Australian Rheumatology Association [URL]. Guidelines are also available from the British Society for
Rheumatology and British Health Professionals in Rheumatology [Note 9]. For breastfeeding compatibility
recommendations and the Australian Therapeutic Goods Administration (TGA) pregnancy categorisation for
individual drugs, see Drug use in pregnancy and breastfeeding. However, note that it is not intended that the
TGA pregnancy category would be the sole basis of decision-making in the use of a drug during pregnancy, in
part because it does not provide information about the balance of harms and benefits in a particular patient.
Furthermore, the category does not indicate the stage(s) of fetal development that might be affected by drug
exposure and may not reflect the most up-to-date information about the drug's use in pregnancy.

Note 8: Contact details for obstetric drug information services available to health professionals and/or
consumers in each Australian state (except Tasmania) are available from the TGA website [URL].
Note 9: Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al. BSR and BHPR
guideline on prescribing drugs in pregnancy and breastfeeding-Part I: standard and biologic disease
modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford) 2016; 55(9):1693-7. [URL]

Perioperative use of immunomodulatory drugs in adults with

rheumatological diseases
When deciding whether to continue immunomodulatory therapy perioperatively, the potential consequences
of postoperative infection should be weighed against the potential consequences of a perioperative flare in
disease activity—seek specialist advice.

Seek specialist advice about the use of immunomodulatory drugs during the perioperative period.

Systemic corticosteroids must be continued perioperatively. Consider the need for higher doses if there is a
risk of hypothalamic–pituitary–adrenal axis suppression (see Glucocorticoid-induced hyperglycaemia).

Most conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) can be safely continued
perioperatively. However, cyclophosphamide should not be continued in patients having elective surgery.
Experience at a single centre suggests that leflunomide increases the risk of early postoperative infections and
wound-healing complications. This risk should be carefully weighed against the risk of disease flare if
treatment is discontinued.

If disease-modifying antirheumatic drug (DMARD) therapy—such as a biological disease-modifying

antirheumatic drug (bDMARD) or a targeted synthetic disease-modifying antirheumatic drug (tsDMARD)—is
to be withheld, consider stopping it 3 to 5 half-lives before planned surgery. Confirm there is no postoperative
infection and good wound healing has occurred before restarting therapy.

Immunomodulatory drug–specific considerations in adults with

rheumatological diseases
Classes of disease-modifying antirheumatic drugs (DMARDs) are summarised in Table 12.2.

Classification of disease-modifying antirheumatic drugs (DMARDs) (Table 12.2)

Drug class Drugs

azathioprine, cyclophosphamide, cyclosporin,
conventional synthetic disease-modifying
hydroxychloroquine, leflunomide, methotrexate,
antirheumatic drugs (csDMARDs)
mycophenolate, sulfasalazine
abatacept, adalimumab, anakinra, belimumab, canakinumab,
biological disease-modifying antirheumatic
certolizumab pegol, etanercept, golimumab, infliximab,
drugs (bDMARDs)
rituximab, secukinumab, tocilizumab, ustekinumab
targeted synthetic disease-modifying
apremilast, tofacitinib
antirheumatic drugs (tsDMARDs)

The following tables give practical information on using systemic corticosteroids (see Table 12.3) and
DMARDs (see Table 12.4 for csDMARDs, Table 12.5 for bDMARDs and Table 12.6 for tsDMARDs) to treat
rheumatological diseases in adults; they do not provide comprehensive drug information. Prescribers should
consider the balance of harms and benefits of each drug in an individual patient, taking into account adverse
effects, precautions and contraindications, and possible drug interactions. For patients treated with
combination therapy, refer to the considerations relevant to each drug. For guidance on when to give
antimicrobial prophylaxis (eg Pneumocystis jirovecii pneumonia [PJP] prophylaxis) for patients taking
corticosteroids or immunomodulatory drugs, see Assessing the need for antimicrobial prophylaxis in
immunocompromised adults without HIV infection.

Systemic corticosteroids in rheumatology: considerations for use (Table 12.3) [NB1]

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

identify comorbidities that might be exacerbated by corticosteroid therapy (eg diabetes, cardiovascular
 disease and its risk factors, depression, osteoporosis) and implement a plan for management and
monitoring
evaluate bone health and implement strategies to minimise bone density loss (see Preventing
osteoporosis)

Throughout therapy:

implement the recommendations in Considerations throughout immunomodulatory therapy; however,

routine blood tests are not recommended with the exception of those needed to monitor the patient's
disease
regularly review corticosteroid therapy; to minimise adverse effects use the lowest dose and shortest
treatment duration required to achieve treatment goals
consider hypothalamic–pituitary–adrenal axis suppression (see Glucocorticoid-induced
hyperglycaemia)
in patients who are predisposed to diabetes or are treated with high doses or prolonged courses of
systemic corticosteroids, monitor blood glucose concentrations (see Glucocorticoid-induced
hyperglycaemia)
monitor and actively manage risk factors for cardiovascular disease, especially with prolonged courses
of corticosteroids at daily doses equivalent to 7.5 mg or more of prednis(ol)one (see Cardiovascular
disease risk stratification)
assess the need for antimicrobial prophylaxis in patients planned for treatment with high doses of
corticosteroids (20 mg or more per day of prednis(ol)one [or equivalent]) for more than 2 weeks. For
details, see Patients taking corticosteroid therapy

Other considerations:

the systemic corticosteroids used in rheumatology are chosen for their anti-inflammatory
(glucocorticoid) effects; equivalent dosages and duration of effect of glucocorticoids are given in Table
19.6
the rate at which corticosteroids can be tapered depends on the starting dose and duration of
corticosteroid use (which influences the risk of adrenal suppression) and the patient's risk of disease
flare

NB1: Systemic corticosteroids commonly used in rheumatology are prednis(ol)one and methylprednisolone.

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in

rheumatology: considerations for use (Table 12.4)

azathioprine
cyclophosphamide
cyclosporin
hydroxychloroquine
leflunomide
methotrexate
mycophenolate
sulfasalazine

azathioprine
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform TPMT genotype testing, because 1 in 300 individuals have a homozygous genetic mutation
causing negligible enzyme activity. In these patients, severe myelosuppression occurs if the dose is not
significantly reduced (eg giving 10% of the usual dose or increasing the dosing interval to 3 times
weekly) [NB2]

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

check full blood count every 2 weeks during dose escalation, then every 4 to 6 weeks once a stable
dose is achieved

Other considerations:

during the first few weeks of therapy, azathioprine may cause hypersensitivity reactions that can be
 mistaken for a flare in the underlying illness

cyclophosphamide
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

consider referral to a reproductive specialist to discuss fertility preservation
perform urinalysis
advise patients treated with oral cyclophosphamide to take their dose in the morning to reduce the risk
of bladder toxicity
advise all patients (while being treated with oral or intravenous cyclophosphamide) to maintain a fluid
intake of 3 litres of water per day and report haematuria or dysuria

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking cyclophosphamide for a
nonmalignant condition
perform monthly urinalysis to check for haematuria and refer for cystoscopy if haemorrhagic cystitis is
suspected [NB3]
check kidney, liver and bone marrow function every 2 weeks for the first 3 months of treatment, then
check monthly thereafter. Implement more frequent monitoring of bone marrow function if there is
evidence of bone marrow toxicity and consider withholding the dose

Other considerations:

perform yearly urinalysis, including urine cytology, once cyclophosphamide therapy has stopped to
check for evidence of premalignant or malignant changes
when possible, avoid use in patients of childbearing potential

cyclosporin
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

measure kidney function, blood pressure, blood glucose concentration and fasting lipid levels

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

regularly assess kidney function, fasting lipid levels and blood pressure

Other considerations:

acute kidney impairment associated with cyclosporin treatment is generally reversible if the dose is
reduced or treatment stopped; however, chronic kidney impairment associated with long-term
cyclosporin treatment is potentially irreversible
plasma cyclosporin concentration monitoring is generally not performed when cyclosporin is used to
treat rheumatological disease. However, cyclosporin has a narrow therapeutic index and plasma
concentration monitoring may be useful; particularly if high doses are used, toxicity is suspected, or
there is inadequate response (eg to rule out absorption problems and nonadherence)

hydroxychloroquine
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

check for known history of G6PD deficiency. An alternative drug may be required in patients with
G6PD deficiency
perform baseline ophthalmological review (within 12 months of starting treatment)

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy; however,

routine blood tests are not recommended with the exception of those needed to monitor the patient's
disease
repeat ophthalmological review yearly if treatment has continued for 5 years or longer [NB4]
leflunomide
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

measure blood pressure and fasting lipid levels

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

regularly assess fasting lipid levels and blood pressure
promptly investigate patients reporting new or worsening pulmonary symptoms

Other considerations:

leflunomide and methotrexate have synergistic bone marrow, liver and pulmonary toxicity
if reversal of leflunomide is required, use cholestyramine washout (cholestyramine 8 g orally, 3 times
daily for 11 days)

methotrexate
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

assess the patient's alcohol intake

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

promptly investigate patients reporting new or worsening pulmonary symptoms

Other considerations:

methotrexate is given weekly rather than daily, and serious toxicity can occur if taken more frequently.
The clinician and patient should agree on which day of the week the patient will take their
methotrexate and this should be specified on the prescription
folic acid and/or calcium folinate supplementation decreases the risk of adverse effects, including
gastrointestinal adverse effects, liver transaminitis and mouth ulcers [NB5]. It should not be taken on
the same day as the weekly methotrexate dose
adverse effects can be limited by administering the methotrexate dose at night, splitting the weekly
dose over 2 consecutive days (usually 12 hours apart) or administering the dose subcutaneously
leflunomide and methotrexate have synergistic bone marrow, liver and pulmonary toxicity
at the doses typically used in rheumatology, there is no risk of toxicity to close contacts of patients
taking methotrexate and special precautions in handling bodily fluids are not required

mycophenolate
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

check full blood count every week for the first month of treatment, every 2 weeks for the second and
third months, monthly for a further 9 months, then as clinically indicated

Other considerations:

mycophenolate is available as mycophenolate mofetil and mycophenolate sodium (mycophenolic acid)

sulfasalazine
Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

check for known history of G6PD deficiency. An alternative drug may be required in patients with
G6PD deficiency
check for history of sulfonamide allergy
Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

G6PD = glucose-6-phosphodehydrogenase; TPMT = thiopurine methyltransferase

NB1: If the patient develops symptoms or signs of infection, withhold therapy until a thorough assessment is completed (see General approach to
immunomodulatory drug use for more information).
NB2: TPMT genotype testing can help predict the risk of myelosuppression; however, a normal result does not rule out the possibility of bone
marrow suppression and close monitoring of blood counts is still essential.
NB3: Accumulation of a toxic cyclophosphamide metabolite (acrolein) can lead to haemorrhagic cystitis, which is a contraindication to further
cyclophosphamide therapy.
NB4: The risk of retinopathy is greater in patients older than 60 years of age, patients taking doses more than 6.5 mg/kg per day, patients taking
hydroxychloroquine for more than 8 years, obese patients, patients who have kidney or liver disease, or patients with pre-existing eye disease.
Consider more frequent ophthalmological review in these patients.
NB5: Folinic acid (available as calcium folinate) is the reduced form of folic acid; it is used in combination with folic acid when the response to
folic acid is inadequate.

Biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatology:

considerations for use (Table 12.5) [NB1]

abatacept
adalimumab
anakinra
belimumab
canakinumab
certolizumab pegol
etanercept
golimumab
infliximab
rituximab
secukinumab
tocilizumab
ustekinumab

abatacept (target: cytotoxic T-lymphocyte-associated protein 4)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

adalimumab (target: tumour necrosis factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform a baseline test for dsDNA antibodies
check history of heart failure and demyelinating disorders (eg multiple sclerosis)

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking tumour necrosis factor inhibitors for
a nonmalignant condition

anakinra (target: interleukin-1)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy; however, it

is not known if anakinra increases the risk of reactivation of latent tuberculosis
measure fasting lipid levels

Throughout therapy [NB2]:

 implement the recommendations in Considerations throughout immunomodulatory therapy
regularly assess fasting lipid levels

belimumab (target: B-cell activating factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

assess for depression and suicidal ideation

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

monitor for the development of depression and suicidal ideation

canakinumab (target: interleukin-1)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy; however, it

is not known if canakinumab increases the risk of reactivation of latent tuberculosis

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

certolizumab pegol (target: tumour necrosis factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform a baseline test for dsDNA antibodies
check history of heart failure and demyelinating disorders (eg multiple sclerosis)

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking tumour necrosis factor inhibitors for
a nonmalignant condition

etanercept (target: tumour necrosis factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform a baseline test for dsDNA antibodies
check history of heart failure and demyelinating disorders (eg multiple sclerosis)

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking tumour necrosis factor inhibitors for
a nonmalignant condition

golimumab (target: tumour necrosis factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform a baseline test for dsDNA antibodies
check history of heart failure and demyelinating disorders (eg multiple sclerosis)

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking tumour necrosis factor inhibitors for
a nonmalignant condition

infliximab (target: tumour necrosis factor)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

perform a baseline test for dsDNA antibodies
check history of heart failure and demyelinating disorders (eg multiple sclerosis)

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

assess the need for antimicrobial prophylaxis—see Patients taking tumour necrosis factor inhibitors for
a nonmalignant condition

rituximab (target: B-cell antigen CD20)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

measure plasma immunoglobulins

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

measure plasma immunoglobulins before each treatment cycle
assess the need for antimicrobial prophylaxis—see Patients taking rituximab for a nonmalignant
condition

secukinumab (target: interleukin-17A)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

tocilizumab (target: interleukin-6)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

check for history of diverticulitis
measure fasting lipid levels

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

regularly assess fasting lipid levels
patients treated with tocilizumab can have normal CRP concentration in the presence of infection

ustekinumab (target: interleukin-12 and interleukin-23)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

Throughout therapy [NB2]:

implement the recommendations in Considerations throughout immunomodulatory therapy

CRP = C-reactive protein; dsDNA = double-stranded DNA

NB1: bDMARDs are produced in biological systems and have complex molecular structures. As a consequence, there are inherently minor
variations between drug molecules, even between batches of the same drug. The term ‘biosimilar’ is used to refer to other brands of an already
registered bDMARD (known as the biological reference drug). Biosimilars must have demonstrable similarity in physiochemical, biological and
immunological characteristics, as well as efficacy and safety, to the biological reference drug. However, while changing from a bDMARD to one
of its biosimilars, or vice-versa, is considered safe and efficacious, there are limited data to determine whether multiple changes (ie changing back
to the product that was initially used or changing to another biosimilar) are appropriate. It is the consensus view of the Rheumatology Expert
Group that both the generic and trade name of the bDMARD should be specified in the prescription to avoid unintended changes between
products.
NB2: If the patient develops symptoms or signs of infection, withhold therapy until a thorough assessment is completed (see General approach to
immunomodulatory drug use for more information).

Targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) in rheumatology:

considerations for use (Table 12.6)

apremilast
tofacitinib

apremilast (target: phosphodiesterase-4)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy; however,

investigations to exclude latent tuberculosis are not required because apremilast is not known to
increase the risk of reactivation
assess for depression and suicidal ideation

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

monitor for the development of depression and suicidal ideation
monitor for weight loss

tofacitinib (target: Janus kinases)

Before starting therapy:

follow the recommendations in Considerations before starting immunomodulatory therapy

measure fasting lipid levels

Throughout therapy [NB1]:

implement the recommendations in Considerations throughout immunomodulatory therapy

regularly assess fasting lipid levels

NB1: If the patient develops symptoms or signs of infection, withhold therapy until a thorough assessment is completed (see General approach to
immunomodulatory drug use for more information).

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diseases

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guidelines on safety of anti-TNF therapies. Rheumatology (Oxford) 2010;49(11):2217–9.

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Published March 2017. Amended June 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Principles of analgesic and anti-inflammatory drug
use for musculoskeletal conditions in adults
Introduction to analgesic and anti-inflammatory drug use for
musculoskeletal conditions in adults
Analgesics and anti-inflammatory drugs have an important role in providing symptom relief for acute and
chronic musculoskeletal conditions; however, they should only be considered as part of an overall pain
management strategy. Lifestyle measures and nonpharmacological therapies should always be considered as
an alternative or adjunct to pharmacological management for conditions in which they have a proven benefit
and/or a low risk of harms. For discussion of lifestyle measures and nonpharmacological therapies for specific
musculoskeletal conditions, see the clinical topics. For an overview of nonpharmacological therapies for pain
relief, see Chronic pain: nonpharmacological management.

The pharmacological management of pain in musculoskeletal conditions requires careful consideration of the
potential benefits and harms of treatments. Because evidence to guide the use of analgesics and anti-
inflammatory drugs is often limited, and patient needs and responses vary, it is recommended that a trial
approach is taken when using these drugs. This involves regular assessment of treatment against the goals of
management to determine if the treatment is safe and of adequate and continued benefit for that individual.
Unhelpful or harmful treatments should be stopped. In patients taking analgesics or anti-inflammatory drugs
on an ongoing basis, periodically consider a trial of treatment cessation.

Clinicians should keep in mind that with the availability of single and combination analgesics and
nonsteroidal anti-inflammatory drugs (NSAIDs) over-the-counter, patients may already have tried or be taking
medications for symptom relief at the time they seek medical advice.

This topic covers practical information on using analgesic and anti-inflammatory drugs for musculoskeletal
conditions in adults; advice on using these drugs for specific musculoskeletal conditions is given in the
clinical topics. For comprehensive drug information, including precautions, contraindications, adverse effects
and drug interactions, consult an appropriate drug information resource. Patient medicine information sheets
for many of the drugs used in rheumatology can be accessed from the Australian Rheumatology Association
website [URL].

Principles of nonsteroidal anti-inflammatory drug use for

musculoskeletal conditions in adults
General considerations

The drug class of nonsteroidal anti-inflammatory drugs (NSAIDs) includes both nonselective cyclo-oxygenase
(COX) inhibitors and COX-2–selective inhibitors (the latter group is sometimes referred to as coxibs).
NSAIDs are commonly used for their analgesic and anti-inflammatory effects. No single NSAID has been
shown to be more effective than any other, but some patients may respond better to one NSAID than to others.
If a patient does not respond to the first NSAID trialled, generally one or two other NSAIDs should be trialled
before confirming nonresponse to NSAIDs.

NSAIDs can cause gastrointestinal, cardiovascular and renal adverse effects. Important adverse effects of
NSAIDs are summarised in Table 1.2. The relative risk of individual adverse effects varies depending on the
NSAID and on patient factors (see Choice of NSAID and approach to NSAID use in patients at increased risk
of specific adverse effects). In general, the risk of harms increases with patient age, and dose and duration of
treatment.

When considering the use of an NSAID, the potential benefits should be weighed against the potential harms
for each patient. Principles of prescribing NSAIDs for musculoskeletal conditions are given in Box 12.5. The
dosages of oral NSAIDs for adults are summarised in Table 12.7.

For advice on NSAID use in pregnancy, see NSAIDs and reproductive health in women. For information on
the use of NSAIDs in children, see Practical prescribing considerations for rheumatological diseases in
children and adolescents; for paediatric dosages of oral NSAIDs, see Table 12.12.
Topical NSAIDs are commonly used for the treatment of local musculoskeletal conditions. NSAIDs that are
available in a topical preparation are noted in Table 12.7. Because of their minimal systemic absorption,
topical NSAIDs are considerably safer than oral NSAIDs; however, topical NSAIDs may only be useful for
superficial sources of musculoskeletal pain.

Principles of prescribing NSAIDs for musculoskeletal conditions (Box 12.5)

Consider lifestyle measures and nonpharmacological therapies if appropriate to reduce the need for
NSAIDs.
Consider using fish oil, paracetamol and topical NSAIDs to reduce the need for oral NSAIDs.
Assess the benefit–harm profile for an NSAID in each patient:
Avoid NSAIDs in patients with active peptic ulcer disease or gastrointestinal bleeding.
Avoid NSAIDs in patients with an eGFR of less than 30 mL/minute. Avoid long-term use of
NSAIDs in patients with an eGFR of 30 to 60 mL/minute unless there is no alternative
treatment available and the patient has no other risk factors for acute kidney injury (see Patients
who have an increased risk of renal toxicity).
If possible, avoid NSAIDs in patients with established cardiovascular disease (eg heart failure,
stroke) or at high risk of cardiovascular disease (see Cardiovascular disease risk stratification).
In particular, assess the need for NSAIDs in older people carefully (see NSAIDs and older
people).
Choose which NSAID to trial based on patient factors (see Choice of NSAID and approach to NSAID
use in patients at increased risk of specific adverse effects).
Use the minimum effective dose of NSAID for the shortest time possible.
Do not use more than one NSAID at a time, except for co-administration with low-dose aspirin if it is
clinically indicated for other reasons.
If possible, avoid concurrent use of NSAIDs and systemic corticosteroids because of the significantly
increased risk of gastrointestinal toxicity, and because NSAIDs are unlikely to have additional benefit
in patients taking systemic corticosteroids [NB1].
For patients with risk factors for increased gastrointestinal toxicity with an NSAID and/or who are
likely to be treated with an NSAID long term, consider co-prescribing a PPI for prophylaxis and
testing for Helicobacter pylori (see Patients who have an increased risk of gastrointestinal toxicity).
Encourage patients taking an NSAID long term to address lifestyle risk factors for gastrointestinal
toxicity (eg smoking, obesity) and cardiovascular disease (see Behavioural risk factor modification).
Monitor treatment response, adverse effects and the ongoing need for an NSAID. Do not continue
NSAIDs if there is no benefit or treatment is harmful. In patients taking an NSAID on an ongoing
basis, periodically consider a trial of treatment cessation.

eGFR = estimated glomerular filtration rate; NSAIDs = nonsteroidal anti-inflammatory drugs; PPI = proton pump inhibitor

NB1: In patients currently taking an NSAID who require a short course of systemic corticosteroid, consider withholding the NSAID while the
patient is treated with the corticosteroid. In patients currently taking a systemic corticosteroid who require acute anti-inflammatory treatment,
consider temporarily increasing the dose of the corticosteroid instead of using an NSAID.

Adult dosages of oral NSAIDs used for musculoskeletal conditions (Table 12.7) [NB1]

Drug Usual dose Dose frequency [NB2] Maximum daily dose

Nonselective COX inhibitors [NB3]
diclofenac [NB4] 25 to 50 mg 2 or 3 doses per day 200 mg
ibuprofen [NB4] 200 to 400 mg 3 or 4 doses per day 2400 mg
indomethacin 25 to 50 mg 2 to 4 doses per day 200 mg
ketoprofen (modified-
200 mg 1 dose per day 200 mg
release)
ketorolac 10 mg 3 or 4 doses per day 40 mg
mefenamic acid 500 mg 3 doses per day 1500 mg
naproxen [NB5] 250 to 500 mg 2 doses per day 1250 mg
naproxen (modified-
750 to 1000 mg 1 dose per day 1000 mg
release)
piroxicam [NB4] 10 to 20 mg 1 dose per day 20 mg
sulindac 100 to 400 mg 1 or 2 doses per day 400 mg
COX-2–selective inhibitors
celecoxib 100 to 200 mg 1 or 2 doses per day 400 mg
etoricoxib 30 to 60 mg 1 dose per day 120 mg
meloxicam 7.5 to 15 mg 1 dose per day 15 mg
COX = cyclo-oxygenase; NSAIDs = nonsteroidal anti-inflammatory drugs
NB1: For indication-specific advice on the use of NSAIDs, see the clinical topics.
NB2: With the exception of modified-release preparations, drugs that require more frequent daily dosing generally have a shorter half-life.
NB3: Aspirin is also a nonselective COX inhibitor, but is rarely used for anti-inflammatory purposes because of the significant risk of harms at the
high dosages required for these effects.
NB4: This NSAID is also available as a topical gel.
NB5: Naproxen sodium is used in some preparations; 250 mg of naproxen is equivalent to 275 mg of naproxen sodium.

Choice of NSAID and approach to NSAID use in patients at increased risk of specific
adverse effects
The relative risk of individual adverse effects varies between NSAIDs, so choice of NSAID is guided by
patient factors.

If possible, avoid NSAIDs in patients with both an increased risk of gastrointestinal toxicity and an increased
cardiovascular risk. If treatment with an NSAID is necessary for these patients, use a nonselective NSAID,
ideally naproxen, and co-prescribe a proton pump inhibitor (PPI) for gastrointestinal prophylaxis (see
discussion below).

Patients who have an increased risk of gastrointestinal toxicity

Risk factors for increased gastrointestinal toxicity with NSAID use include older age, history of upper
gastrointestinal bleeding or peptic ulcer disease, Helicobacter pylori infection, the concomitant use of drugs
that increase the risk of upper gastrointestinal bleeding or perforation (eg anticoagulants, antiplatelet drugs,
selective serotonin reuptake inhibitors [SSRIs], serotonin and noradrenaline reuptake inhibitors [SNRIs],
systemic corticosteroids), significant comorbidity, and smoking.

Avoid NSAIDs in patients with active peptic ulcer disease or gastrointestinal bleeding.

If treatment with an NSAID is necessary for a patient with risk factor(s) for increased gastrointestinal toxicity
and/or if NSAID use is likely to be long term, consider the gastrointestinal risk of the NSAID, including the
following factors:

Drug half-life—NSAIDs with a longer half-life (eg piroxicam; see Table 12.7) are more likely to cause
serious gastrointestinal complications.
COX-2–selectivity—NSAIDs that selectively inhibit COX-2 (celecoxib, etoricoxib, meloxicam) have a
lower risk of causing NSAID-induced gastrointestinal toxicity, but the risk is not completely eliminated
and some COX-2–selective NSAIDs are only selective at low doses (eg meloxicam). COX-2–selective
NSAIDs do not cause fewer dyspeptic symptoms than nonselective NSAIDs. The concomitant use of
low-dose aspirin eliminates any upper gastrointestinal safety advantage of COX-2–selective NSAIDs.

For these patients, also consider co-prescribing a proton pump inhibitor (PPI) for prophylaxis, and testing for
H. pylori infection. Limited data suggest using a COX-2–selective NSAID with a PPI provides the greatest
gastrointestinal prophylaxis. For more information on prophylaxis and treatment of NSAID-induced ulcers,
see NSAID-induced ulcers.

If NSAID use is likely to be long term, provide additional encouragement for patients to address lifestyle risk
factors for gastrointestinal toxicity (eg smoking, obesity).

Patients who have an increased cardiovascular risk

If possible, avoid NSAIDs in patients with established cardiovascular disease (eg heart failure, stroke) or at
high risk of cardiovascular disease (see Cardiovascular disease risk stratification).

If treatment with an NSAID is necessary for patients who have an increased cardiovascular risk, consider the
cardiovascular risk of the NSAID, including the following factors:

Naproxen appears to confer the least cardiovascular risk of all the NSAIDs, but has a higher risk of
gastrointestinal adverse effects.
Diclofenac has a lower risk of gastrointestinal adverse effects, but a higher cardiovascular risk; avoid
diclofenac in patients who have an increased cardiovascular risk.
 COX-2–selective NSAIDs have a higher risk of adverse vascular events (eg myocardial infarction). A
single randomised controlled trial suggests celecoxib at low to moderate doses has no greater
cardiovascular risk than naproxen or ibuprofen [Note 1]; however, this study has limitations and caution
is still advised in the use of all COX-2–selective NSAIDs in patients at increased cardiovascular risk.

If NSAID use is likely to be long term, provide additional encouragement for patients to address lifestyle risk
factors for cardiovascular disease (see Behavioural risk factor modification). In patients taking NSAIDs on an
ongoing basis, cardiovascular disease risk factors should be closely monitored and actively managed.

Low-dose aspirin may reduce the increased cardiovascular risk associated with NSAIDs, but it increases the
risk of gastrointestinal adverse effects. Advise patients who are prescribed low-dose aspirin for secondary
prevention of vascular events to continue it regardless of their use of other NSAIDs.

Note 1: Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, et al. Cardiovascular
safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016;375(26):2519-29. [URL]

Patients who have an increased risk of renal toxicity

General considerations

Risk factors for NSAID-induced acute kidney injury include pre-existing renal impairment; volume depletion
(eg dehydration, sepsis) or effective arterial volume depletion (eg due to heart failure, cirrhosis, nephrotic
syndrome); co-administration with angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor
blockers (ARBs), diuretics or other nephrotoxic drugs; and older age. The risk of acute kidney injury is
cumulative—for example, the risk is significantly increased if an NSAID is co-administered with an ACEI
plus a diuretic, or if an older patient taking an NSAID develops an acute illness associated with dehydration.

For specific considerations with NSAID use in patients with pre-existing renal impairment, see Patients with
chronic kidney disease.

If treatment with an NSAID is necessary for a patient with risk factor(s) for NSAID-induced acute kidney
injury, NSAIDs with a short half-life are preferred (see Table 12.7). Nonselective NSAIDs and COX-2–
selective NSAIDs have a similar risk of acute kidney injury. For patients with pre-existing renal impairment,
see monitoring advice in Patients with chronic kidney disease. In patients with other risk factors for NSAID-
induced acute kidney injury, check renal function periodically if NSAID use is ongoing.

Patients with chronic kidney disease

The use of NSAIDs in patients with chronic kidney disease requires particular consideration for three reasons.
Firstly, in these patients, NSAIDs can cause an acute reduction in renal perfusion and glomerular filtration
rate, which can lead to a reversible reduction in renal function, hyperkalaemia, or acute ischaemic kidney
injury. This risk is significantly increased in patients concurrently taking ACEIs, ARBs and/or diuretics.
Secondly, NSAIDs can increase blood pressure in patients with hypertension, a common comorbidity in
patients with chronic kidney disease. Finally, long-term use of NSAIDs can increase the rate of progression of
chronic kidney disease when used at higher doses or in patients with more severe chronic kidney disease.
However, observational data in patients with mild to moderate chronic kidney disease taking standard doses of
NSAIDs have been reassuring, with no evidence of a detrimental effect on renal function over time.

In all patients with chronic kidney disease in whom an NSAID is being considered, the potential benefits of an
NSAID should be weighed against its potential harms, taking into account the degree of renal impairment and
the presence of other risk factors for NSAID-induced acute kidney injury (see General considerations for risk
factors).

Avoid NSAIDs in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/minute. In
patients with an eGFR of 30 to 60 mL/minute, avoid long-term use of NSAIDs unless there is no alternative
treatment available and the patient has no other risk factors for acute kidney injury. Check renal function and
blood pressure early after starting the NSAID to detect any acute change, and monitor closely if use is
ongoing. Withhold the NSAID during any serious illness associated with risk of acute kidney injury. Even in
patients with mild renal impairment (eGFR 60 to 90 mL/minute), use NSAIDs with caution if other risk
factors for acute kidney injury are present and check renal function periodically if NSAID use is ongoing. In
any patient with chronic kidney disease, use the minimum effective NSAID dose.

NSAIDs and older people

Older people are generally at increased risk of individual NSAID-related adverse effects (eg older age is a risk
factor for increased gastrointestinal toxicity with NSAID use, a consideration in the calculation of absolute
cardiovascular risk, and a risk factor for NSAID-induced acute kidney injury). Older patients are also more
likely to have comorbidities and take other drugs that increase their risk of NSAID-related adverse effects.

Assess the need for NSAIDs in older people more carefully. NSAIDs with a short half-life are preferred in
older patients (see Table 12.7), but see also the considerations for specific toxicity risks: Patients who have an
increased risk of gastrointestinal toxicity, Patients who have an increased cardiovascular risk, and Patients
who have an increased risk of renal toxicity.

NSAIDs and reproductive health in women

NSAID use in women planning pregnancy

Older studies of women with rheumatoid arthritis taking NSAIDs show fertility rates the same as the general
population; however, these studies had several limitations and may have underestimated the risk of harm.
Recent evidence suggests NSAIDs may reduce fertility in women and this association is supported by a
plausible biological mechanism. Therefore, guidelines recommend avoiding NSAIDs (with the exception of
low-dose aspirin) in women who are planning pregnancy [Note 2]. See also the discussion on risk of
miscarriage in NSAID use in women who are pregnant.

Note 2: See the Australian Rheumatology Association Prescriber's information on medications for
rheumatic diseases in pregnancy [URL].

NSAID use in women who are pregnant

Older studies suggest an increased risk of miscarriage in women taking NSAIDs in early pregnancy, with the
greatest risk when NSAIDs are taken close to the time of conception; however, a lack of controlling for
increased maternal age in the study designs may have confounded the results. A recent population-wide cohort
study that adjusted for potential confounders found no increase in the risk of miscarriage in women taking
NSAIDs in early pregnancy [Note 3]; however, guidelines still recommend avoiding NSAIDs or using
NSAIDs with caution in pregnant women up to 8 weeks' gestation [Note 4].

Despite NSAIDs being listed as Therapeutic Goods Administration (TGA) category C drugs (with the
exception of celecoxib, which is category B3) [Note 5], NSAIDs may be used judiciously in pregnant women
up to 32 weeks' gestation because data suggest there is no increased risk of congenital malformations. There
are fewer data on the use of COX-2–selective NSAIDs than nonselective NSAIDs in pregnancy, so if a
decision is taken to use an NSAID in a pregnant woman up to 32 weeks' gestation, a nonselective NSAID is
preferred.

NSAIDs should not be used in pregnant women beyond 32 weeks' gestation.

Anti-inflammatory doses of aspirin, and likely of the other NSAIDs, affect maternal platelet function and are
associated with an increased risk of peripartum haemorrhage, especially with complicated deliveries. NSAIDs
may also cause premature closure of the fetal ductus arteriosus, delay labour and birth, and/or cause
oligohydramnios via an effect on fetal renal function. Therefore, NSAIDs should not be used in pregnant
women beyond 32 weeks' gestation.

Low-dose aspirin (up to 150 mg orally, daily) can be continued throughout pregnancy.

Note 3: Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal exposure to nonsteroidal anti-
inflammatory drugs and spontaneous abortions. CMAJ 2014;186(5):E177-82. [URL]

Note 4: See the Australian Rheumatology Association Prescriber's information on medications for
rheumatic diseases in pregnancy [URL].

Note 5: TGA pregnancy categories are explained in Australian categorisation of drugs in pregnancy.

NSAID use in women who are breastfeeding

For breastfeeding compatibility recommendations for individual NSAIDs, see Drug use in pregnancy and
breastfeeding.

Principles of paracetamol use for musculoskeletal conditions in

adults
Although paracetamol is generally less effective than nonsteroidal anti-inflammatory drugs (NSAIDs) for
musculoskeletal pain, its favourable safety profile in therapeutic doses justifies a trial of paracetamol first line
for mild to moderate pain in most indications. Paracetamol may also be used to reduce the use of NSAIDs and
thus the risk of NSAID adverse effects.

The maximum daily dose of paracetamol is 4 g, but the dose should be reduced in frail older patients, or in
people who have significant liver disease, are malnourished or fasting, or have a low bodyweight. The
differences in onset of action between paracetamol preparations are not clinically important for most
indications. Paracetamol preparations that require less frequent administration may be preferred for
convenience.

Dose-related gastrointestinal, cardiovascular and renal adverse effects have been occasionally observed in
patients taking paracetamol long term. Metabolite production in paracetamol overdose may lead to severe
hepatic toxicity. Overdose from inadvertent ingestion of higher than recommended doses of paracetamol is a
possibility, and patients should be advised to consider the paracetamol content of all medications. For more
information on paracetamol toxicity, see Toxicology: paracetamol.

Patients taking paracetamol should be monitored for treatment response, adverse effects and the ongoing need
for treatment. Do not continue paracetamol if there is no benefit or treatment is harmful. In patients taking
paracetamol on an ongoing basis, periodically consider a trial of treatment cessation.

Principles of fish oil use for musculoskeletal conditions in adults

Fish oil contains the omega-3 long-chain polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), which have anti-inflammatory properties. Fish oil may also be used to reduce
the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and thus the risk of NSAID adverse effects. Fish
oil may take up to 3 months for maximal effectiveness, so it may be necessary to co-prescribe fish oil with
other analgesics initially (eg an NSAID and/or paracetamol).

Numerous fish oil preparations are available with varying strengths of fish oil, omega-3, and EPA and DHA,
including in combination with other active ingredients. For an anti-inflammatory effect, the recommended
daily dose of total omega-3 (EPA + DHA) for adults is at least 2.7 g. The content of selected fish oil
preparations and their minimum daily anti-inflammatory dose is given in Table 12.8. Cod liver oil is not
recommended as a source of omega-3 because it contains cholesterol and, in the dose required for an anti-
inflammatory effect, potentially toxic amounts of vitamins A and D.

The size and number of fish oil capsules required for daily dosing may not be tolerated by patients. An
alternative is to use fish oil liquid; the palatability of fish oil liquid can be improved by using a ‘two-glass’
technique [Note 6].

Gastrointestinal adverse effects of fish oil include a ‘fishy’ aftertaste, heartburn and diarrhoea. Fish oil has
been shown to have a low risk of harm in clinical trials assessing efficacy, but there is a theoretical risk of
bleeding.

Content of selected fish oil preparations and minimum daily anti-inflammatory dose for
adults (Table 12.8) [NB1] [NB2]

Total omega-3
Minimum daily
Fish oil preparation EPA content DHA content content (EPA +
dose [NB3]
DHA)
1 g capsules 180 mg 120 mg 300 mg 9 capsules
1.5 g capsules 270 mg 180 mg 450 mg 6 capsules
2 g capsules 360 mg 240 mg 600 mg 5 capsules
1.5 g concentrated
540 mg 360 mg 900 mg 3 capsules
capsules
4.5 g/5 mL liquid 810 mg/5 mL 540 mg/5 mL 1.35 g/5 mL 10 mL
4.6 g/5 mL
concentrated liquid 1.9 g/5 mL 927 mg/5 mL 2.8 g/5 mL 5 mL
DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; omega-3 = omega-3 long-chain polyunsaturated fatty acids
NB1: Other preparations are available with different strengths of fish oil, omega-3, and EPA and DHA.
NB2: Cod liver oil is not recommended as a source of omega-3 because it contains cholesterol and, in the dose required for an anti-inflammatory
effect, potentially toxic amounts of vitamins A and D.
NB3: This is calculated to give a daily dose of at least 2.7 g of total omega-3 (EPA + DHA) for anti-inflammatory effect.

Note 6: For information on this technique, see Cleland LG, James MJ, Proudman SM. Fish oil: what the
prescriber needs to know. Arthritis Res Ther 2006;8(1):202. [URL]

Principles of using local corticosteroid injections for musculoskeletal

conditions in adults
Intra-articular injection, or injection into soft tissue, of a long-acting or depot corticosteroid can provide pain
relief in musculoskeletal conditions. Because the potential benefits and harms of use vary with different
musculoskeletal conditions and patient factors, local corticosteroid injections should only be given by, or
under the supervision of, clinicians with appropriate training and experience. Radiological guidance does not
increase the efficacy of local corticosteroid injections and is only required for joints that are difficult to access
(eg hip joint).

Only corticosteroids specifically formulated for intra-articular injection or injection into soft tissue should be
used for this purpose. Local anaesthetic may be used before, or mixed with, the corticosteroid. Example doses
of local corticosteroid injections for adults are given in Table 12.9. Triamcinolone hexacetonide is the most
common local corticosteroid injection used in children; example doses of triamcinolone hexacetonide
injection for children are given in Table 12.13.

The following factors may assist in choosing a local corticosteroid injection in adults:

Betamethasone sodium phosphate plus betamethasone acetate is usually used for injection into smaller
joints.
Methylprednisolone acetate is crystalline and is formulated as a suspension; it is usually used for
injection into larger joints.
Triamcinolone acetonide is the least soluble injection and provides the longest duration of action (up to
21 weeks).

The following are absolute contraindications to local corticosteroid injection: infection of the skin at the
injection site or systemic infection (because it may seed a deep infection) and infection of the joint or soft
tissue (because it may worsen infection). Similarly, because of infection risk, local corticosteroid injection
should not be given into a joint that is to be replaced less than 3 months before the planned surgery.
Therapeutic anticoagulation is not a contraindication to local corticosteroid injection.

Systemic adverse effects of local corticosteroid injections include increase in blood glucose concentration for
up to 48 hours, sleep disturbance and flushing. Local adverse effects of corticosteroid injections include
temporary worsening of musculoskeletal symptoms, skin hypopigmentation and tissue atrophy. Although
tendon rupture has been reported in patients injected with corticosteroids, a causal relationship is unproven.
Peritendinous corticosteroid injections should be used with caution if the major weightbearing tendons (eg the
patellar, tibialis posterior and Achilles tendons) are involved; consider seeking specialist advice. Septic
arthritis is a rare but serious complication of intra-articular corticosteroid injections.

If local corticosteroid injection is effective for an extended duration (eg months), and in the absence of a safer
therapeutic alternative, the injection may be repeated. A maximum of four injections per joint per year is
recommended because of the risk of local tissue atrophy and systemic adverse effects. Avoid multiple
injections involving the major weightbearing tendons.

For principles of use of systemic corticosteroids, see Principles of immunomodulatory drug use for
rheumatological diseases in adults.

Example doses of local corticosteroid injections for adults (Table 12.9) [NB1] [NB2]

Dose for small Dose for medium Dose for large Dose for soft tissues
Corticosteroid
joints (eg hand) joints (eg wrist) joints (eg knee) (eg bursa)
betamethasone
sodium phosphate +
0.25 to 0.5 mL 0.5 to 1 mL 1 to 2 mL 1 mL
betamethasone
acetate 5.7 mg/mL
methylprednisolone 0.1 to 0.25 mL 0.25 to 1 mL 0.5 to 2 mL 0.1 to 0.75 mL
acetate 40 mg/mL
triamcinolone
0.25 to 1 mL 1 mL 0.5 to 2 mL 1 to 2 mL
acetonide 10 mg/mL
triamcinolone
0.1 to 0.25 mL 0.25 mL 0.5 to 1 mL 0.5 mL
acetonide 40 mg/mL
triamcinolone
hexacetonide 20 0.1 to 0.3 mL 0.25 to 0.5 mL 0.5 to 1 mL 0.5 to 1 mL
mg/mL [NB3]
NB1: For indication-specific advice on the use of local corticosteroid injections, see the clinical topics.
NB2: These are example doses; the dose should be individualised for each patient depending on the size of the joint or soft-tissue lesion, the
severity of the condition, the response obtained, and the patient's tolerance of the corticosteroid. The total volume of the injection administered will
vary depending on the amount of local anaesthetic solution added.
NB3: Triamcinolone hexacetonide is not registered for use in Australia but is available via the Special Access Scheme.

Drugs that have limited use in the management of musculoskeletal

conditions in adults
Opioids
Opioids, including tramadol and tapentadol, are often used to treat musculoskeletal pain because of concerns
about paracetamol efficacy and nonsteroidal anti-inflammatory drug (NSAID) adverse effects; however, they
in fact have a very limited role in the management of acute and chronic musculoskeletal conditions because of
modest benefits and a significant risk of harms. Harms of opioids include tolerance, dependence, inadvertent
(potentially fatal) overdose, cognitive effects, endocrinopathy, cardiovascular effects, falls, fractures, pruritus,
dry mouth, anorexia, urinary retention and overflow incontinence, and constipation. Opioids have also been
associated with an increased risk of hospitalisation for serious infection in patients with rheumatoid arthritis,
and a significantly increased risk of all-cause mortality in patients with chronic nonmalignant pain. Important
short-term adverse effects of opioids are summarised in Table 1.3 and important long-term adverse effects of
opioids are summarised in Table 1.15.

Opioids have a very limited role in the management of musculoskeletal conditions.

Notwithstanding their modest benefits and significant risk of harms, opioids may be considered for severe
musculoskeletal pain that is not relieved by other indicated measures (eg nonpharmacological therapies,
paracetamol, NSAIDs, immunomodulatory drugs, analgesic adjuvants). The need for opioids should flag
consideration of patient referral to a rheumatologist. If opioids are used, they should be prescribed on a short-
term trial basis, as part of an overall pain management strategy, with clear goals and regular review of
treatment response and adverse effects. Before starting an opioid, a plan for ceasing ineffective therapy should
be in place and discussed with the patient. If treatment response is inadequate, caution should be exercised
before increasing the dose as there may be no added benefit and an increased risk of harms.

Prolonged use of opioids for severe persisting musculoskeletal pain should only be undertaken in consultation
with a rheumatologist to ensure that all alternative options have been explored and optimised. Most placebo-
controlled trials of opioids in chronic pain have assessed only short-term effects, so evidence for long-term
benefit is lacking. In patients with chronic pain, opioids may worsen pain and function, possibly by
potentiating pain perception.

For patients already taking opioids, regular clinical review of the benefits and harms are recommended
together with attempts at dose weaning and/or cessation if possible.

For further discussion on the use of opioids for acute pain, see Acute pain: a general approach. For further
discussion on the use of opioids for chronic pain, see Chronic pain: pharmacological management.

Complementary medicines
Patients often initiate the use of complementary medicines for chronic pain. Some complementary medicines
have been shown to provide no benefit in the treatment of pain, but for the majority of complementary
medicines there is no evidence for or against benefit. The concentration of active ingredients in
complementary medicines can vary between brands because of the range of sources used and different
methods of processing. The role of glucosamine, chondroitin and other complementary therapies for
osteoarthritis are discussed in Complementary medicines in osteoarthritis.
Complementary medicines can cause adverse effects or interact with conventional medicines. Patients often
do not spontaneously disclose their use of complementary medicines so, as part of a thorough medication
history, actively inquire about the use of complementary medicines, as well as over-the-counter and
prescription medicines.

The National Institute of Health (US) website [URL] has links for health information and research about
complementary medicines.

Key references
Nonsteroidal anti-inflammatory drugs

Australian Rheumatology Association. Prescriber's information on medications for rheumatic diseases in

pregnancy. Sydney: Australian Rheumatology Association; 2016. https://rheumatology.org.au/gps/clinical-
guidelines.asp

Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth
Analg 2013;116(5):1063–75.

Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal exposure to nonsteroidal anti-inflammatory
drugs and spontaneous abortions. CMAJ 2014;186(5):E177–82.

Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ 2013;346:f3195.

Derry S, Conaghan P, Da Silva JA, Wiffen PJ, Moore RA. Topical NSAIDs for chronic musculoskeletal pain in
adults. Cochrane Database Syst Rev 2016;(4):CD007400.

Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Topical NSAIDs for acute musculoskeletal pain in adults.
Cochrane Database Syst Rev 2015;(6):CD007402.

Dreischulte T, Morales DR, Bell S, Guthrie B. Combined use of nonsteroidal anti-inflammatory drugs with diuretics
and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury. Kidney Int
2015;88(2):396–403.

European Medicines Agency. Assessment report for non-steroidal anti-inflammatory drugs (NSAIDs) and
cardiovascular risk. London: EMA; 2012.
http://www.ema.europa.eu/docs/en_GB/document_library/Report/2012/11/WC500134717.pdf

Felson DT. Safety of Nonsteroidal Antiinflammatory Drugs. New England Journal of Medicine 2016;375(26):2595–
2596.

FitzGerald GA. Imprecision: limitations to interpretation of a large randomized clinical trial. Circulation
2017;135(2):113–115.

Flint J, Panchal S, Hurrell A, van de Venne M, Gayed M, Schreiber K, et al. BSR and BHPR guideline on
prescribing drugs in pregnancy and breastfeeding-Part II: analgesics and other drugs used in rheumatology
practice. Rheumatology (Oxford) 2016;55(9):1698–702. .

Gooch K, Culleton BF, Manns BJ, Zhang J, Alfonso H, Tonelli M, et al. NSAID use and progression of chronic
kidney disease. Am J Med 2007;120(3):280 e1–7.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical practice guideline
for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:5–14.
http://kdigo.org/guidelines/ckd-evaluation-and-management/

Kuo HW, Tsai SS, Tiao MM, Liu YC, Lee IM, Yang CY. Analgesic use and the risk for progression of chronic
kidney disease. Pharmacoepidemiol Drug Saf 2010;19(7):745–51.

Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme
inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney
injury: nested case-control study. BMJ 2013;346:e8525.

McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of
population-based controlled observational studies. PLoS Med 2011;8(9):e1001098.

Moller B, Pruijm M, Adler S, Scherer A, Villiger PM, Finckh A, et al. Chronic NSAID use and long-term decline of
renal function in a prospective rheumatoid arthritis cohort study. Ann Rheum Dis 2015;74(4):718–23.

Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT. Non-steroidal anti-inflammatory drugs and chronic kidney
disease progression: a systematic review. Fam Pract 2013;30(3):247–55.

Nissen SE, Yeomans ND, Solomon DH, Luscher TF, Libby P, Husni ME, et al. Cardiovascular safety of celecoxib,
naproxen, or ibuprofen for arthritis. N Engl J Med 2016;375(26):2519–29.

O'Neil CK, Hanlon JT, Marcum ZA. Adverse effects of analgesics commonly used by older adults with
osteoarthritis: focus on non-opioid and opioid analgesics. Am J Geriatr Pharmacother 2012;10(6):331–42.

Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5(7):382–
90.

Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood
pressure. Arch Intern Med 1993;153(4):477–84.

Salman S, Sherif B, Al-Zohyri A. Effects of some non steroidal anti-inflammatory drugs on ovulation in women
with mild musculoskeletal pain [oral presentation: OP0131] Ann Rheum Dis 2015;74(Suppl. 2):117–8.
http://ard.bmj.com/content/74/Suppl_2/117.3

Scheiman JM, Fendrick AM. Practical approaches to minimizing gastrointestinal and cardiovascular safety
concerns with COX-2 inhibitors and NSAIDs. Arthritis Res Ther 2005;7 Suppl 4:S23–9.

Solomon DH, Gurwitz JH. Toxicity of nonsteroidal anti-inflammatory drugs in the elderly: is advanced age a risk
factor? Am J Med 1997;102(2):208–15.

Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, et al. Cardiovascular safety of non-
steroidal anti-inflammatory drugs: network meta-analysis. BMJ 2011;342:c7086.

Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs
and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med
2015;26(4):285–91.

Wei L, MacDonald TM, Jennings C, Sheng X, Flynn RW, Murphy MJ. Estimated GFR reporting is associated with
decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function. Kidney Int
2013;84(1):174–8.

Working Group of the Australian and New Zealand College of Anaesthetists (ANZCA) and Faculty of Pain
Medicine (FPM) Acute pain management: scientific evidence. 4th ed. ANZCA & FPM; Melbourne, VIC: 2015.
http://www.anzca.edu.au/Resources/College-books-and-reports.

Paracetamol

Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, et al. Paracetamol: not as safe as we
thought? A systematic literature review of observational studies. Ann Rheum Dis 2016;75(3):552–9.

Fish oil

Boyd Turner M. Safety of fish oil and omega-3 fatty acids. Medicines Safety Update 2010;2.
https://www.tga.gov.au/publication-issue/medicines-safety-update-no2-2010

Cleland LG, James MJ, Proudman SM. Fish oil: what the prescriber needs to know. Arthritis Res Ther
2006;8(1):202.

Local corticosteroid injections

Bedard NA, Pugely AJ, Elkins JM, Duchman KR, Westermann RW, Liu SS, et al. The John N. Insall Award: Do
intraarticular injections increase the risk of infection after TKA?. Clin Orthop Relat Res 2017;475(1):45–52.
.

Conway R, O'Shea FD, Cunnane G, Doran MF. Safety of joint and soft tissue injections in patients on warfarin
anticoagulation. Clin Rheumatol 2013;32(12):1811–4.

Schairer WW, Nwachukwu BU, Mayman DJ, Lyman S, Jerabek SA. Preoperative hip injections increase the rate
of periprosthetic infection after total hip arthroplasty. J Arthroplasty 2016;31(9 Suppl):166–9 e1.

Opioids

Currow DC, Phillips J, Clark K. Using opioids in general practice for chronic non-cancer pain: an overview of
current evidence. Med J Aust 2016;204(8):305–9.

Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain - United States, 2016.
MMWR Recomm Rep 2016;65(1):1–49.

Frieden TR, Houry D. Reducing the risks of relief--The CDC opioid-prescribing guideline. N Engl J Med
2016;374(16):1501–4.

Karanges EA, Blanch B, Buckley NA, Pearson SA. Twenty-five years of prescription opioid use in Australia: A
whole-of-population analysis using pharmaceutical claims. Br J Clin Pharmacol 2016;82(1):255–67. .

Pilgrim JL, Yafistham SP, Gaya S, Saar E, Drummer OH. An update on oxycodone: lessons for death
investigators in Australia. Forensic Sci Med Pathol 2015;11(1):3–12.

Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Prescription of long-acting opioids and mortality in patients with
chronic noncancer pain. JAMA 2016;315(22):2415–23.

Wiese AD, Griffin MR, Stein CM, Mitchel EF, Grijalva CG. Opioid analgesics and the risk of serious infections
among patients with rheumatoid arthritis: A self-controlled case series study. Arthritis Rheumatol 2016;68(2):323–
31. .

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Practical prescribing considerations for
rheumatological diseases in children and
adolescents
Practical prescribing considerations for rheumatological diseases in
children and adolescents
The objective of pharmacological therapy in children, as in adults, is to use therapy that is acceptable to the
patient to cure or control disease, without causing adverse effects that might outweigh the benefits of
treatment.

Perhaps the greatest challenge of prescribing for children or adolescents is to ensure that drug therapy is
acceptable to both the patient and their parents. Common issues are listed below:

Many parents are reluctant to embark on long-term therapy with drugs they perceive to be dangerous
(eg corticosteroids, methotrexate) or only suitable for short-term use (eg nonsteroidal anti-
inflammatory drugs [NSAIDs]). A detailed discussion about the diagnosis, likely outcome without
therapy, and possible adverse effects of the proposed treatment is an essential part of obtaining
informed consent before starting treatment, and helps ensure good parent-administered medication
adherence.
Most preschool-aged children, many older children and even a few adolescents, are unable to swallow
tablets, no matter how much coaching they have. For these patients, drug formulation significantly
affects drug choice; dispersible tablets or liquid formulations are preferred, provided they can be
supplied in quantities that allow the drug to be given for the required duration without undue expense.
Occasionally parenteral formulations may be administered orally (eg methotrexate).
Multiple daily doses can be impractical if a child routinely refuses to take medications, or inconvenient
if it necessitates administration at school. Therefore, drugs dosed once or twice daily are preferred for
long-term therapy. Similarly, choice of once-daily medications for adolescent patients may improve
adherence to therapy.
Adolescent patients are often reluctant to adhere to corticosteroid therapy, especially for connective
tissue diseases, because of concerns about long-term adverse effects, particularly weight gain. It may
be necessary to modify the corticosteroid regimen to achieve adherence to therapy (eg using
intermittent high doses of intravenous corticosteroid or a lower-than-usual daily dose of oral
corticosteroid). For adolescent patients in particular, it is essential to have a willingness to balance the
treatment needs of the patient with the treatment needs of their disease.

Adverse effects of drugs used in the treatment of rheumatological diseases are generally the same in adults
and children (for general guidance on adverse effects see Principles of immunomodulatory drug use for
rheumatological disease in adults and Principles of analgesic and anti-inflammatory drug use for
musculoskeletal conditions in adults; for comprehensive drug information, consult an appropriate drug
information resource). Some specific concerns with the treatment of children are listed below:

Obvious symptoms of gastrointestinal intolerance to NSAIDs are less common in children than in
adults, especially in preschool-aged children. Less obvious symptoms, such as irritability or loss of
appetite, may be the only clues to NSAID intolerance.
Pseudoporphyria (photosensitivity causing facial skin blisters and scarring) is a well-recognised
adverse reaction to naproxen, which is described mainly in children. If this occurs, immediately stop
naproxen.
Corticosteroids can impair linear growth and accrual of bone mass in children, so must be used with
particular care. These effects may be profound with long-term high-dose corticosteroid therapy.

Paediatric prescribing generally involves calculating drug doses based on body weight. In cases of significant
obesity, consider using ideal body weight to calculate doses.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Gout
Overview of gout
Gout is a chronic disease that involves the deposition of monosodium urate crystals in the body, in particular the
joints, soft tissues and kidneys. The main symptoms of gout are joint pain and swelling, which may represent an
initial or recurrent acute attack, chronic gouty arthritis, or an acute attack in a patient with underlying chronic
gouty arthritis (see Clinical presentations of gout). The major manifestations of gout in the kidney are
nephrolithiasis and chronic urate nephropathy; both of which can progress to chronic kidney disease.

Gout occurs when the serum uric acid concentration is sufficiently elevated (usually greater than 0.42 mmol/L [7
mg/dL]), and the solubility coefficient of monosodium urate exceeded, long enough for crystals to form in tissues.
While the presence of hyperuricaemia is important in the diagnosis of gout, patients with acute gout may have a
normal serum uric acid concentration (see Diagnosis of gout). Furthermore, the presence of hyperuricaemia does
not necessarily indicate that gout is the explanation for a patient's symptoms. Patients can also have asymptomatic
hyperuricaemia, which is a risk factor for developing gout (see Pathogenesis of and risk factors for gout).

The incidence of gout increases with age, and in women gout rarely occurs before menopause. Gout is rare in
children; a diagnosis of gout in a child is not tenable unless the child has a genetic defect in urate metabolism.

The prevalence of gout is increasing worldwide, particularly in affluent countries such as Australia and New
Zealand. In these countries, increasing prevalence relates to the ageing population, higher consumption of alcohol
and fructose-sweetened drinks, other changes in dietary habits, and increasing rates of obesity. Certain ethnic
groups have a higher prevalence of gout; in particular, the prevalence of gout is higher in indigenous populations,
including in Australia and New Zealand.

Gout can be effectively treated and its complications prevented with adherence to lifelong urate-lowering therapy
using a treat-to-target approach (see General management approach for gout); however, gout is often poorly
managed in Australian primary care, with low rates of allopurinol prescribing, serum uric acid monitoring and
achievement of serum uric acid targets. Patient adherence to urate-lowering therapy is also often suboptimal.

Pathogenesis of and risk factors for gout

Serum uric acid concentration is the most important determinant of developing gout; the incidence of gout
increases exponentially with serum uric acid concentrations greater than 0.54 mmol/L (9 mg/dL).

Uric acid is formed in the liver from dietary and endogenous purines. Consumption of purine-rich foods
(particularly meat and seafood), alcohol (particularly beer and spirits) and fructose-sweetened drinks can increase
serum uric acid concentration and the risk of gout in susceptible individuals. Disorders involving a high cell
turnover (eg haematological malignancies, severe psoriasis) can also increase serum uric acid concentration and
the risk of gout in susceptible individuals.

Uric acid is eliminated by the kidneys (two-thirds) and the gut (one-third). Drugs that inhibit the renal excretion of
uric acid can increase serum uric acid concentration and the risk of gout in susceptible individuals. These drugs
include thiazide diuretics (often taken as a combination product with an angiotensin converting enzyme inhibitor
or angiotensin II receptor blocker), loop diuretics and cyclosporin. Diuretics are the most important cause of
secondary gout in middle-aged and older people.

Comorbidities including hypertension, chronic kidney disease, dyslipidaemia, type 2 diabetes and obesity are risk
factors for gout. A high concentration of endogenous insulin, as seen in patients with obesity, also inhibits the renal
excretion of uric acid.

Patients who are in a catabolic state (eg septic) or are dehydrated are at an increased risk of developing an acute
attack of gout. This often occurs during or immediately following a period of hospitalisation.

Essentially any drug, condition or dietary change that causes a rapid rise or decrease in serum uric acid
concentration can precipitate or prolong an acute attack of gout. This includes starting or increasing urate-lowering
therapy for the long-term management of gout, or implementing other dietary changes for the management of gout
(eg stopping excessive alcohol consumption).

Clinical presentations of gout

Acute gout
The first acute attack of gout is usually monoarticular, and often occurs in the big toe (the first metatarsophalangeal
joint) or other part of the foot. The joint is usually very painful, red and swollen. The first attack can be severe and
may mimic septic arthritis; patients may present with fever, malaise, leucocytosis, and elevated inflammatory
markers. If the acute attack is not treated, symptoms usually subside over a few days to 1 to 2 weeks.

In women, the first attack may be polyarticular, typically in the hands and with gouty tophi. The presentation may
be an acute inflammation in joints already affected by arthritis (eg the distal or proximal interphalangeal joints).

Most patients who are not started on urate-lowering therapy will have a second acute attack of gout within 2 years.
Ischaemic heart disease, hypertension and chronic kidney disease are independent risk factors for recurrent attacks.
Recurrent attacks may be misdiagnosed as a sprain or other soft-tissue injury. Initially, recurrent attacks may be
separated by long intervals of relatively normal joint function. Eventually, recurrent attacks occur more frequently,
are of longer duration, and involve more joints.

Chronic gout
If gout remains untreated with urate-lowering therapy, recurrent attacks may fail to resolve completely, slowly
leading to a chronic crippling, destructive arthritis. Even in the absence of recognised recurrent attacks, urate
crystals can deposit in the joints, soft tissues and kidneys, and can lead to joint damage and chronic kidney disease.

Chronic gout may be oligoarticular or polyarticular, and symmetrical involvement of the small joints of the hands
can mimic rheumatoid arthritis and psoriatic arthritis. Serum uric acid concentration may also be elevated in
psoriasis due to increased cell turnover, which further complicates the differential diagnosis of psoriatic arthritis.

Chronic gout may be the first diagnosed clinical presentation of gout in some patients because of unrecognised
previous acute attacks. Patients with chronic gout can also experience acute attacks (ie acute-on-chronic gout).

Gouty tophi are frequently seen in patients with chronic gout, and are usually present in the elbows (olecranon
bursae), knees (prepatellar bursae) and peripheral joints (eg the toes and fingers). Chronic tophaceous gout is
destructive and, unless treated, may cause significant disability.

Diagnosis of gout
While a diagnosis of gout is suspected based on clinical assessment (see Clinical presentations of gout), a
definitive diagnosis requires the identification of monosodium urate crystals under polarised microscopy in
synovial (or bursal) fluid or tophi (see Joint aspiration in adults). Confirmation of the diagnosis is important
because gout requires lifelong urate-lowering therapy. Microscopy and culture of the synovial (or bursal) fluid
should also be undertaken to exclude infection. Once a definitive diagnosis of gout has been made, diagnostic
aspiration is not required for recurrent attacks unless infection is suspected.

Aspiration of an affected joint, bursa or tophus is required to confirm the diagnosis of gout.

Serum uric concentration should be measured in all patients with suspected gout. However, the presence of
hyperuricaemia alone is insufficient to diagnose gout and, in patients with acute gout, serum uric concentration
may be normal. Other than the presence of tophi, individual clinical features (eg history of painful or swollen big
toe, unilateral podagra) have a low diagnostic utility. Response to colchicine does not replace aspiration in the
diagnosis of gout; it can support a diagnosis of crystal arthritis, but does not distinguish between gout and acute
calcium pyrophosphate crystal arthritis.

Monosodium urate crystals are not seen on plain X-ray because they are not radiopaque; however, a plain X-ray
may be useful to identify joint damage due to gout. In complex or difficult cases, specialists may use other imaging
modalities in the diagnosis of gout, but these have not yet been fully validated.

In patients with suspected gout, renal function should be measured as impaired renal function is both a risk factor
and a consequence of gout, and can affect treatment choice and dosing. A search for other secondary causes of
gout should be undertaken as appropriate (see Pathogenesis of and risk factors for gout).

General management approach for gout

Management of gout involves:

providing rapid symptom relief for acute attacks (see Management of acute gout)
prescribing lifelong urate-lowering therapy, using a treat-to-target approach, to prevent further acute attacks
and to prevent and treat the complications of gout, such as tophi, chronic kidney disease and chronic
 destructive arthritis
prescribing prophylaxis to prevent gout flares when starting or increasing urate-lowering therapy (see Flare
prophylaxis when starting or increasing urate-lowering therapy)
addressing modifiable risk factors for gout and optimising the management of associated comorbidities (see
Pathogenesis of and risk factors for gout), including closely monitoring and actively managing
cardiovascular disease risk factors (see Cardiovascular disease risk stratification):
if drug therapy is contributing to gout (eg use of a thiazide or loop diuretic), switch to an alternative
drug or reduce the dosage of the contributing drug if switching is not possible
losartan and fenofibrate have modest uricosuric effects and, if clinically appropriate, may be
preferable for the treatment of hypertension and dyslipidaemia respectively in a patient with gout
low-dose aspirin can inhibit the excretion of uric acid and increase the risk of recurrent acute attacks
of gout. However, given the substantial cardiovascular comorbidity associated with gout, low-dose
aspirin should usually be continued with adjustment of urate-lowering therapy as necessary to achieve
the target serum uric acid concentration
providing patient education; components include:
explanation of the nature of the condition, the likelihood of recurrent acute attacks and long-term
damage to the joints and kidneys if urate-lowering therapy is not started, and the need for adherence to
lifelong urate-lowering therapy
advice on maintaining a healthy lifestyle (eg maintaining ideal body weight, exercising regularly,
stopping smoking); and limiting the intake of alcohol (especially beer and spirits), fructose-sweetened
drinks and purine-rich foods. However, while there is strong evidence that lifestyle factors increase the
risk of gout, there is a lack of evidence that correcting these factors improves outcomes in patients
with gout
printed or online information that reinforces education messages; useful patient information leaflets on
‘Gout’ and ‘Gout and diet’ are available on the Arthritis Australia website [URL] [Note 1].

Note 1: Any management advice given in these patient information leaflets should be considered in the context of the recommendations in these
guidelines.

Management of acute gout

In early disease, an acute attack of gout can subside spontaneously within a week, but patients usually seek
medical advice. The aim of management is to provide rapid symptom relief. Nonsteroidal anti-inflammatory drugs
(NSAIDs), corticosteroids (local injection or systemic use) and low-dose colchicine are all effective in treating
acute gout. Drug choice is influenced by patient factors (including comorbidities), potential drug interactions and
adverse effects, and drug cost.

In terms of oral therapy, the NSAID indomethacin has traditionally been used to treat acute attacks of gout because
it is short-acting and the dose can be easily titrated according to symptomatic response; however, any NSAID may
be used. For discussion on NSAID choice, see Choice of NSAID and approach to NSAID use in patients at
increased risk of specific adverse effects. Evidence suggests that systemic corticosteroids (oral or intramuscular)
are as effective as NSAIDs in the treatment of acute gout, but systemic corticosteroids have a lower incidence of
acute adverse effects than NSAIDs. Colchicine is effective in reducing pain and inflammation in acute gout, but
has a high frequency of adverse effects (mainly gastrointestinal) that limit its usefulness. Paracetamol may be
useful as an analgesic adjunct, but is not recommended as monotherapy.

There are no randomised controlled trials investigating intra-articular or soft-tissue (eg bursal) corticosteroid
injections for acute gout, but their use is supported by evidence of benefit in other types of inflammatory arthritis
(eg rheumatoid arthritis) and the proven effectiveness of systemic corticosteroids in acute gout. Local
corticosteroid injection is appropriate if the acute attack involves one or two joints (or bursae) and joint (or bursal)
infection has been excluded. Aspiration of synovial (or bursal) fluid for microscopy and culture may be required to
exclude infection (see Joint aspiration in adults). If a definitive diagnosis of gout has not yet been made, aspiration
should be undertaken to confirm the diagnosis of gout and exclude infection before injecting the corticosteroid;
however, unless there is a high clinical suspicion of infection (eg recent history of penetrating trauma), the
corticosteroid can be injected before test results are available. Once a definitive diagnosis of gout has been made,
aspiration to exclude infection is not required before local corticosteroid injection for recurrent attacks unless
infection is suspected. For principles of use of local corticosteroid injections, see Principles of using local
corticosteroid injections for musculoskeletal conditions in adults.

For rapid symptom relief in acute gout, use:

1 a local corticosteroid injection at up to a maximum of two affected sites (see Table 12.9
for example doses)

OR
 1 an NSAID orally, until symptoms abate (typically 3 to 5 days) (see Table 12.7 for dosing;
the upper end of the dosing range is often required)

OR

1 prednis(ol)one 15 to 30 mg orally, daily until symptoms abate (typically 3 to 5 days)

[Note 2]

OR

2 colchicine 1 mg orally initially, then 500 micrograms 1 hour later, as a single one-day
course (total dose is 1.5 mg).

The low-dose regimen of colchicine recommended above is as effective as higher-dose regimens and is
significantly safer. Other low-dose regimens of colchicine may also be effective but their benefit has not been
proven (eg 500 micrograms orally, 8- to 12-hourly until symptoms abate [maximum of 6 mg over 4 days]; reduce
dosage in renal impairment). Other low-dose regimens may be considered if the patient's symptoms have not
abated after the single one-day course; however, the total dose of colchicine given in an acute attack should not
exceed 6 mg over 4 days.

Once the acute attack has settled, implement the other aspects of gout management (see General management
approach for gout), including patient education and lifelong urate-lowering therapy. If patients are already taking
urate-lowering therapy, advise them not to stop or change therapy during an acute attack because sudden changes
in serum uric acid concentration can prolong or worsen the attack.

Avoid changes to urate-lowering therapy during an acute attack of gout.

Note 2: A single dose of intramuscular corticosteroid may be used as an alternative to oral therapy (eg in patients who are vomiting or unable to
swallow tablets).

Long-term management of gout with urate-lowering therapy

General considerations
Lifelong urate-lowering therapy is recommended for all patients with a confirmed diagnosis of gout, but is
especially important for patients who present with tophaceous gout, renal manifestations of gout, or chronic gouty
arthritis.

Following an initial acute attack of gout, patients may be reluctant to start lifelong urate-lowering therapy. Patient
education is pivotal to encourage starting therapy; see General management approach for gout for components of
patient education. If patients decide not to embark on urate-lowering therapy, arrange regular follow-up
appointments (eg at 6-monthly intervals) to monitor disease progression. Advise patients to return for review
earlier if they have another acute attack of gout.

Titrate urate-lowering therapy using a treat-to-target approach.

Urate-lowering therapy is titrated using a treat-to-target approach. The aim of therapy is to lower serum uric acid
to a concentration that:

dissolves existing monosodium urate crystals in the joints, soft tissues and kidneys; and prevents the
formation of new crystals
reduces the frequency and severity of acute attacks, eventually leading to the absence of acute attacks
resolves tophi.

The target serum uric acid concentration is less than 0.36 mmol/L (6 mg/dL) for patients with non-tophaceous
gout, and less than 0.30 mmol/L (5 mg/dL) for patients with tophaceous gout. The presence of tophi indicates a
higher urate load and necessitates a lower target serum uric acid concentration. Failure to adjust the dose of urate-
lowering therapy to achieve the target serum uric acid concentration is a common reason for treatment failure.
Once the target serum uric acid concentration has been achieved, urate-lowering therapy should be continued to
maintain the target concentration.

Starting or increasing urate-lowering therapy is associated with a high risk of gout flare. Patients may be reluctant
to take urate-lowering therapy because of a previous acute attack precipitated by starting or increasing therapy.
Starting on a low dose of urate-lowering therapy minimises the risk of flares; the dose is then gradually increased
until the target serum uric acid concentration is achieved. Flare prophylaxis is recommended for all patients
starting or increasing urate-lowering therapy (see Flare prophylaxis when starting or increasing urate-lowering
therapy). Advise patients of the high risk of gout flare and the recommended management as for an acute attack
(see Management of acute gout).

Nonadherence to urate-lowering therapy also increases the risk of flare and is another common reason for
treatment failure. Nonadherence to treatment is a particular problem in patients with gout because of the presence
of relatively normal joint function between acute attacks initially, the complexity of the initial management
regimen, and a natural reluctance of patients to take lifelong medication. Patient education has an important role in
encouraging treatment adherence.

There are no data on the optimal time to start urate-lowering therapy after an acute attack. Starting urate-lowering
therapy has traditionally been delayed until the acute attack has resolved; however, starting urate-lowering therapy
concurrently with treatment for the acute attack may be appropriate, provided that treatment for the acute attack is
adequate and the patient is well informed about the risk of flare. This may be best done under specialist guidance.

Advise patients not to stop or change urate-lowering therapy during an acute attack because sudden changes in
serum uric acid concentration can prolong or worsen the attack.

First-line urate-lowering therapy

High-quality evidence indicates that allopurinol, a xanthine oxidase inhibitor, is effective in lowering serum uric
acid concentration by reducing uric acid production in the body. There is strong consensus that allopurinol should
be used as first-line urate-lowering therapy:

allopurinol 50 mg orally, daily for 4 weeks; then increase the daily dose by 50 mg every 2
to 4 weeks or by 100 mg every 4 weeks to achieve the target serum uric acid
concentration, up to a maximum maintenance dose of 900 mg daily.

Measure serum uric acid concentration monthly during the dose titration phase. The target serum uric acid
concentration is less than 0.36 mmol/L (6 mg/dL) or, if tophi are present, less than 0.30 mmol/L (5 mg/dL).
Patients with a higher baseline serum uric acid concentration are likely to need a higher allopurinol dose to achieve
the target serum uric acid concentration. A substantial proportion of patients require allopurinol doses above 300
mg daily to achieve the target serum uric acid concentration; however, nonadherence should always be ruled out
before increasing allopurinol to higher doses.

Renal impairment is not a contraindication to the use of allopurinol. The same (or lower) starting dose of
allopurinol and the same (or slower) rate of up-titration to achieve the target serum uric acid concentration is
recommended for patients with renal impairment, with close monitoring of renal function.

Allopurinol reduces the metabolism of azathioprine and mercaptopurine, increasing the risk of severe bone marrow
toxicity. If possible, avoid the combination of allopurinol with either azathioprine or mercaptopurine. If these
combinations cannot be avoided, reduce the dose of azathioprine or mercaptopurine to approximately one-quarter
to one-third of the usual dose and monitor full blood count closely.

Adverse effects occur in less than 1% of patients treated with allopurinol. Skin rash is the most common adverse
effect and may represent a maculopapular rash or allopurinol hypersensitivity syndrome. Allopurinol
hypersensitivity syndrome is a rare, but potentially fatal, adverse effect comprising erythematous desquamating
rash, fever, hepatitis, eosinophilia, and worsening renal function. The majority of cases of allopurinol
hypersensitivity syndrome occur in the first 3 months of treatment. Risk factors for allopurinol hypersensitivity
syndrome include use of a high starting dose and rapid up-titration, renal impairment, older age, and the presence
of human leucocyte antigen (HLA)-B*5801 allele, which is more common in people of Asian ethnicity, especially
the Han Chinese. Allopurinol hypersensitivity syndrome is a contraindication to further exposure to allopurinol.
Advise patients to stop allopurinol immediately and seek medical advice if a skin rash develops. Patients who
develop a maculopapular rash alone may be treated with an allopurinol desensitisation program; refer patients to a
specialist for desensitisation.

If the target serum uric acid concentration cannot be achieved with allopurinol monotherapy (eg the dose of
allopurinol required to achieve the target concentration is not tolerated), probenecid (a weak uricosuric) may be
added to allopurinol. Use:

probenecid 250 mg orally, twice daily for 1 week, then increase to 500 mg twice daily;
then increase the daily dose by 500 mg every 4 weeks to achieve the target serum uric acid
concentration, up to a maximum maintenance dose of 2 g daily in divided doses.

The efficacy of probenecid declines with declining renal function, but some efficacy is retained down to a
glomerular filtration rate of 30 mL/minute. Probenecid can increase the risk of urate nephrolithiasis and should be
avoided in patients with known urate nephrolithiasis.
Once the patient is stable and the target serum uric acid concentration has been achieved, serum uric acid
concentration can be checked annually to ensure the target concentration is maintained. Ongoing monitoring
should also include renal function, liver biochemistry, and full blood count (in patients taking probenecid), as well
as the frequency of gout attacks and, if applicable, tophi size.

Second-line urate-lowering therapies

Allopurinol is the treatment of choice to lower serum uric acid concentration in patients with gout (see First-line
urate-lowering therapy); however, if allopurinol is contraindicated or not tolerated at any dose, the following
second-line urate-lowering therapies are recommended: febuxostat (a xanthine oxidase inhibitor) or probenecid.

Instead of allopurinol, use:

1 febuxostat 40 mg orally, daily for 2 to 4 weeks; then increase the daily dose by 40 mg
every 2 to 4 weeks to achieve the target serum uric acid concentration, up to a maximum
maintenance dose of 120 mg daily [Note 3]

OR

2 probenecid 250 mg orally, twice daily for 1 week, then increase to 500 mg twice daily;
then increase the daily dose by 500 mg every 4 weeks to achieve the target serum uric
acid concentration, up to a maximum maintenance dose of 2 g daily in divided doses.

Measure serum uric acid concentration monthly during the dose titration phase. The target serum uric acid
concentration is less than 0.36 mmol/L (6 mg/dL) or, if tophi are present, less than 0.30 mmol/L (5 mg/dL).

Once the patient is stable and the target serum uric acid concentration has been achieved, serum uric acid
concentration can be checked annually to ensure the target concentration is maintained. Ongoing monitoring
should also include renal function, liver biochemistry (in patients taking febuxostat), and full blood count (in
patients taking probenecid), as well as the frequency of gout attacks and, if applicable, tophi size.

Febuxostat is not recommended for patients with pre-existing major cardiovascular disease [Note 4]. Febuxostat
should be used with caution in patients with hepatic impairment or moderate to severe renal impairment; seek
specialist advice. Febuxostat is thought to behave similarly to allopurinol in reducing the metabolism of
azathioprine and mercaptopurine, and increasing the risk of severe bone marrow toxicity. If possible, avoid the
combination of febuxostat with either azathioprine or mercaptopurine. If these combinations cannot be avoided,
reduce the dose of azathioprine or mercaptopurine and monitor full blood count closely.

The efficacy of probenecid declines with declining renal function, but some efficacy is retained down to a
glomerular filtration rate of 30 mL/minute. Probenecid can increase the risk of urate nephrolithiasis and should be
avoided in patients with known urate nephrolithiasis.

Note 3: The maximum daily dose of febuxostat in the Australian approved product information is 80 mg; however, daily doses of up to 120 mg are
approved in other countries.

Note 4: For more information, see the Therapeutic Goods Administration (TGA) safety advisory.

Flare prophylaxis when starting or increasing urate-lowering therapy

Starting or increasing urate-lowering therapy is associated with a high risk of gout flare, so flare prophylaxis is
recommended. Colchicine has the strongest evidence as a prophylactic drug for gout flares. Nonsteroidal anti-
inflammatory drugs (NSAIDs) may be considered for patients in whom colchicine is contraindicated or ineffective.
The potential benefit of NSAIDs should be weighed up against their potential harms, particularly in patients at
high risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).
Oral corticosteroids are usually only used under specialist advice and are associated with long-term adverse effects
(see Principles of immunomodulatory drug use for rheumatological diseases in adults). If a patient has had
multiple recurrent attacks of gout despite prophylaxis, combination therapy with colchicine plus either an NSAID
or prednis(ol)one may be required. Avoid concurrent use of NSAIDs and oral corticosteroids because of the
significantly increased risk of gastrointestinal toxicity, and because NSAIDs are not likely to have additional
benefit in patients taking oral corticosteroids.

To prevent gout flares, use:

1 colchicine 500 micrograms orally, once or twice daily. Reduce dosage in renal impairment
 OR

2 an NSAID orally (see Table 12.7 for dosing; the lower end of the dosing range is usually
adequate)

OR

3 prednis(ol)one 5 mg orally, daily.

The optimal duration of flare prophylaxis is unclear, but the frequency of flares, the duration of gout and the
presence and size of tophi should be taken into account. Evidence supports the use of flare prophylaxis for at least
6 months, but the presence of tophi may warrant prolonged flare prophylaxis. In general, flare prophylaxis should
be continued until the patient has no further attacks and the target serum uric acid concentration has been achieved.
Typically, this takes at least 6 months, but may take longer in some individuals.

If the patient has a gout flare, the recommended management is as for an acute attack (see Management of acute
gout) and urate-lowering therapy should be continued. If the patient has a gout flare after prophylaxis has been
stopped, restart prophylaxis and reassure patients that the urate-lowering therapy is working.

Key references
Overview of gout

Hak AE, Curhan GC, Grodstein F, Choi HK. Menopause, postmenopausal hormone use and risk of incident gout. Ann
Rheum Dis 2010;69(7):1305–9.

Robinson PC, Taylor WJ, Dalbeth N. An observational study of gout prevalence and quality of care in a national
Australian general practice population. J Rheumatol 2015;42(9):1702–7.

Robinson PC, Taylor WJ, Merriman TR. Systematic review of the prevalence of gout and hyperuricaemia in Australia.
Intern Med J 2012;42(9):997–1007.

Roughley MJ, Belcher J, Mallen CD, Roddy E. Gout and risk of chronic kidney disease and nephrolithiasis: meta-
analysis of observational studies. Arthritis Res Ther 2015;17:90.

Smith E, Hoy D, Cross M, Merriman TR, Vos T, Buchbinder R, et al. The global burden of gout: estimates from the
Global Burden of Disease 2010 study. Ann Rheum Dis 2014;73(8):1470–6.

Ting K, Gill TK, Keen H, Tucker GR, Hill CL. Prevalence and associations of gout and hyperuricaemia: results from an
Australian population-based study. Intern Med J 2016;46(5):566–73. .

Pathogenesis of and risk factors for gout

Singh JA, Reddy SG, Kundukulam J. Risk factors for gout and prevention: a systematic review of the literature. Curr
Opin Rheumatol 2011;23(2):192–202.

Clinical presentations of gout

Rothenbacher D, Primatesta P, Ferreira A, Cea-Soriano L, Rodriguez LA. Frequency and risk factors of gout flares in a
large population-based cohort of incident gout. Rheumatology (Oxford) 2011;50(5):973–81.

Diagnosis of gout

Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e
Initiative. Int J Rheum Dis 2015;18(3):341–51.

Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 Gout Classification Criteria: an
American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol
2015;67(10):2557–68.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations for the
diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of
rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.
 Sivera F, Andres M, Falzon L, van der Heijde DM, Carmona L. Diagnostic value of clinical, laboratory, and imaging
findings in patients with a clinical suspicion of gout: a systematic literature review. J Rheumatol Suppl 2014;92:3–8.

General management approach for gout

Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e
Initiative. Int J Rheum Dis 2015;18(3):341–51.

Moi JH, Sriranganathan MK, Edwards CJ, Buchbinder R. Lifestyle interventions for acute gout. Cochrane Database
Syst Rev 2013;(11):CD010519.

Moi JH, Sriranganathan MK, Edwards CJ, Buchbinder R. Lifestyle interventions for chronic gout. Cochrane Database
Syst Rev 2013;(5):CD010039.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations for the
diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of
rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.

Zhang Y, Neogi T, Chen C, Chaisson C, Hunter DJ, Choi H. Low-dose aspirin use and recurrent gout attacks. Ann
Rheum Dis 2014;73(2):385–90.

Management of acute gout

Finch A, Kubler P. The management of gout. Australian Prescriber 2016;39:119–22. www.nps.org.au/australian-

prescriber/articles/the-management-of-gout

Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e
Initiative. Int J Rheum Dis 2015;18(3):341–51.

Rainer TH, Cheng CH, Janssens HJ, Man CY, Tam LS, Choi YF, et al. Oral prednisolone in the treatment of acute
gout: a pragmatic, multicenter, double-blind, randomized trial. Ann Intern Med 2016;164(7):464–71.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations for the
diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of
rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.

Sivera F, Wechalekar MD, Andres M, Buchbinder R, Carmona L. Interleukin-1 inhibitors for acute gout. Cochrane
Database Syst Rev 2014;(9):CD009993.

Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for
early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled,
parallel-group, dose-comparison colchicine study. Arthritis Rheum 2010;62(4):1060–8.

van Durme CM, Wechalekar MD, Buchbinder R, Schlesinger N, van der Heijde D, Landewe RB. Non-steroidal anti-
inflammatory drugs for acute gout. Cochrane Database Syst Rev 2014;(9):CD010120.

van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane
Database Syst Rev 2014;(8):CD006190.

Wechalekar MD, Vinik O, Moi JH, Sivera F, van Echteld IA, van Durme C, et al. The efficacy and safety of treatments
for acute gout: results from a series of systematic literature reviews including Cochrane reviews on intraarticular
glucocorticoids, colchicine, nonsteroidal antiinflammatory drugs, and interleukin-1 inhibitors. J Rheumatol Suppl
2014;92:15–25.

Wechalekar MD, Vinik O, Schlesinger N, Buchbinder R. Intra-articular glucocorticoids for acute gout. Cochrane
Database Syst Rev 2013;(4):CD009920.

Long-term management of gout with urate-lowering therapy

Becker MA, Schumacher HR, Jr., Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared
with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353(23):2450–61.
Becker MA, Schumacher HR, Jr., Wortmann RL, MacDonald PA, Palo WA, Eustace D, et al. Febuxostat, a novel
nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind,
placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum
2005;52(3):916–23.

Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e
Initiative. Int J Rheum Dis 2015;18(3):341–51.

Graham GG, Kannangara DR, Stocker SL, Portek I, Pile KD, Indraratna PL, et al. Understanding the dose-response
relationship of allopurinol: predicting the optimal dosage. Br J Clin Pharmacol 2013;76(6):932–8.

Hill EM, Sky K, Sit M, Collamer A, Higgs J. Does starting allopurinol prolong acute treated gout? A randomized clinical
trial. J Clin Rheumatol 2015;21(3):120–5.

Kiltz U, Smolen J, Bardin T, Cohen Solal A, Dalbeth N, Doherty M, et al. Treat-to-target (T2T) recommendations for
gout. Ann Rheum Dis 2016;[Online first]. .

Kydd AS, Seth R, Buchbinder R, Edwards CJ, Bombardier C. Uricosuric medications for chronic gout. Cochrane
Database Syst Rev 2014;(11):CD010457.

Kydd AS, Seth R, Buchbinder R, Falzon L, Edwards CJ, van der Heijde DM, et al. Urate-lowering therapy for the
management of gout: a summary of 2 Cochrane reviews. J Rheumatol Suppl 2014;92:33–41.

Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ. Allopurinol for chronic gout. Cochrane Database Syst
Rev 2014;(10):CD006077.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations for the
diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of
rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.

Stocker SL, Graham GG, McLachlan AJ, Williams KM, Day RO. Pharmacokinetic and pharmacodynamic interaction
between allopurinol and probenecid in patients with gout. J Rheumatol 2011;38(5):904–10.

Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Febuxostat for treating chronic gout. Cochrane Database Syst Rev
2012;(11):CD008653.

Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute
attacks of gout: a randomized clinical trial. Am J Med 2012;125(11):1126–34 e7.

Flare prophylaxis when starting or increasing urate-lowering therapy

Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion in the 3e
Initiative. Int J Rheum Dis 2015;18(3):341–51.

Seth R, Kydd AS, Falzon L, Bombardier C, van der Heijde DM, Edwards CJ. Preventing attacks of acute gout when
introducing urate-lowering therapy: a systematic literature review. J Rheumatol Suppl 2014;92:42–7.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations for the
diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of
rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.

Published March 2017. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Asymptomatic hyperuricaemia
Introduction to asymptomatic hyperuricaemia
In adults, hyperuricaemia is generally defined as a serum uric acid concentration greater than 0.42 mmol/L (7
mg/dL) for males and 0.36 mmol/L (6 mg/dL) for females. The prevalence of hyperuricaemia is increasing
and it currently affects approximately one-fifth of both males and females. The prevalence is much higher in
Maori and Pacific Islander populations. Clinical experience suggests that the prevalence is also higher in
Aboriginal and Torres Strait Islander populations, but there are no data to confirm this. The prevalence of
hyperuricaemia increases with age.

While the majority of people with hyperuricaemia do not have gout, the risk of gout increases with increasing
concentration of serum uric acid. For a discussion of risk factors for hyperuricaemia and gout, see
Pathogenesis of and risk factors for gout.

There is increasing evidence that hyperuricaemia plays a pathogenic role in the development of hypertension,
type 2 diabetes, and atherosclerotic cardiovascular disease and its consequences (stroke, myocardial
infarction and cardiovascular death). Hyperuricaemia may also contribute to kidney disease.

Management of asymptomatic hyperuricaemia

There is no evidence to support the pharmacological management of isolated asymptomatic hyperuricaemia
to prevent the development of gout, kidney disease or cardiovascular disease. However, the patient's renal
function should be measured and their cardiovascular disease risk factors should be closely monitored and
actively managed (see Cardiovascular disease risk stratification). Management may include providing advice
on maintaining ideal body weight and addressing other lifestyle risk factors, and treating associated
comorbidities.

Pharmacological management of asymptomatic hyperuricaemia may be indicated if the patient has an

underlying condition (eg severe kidney disease) that may be improved by lowering serum uric acid
concentration. Treatment of asymptomatic hyperuricaemia may also be indicated for some haematological
disorders associated with increased cell turnover (eg myeloproliferative disease). If pharmacological
management is indicated, urate-lowering therapy is used as for the management of gout (see First-line urate-
lowering therapy and Second-line urate-lowering therapies).

If asymptomatic hyperuricaemia is due to drug therapy (eg a thiazide or loop diuretic), consider switching to
an alternative drug or reducing the dosage of the contributing drug if switching is not possible.

Key references
Graf SW, Whittle SL, Wechalekar MD, Moi JH, Barrett C, Hill CL, et al. Australian and New Zealand
recommendations for the diagnosis and management of gout: integrating systematic literature review and expert
opinion in the 3e Initiative. Int J Rheum Dis 2015;18(3):341–51.

Neogi T, George J, Rekhraj S, Struthers AD, Choi H, Terkeltaub RA. Are either or both hyperuricemia and
xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum 2012;64(2):327–38.

Robinson PC, Taylor WJ, Merriman TR. Systematic review of the prevalence of gout and hyperuricaemia in
Australia. Intern Med J 2012;42(9):997–1007.

Sivera F, Andres M, Carmona L, Kydd AS, Moi J, Seth R, et al. Multinational evidence-based recommendations
for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad
panel of rheumatologists in the 3e initiative. Ann Rheum Dis 2014;73(2):328–35.

Ting K, Gill TK, Keen H, Tucker GR, Hill CL. Prevalence and associations of gout and hyperuricaemia: results
from an Australian population-based study. Intern Med J 2016;46(5):566–73. .
Vinik O, Wechalekar MD, Falzon L, Buchbinder R, van der Heijde DM, Bombardier C. Treatment of
asymptomatic hyperuricemia for the prevention of gouty arthritis, renal disease, and cardiovascular events: a
systematic literature review. J Rheumatol Suppl 2014;92:70–4.

Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National
Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum 2011;63(10):3136–41.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Calcium pyrophosphate deposition
Introduction to calcium pyrophosphate deposition
Calcium pyrophosphate deposition is a disease of the older patient, with the mean age at presentation
reported to be between 65 and 75 years.

Calcium pyrophosphate deposition occurs when excessive calcium pyrophosphate production results in local
supersaturation and subsequent crystallisation. Deposition of calcium pyrophosphate dihydrate crystals
occurs almost exclusively in the joints and is the most common cause of chondrocalcinosis (cartilage
calcification).

Calcium pyrophosphate deposition is often asymptomatic, but can present clinically as:

osteoarthritis with calcium pyrophosphate deposition

acute calcium pyrophosphate crystal arthritis (formerly known as pseudogout), which is the most
common cause of an acute monoarthritis in the older patient
chronic calcium pyrophosphate crystal inflammatory arthritis (formerly known as pseudorheumatoid
arthritis).

See Clinical presentations of calcium pyrophosphate deposition for further discussion.

Risk factors for calcium pyrophosphate deposition

The main risk factors for calcium pyrophosphate deposition are increasing age and the presence of
osteoarthritis.

Other risk factors for calcium pyrophosphate deposition may include previous joint injury, primary
hyperparathyroidism, haemochromatosis and hypomagnesaemia. Checking serum calcium, ferritin and
magnesium concentrations may be considered, particularly in younger patients with calcium pyrophosphate
deposition. Although correction of these risk factors may not affect the course of the joint disease, it is
important to prevent other complications.

Loop diuretics, but not thiazide diuretics, appear to be associated with the development of acute calcium
pyrophosphate crystal arthritis.

Evidence does not support familial aggregation for chondrocalcinosis, but family history could relate to
earlier onset of clinical disease.

Clinical presentations of calcium pyrophosphate deposition

Acute calcium pyrophosphate crystal arthritis presents as an acutely inflamed joint, mimicking gout. The
knee and the wrist are the most commonly affected sites, a point of difference from gout, but the disease may
involve other joints and tendons. Acute attacks can be accompanied by fever and leucocytosis, mimicking
septic arthritis.

A rare manifestation of acute calcium pyrophosphate crystal arthritis is the ‘crowned dens’ syndrome, which
affects females more commonly than males. It presents as acute neck pain and stiffness, often accompanied
by fever and elevated inflammatory markers. Typically, there is periodontoid ‘crown-like’ calcification above
the dens. This can be observed on coronal views on cervical computed tomography (CT) scan, but is not
typically visible on plain X-rays.

Acute calcium pyrophosphate crystal arthritis may also present as pseudoneuropathic joint disease, with
severe destruction resembling a Charcot joint.

Chronic calcium pyrophosphate crystal inflammatory arthritis refers to the occasional presentation of
chronic oligoarthritis or polyarthritis with inflammatory features, and superimposed flares. It may involve the
knees, second and third metacarpophalangeal joints, wrists, shoulders, elbows, hips and midtarsal joints.
Chronic calcium pyrophosphate crystal inflammatory arthritis should be considered in the differential
diagnosis of rheumatoid arthritis in older adults.

Osteoarthritis with calcium pyrophosphate deposition may be distinguished from osteoarthritis without
calcium pyrophosphate deposition by the presence of more osteophytes, the involvement of different joints,
and more inflammatory features.

Diagnosis of calcium pyrophosphate deposition

A definitive diagnosis of calcium pyrophosphate deposition is made by identifying calcium pyrophosphate
dihydrate crystals in synovial fluid (see Joint aspiration in adults). The synovial fluid may contain both
monosodium urate and calcium pyrophosphate dihydrate crystals—if identified, seek specialist advice.
Microscopy and culture of the synovial fluid should also be undertaken to exclude septic arthritis.

While the presence of chondrocalcinosis supports the diagnosis of calcium pyrophosphate deposition, it is
neither highly sensitive nor specific. Furthermore, the finding of chondrocalcinosis on X-ray does not
necessarily indicate the presence of clinical disease; it may be asymptomatic without need of management.
The incidence of chondrocalcinosis increases with age: from 65 to 74 years the incidence is 15%, from 75 to
84 years it is 36%, and after the age of 84 years it is almost 50%. Chondrocalcinosis most commonly affects
fibrocartilage (particularly the knee and triangular cartilage of the wrist) but may also occur in hyaline
cartilage (mainly knee and glenohumeral joints) as linear opacities separate from, and often parallel to,
subchondral bone. The location of the chondrocalcinosis is important for determining its relevance to clinical
disease. For example, chondrocalcinosis involving the triangular cartilage of the wrist is much more likely to
be associated with clinical disease than chondrocalcinosis involving the knee.

Ultrasound has promising utility in the diagnosis of calcium pyrophosphate deposition; it may be useful to
detect hyperechoic lesions in hyaline and fibrous cartilage, tendons, bursa and/or joints, but further study is
needed before it can be recommended.

Management of calcium pyrophosphate deposition

There is a lack of evidence to guide the optimal management of acute calcium pyrophosphate crystal arthritis
and current management recommendations are based on extrapolating the evidence from treatment of acute
gout. As patients with acute calcium pyrophosphate crystal arthritis are often older and more likely to have
age-related comorbidities (eg chronic kidney disease), intra-articular corticosteroid injection may be the
safest treatment option (after excluding septic arthritis). Other treatment options include nonsteroidal anti-
inflammatory drugs (NSAIDs), systemic corticosteroids and colchicine; see Management of acute gout for
principles of drug use and dosing.

Currently, no treatment has been demonstrated to prevent or slow calcium pyrophosphate crystal deposition,
prevent recurrent acute attacks or treat chronic disease. However, treatment options that may be trialled
include NSAIDs, colchicine and hydroxychloroquine.

Key references
Finckh A, Mc Carthy GM, Madigan A, Van Linthoudt D, Weber M, Neto D, et al. Methotrexate in chronic-recurrent
calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. Arthritis Res Ther
2014;16(5):458.

Gamon E, Combe B, Barnetche T, Mouterde G. Diagnostic value of ultrasound in calcium pyrophosphate

deposition disease: a systematic review and meta-analysis. RMD Open 2015;1(1):e000118.

Rho YH, Zhu Y, Zhang Y, Reginato AM, Choi HK. Risk factors for pseudogout in the general population.
Rheumatology (Oxford) 2012;51(11):2070–4.

Uh M, Dewar C, Spouge D, Blocka K. Crowned dens syndrome: a rare cause of acute neck pain. Clin Rheumatol
2013;32(5):711–4.

Wilkins E, Dieppe P, Maddison P, Evison G. Osteoarthritis and articular chondrocalcinosis in the elderly. Ann
Rheum Dis 1983;42(3):280–4.

Zhang W, Doherty M, Bardin T, Barskova V, Guerne PA, Jansen TL, et al. European League Against
Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann
Rheum Dis 2011;70(4):563–70.
Zhang W, Doherty M, Pascual E, Barskova V, Guerne PA, Jansen TL, et al. EULAR recommendations for
calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis 2011;70(4):571–5.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Osteoarthritis
Introduction to osteoarthritis
Osteoarthritis is a chronic musculoskeletal condition that affects the joints and peri-articular structures. The
changes of osteoarthritis can affect the whole joint, including the cartilage, bone, synovial lining and synovial
fluid. The prevalence of osteoarthritis increases significantly with age and osteoarthritis affects more than 50% of
people aged 65 years and older. Although symptoms are less common before the age of 40 years, osteoarthritis can
also affect younger people. In these patients, osteoarthritis can have a significant impact on the ability to work, in
addition to the impact on physical function and quality of life experienced by all people with osteoarthritis.

Osteoarthritis can affect any joint; however, the most commonly affected joints are those of the hands (particularly
the distal interphalangeal joints and the first carpometacarpal joints), the cervical spine, the lumbar spine, and the
knees and hips. Osteoarthritis can be monoarticular, oligoarticular or polyarticular. Osteoarthritis may occur
secondary to another joint pathology, including major injury, inflammatory arthritis or infection; or it may be a
primary condition, in which case it is more likely to be generalised (involve three or more joint sites) and have a
stronger genetic link.

Osteoarthritis with calcium pyrophosphate deposition is discussed in Calcium pyrophosphate deposition.

Symptoms and clinical course of osteoarthritis

The major symptoms of osteoarthritis are pain, stiffness and swelling, which can lead to impaired mobility and
physical function. Deterioration in quality of life is common due to the physical and psychosocial impacts of the
condition. Stiffness following inactivity or morning stiffness in osteoarthritis is usually of shorter duration than in
rheumatoid arthritis. The joint swelling in osteoarthritis may be bony (hard) due to osteophyte formation and/or
spongy (soft) due to effusion or synovial thickening. Soft-tissue swelling in osteoarthritis is usually not as great as
that observed in rheumatoid arthritis.

Osteoarthritis usually follows a slowly progressive course and many patients have minimal disease progression;
however, a sudden and severe deterioration in symptoms can occur. Symptoms can also fluctuate over many years.
Patients with knee osteoarthritis are more likely to experience fluctuating symptoms, while patients with hip
osteoarthritis tend to have a more progressive disease course and can deteriorate rapidly. Some patients with
osteoarthritis only experience symptoms with physical activity rather than symptoms throughout the day. Knee
osteoarthritis tends to be associated with greater disability than osteoarthritis of the other joints.

For specific discussion on hand osteoarthritis, see Osteoarthritis of the hand.

Pathogenesis of osteoarthritis
Osteoarthritis has traditionally been considered to have a noninflammatory aetiology; however, it has become
increasingly recognised that inflammatory mediators (eg cytokines, prostaglandins) released from cartilage, bone
and the synovium contribute to both the development and progression of osteoarthritis. Low-grade inflammation
associated with obesity, insulin resistance, dyslipidaemia, hypertension and ageing may also contribute to disease
pathogenesis. Some patients with osteoarthritis have significant inflammation; late-onset rheumatoid arthritis is an
important differential diagnosis in these patients.

There are multiple sources of nociception in osteoarthritis, including structures within and around the joint; the
sources of nociception often fluctuate over time in an individual patient. Intra-articular sources of nociception
include synovitis, subchondral bone changes (reported as bone marrow oedema on magnetic resonance imaging
[MRI]), periosteum disruption associated with osteophyte formation, microfractures, ligament degeneration, and
capsular distension with effusions. Peri-articular sources of nociception include inflammation of tendon, fascia or
bursa; muscle spasm; and nerve pressure. For example, pes anserinus bursitis at the medial aspect of the knee is
commonly associated with knee osteoarthritis. Although osteoarthritis is characterised by the loss of articular
cartilage, this is not a source of nociception because articular cartilage contains no neural or vascular structures.

Central sensitisation can also contribute to the experience of pain and its sequelae in osteoarthritis.

Risk factors for osteoarthritis

Risk factors for the development and progression of osteoarthritis can vary depending on the affected joint;
however, the majority of epidemiological and risk factor studies have been in patients with knee osteoarthritis and
these findings are often generalised to osteoarthritis at other sites.

Obesity and injury are important modifiable risk factors for osteoarthritis (see also Weight loss). Malalignment is a
potentially modifiable risk factor for osteoarthritis. Nonmodifiable risk factors for osteoarthritis are older age,
female gender, and family history of osteoarthritis.

Certain occupations are associated with osteoarthritis of particular joints because of the physical load placed on the
joint by the occupation. Examples of associations include farming and hip osteoarthritis, occupations involving
repeated knee bending and/or lifting heavy objects and knee osteoarthritis, and occupations involving manual
labour and hand osteoarthritis.

Psychosocial factors can influence the experience of osteoarthritis. People with lower education levels, lower
socioeconomic status and psychological comorbidities tend to experience greater pain and disability. See also
Psychological therapies.

Diagnosis of osteoarthritis
The diagnosis of osteoarthritis is largely based on clinical assessment, which should include a thorough symptom
history, physical examination, and functional and psychosocial assessment (see Symptoms and clinical course of
osteoarthritis for a description of osteoarthritis symptoms).

Radiological findings of osteoarthritis are poorly correlated with osteoarthritis symptoms.

Radiological findings of osteoarthritis are common in asymptomatic individuals, particularly with increasing age,
and in isolation do not indicate the need for management. Furthermore, even in symptomatic patients, radiological
findings of osteoarthritis may not explain the patient's symptoms or reflect the severity of their symptoms. The
majority of patients with osteoarthritis have stable radiological findings over at least 10 years regardless of clinical
disease progression.

Laboratory investigations are usually not required for the diagnosis of osteoarthritis, and inflammatory markers are
usually normal or only minimally raised.

The diagnosis of osteoarthritis can be complicated by the presence of comorbid rheumatological diagnoses, such as
fibromyalgia and rheumatoid arthritis; these conditions are also differential diagnoses of osteoarthritis.

General management approach for osteoarthritis

Osteoarthritis is best managed by an integrated chronic disease model of care that supports multidisciplinary
involvement and is underpinned by a biopsychosocial approach. Besides their general practitioner, based on the
patient's needs, other members of the multidisciplinary team may include a physiotherapist, an exercise
physiologist, a dietician, a psychologist, a nurse, an occupational therapist, a rheumatologist and/or an orthopaedic
surgeon. The general practitioner is usually the care coordinator.

Patients with osteoarthritis should be followed up through all stages of the disease. There is no cure or proven
disease-modifying treatment for osteoarthritis; the following goals of management are relevant at all stages of the
disease and should be individualised to the patient:

enable pain coping and, where possible, reduce symptoms

maintain and optimise physical function
maintain and optimise ability to perform daily activities (eg participation in social, recreational and
occupational activities)
minimise associated disability
maximise health-related quality of life.

Box 12.6 summarises the essential features of osteoarthritis management. Although not an exhaustive list, it should
be considered the minimum standard of care for all patients. The evidence base for intervention in osteoarthritis
largely comprises clinical trials in patients with knee osteoarthritis. A smaller number of trials have been
performed for osteoarthritis of the hip and hand and very few for spinal osteoarthritis, in part because of the
difficulties in defining the patient population. While there are specific considerations in the management of
osteoarthritis at different joints, the essential features of management apply to osteoarthritis at any joint. For
specific considerations in the management of hand osteoarthritis, see Osteoarthritis of the hand.

The majority of patients with osteoarthritis have at least one comorbid condition, including other rheumatological
diagnoses. Patients with osteoarthritis are more likely than their age- and gender-matched peers to have
hypertension, diabetes, depression and obesity. Comorbidities can impact, and be impacted by, osteoarthritis and
its management. Therefore, optimising the management of comorbidities should be addressed in every
osteoarthritis management plan.

Assessing the benefit of interventions in osteoarthritis can be challenging because of the nature of the disease. In
placebo-controlled trials, benefit is often observed in the placebo group, which may be in part due to a natural
fluctuation in osteoarthritis symptoms. Where a comparative benefit for an intervention has been shown, the
average effect size is often only small or moderate, which may be in part due to the slow progression of the
disease. Application of the evidence is further limited by many trials assessing only short-term outcomes for what
is a chronic condition, and only assessing harms as a secondary outcome measure.

As the goals of osteoarthritis management are individualised and some patients experience a greater benefit from a
given intervention than others, the benefit of a specific intervention experienced by an individual patient may be
adequate for their needs. Because of the limitations in the evidence base and the variability in patient needs and
responses to a given intervention, it is recommended that a trial approach is taken to the use of interventions in
osteoarthritis. This involves regular assessment of an intervention against the goals of osteoarthritis management
to determine if the intervention is safe and of adequate and continued benefit for that individual.

While oral analgesia may be considered for pain relief, it is not an inevitable component of the management of
osteoarthritis. In particular, the risk of harms should be taken into account in the decision to initiate oral analgesia.

Essential features of osteoarthritis management (Box 12.6) [NB1]

Individualise the goals of management and the management plan through shared decision-making, taking
into account the patient's affected joints, the stage and severity of their disease, their functional
impairments, their risk factors for osteoarthritis, and their age, comorbidities and concomitant treatments.
Educate and reassure the patient about the nature of the condition and provide support for self-
management (see Patient education for and self-management of osteoarthritis).
Optimise the management of comorbidities, including other rheumatological diagnoses.
If the patient is overweight or obese, provide advice about weight loss and refer to services as required.
Provide advice about exercise and refer to services as required.
Provide advice about nonpharmacological interventions (see Physical treatments and Psychological
therapies).
If topical analgesia is needed, trial a topical NSAID or capsaicin.
If oral analgesia is needed, both paracetamol and oral NSAIDs have a role (see Paracetamol and oral
nonsteroidal anti-inflammatory drugs for further discussion).
Organise regular clinical review to monitor goals of management, and modify goals and the management
plan as needed. If there are concerns about the patient's progress, consider specialist referral.
Following an adequate trial period, assess interventions against management goals:
Cease unhelpful or harmful treatments.
Optimise oral analgesia to enable physical function, rather than to abolish pain.
Osteoarthritis symptoms can fluctuate; if symptoms improve, trial a cessation of oral analgesia.

NSAIDs = nonsteroidal anti-inflammatory drugs

NB1: See also the Australian Commission on Safety and Quality in Health Care (ACSQHC) Osteoarthritis of the Knee Clinical Care Standard
[URL].

For patients with persisting functional impairment and pain despite implementing the strategies in Box 12.6, a trial
of other interventions may be considered depending on the affected joints, and the stage and severity of the
disease. These include intra-articular corticosteroid injections, intra-articular hyaluronan injections and duloxetine.
Therapies for central sensitisation may be considered for patients with more widespread nonspecific pain (see
Management of fibromyalgia). Options for end-stage disease include surgery and opioids. In all cases, patients
should be encouraged to maintain lifestyle measures, such as exercise and weight loss.

Formal osteoarthritis chronic care programs have been established in some public and private care settings. These
programs use an integrated multidisciplinary approach targeted to the patient's needs. Although these programs are
evolving and not yet widely available, referral to such programs may be considered for patients who do not
respond to the strategies in Box 12.6, or who do not have access to co-located multidisciplinary care.

Patient education for and self-management of osteoarthritis

All patients with osteoarthritis, irrespective of the stage of the disease, should receive education about the
condition and advice on self-management. Patient education and self-management advice can help reduce pain,
and improve physical function and quality of life. It should be targeted to the needs of the patient, their general
health literacy, and their stage of acceptance of the condition. Use positive and non-catastrophic language to
empower patients to proactively and positively manage their osteoarthritis. When describing osteoarthritis to
patients, avoid the use of negative terms such as ‘bone on bone’, ‘normal wear and tear’ and ‘cartilage erosion’.

Follow-up patient education and self-management advice at regular clinical review appointments is also
recommended. This has been associated with symptom improvement in part because of better adherence to
interventions, but also because of improved self-efficacy and coping.

Patient education should include discussion about:

the likelihood of slow or minimal disease progression

the fluctuating nature of osteoarthritis symptoms
the poor correlation between symptoms and radiological findings of osteoarthritis
modifiable risk factors for disease progression (see Risk factors for osteoarthritis)
realistic management goals and expectations of treatment.

Strategies for self-management include:

coping strategies for living with chronic pain (see also Psychological therapies)
pacing physical activities (eg spreading physically hard jobs throughout the day with breaks in between to
reduce sustained physical loading)
lifestyle measures, such as exercise and weight loss
use of physical aids (see Nonpharmacological management)
strategies to minimise symptoms when performing activities of daily living (often referred to as joint
protection techniques); specific strategies are recommended for hand osteoarthritis (see Osteoarthritis of the
hand) and similar principles may be applied to osteoarthritis of the other joints
topical or oral analgesia for evoked pain (see Topical nonsteroidal anti-inflammatory drugs and capsaicin
and Paracetamol and oral nonsteroidal anti-inflammatory drugs)
monitoring pain levels using a pain management diary [Note 1].

The success of patient education and self-management largely relies on consistency in the messages provided to
patients. Allied health professionals who are trained in both the management principles of osteoarthritis and in
health coaching and behavioural change can assist in the education process (eg occupational therapists,
physiotherapists, podiatrists). Evidence does not support a benefit from formal self-management education
programs; however, these are unlikely to be harmful.

Printed or online information is useful to reinforce education and self-management advice. Patient support
organisations such as Arthritis Australia provide educational materials and participation in their activities may be
valuable for social support; see [URL]. The ‘My Joint Pain’ [URL] and ‘painHEALTH’ [URL] websites also
provide useful tips for self-management [Note 2].

Note 1: The Helping you manage pain diary is available from NPS MedicineWise [URL].

Note 2: These websites provide patient information; any management advice given on these websites should be
considered in the context of the recommendations in these guidelines.

Lifestyle management of osteoarthritis

Exercise
Exercise is important for all patients with osteoarthritis, irrespective of the affected joints or the stage or severity of
the disease (including for patients awaiting surgery). Reported benefits of exercise include reduction in pain, and
improvements in physical function and quality of life.

No specific exercise program has been proven to be substantially better than another in the management of
osteoarthritis. The success of exercise depends on patient adherence to the program in the long term, so choice of
exercise program should take into account the patient's functional impairments, comorbidities, and physical
activity preferences.

For osteoarthritis of the knee or hip, programs that incorporate aerobic exercise with functional and progressive
lower limb muscle strengthening are generally recommended. These have been shown to be safe and effective,
even among older patients. Strengthening and aerobic exercise should be undertaken at least 3 times per week.
People with lower limb osteoarthritis have an increased risk of falls, so balance training should be incorporated as
part of functional exercise. There is evidence that a program of strengthening, flexibility and functional exercises
can delay the need for surgery in patients with hip osteoarthritis.

In terms of specific modes of exercise, there is evidence for both land-based exercises, including Tai Chi, and
water-based exercises, such as aqua aerobics, for knee and hip osteoarthritis. An example exercise program for
knee osteoarthritis can be found on the HANDI (The Handbook of Non-Drug interventions) website [URL].

For osteoarthritis of other joints, a functional exercise approach is recommended. For discussion of exercise for
hand osteoarthritis, see Osteoarthritis of the hand.

Regular aerobic exercise has multiple well-recognised general health benefits that are relevant to patients with
osteoarthritis. These include reduced risk of cardiovascular disease, weight loss, improved quality of life,
improved mood and sleep patterns, and reduced risk of falling in older patients. Weight loss is particularly
important because obesity is a modifiable risk factor for the development and progression of osteoarthritis.

Patients with osteoarthritis often need additional encouragement to undertake exercise because of joint pain and
perceived instability. Reassure patients that some discomfort at the affected joint during exercise is likely and this
does not indicate disease progression. Encourage patients using supportive and non-catastrophic language such as
‘hurt does not mean harm’ and ‘sore but safe’. Topical or oral analgesia may be required to facilitate exercise (see
Topical nonsteroidal anti-inflammatory drugs and capsaicin and Paracetamol and oral nonsteroidal anti-
inflammatory drugs).

Appropriate exercise can be undertaken safely in a variety of settings (eg home, gym, group class or under clinical
supervision). Referral to an appropriate health professional (eg physiotherapist, exercise physiologist) may be
beneficial to initiate and reinforce an exercise program; this may include prescribing a personalised program of
simple exercises (eg swimming, walking) that the patient can do unsupervised. Involving the patient's social
supports (eg spouse) in the exercise program may also improve outcomes.

Depending on their functional impairments and comorbidities, some patients may require clinician-guided exercise
instruction and support, combined with cognitive and behavioural pain education. Physiotherapist-delivered
exercise integrated with training in pain-coping skills has been demonstrated to improve functional outcomes
compared with either intervention alone in patients with knee osteoarthritis.

Weight loss

Obesity is a risk factor for both the development and progression of knee osteoarthritis. The majority of patients
with knee osteoarthritis are overweight or obese. Of those patients undergoing joint replacement surgery for knee
osteoarthritis, 60% are reported as obese. Obesity also appears to be a risk factor for hip, hand and spinal
osteoarthritis; 40% of patients undergoing joint replacement surgery for hip osteoarthritis are reported as obese.

Weight loss is recommended for all patients with osteoarthritis who are overweight or obese, irrespective of the
affected joints or the stage or severity of the disease (including for patients awaiting surgery). There is strong
evidence that weight loss is beneficial for knee osteoarthritis. Despite no good evidence that it helps hip or other
forms of osteoarthritis, weight loss is still recommended because of the general health benefits.

Improvement in osteoarthritis symptoms and physical function is proportional to the percentage of weight loss. A
range of weight loss targets has been identified as necessary for a clinically significant improvement; a reasonable
target is a more than 5% weight reduction. Reduction in pain and improvement in physical function are greater if
exercise and weight loss are combined. For information on weight loss strategies, see Management of overweight
patients. Refer patients to weight management services if appropriate.

Nonpharmacological management of osteoarthritis

Physical treatments
Physical treatments are often used as adjunctive therapy in the management of osteoarthritis; however, apart from
exercise, physical treatments have a limited role in osteoarthritis management because of a lack of evidence, weak
or unclear evidence of benefit, or evidence suggesting they are not effective. However, because some patients
report a benefit and these interventions are unlikely to be harmful, a trial may be reasonable based on patient
preference.

In patients with knee or hip osteoarthritis, thermotherapy (application of heat or cold), or the use of a walking stick
may reduce pain and enable physical activity. In patients with patellofemoral osteoarthritis, there is limited
evidence that medially directed taping of the patella may provide short-term pain relief. Taping should not be used
in isolation and is most useful as an adjunct to encourage patients to start their exercise program. Long-term use of
taping may be limited by local skin reactions. There is also some evidence to support the use of a patellofemoral
brace for pain relief in patients with patellofemoral osteoarthritis and this may be considered as an alternative to
taping.

Evidence suggests that acupuncture, transcutaneous electrical nerve stimulation (TENS), lateral heel wedge
insoles, manual therapy, magnets and valgus braces are not effective in the management of osteoarthritis.
For discussion of physical treatments for hand osteoarthritis, see Osteoarthritis of the hand.

Psychological therapies

Patients with osteoarthritis who live with chronic pain, functional impairment and impaired quality of life are
likely to experience a negative psychological impact. Psychological impairments may increase disability, affect
adherence to self-management strategies and reinforce central sensitisation. Psychological therapies (eg cognitive
behavioural therapy) may be useful to address psychological impairments and pain coping. Recent data also
suggest a potential benefit from internet-delivered pain-coping programs.

For more information on psychological techniques for chronic pain, see Psychological techniques. Treat specific
psychological diagnoses if present (eg depression or anxiety).

Pharmacological management of osteoarthritis

Topical nonsteroidal anti-inflammatory drugs and capsaicin
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and capsaicin can be considered as an adjunct to other
treatment strategies and as part of short-term self-management.

Topical NSAIDs have been shown to have a small benefit in pain relief compared to topical placebo preparations
in studies up to 12 weeks and mainly in patients with knee osteoarthritis. Because of minimal systemic absorption,
topical NSAIDs are considerably safer than oral NSAIDs and limited evidence suggests they have similar efficacy
to oral NSAIDs in patients with osteoarthritis. If a trial of a topical NSAID is considered appropriate, use:

a topical NSAID applied directly to the painful area, up to 4 times daily (see Table 12.7
for available topical preparations).

Topical capsaicin has also been shown to have a small benefit in pain relief compared to topical placebo
preparations in studies up to 12 weeks. The main adverse effect is a transient burning at the site of application,
which decreases over time. If a trial of topical capsaicin is considered appropriate, use:

capsaicin 0.025% cream applied directly to the painful area, 3 to 4 times daily.

Paracetamol and oral nonsteroidal anti-inflammatory drugs

Both paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) have a role in oral analgesia for
osteoarthritis symptoms.

Oral NSAIDs are more effective than paracetamol and can improve symptoms in most patients. However, oral
NSAIDs also have a greater potential for harm, particularly in older people, who are the population most
commonly affected by osteoarthritis. For patients at low risk of harms from NSAID use, a trial of an oral NSAID
may be considered first line (see Principles of NSAID use for musculoskeletal conditions in adults for more
information on assessing the risk of harms from NSAID use). Avoid first-line use of oral NSAIDs in all other
patients.

Only consider using an oral NSAID first line for patients at low risk of harms from NSAID use.

The evidence for paracetamol in osteoarthritis is mainly from older clinical trials and all in patients with knee or
hip osteoarthritis. The evidence indicates that on average paracetamol has small, but statistically significant, short-
term benefits compared to placebo; there are differing interpretations of the clinical significance of this, but an
individual patient may experience adequate benefit for their needs. Paracetamol also has a more favourable safety
profile compared to other oral analgesics. Therefore, a trial of paracetamol remains appropriate for any patient
requiring oral analgesia for osteoarthritis symptoms.

For patients with symptoms evoked by exercise or other physical activity, consider a trial of ‘as necessary’
paracetamol or oral NSAID. Use:

1 paracetamol 1 g orally, 4- to 6-hourly as necessary, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly as necessary

 OR (for patients at low risk of harms from NSAID use)

1 an NSAID orally (see Table 12.7 for dosing).

For patients with symptoms that persist throughout the day, consider a trial of regular dosing, rather than ‘as
necessary’ dosing.

Ensure the duration of the trial is adequate and assess treatment response against the goals of management. Goals
related to physical function should be the focus; explain to the patient that the aim is to reduce, rather than abolish,
pain so that physical function can be maintained.

If response to paracetamol is inadequate, a judicious trial of NSAID use may be considered instead of, or in
combination with, paracetamol. This decision should be based on an assessment of the benefit–harm profile for an
NSAID in the individual patient.

Do not continue paracetamol and/or oral NSAIDs if there is no benefit or treatment is harmful. Osteoarthritis
symptoms can fluctuate; if symptoms improve, consider a trial of cessation of oral analgesia.

Intra-articular injections

A single intra-articular corticosteroid injection may provide symptom relief lasting from 4 to 12 weeks in
patients with knee osteoarthritis; however, most trials supporting the use of intra-articular corticosteroid injections
have been reported to have a high or unclear risk of bias. Because of their rapid onset of action, intra-articular
corticosteroid injections may be useful if patients have to travel or participate in an important occasion; they may
also enable participation in strengthening exercises. Knee injections are easily performed with landmark guidance;
radiological guidance, such as ultrasound, does not increase the effectiveness of the injection. Intra-articular
corticosteroid injection may be repeated at 3-monthly intervals if needed; evidence suggests that repeat injections
are effective and do not alter disease progression.

Small randomised controlled trials have shown that a single intra-articular corticosteroid injection may provide
pain relief for up to 12 weeks in hip osteoarthritis; however, these injections are logistically difficult to administer
because radiological guidance is needed.

For principles of use and example doses of local corticosteroid injections, see Principles of using local
corticosteroid injections for musculoskeletal conditions in adults.

Intra-articular hyaluronan can be given as a single injection or as a weekly injection for 3 to 5 weeks depending
on the preparation. The evidence for intra-articular hyaluronan injection in patients with knee osteoarthritis is
inconsistent because of the range of preparations studied and the quality and design of the studies. Conclusions of
systematic reviews have been conflicting, and larger trials in which participants were adequately blinded reported
only a small and clinically insignificant benefit. Intra-articular corticosteroid injection provides greater short-term
benefits in knee osteoarthritis than intra-articular hyaluronan injection, but pain relief from intra-articular
hyaluronan injection may last slightly longer in patients who respond. Intra-articular hyaluronan injection may be
associated with temporary worsening of osteoarthritis symptoms, and the unit cost of intra-articular hyaluronan
injection is much higher than the unit cost of intra-articular corticosteroid injection. As with intra-articular
corticosteroid injections, hyaluronan injections into the knee joint are easily performed using landmark guidance.
Small studies of intra-articular hyaluronan injections have been conducted in hip, ankle and shoulder osteoarthritis
with conflicting results.

Intra-articular injections of platelet-rich plasma, adipocyte cell suspensions and mesenchymal stem cells are being
increasingly used for the treatment of osteoarthritis. Despite the favourable conclusions of systematic reviews of
intra-articular injections of platelet-rich plasma, the results should be interpreted with caution because the
individual studies in the reviews were generally at high risk of bias. The evidence to support the use of adipocyte
cell suspensions and mesenchymal stem cells is also weak. None of these treatments is recommended.

For discussion of intra-articular injections for hand osteoarthritis, see Osteoarthritis of the hand.

Duloxetine

Duloxetine has been shown to reduce pain and improve physical function compared to placebo in patients with
chronic pain due to knee osteoarthritis. Evidence suggests that duloxetine may have a similar efficacy to oral
nonsteroidal anti-inflammatory drugs (NSAIDs), but head-to-head comparisons are lacking. Duloxetine has also
been shown to be an effective adjunct to oral NSAIDs. The duration of the studies ranged from 10 to 16 weeks.
Duloxetine may be considered for patients with knee osteoarthritis who have persisting functional impairment and
pain despite implementing the strategies in Box 12.6.

If a trial of duloxetine is considered appropriate, use:

 duloxetine 30 mg orally, daily for 1 week, then increase to 60 mg daily. Maximum daily
dose is 120 mg.

Opioids

Opioids have a very limited role in the management of osteoarthritis because of modest, if any, benefits and a
significant risk of harms.

Opioids may be considered for patients with severe persisting functional impairment due to pain, despite maximal
conservative management (see General management approach for osteoarthritis); this may include patients
awaiting surgery or in whom surgery is not possible. Opioids are not recommended for osteoarthritis of the hand.

If opioids are used, they should be prescribed on a short-term trial basis, as part of an overall pain management
strategy, with clear goals and regular review of treatment response and adverse effects. Before starting an opioid, a
plan for ceasing ineffective therapy should be in place and discussed with the patient. If treatment response is
inadequate, caution should be exercised when increasing the dose of opioids as there is an increased risk of harm
and potentially no added benefit. Prolonged use of opioids indicates the need for specialist assessment. See
Opioids for more information.

Studies up to 1 year in patients with knee or hip osteoarthritis indicate that tapentadol may have a more favourable
safety profile than oxycodone; however, the long-term safety of tapentadol is not known and the same precautions
as for other opioids should be applied to tapentadol.

Complementary medicines in osteoarthritis

Fish oil, glucosamine and chondroitin are commonly used treatments for osteoarthritis.

There are no placebo-controlled trials of fish oil in the management of osteoarthritis. A recent trial compared an
anti-inflammatory dose of fish oil with a low dose of fish oil in patients with knee osteoarthritis and found a
reduction in pain and improvement in physical function in both groups, but the anti-inflammatory dose of fish oil
offered no benefit over low-dose fish oil [Note 3].

Although the combination of glucosamine and chondroitin has been suggested to have a disease-modifying effect
in knee osteoarthritis, there is inadequate evidence to support its use for this purpose. In terms of symptom benefit,
the evidence for glucosamine is inconsistent because of the range of different brands studied; however, large
randomised controlled studies of glucosamine suggest that the benefit is no greater than placebo. The evidence for
chondroitin is unclear, but limited evidence suggests it may have a small to moderate benefit compared to placebo.
There is conflicting evidence regarding a symptom benefit with the combination of glucosamine and chondroitin in
patients with painful knee osteoarthritis, with some studies suggesting a small benefit and others showing no
benefit.

For patients with osteoarthritis who want to trial these therapies, the usual dosages are glucosamine sulfate 1500 to
2000 mg orally, daily, and chondroitin sulfate 800 to 1200 mg orally, daily. An appropriate trial duration is 3 to 6
months. Most formulations of glucosamine are prepared from shellfish and should not be used in patients with
significant seafood allergy. There may be variation in the effect between different brands because of the range of
sources used and different methods of processing.

There is no evidence for krill oil in the management of osteoarthritis, and there is inadequate evidence to support
the use of turmeric (active ingredient is curcumin) or Ayurvedic medicine.

Note 3: Hill CL, March LM, Aitken D, Lester SE, Battersby R, Hynes K, et al. Fish oil in knee osteoarthritis: a
randomised clinical trial of low dose versus high dose. Ann Rheum Dis 2016;75(1):23-9. [URL]

Surgery for osteoarthritis

Surgical options for hip and knee osteoarthritis include osteotomy and joint replacement. Refer patients for surgery
if they have severe persisting functional impairment and/or pain despite maximal conservative management (see
General management approach for osteoarthritis). Timely referral is important (ie before significant functional
decline occurs). Around 30% of patients with knee osteoarthritis will require surgery, and this figure is likely to be
higher for patients with hip osteoarthritis. For discussion of surgery for hand osteoarthritis, see Osteoarthritis of the
hand.

Patients referred for surgery should be advised of the realistic degree of reduction in pain and improvement in
physical function that can be expected from surgery. Weight change following surgery is variable and obesity can
persist for a large proportion of patients postoperatively.

While awaiting surgery, patients should be encouraged to persist with lifestyle measures, such as weight loss and
exercise, as a higher preoperative level of functioning may improve outcomes from surgery and will enable better
participation in postoperative rehabilitation. Weight loss before surgery is often recommended because obesity
increases the risk of perioperative complications, delays the benefits of surgery, and is associated with higher rates
of surgical revision. Management of patients who are awaiting joint replacement is discussed in The Royal
Australian College of General Practitioners (RACGP) management guide on referral for joint replacement [Note
4].

Arthroscopic lavage and/or debridement are not recommended for osteoarthritis of the knee, and partial
meniscectomy is not recommended for degenerative meniscal tears (with or without underlying osteoarthritis),
because these treatments have not been found to be more effective than placebo or exercise, and have the potential
for harm. There are no randomised controlled trials of arthroscopy for hip osteoarthritis.

Note 4: The RACGP management guide on referral for joint replacement is available at the RACGP website
[URL].

Osteoarthritis of the hand

In osteoarthritis of the hand, the most commonly affected joints are the distal interphalangeal joints and the first
(thumb) carpometacarpal joints. Affected distal interphalangeal joints may go through a painful inflammatory
phase, lasting from a few months to a few years, which then settles leaving residual bony deformity (Heberden
nodes) that does not significantly impact on physical function. Primary generalised nodal osteoarthritis is a subtype
of osteoarthritis that can involve multiple distal and proximal interphalangeal joints, and can have a significant
impact on physical function. Thumb-based carpometacarpal osteoarthritis can occur in isolation or as part of
primary generalised nodal osteoarthritis. It usually has a significant impact on physical function.

Relatively few randomised controlled trials have been conducted for osteoarthritis of the hand; however, there is
evidence that conservative management can prevent the need for surgery. For initial management, the following
interventions may be beneficial:

strategies to minimise symptoms when performing activities of daily living (often referred to as joint
protection techniques) (see Box 12.7)
assistive devices as needed for performing activities of daily living (eg tap turner), based on an assessment
of the patient's abilities
splints for thumb-based carpometacarpal osteoarthritis [Note 5]
strengthening and stretching hand exercises
application of heat.

If needed, the above interventions can be combined with topical or oral analgesia (see Topical nonsteroidal anti-
inflammatory drugs and capsaicin and Paracetamol and oral nonsteroidal anti-inflammatory drugs). Opioids are not
recommended for osteoarthritis of the hand.

Strategies to minimise symptoms of hand osteoarthritis when performing activities of daily

living (Box 12.7) [NB1]

Distribute the weight of lifted objects over several joints (eg spread the load over two hands).
Avoid repetitive thumb movements and putting strain on the thumb.
Avoid a prolonged grip in one position.
Use as large a grip as possible.
Reduce the effort needed to do a task (eg use labour-saving gadgets, avoid lifting heavy objects, and
reduce the weight of what is lifted).
Conserve energy by planning activities (eg organise tasks more efficiently) and pacing them (eg take
regular short breaks).

NB1: More information on these strategies can be found on the HANDI (The Handbook of Non-Drug interventions) website [URL]

Source: Dziedzic K, Nicholls E, Hill S, Hammond A, Handy J, Thomas E, et al. Self-management approaches for osteoarthritis in the hand: a 2x2
factorial randomised trial. Ann Rheum Dis 2015;74(1):108-18. [URL]

Intramuscular corticosteroids can reduce inflammation and improve symptoms in patients with primary generalised
nodal osteoarthritis; however, their use is not recommended because of the lack of long-term effectiveness data and
the potential for long-term adverse effects. Evidence suggests intra-articular corticosteroid injections and intra-
articular hyaluronan injections are not more effective than placebo for carpometacarpal osteoarthritis, including
thumb-based carpometacarpal osteoarthritis. The suggested benefit of intra-articular corticosteroids in
interphalangeal osteoarthritis requires confirmation.

There is insufficient evidence to recommend hydroxychloroquine, methotrexate or sulfasalazine for osteoarthritis

of the hand, although they are sometimes considered for inflammatory and erosive osteoarthritis. These drugs
should only be started in consultation with a rheumatologist.

Surgery may be considered for advanced thumb-based carpometacarpal joint osteoarthritis if pain and functional
impairment persist despite maximal conservative management. However, the evidence for benefit of surgery is
inconclusive.

Note 5: Information on splints for hand osteoarthritis can be found on the HANDI (The Handbook of Non-Drug
interventions) website [URL].

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in combination for painful knee osteoarthritis. N Engl J Med 2006;354(8):795–808.

Eriksen P, Bartels EM, Altman RD, Bliddal H, Juhl C, Christensen R. Risk of bias and brand explain the observed
inconsistency in trials on glucosamine for symptomatic relief of osteoarthritis: a meta-analysis of placebo-controlled
trials. Arthritis Care Res (Hoboken) 2014;66(12):1844–55.

Fransen M, Agaliotis M, Nairn L, Votrubec M, Bridgett L, Su S, et al. Glucosamine and chondroitin for knee
osteoarthritis: a double-blind randomised placebo-controlled clinical trial evaluating single and combination regimens.
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Hill CL, March LM, Aitken D, Lester SE, Battersby R, Hynes K, et al. Fish oil in knee osteoarthritis: a randomised
clinical trial of low dose versus high dose. Ann Rheum Dis 2016;75(1):23–9.

Hochberg MC, Martel-Pelletier J, Monfort J, Moller I, Castillo JR, Arden N, et al. Combined chondroitin sulfate and
glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus
celecoxib. Ann Rheum Dis 2016;75(1):37–44.

Roman-Blas JA, Castaneda S, Sanchez-Pernaute O, Largo R, Herrero-Beaumont G. CS/GS Combined Therapy

Study Group. Chondroitin sulfate plus glucosamine sulfate shows no superiority over placebo in a randomized, double-
blind, placebo-controlled clinical trial in patients with knee osteoarthritis. Arthritis Rheumatol 2017;69(1):77–85.
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Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for osteoarthritis. Cochrane Database Syst Rev
2015;(1):CD005614.

Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating
osteoarthritis. Cochrane Database Syst Rev 2005;(2):CD002946.

Surgery for osteoarthritis

Ast MP, Abdel MP, Lee YY, Lyman S, Ruel AV, Westrich GH. Weight changes after total hip or knee arthroplasty:
prevalence, predictors, and effects on outcomes. J Bone Joint Surg Am 2015;97(11):911–9.

Buchbinder R, Richards B, Harris I. Knee osteoarthritis and role for surgical intervention: lessons learned from
randomized clinical trials and population-based cohorts. Curr Opin Rheumatol 2014;26(2):138–44.

Kerkhoffs GM, Servien E, Dunn W, Dahm D, Bramer JA, Haverkamp D. The influence of obesity on the complication
rate and outcome of total knee arthroplasty: a meta-analysis and systematic literature review. J Bone Joint Surg Am
2012;94(20):1839–44.

Kise NJ, Risberg MA, Stensrud S, Ranstam J, Engebretsen L, Roos EM. Exercise therapy versus arthroscopic partial
meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-
up. BMJ 2016;354:i3740.

Lamplot JD, Brophy RH. The role for arthroscopic partial meniscectomy in knees with degenerative changes: a
systematic review. Bone Joint J 2016;98-B(7):934–8.

Marsh JD, Birmingham TB, Giffin JR, Isaranuwatchai W, Hoch JS, Feagan BG, et al. Cost-effectiveness analysis of
arthroscopic surgery compared with non-operative management for osteoarthritis of the knee. BMJ Open
2016;6(1):e009949.

Sadr Azodi O, Bellocco R, Eriksson K, Adami J. The impact of tobacco use and body mass index on the length of stay
in hospital and the risk of post-operative complications among patients undergoing total hip replacement. J Bone Joint
Surg Br 2006;88(10):1316–20.

Spector TD, Dacre JE, Harris PA, Huskisson EC. Radiological progression of osteoarthritis: an 11 year follow up study
of the knee. Ann Rheum Dis 1992;51(10):1107–10.

Teichtahl AJ, Quirk E, Harding P, Holland AE, Delany C, Hinman RS, et al. Weight change following knee and hip joint
arthroplasty-a six-month prospective study of adults with osteoarthritis. BMC Musculoskelet Disord 2015;16:137.

Thorlund JB, Juhl CB, Roos EM, Lohmander LS. Arthroscopic surgery for degenerative knee: systematic review and
meta-analysis of benefits and harms. BMJ 2015;350:h2747.

Osteoarthritis of the hand

Berggren M, Joost-Davidsson A, Lindstrand J, Nylander G, Povlsen B. Reduction in the need for operation after
conservative treatment of osteoarthritis of the first carpometacarpal joint: a seven year prospective study. Scand J Plast
Reconstr Surg Hand Surg 2001;35(4):415–7.
Dziedzic K, Nicholls E, Hill S, Hammond A, Handy J, Thomas E, et al. Self-management approaches for osteoarthritis
in the hand: a 2x2 factorial randomised trial. Ann Rheum Dis 2015;74(1):108–18.

Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology
2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip,
and knee. Arthritis Care Res (Hoboken) 2012;64(4):465–74.

Keen HI, Wakefield RJ, Hensor EM, Emery P, Conaghan PG. Response of symptoms and synovitis to intra-muscular
methylprednisolone in osteoarthritis of the hand: an ultrasonographic study. Rheumatology (Oxford) 2010;49(6):1093–
100.

Kroon FP, Rubio R, Schoones JW, Kloppenburg M. Intra-articular therapies in the treatment of hand osteoarthritis: a
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Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Viral arthritis
Introduction to viral arthritis
Symmetrical polyarthritis is a well-recognised manifestation of infection with the following viruses:

alphaviruses (Ross River virus, Barmah Forest virus, and chikungunya virus)
flaviviruses (dengue virus, Zika virus, and yellow fever virus)
parvovirus B19
rubella virus (and its vaccine, which is an attenuated form of the virus)
hepatitis B and C viruses
HIV.

Herpesviruses (eg Epstein–Barr virus, cytomegalovirus, varicella-zoster virus), adenovirus and enterovirus can
also cause arthritis, but this occurs less frequently because these viruses have a low predilection for the joints.

Alphaviruses and flaviviruses are transmitted by arthropod vectors (typically mosquitoes). Measures to minimise
the potential for mosquito bites (eg using insect repellent, and wearing long trousers and long-sleeved shirts in the
evening) may be helpful in preventing infection with these viruses.

Most cases of viral arthritis are self-limiting and do not require investigations, specific treatment or specialist
referral. Management is focused on patient reassurance and symptomatic relief.

Diagnosis of viral arthritis

The diagnosis of viral arthritis is largely based on clinical assessment. Investigations are usually not required
unless there is uncertainty about the diagnosis at presentation or the patient has persisting symptoms.

Clinical assessment
Arthritis due to a viral infection most commonly presents as a symmetrical polyarthritis, but the presentation can
vary depending on the virus. Arthritis is rarely the only symptom of a viral infection and may not be the presenting
symptom. Patients who have a viral infection typically also present with influenza-like symptoms, including
myalgia, fever, headache and red eyes. Maculopapular rash is also common. Gastrointestinal symptoms (eg
abdominal pain, diarrhoea) and lymphadenopathy are less common. In most cases of viral arthritis, symptoms peak
at 1 to 2 weeks and are largely resolved by 6 weeks; however, occasionally, arthritis and myalgia persist for several
months.

The main differential diagnosis of viral arthritis is early rheumatoid arthritis because this also presents as a
symmetrical polyarthritis; however, in rheumatoid arthritis, symptoms are likely to be persisting without
improvement or worsening at 6 weeks. See Diagnosis of rheumatoid arthritis for features suggesting rheumatoid
arthritis, and see Undifferentiated polyarthritis in adults for approach to diagnosis and management of patients
with an undifferentiated polyarthritis.

Monoarthritis is rarely due to a viral infection; promptly investigate a patient presenting with monoarthritis for
other conditions, such as septic arthritis or gout, before considering a diagnosis of viral arthritis (see
Undifferentiated monoarthritis in adults).

Investigations
Routine testing for all viruses that may be associated with arthritis is not recommended because testing is of
limited clinical utility. Test results can be difficult to interpret, often a causative pathogen cannot be identified and,
even if a pathogen is identified, this is unlikely to change management.

If testing for specific viruses is deemed necessary, this should be informed by the clinical presentation and the
presence of risk factors (eg history of exposure to infected individuals or children with ‘slapped cheek’ rash
[parvovirus B19], insect bites, administration of the rubella vaccine, history of injecting drugs, sexual history,
history of travel). In patients with hepatitis B or C viral infection, or HIV infection, arthritis can occur during
seroconversion. Testing for hepatitis B or C virus or HIV should be performed if infection is suspected clinically
because these viruses have broader health implications and can be specifically treated. Arthritis can also occur in
chronic hepatitis C infection.
If viral serology is performed, confirmation of a recent viral infection requires an appropriate change in paired
acute and convalescent serology. The acute sample should ideally be collected within 1 week of symptom onset,
and the convalescent sample should be collected 14 to 21 days after symptom onset. Testing for both
immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies is recommended. Although there are virus-
specific IgM and IgG antibody tests, cross-reactions with related viruses are not uncommon, particularly in those
with a past history of related viral infection or vaccination. Furthermore, IgM antibodies may persist for up to 2
years following viral exposure and their presence may not reflect recent acute infection. False positive results can
also occur in evolving inflammatory diseases.

While rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody testing are useful in the
differential diagnosis of rheumatoid arthritis (see Diagnosis of rheumatoid arthritis), early testing (eg before 6
weeks) is unlikely to be helpful in patients with clinical features of a viral infection (eg arthritis in combination
with myalgia, fever and a maculopapular rash). Early testing increases the likelihood of a false positive result
because RF can also be present in viral arthritis. Although RF is usually only present at low titre and transient in
viral arthritis, it can be present for up to 6 months. It is uncommon for anti-CCP antibody testing to be positive in
viral arthritis.

Management of viral arthritis

There are no antiviral drugs available for the treatment of viral arthritis and, as most cases of viral arthritis are self-
limiting, no specific treatment is required. Reassure patients about the favourable prognosis of the condition.

For relief of musculoskeletal symptoms, nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended first
line. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Paracetamol may be used for symptom relief in combination with an NSAID, or instead of an NSAID if an
NSAID is contraindicated or not tolerated. Use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

Corticosteroids are not recommended for the treatment of viral arthritis unless symptoms are disabling and the
patient has a contraindication or intolerance to NSAIDs. If indicated, use a short course of low-dose therapy. An
example dosage is:

prednis(ol)one 10 mg orally, daily for up to 2 weeks.

Treatment with disease-modifying antirheumatic drugs (DMARDs) is discouraged because onset of effect takes
several weeks and viral arthritis symptoms have usually resolved by this time.

If symptoms are not improving by 6 weeks or, regardless of improvement, if significant symptoms persist beyond
12 weeks, reconsider a possible diagnosis of rheumatoid arthritis (see Diagnosis of rheumatoid arthritis) and refer
patients to a specialist.

Key references
Holland R, Barnsley L, Barnsley L. Viral arthritis. Aust Fam Physician 2013;42(11):770–3.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Rheumatoid arthritis
Introduction to rheumatoid arthritis
Rheumatoid arthritis is a chronic autoimmune disease characterised by persistent synovitis, systemic inflammation
and the presence of autoantibodies. Persistent joint inflammation can lead to the development of bony erosions,
cartilage and tendon degradation, and joint deformity. In about 40% of patients, inflammation also occurs at other
sites (eg skin, eyes, lungs, heart, kidneys, blood vessels, salivary glands, central and peripheral nervous systems,
and bone marrow). The pathophysiology of rheumatoid arthritis involves various cytokines, effector cells and
signalling pathways; tumour necrosis factor, interleukin-6 and interleukin-1 appear to be the key cytokine
mediators of the disease process.

The prevalence of rheumatoid arthritis is about 1%, with women more commonly affected than men. The risk of
developing rheumatoid arthritis may be increased by genetic factors; the most established genetic link is the human
leucocyte antigen DR4 (HLA-DR4). A healthy lifestyle (eg avoiding smoking, maintaining ideal body weight,
eating a healthy diet) decreases the likelihood of developing rheumatoid arthritis.

Rheumatoid arthritis has the potential to cause disability and death; however, the prognosis has substantially
improved in the last 20 years due to early use of conventional synthetic disease-modifying antirheumatic drugs
(csDMARDs) and the availability of biological disease-modifying antirheumatic drugs (bDMARDs).

Diagnosis of rheumatoid arthritis

It can be difficult to definitively diagnose rheumatoid arthritis in the early phase of an inflammatory arthritis (see
Undifferentiated polyarthritis in adults); however, prompt diagnosis is crucial because of the need for early
treatment with disease-modifying therapy to prevent irreversible joint damage. Urgently refer any patient with
suspected rheumatoid arthritis to a specialist. Rheumatologists often have fast-track triage systems for these
patients and general practitioners are strongly encouraged to make direct contact to expedite referral or to obtain
advice on treatment. The appropriate time frame for referral is further influenced by the results of investigations
(see below).

Urgently refer any patient with suspected rheumatoid arthritis to a specialist.

The diagnosis of rheumatoid arthritis is made on the basis of clinical presentation, in association with
autoantibodies and evidence of systemic inflammation (eg elevated erythrocyte sedimentation rate and C-reactive
protein concentration). Other features suggestive of rheumatoid arthritis are given in Box 12.8. The most
commonly affected joints include the wrists, metacarpophalangeal joints, proximal interphalangeal joints and
metatarsophalangeal joints. The carpometacarpal and distal interphalangeal joints are not typically affected. Other
large joints may also be affected by rheumatoid arthritis.

Detection of rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (CCP) can help resolve
diagnostic uncertainty in patients with suspected rheumatoid arthritis. While RF is present in about 70% of patients
with established rheumatoid arthritis, it is detected less frequently in early disease. Antibodies to CCP are usually
present before the development of symptoms and have a 96% specificity for rheumatoid arthritis. However, up to
30% of patients with rheumatoid arthritis never develop RF or antibodies to CCP and are said to have seronegative
disease.

For symptomatic patients who have RF or antibodies to CCP, immediate referral to a specialist is required because
early joint damage is likely. For patients who do not have RF or antibodies to CCP but have persistently swollen
joints, referral should be made within 6 weeks of symptom onset.
Features suggesting rheumatoid arthritis (Box 12.8)

family history of inflammatory arthritis

early morning stiffness lasting longer than 1 hour
swelling in five or more joints
symmetry of the areas affected
bilateral compression tenderness of the metatarsophalangeal joints
RF positivity
anti-CCP antibody test positivity
symptoms present for longer than 6 weeks
bony erosions evident on X-rays of the wrists, hands or feet (uncommon in early disease)
raised inflammatory markers, such as CRP or ESR, in the absence of infection
presence of rheumatoid nodules

CCP = cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor

Prognosis of patients with rheumatoid arthritis

Key indicators of poor prognosis in patients with rheumatoid arthritis are listed in Box 12.9. No single feature is
entirely reliable in determining prognosis. Patients with poor prognosis should be intensively managed, and
treatment should be started as early as possible, as it should for all patients with rheumatoid arthritis.

Key indicators of poor prognosis in patients with rheumatoid arthritis (Box 12.9)

a high RF titre and/or a positive anti-CCP antibody test

sustained raised inflammatory markers (CRP or ESR)
swelling in more than 20 joints
impaired function early in disease
bony erosions evident on X-rays early in disease
smoking

CCP = cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor

General management approach for rheumatoid arthritis

Patients with rheumatoid arthritis require integrated, multidisciplinary care that is designed to manage the broad
spectrum of patient needs in a timely manner. All patients should have an individualised management plan that is
negotiated between the patient, their specialist and general practitioner, and other health professionals involved in
their care (eg physiotherapist, occupational therapist, podiatrist, psychologist). The management plan should
include support for self-management, including advice on managing symptom exacerbations until specialist
review.

The goal of rheumatoid arthritis management is to maximise long-term health-related quality of life by:

controlling symptoms
normalising physical function
enabling participation in social and work-related activities
preventing joint damage
minimising cardiovascular complications.

Management of rheumatoid arthritis involves:

inducing clinical remission as early as possible (see Inducing and maintaining clinical remission in patients
with rheumatoid arthritis)
maintaining clinical remission (see Inducing and maintaining clinical remission in patients with rheumatoid
arthritis)
developing an individualised self-management plan for early management of an exacerbation of
inflammatory joint pain while awaiting specialist review
proactively inquiring about and managing pain, fatigue and mood disturbances (see Managing symptoms in
 patients with rheumatoid arthritis)
optimising the patient's immune status, including ensuring that recommended vaccinations are up to date,
because both rheumatoid arthritis and its treatment can increase the risk of infection (see Screening for
infection and vaccinations in adults with rheumatological diseases)
monitoring for drug adverse effects, including appropriate blood tests (see Principles of immunomodulatory
drug use for rheumatological diseases in adults)
monitoring for and managing potential complications of rheumatoid arthritis, including atherosclerosis,
osteoporosis, depression, vasculitis, peptic ulcer disease, lung disease, neuropathy and atlanto-axial
involvement (see Neck pain and rheumatoid arthritis). Systemic inflammation is the main contributor to the
increased risk of developing atherosclerosis in patients with rheumatoid arthritis, but other risk factors for
cardiovascular disease should be closely monitored and actively managed (see Cardiovascular disease risk
stratification)
educating the patient about their disease and its management, the need for long-term treatment, and
appropriate lifestyle management. Printed or online information is useful to reinforce education provided by
the clinician. Patient support organisations such as Arthritis Australia provide educational materials, and
participation in their activities may be valuable for social support [URL]. The ‘painHEALTH’ website also
provides useful tips for self-management [URL] [Note 1]
evaluating the impact of rheumatoid arthritis treatment on the patient's reproductive health. For general
advice on the use of immunomodulatory drugs in patients of childbearing potential, see Immunomodulatory
drug use and reproductive health in adults with rheumatological diseases. For advice on nonsteroidal anti-
inflammatory drugs (NSAIDs) and reproductive health, see NSAIDs and reproductive health in women.

For specific advice on the management of patients treated with immunomodulatory drugs, see Principles of
immunomodulatory drug use for rheumatological diseases in adults.

Note 1: This website provides patient information; any management advice given on this website should be
considered in the context of the recommendations in these guidelines.

Inducing and maintaining clinical remission in patients with

rheumatoid arthritis
General considerations
Induction and maintenance of clinical remission of rheumatoid arthritis requires specialist management. Disease
activity is monitored and used to adjust therapy to attain clinical remission; this approach is known as ‘treat to
target’. Clinical remission is defined as all of the following:

symptom relief
normalisation of inflammatory markers
the absence of joint swelling.

Disease-modifying antirheumatic drugs (DMARDs) reduce or eradicate synovitis and thus prevent joint damage.
To induce clinical remission of rheumatoid arthritis and prevent joint damage, therapy with conventional synthetic
disease-modifying antirheumatic drugs (csDMARDs) should be started as soon as possible; treatment choice can
be complex and combination therapy may be required. Corticosteroids are often combined with csDMARDs
during the induction stage of treatment to provide rapid symptom relief. Patients with an inadequate response to
csDMARDs may require treatment with a biological disease-modifying antirheumatic drug (bDMARD) or a
targeted synthetic disease-modifying antirheumatic drug (tsDMARD) (see Biological and targeted synthetic
disease-modifying antirheumatic drugs).

While the aim of management is for the patient to have normal inflammatory markers and no swollen joints,
decisions to escalate DMARD therapy should also be informed by comorbidities, patient preference and drug
toxicity. Clinical remission (as defined above) can be achieved in up to 40% of patients. Most patients need to be
maintained on treatment indefinitely because rheumatoid arthritis rarely goes into drug-free remission and may be
more difficult to control if it recurs after stopping treatment. Even patients with well-controlled disease may have
persisting symptoms (see Managing symptoms in patients with rheumatoid arthritis for advice on the management
of pain and fatigue).

Disease activity is routinely monitored at a frequency tailored to the patient's disease severity and stage of
treatment. Measures of inflammation and patient-reported outcomes should be considered in the assessment of
disease activity and together should inform decisions about adjusting DMARD therapy. Inflammation is most
reliably assessed by the number of swollen or tender joints as well as the inflammatory markers C-reactive protein
(CRP) and/or erythrocyte sedimentation rate (ESR); neither measure should be used alone. Patient-reported
outcomes include pain, physical function, psychological health, sleep patterns, relationships, and participation in
social and work-related activities. These outcomes can be measured formally or informally. Examples of formal
assessment tools are the Stanford health assessment questionnaire (HAQ) and the routine assessment of patient
index data-3 (RAPID3) questionnaire. Patient-reported pain without evidence of inflammation suggests that the
pain may be caused by joint damage, central sensitisation or other painful processes (see Residual joint pain in
patients in clinical remission). Joint damage is usually assessed throughout the disease course by plain X-rays and
ultrasound. Magnetic resonance imaging (MRI) may occasionally be used by specialists.

Rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (CCP) are not used to monitor disease
activity.

Conventional synthetic disease-modifying antirheumatic drugs

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used by specialists to induce and
then maintain clinical remission of rheumatoid arthritis.

The initial induction strategy is determined by disease severity, prognosis and patient factors, such as age,
childbearing status, and comorbidities. Therapy may be with either a single csDMARD or a combination of
csDMARDs, with or without a corticosteroid. Methotrexate is the drug of choice for most patients, and should
form the backbone of the regimen when combination therapy is required. It may be used in combination with other
csDMARDs (leflunomide, sulfasalazine, hydroxychloroquine) for patients with active disease and significantly
impaired function, or if there are indicators of poor prognosis (see Box 12.9). If methotrexate is contraindicated or
not tolerated, leflunomide is often substituted. Monotherapy with hydroxychloroquine or sulfasalazine may be
used if the patient has low-grade inflammation, few affected joints and no indicators of poor prognosis.

Methotrexate is the drug of choice for most patients.

When csDMARD therapy is started, disease activity is regularly monitored and therapy adjusted to achieve clinical
remission. A response to csDMARDs should be apparent within 12 weeks. If remission is not achieved despite an
adequate dose of csDMARD, adjustment of the csDMARD regimen is considered (eg switching to a different
combination regimen, addition of a second or third csDMARD to an existing regimen).

For considerations in the management of csDMARD therapy (including monitoring, screening for infection, and
vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in adults.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

The usual dosage of leflunomide is:

leflunomide 10 to 20 mg orally, daily.

The usual dosage of sulfasalazine is:

sulfasalazine (enteric-coated) 500 mg orally, twice daily, increasing gradually up to 1.5 g

twice daily.

The usual dosage of hydroxychloroquine is:

hydroxychloroquine 200 to 400 mg orally, daily.

When disease control has been achieved and maintained with csDMARD therapy, the csDMARD dose may be
reduced to the lowest dose that maintains disease control. Dose reductions should only occur in consultation with
the treating specialist, and usually take place after corticosteroid therapy has been completely tapered.

If remission is not achieved or significant disease activity persists after trialling csDMARD combination therapy,
specialist review is required for consideration of treatment with a biological disease-modifying antirheumatic drug
(bDMARD) or a targeted synthetic disease-modifying antirheumatic drug (tsDMARD).

Corticosteroids

Corticosteroids have anti-inflammatory and disease-modifying effects in rheumatoid arthritis. Because of their
rapid onset of action, corticosteroids are often used by specialists to achieve rapid symptom control at presentation,
or during an exacerbation of disease, while awaiting a response to conventional synthetic disease-modifying
antirheumatic drug (csDMARD) therapy (which can often take between 6 and 12 weeks).

Parenteral administration of corticosteroids is sometimes used, based on a theoretical reduction in overall

corticosteroid exposure compared to oral therapy. A single dose of intramuscular corticosteroid has a prolonged
effect (up to 8 weeks) and repeat doses are often unnecessary.

If intramuscular therapy is indicated, the usual dosage is:

methylprednisolone acetate 120 mg intramuscularly, as a single dose.

Intravenous therapy is sometimes used by specialists for severe flares.

If oral therapy is indicated, the usual initial dosage is:

prednis(ol)one 5 to 15 mg orally, daily.

Although corticosteroids are effective, significant adverse effects limit their use. When disease remission is
achieved, the dose of corticosteroid should be slowly tapered until the corticosteroid can be stopped.
Unfortunately, this is not possible in all patients.

See Principles of immunomodulatory drug use for rheumatological diseases in adults for information on adverse
effects associated with long-term corticosteroid therapy (such as bone density loss) and advice on how to minimise
and monitor for such complications.

Intra-articular corticosteroid injections are effective if a small number of accessible joints are involved, and can
minimise the use of systemic corticosteroids. For principles of use and example doses of local corticosteroid
injections, see Principles of using local corticosteroid injections for musculoskeletal conditions in adults.

Biological and targeted synthetic disease-modifying antirheumatic drugs

Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying

antirheumatic drugs (tsDMARDs) are used by specialists for the treatment of rheumatoid arthritis if remission is
not achieved, or significant disease activity persists, after trialling conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs). They are usually used in combination with csDMARD therapy. Several
bDMARDs, with different mechanisms of action, are available. At the time of writing, tofacitinib is the only
tsDMARD indicated for rheumatoid arthritis.

Patients taking bDMARDs or tofacitinib are at increased risk of infections. Clinicians must always be alert to the
possibility of infection (including opportunistic infection), particularly because the usual symptoms and signs (eg
fever) are often absent. For other considerations in the management of bDMARD or tofacitinib therapy (including
monitoring, screening for infection, and vaccination), see Principles of immunomodulatory drug use for
rheumatological diseases in adults.

The first-line bDMARDs are generally considered to be equally efficacious and drug choice is influenced by
patient preference regarding route of administration and dosing frequency. The usual dosages for first-line
bDMARDs (listed in alphabetical order) are:

abatacept 500 to 1000 mg intravenously, as a single dose at 0, 2 and 4 weeks, and

thereafter every 4 weeks

OR

abatacept 125 mg subcutaneously, once weekly

OR

adalimumab 40 mg subcutaneously, every 2 weeks

OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

thereafter 200 mg every 2 weeks

OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

 thereafter every 4 weeks

OR

etanercept 50 mg subcutaneously, once weekly [Note 2]

OR

golimumab 50 mg subcutaneously, every 4 weeks

OR

infliximab 3 mg/kg intravenously, as a single dose at 0, 2 and 6 weeks, and thereafter

every 8 weeks

OR

tocilizumab 8 mg/kg intravenously, every 4 weeks

OR

tocilizumab 162 mg subcutaneously, once weekly [Note 3].

If response to initial drug choice is inadequate, an alternative first-line bDMARD may be used.

Rituximab is reserved for use by specialists when first-line bDMARD, specifically tumour necrosis factor inhibitor,
therapy has failed. The two doses (1 g by intravenous infusion) are given 2 weeks apart. For patients who respond
to the initial rituximab course, treatment may be repeated (usually after 6 to 12 months) depending on disease
activity.

The tsDMARD tofacitinib is an alternative to first-line bDMARD therapy. The usual dosage is:

tofacitinib 5 mg orally, twice daily.

Note 2: An alternative regimen is: etanercept 25 mg subcutaneously, twice weekly.

Note 3: At the time of writing, tocilizumab is not available on the Pharmaceutical Benefits Scheme (PBS) for
subcutaneous use for treatment of rheumatoid arthritis. See the PBS website for current information [URL].

Managing symptoms in patients with rheumatoid arthritis

Pain

General considerations

Pain is common in patients with rheumatoid arthritis, even when disease-modifying antirheumatic drugs
(DMARDs) are used. It may result in substantial disability in some patients. Pain may be due to joint inflammation
or noninflammatory causes, such as peripheral sensitisation from joint damage or central sensitisation.

Exclude serious conditions, such as avascular necrosis, fracture, infection, malignancy or vasculitis, if pain is
associated with an alerting feature. Alerting features include fever, weight loss, malaise, acute severe pain
(different to usual rheumatoid arthritis pain), focal or diffuse muscle weakness, history of significant trauma, night
pain, neurogenic pain or claudication, a single hot and swollen joint, and rash.

Assessment of pain severity (using a visual analogue scale or numerical rating scale), and its impact, and the cause
of pain is important to guide management (see also Clinical assessment of pain).

Consider referring patients with persisting inflammatory joint pain to their specialist for adjustment of the
DMARD regimen. Acute inflammatory joint pain suggestive of an exacerbation of disease activity should be
managed according to the patient's individualised self-management plan until they can be reviewed by their
specialist.

Residual joint pain in patients in clinical remission

If a patient with well-controlled disease (ie in clinical remission) experiences ongoing pain, it is likely to be
noninflammatory in nature.

If osteoarthritis is thought to be responsible for the patient's residual symptoms, see Pharmacological management
of osteoarthritis for management advice.

Management of noninflammatory residual joint pain associated with rheumatoid arthritis should follow the same
principles as for other types of noninflammatory chronic pain (see Chronic pain: overview). Combine
nonpharmacological and pharmacological strategies, tailored to the individual patient. Factors that influence
treatment choice include patient comorbidities, adverse effects, the potential for dependence, patient preference,
likelihood of adherence to treatment, and cost.

Nonpharmacological strategies for residual noninflammatory joint pain include: rest and pacing activities,
thermotherapy, splints/orthoses, exercise therapy, cognitive behavioural therapy (CBT), transcutaneous electrical
nerve stimulation (TENS), psychotherapy, and relaxation, mindfulness and meditation. Although these strategies
may provide pain relief, there is limited evidence to support their use. For more information on these strategies,
see Chronic pain: nonpharmacological management.

When analgesia is indicated, the primary goals of management are to improve function and reduce disability, not
just reduce the intensity of pain. Before escalating analgesia, consider and address biopsychosocial and
environmental factors that may be contributing to the patient's experience of pain. Continuing to increase the dose
of analgesia or introducing multiple drugs may increase the risk of harms without additional benefit.

If a nonsteroidal anti-inflammatory drug (NSAID) is indicated, use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Evidence suggests fish oil has a mild anti-inflammatory effect in rheumatoid arthritis. For patients with mild
residual joint pain, it is a reasonable treatment option because of its low risk of harms. Use:

fish oil at least 2.7 g (omega-3) orally, daily (see Table 12.8 for preparations).

Fish oil may take up to 3 months for maximal effectiveness, so it may be necessary to co-prescribe fish oil with an
NSAID initially. See Principles of fish oil use for musculoskeletal conditions in adults for more information.

If neuropathic pain or fibromyalgia are contributing significantly to the patient's pain, consider adding a drug
effective for these conditions to the analgesic regimen; see Neuropathic pain or Pharmacological management of
fibromyalgia.

For patients with severe pain, consider referral to a rheumatologist or pain management specialist. Structural joint
damage or coexistent osteoarthritis may require joint replacement surgery.

Opioids have a very limited role in the management of pain associated with rheumatoid arthritis because of
modest, if any, benefits and a significant risk of harms. Opioids may be considered for patients with severe pain
that is not adequately relieved by other analgesics (eg paracetamol plus an NSAID) and is interfering with their
ability to function. If opioids are used, they should be prescribed on a short-term trial basis, as part of an overall
pain management strategy, with clear goals and regular review of treatment response and adverse effects. Before
starting an opioid, a plan for ceasing ineffective therapy should be in place and discussed with the patient. If
treatment response is inadequate, caution should be exercised when increasing the dose of opioids. Prolonged use
of opioids indicates the need for specialist assessment. See Opioids for more information.

If opioids are used, they should be prescribed on a short-term trial basis with regular review of treatment response and adverse
effects.

Systemic corticosteroids are not recommended for the routine management of chronic pain in patients with
rheumatoid arthritis in the absence of signs or symptoms of inflammation.

Fatigue

Fatigue is a common complaint in patients with rheumatoid arthritis. Consider and manage potential contributors
to fatigue, such as anaemia, hypothyroidism, drug adverse effects, depression, insomnia due to underlying pain, or
loss of muscle mass. See Conditions commonly associated with fatigue for more information on the assessment of
patients with fatigue.
There are no pharmacological treatments for fatigue in rheumatoid arthritis. There is some evidence that physical
activity (eg pool-based therapy, yoga, dynamic strength training, stationary cycling, low-impact aerobics, Tai Chi)
and psychosocial interventions (eg cognitive behavioural therapy, mindfulness) have a small benefit, but the
optimal treatment strategy is not yet established.

Lifestyle management of rheumatoid arthritis

Exercise
Land- and water-based aerobic exercises are beneficial for patients with rheumatoid arthritis at all stages of
disease. Regular aerobic exercise improves physical function, helps maintain ideal body weight and also benefits
psychological and cardiovascular health. Low-impact land exercise (eg stationary cycling, walking) or low- to
moderate-intensity water-based exercise is preferred for patients with painful joints or high disease activity.
Strengthening (anaerobic) exercise is also recommended to prevent muscle wasting. Weightbearing exercise
improves bone health.

Patients may worry that rheumatoid arthritis disease activity is increased by exercise. Although some pain with
exercise can be expected, patients should be reassured that the benefits of exercise significantly outweigh the risks.

Diet
The role of diet in rheumatoid arthritis remains controversial. Several studies have shown that dietary
modifications including strict vegan diets, gluten-free diets and the Mediterranean-style diet produce small
reductions in rheumatoid arthritis symptoms. However, no single diet results in consistent improvement for all
patients with rheumatoid arthritis. The Mediterranean-style diet, characterised by a high consumption of fruit,
vegetables, cereals and legumes, a little red meat but more fish, olive oil as the main source of fat, and a moderate
intake of wine, appears to be the most universally accepted dietary intervention; it has the added benefit of weight
control and reducing cardiovascular risk.

Smoking cessation

All patients with rheumatoid arthritis should be strongly advised to stop smoking. Not only is smoking linked to
the development of rheumatoid arthritis, it is also linked to poor prognosis and is a predictor of poor response to
therapy. Smoking also increases the risk of developing cardiovascular disease in a patient group already at
increased risk. Patient resources and help for smoking cessation are available from the Quitnow website [URL].
See Smoking cessation for more information on assessment of patients' smoking and advice on smoking cessation.

Key references
Introduction to rheumatoid arthritis

Eshed I, Feist E, Althoff CE, Hamm B, Konen E, Burmester GR, et al. Tenosynovitis of the flexor tendons of the hand
detected by MRI: an early indicator of rheumatoid arthritis. Rheumatology (Oxford) 2009;48(8):887–91.

Liao KP, Karlson EW. Classification and epidemiology of rheumatoid arthritis. In: Hochberg MC, Silman AJ, Smolen
JS, Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 691–7.

MacGregor AJ, Snieder H, Rigby AS, Koskenvuo M, Kaprio J, Aho K, et al. Characterizing the quantitative genetic
contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 2000;43(1):30–7.

Myasoedova E, Crowson CS, Turesson C, Gabriel SE, Matteson EL. Incidence of extraarticular rheumatoid arthritis in
Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a population-based study. J Rheumatol 2011;38(6):983–
9.

Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol 2006;35(3):169–74.

Plenge RM. The contribution of genetic factors to rheumatoid arthritis. In: Hochberg MC, Silman AJ, Smolen JS,
Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 735–42.

Turk SA, van Beers-Tas MH, van Schaardenburg D. Prediction of future rheumatoid arthritis. Rheum Dis Clin North Am
2014;40(4):753–70.

Diagnosis of rheumatoid arthritis

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, et al. 2010 rheumatoid arthritis classification
criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann
Rheum Dis 2010;69(9):1580–8.

Hoffmann M, Lundberg K, Steiner G. Autoantibodies in rheumatoid arthritis. In: Hochberg MC, Silman AJ, Smolen JS,
Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 750–7.

Whiting PF, Smidt N, Sterne JA, Harbord R, Burton A, Burke M, et al. Systematic review: accuracy of anti-citrullinated
Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med 2010;152(7):456–64; W155–66.

General management approach for rheumatoid arthritis

Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, et al. EULAR recommendations for
cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint
disorders: 2015/2016 update. Ann Rheum Dis 2017;76(1):17–28.

Markusse IM, Dirven L, Gerards AH, van Groenendael JH, Ronday HK, Kerstens PJ, et al. Disease flares in
rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study.
Arthritis Res Ther 2015;17:232.

Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating rheumatoid arthritis to
target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 2016;75(1):3–15.
.

Inducing and maintaining clinical remission in patients with rheumatoid arthritis

Colebatch AN, Edwards CJ, Ostergaard M, van der Heijde D, Balint PV, D'Agostino MA, et al. EULAR
recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum
Dis 2013;72(6):804–14.

Dale J, Stirling A, Zhang R, Purves D, Foley J, Sambrook M, Conaghan PG, van der Heijde D, McConnachie A,
McInnes IB, Porter D. Targeting ultrasound remission in early rheumatoid arthritis: the results of the TaSER study, a
randomised clinical trial. Ann Rheumatic Dis 2016;75(6):1043–1050. .

Gaujoux-Viala C, Nam J, Ramiro S, Landewé R, Buch MH, Smolen JS, et al. Efficacy of conventional synthetic
disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the
2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis
2014;73(3):510–5.

Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe DJ, Bombardier C. Methotrexate monotherapy and
methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid
arthritis: A network meta-analysis. Cochrane Database Syst Rev 2016;(8):CD010227.

O'Dell JR, Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, et al. Therapies for active rheumatoid arthritis
after methotrexate failure. N Engl J Med 2013;369(4):307–18.

Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients with rheumatoid arthritis, without
formal joint counts: similar results to DAS28 and CDAI in clinical trials and clinical care. Rheum Dis Clin North Am
2009;35(4):773–8, viii.

Singh JA, Saag KG, Bridges SL, Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology
Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2016;68(1):1–25.

Smolen JS, Landewe R, Breedveld FC, Buch M, Burmester G, Dougados M, et al. EULAR recommendations for the
management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update.
Ann Rheum Dis 2014;73(3):492–509.

van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab
versus placebo in rheumatoid arthritis. N Engl J Med 2012;367(6):508–19.

van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination
treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the
randomised, non-blinded, parallel-group Swefot trial. Lancet 2012;379(9827):1712–20.

Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J, et al. Multinational evidence-based
recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating
systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.
Ann Rheum Dis 2009;68(7):1086–93.

Managing symptoms in patients with rheumatoid arthritis

Cramp F, Hewlett S, Almeida C, Kirwan JR, Choy EH, Chalder T, et al. Non-pharmacological interventions for fatigue
in rheumatoid arthritis. Cochrane Database Syst Rev 2013;(8):CD008322.

Richards B, March L. Disease control versus pain management in rheumatoid arthritis. Pain Management Today
2014;1(1):19–23. http://painmanagementtoday.com.au/2014/january/regular-series/disease-control-versus-pain-
management-rheumatoid-arthritis.

Richards BL, Whittle S, Buchbinder R, Barrett C, Lynch N, Major G, et al. Australian and New Zealand evidence-based
recommendations for pain management by pharmacotherapy in adult patients with inflammatory arthritis. Int J Rheum
Dis 2014;17(7):738–48.

Whittle SL, Colebatch AN, Buchbinder R, Edwards CJ, Adams K, Englbrecht M, et al. Multinational evidence-based
recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature
research and expert opinion of a broad panel of rheumatologists in the 3e Initiative. Rheumatology (Oxford)
2012;51(8):1416–25.

Whittle SL, Richards BL, van der Heijde DM, Buchbinder R. The efficacy and safety of opioids in inflammatory arthritis:
a Cochrane systematic review. J Rheumatol Suppl 2012;90:40–6.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Spondyloarthritides, including psoriatic arthritis
Overview of spondyloarthritides
The spondyloarthritides are related inflammatory arthropathies including:

axial spondyloarthritis, including ankylosing spondylitis

reactive arthritis
enteropathic arthritis
psoriatic arthritis.

For management of psoriatic arthritis in children and adolescents, see Juvenile idiopathic arthritis: psoriatic
arthritis. For management of other spondyloarthritides in children and adolescents, see Juvenile idiopathic arthritis:
enthesitis-related arthritis.

The spondyloarthritides share clinical (see Box 12.10) and radiological features, and many clinicians now consider
spondyloarthritis to be a single disease with clinical features in the peripheral joints, spine, entheses, skin,
gastrointestinal tract and other organs. Enthesitis (inflammation at the sites of tendon and ligament attachment to
bone) is the hallmark of all spondyloarthritides and can occur in numerous locations. It most commonly affects the
heels (Achilles tendinitis and plantar fasciitis), anterior chest wall and pelvis.

The spondyloarthritides share a genetic link with human leucocyte antigen B27 (HLA-B27).

A comparison of features of spondyloarthritides is given in Table 12.10.

Some patients have features suggestive of an axial spondyloarthritis, but do not meet the formal classification
criteria for ankylosing spondylitis. While these patients have often been described as having ‘undifferentiated
spondyloarthritis’, the term ‘nonradiographic axial spondyloarthritis’ has more recently been used; however, a
proportion of these patients will progress to overt ankylosing spondylitis. Management of nonradiographic axial
spondyloarthritis is the same as for ankylosing spondylitis (see General management approach for ankylosing
spondylitis); lifestyle management is particularly important in these patients.

Clinical features of spondyloarthritides (Box 12.10)

Articular and peri-articular features

enthesitis (inflammation at the sites of tendon and ligament attachment to bone)

spondylitis (inflammation of the spine) characterised by sacroiliitis (inflammation of sacroiliac joints)
peripheral arthritis that, characteristically:
is oligoarticular
is asymmetrical
affects the lower limbs
affects large joints
dactylitis (inflammation of a whole finger or toe, ‘sausage digits’)

Possible extra-articular features

psoriasis-like skin and nail lesions

conjunctivitis or acute anterior uveitis
chronic gastrointestinal inflammation
chronic genitourinary inflammation

Comparison of features of spondyloarthritides (Table 12.10)

Ankylosing Enteropathic
Reactive arthritis Psoriatic arthritis
spondylitis [NB1] arthritis
adolescence to 40 childhood to middle childhood to middle childhood to middle
age of onset
years of age age age age [NB2]
predominantly males,
but 1:1 for reactive
gender distribution predominantly males arthritis following a 1:1 1:1
gastrointestinal
infection
onset gradual acute variable variable
24% with peripheral
more than 25% with
arthritis
prevalence of HLA- peripheral arthritis
more than 90% 75%
B27 more than 60% with
60% with sacroiliitis
sacroiliitis and
and spondylitis
spondylitis
prevalence of articular involvement:
common; spinal
inflammation is
spine 100% less than 50% typically independent up to 20%
of intestinal disease
activity
common; peripheral
joint inflammation is
peripheral joints up to 20% 90% often associated with 95%
intestinal
inflammation
prevalence of extra-articular involvement:
in patients with IBD,
up to 30% (acute up to 33%
eyes less than 15% (acute 50% (conjunctivitis)
anterior uveitis) (conjunctivitis)
anterior uveitis)
heart, blood vessels
1 to 4% uncommon rare rare
or lungs
streptococcal
infection of the skin
and soft tissues can
skin and/or nails less than 20% trigger reactive uncommon extremely common
arthritis; skin lesions
can also be a disease
manifestation
bacterial
gastrointestinal tract
infection is a common
IBD usually precedes
IBD in 7%; trigger, but symptoms
the diagnosis of
subclinical have usually resolved
gastrointestinal arthritis; however, increased incidence of
gastrointestinal before the onset of
tract arthritis may IBD
inflammation in up to arthritis;
occasionally present
66% gastrointestinal
first
symptoms are an
uncommon disease
manifestation
bacterial
genitourinary tract
infection is a common
genitourinary tract rare trigger; genitourinary uncommon rare
symptoms are also a
common disease
manifestation
HLA-B27 = human leucocyte antigen B27; IBD = inflammatory bowel disease
NB1: The features of nonradiographic axial spondyloarthritis are similar to the features of ankylosing spondylitis.
NB2: For patients younger than 16 years, see Juvenile idiopathic arthritis: psoriatic arthritis for a disease overview, as well as advice on management.

Ankylosing spondylitis
Introduction
Ankylosing spondylitis affects up to 0.5% of the population and occurs predominantly in men.

The human leucocyte antigen B27 (HLA-B27) is found in more than 90% of patients with ankylosing spondylitis,
but it is not a useful diagnostic indicator in isolation because it is also present in about 10% of the normal
Australian population. The presence of HLA-B27 confers a risk of approximately 8% of developing ankylosing
spondylitis in that individual; this risk is increased to 20% if, in addition, a first-degree relative has ankylosing
spondylitis.

Ankylosing spondylitis follows a chronic relapsing and remitting course. Disease severity varies considerably
between patients.

See Table 12.10 for comparative features of ankylosing spondylitis and other spondyloarthritides.

Clinical features of ankylosing spondylitis

Inflammation in ankylosing spondylitis is centred in the spine (spondylitis). It predominantly affects the sacroiliac
joints (sacroiliitis) initially, before involving other areas of the spine, usually the lumbar spine and then the
thoracic and cervical spine. Enthesitis (inflammation at the sites of tendon and ligament attachment to bone) is a
hallmark of the disease. Dactylitis (inflammation of a whole finger or toe) and extra-articular features also occur.

Spondylitis results in pain and stiffness of the spine; in ankylosing spondylitis it is characterised by:

a gradual onset before the age of 40 years

a duration of symptoms of longer than 3 months
prolonged morning stiffness and night pain
improvement with physical activity or exercise, and failure to improve with rest
response to nonsteroidal anti-inflammatory drugs (NSAIDs).

Sacroiliitis manifests as stiffness and pain in the buttock, sometimes radiating into the thigh. Alternating buttock
pain is characteristic.

Following inflammation and ossification of the axial entheses, the spine progressively stiffens (ankylosis).
Involvement of the costovertebral joints leads to reduced chest expansion. With time, abnormal posture and
impaired function may occur. Spinal osteoporosis is common; suspect fracture in patients with longstanding
disease and a sudden increase in spinal pain.

Peripheral enthesitis and peripheral arthritis occur less commonly. In ankylosing spondylitis, peripheral enthesitis
usually affects the heels (Achilles tendinitis and plantar fasciitis) and the peripheral arthritis is usually
oligoarticular, asymmetrical and predominantly affects the lower limbs. Arthritis of the hips and shoulder joints
(including the acromioclavicular and sternoclavicular joints) occurs in some patients and can be disabling. Arthritis
of the costochondral joints of the chest wall can occur and may be associated with more severe disease.

The most common extra-articular feature of ankylosing spondylitis is acute anterior uveitis, which is experienced
by up to 30% of patients at some point. Advise patients to seek medical advice immediately if they experience
sudden onset of unilateral eye pain, photophobia and increased lacrimation. Conjunctival injection around the rim
of the iris is a characteristic finding. Urgently refer any patient with suspected acute anterior uveitis to an
ophthalmologist. Treatment involves corticosteroid eye drops and mydriatics to reduce inflammation and prevent
sequelae such as synechiae.

Urgently refer any patient with suspected acute anterior uveitis to an ophthalmologist.

Less common extra-articular features of ankylosing spondylitis include aortic insufficiency secondary to aortitis,
cardiac conduction defects, and apical pulmonary fibrosis.

Diagnosis of ankylosing spondylitis

History and physical examination give the most useful information in the diagnosis of ankylosing spondylitis (see
Clinical features of ankylosing spondylitis). Inflammatory markers such as erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP) are usually elevated at some point, but have a limited role in diagnosis and disease
monitoring because they do not always correlate with disease activity. However, an elevated CRP concentration in
early axial spondyloarthritis is associated with an increased risk of eventual structural damage to the axial skeleton,
as seen on X-rays of the sacroiliac joints and spine.

Plain X-rays can assist in assessing the extent of joint and entheseal involvement and damage, as well as the rate of
disease progression, but changes may not occur for some years.

Magnetic resonance imaging (MRI) is a sensitive tool for detecting axial inflammation, but the inflammatory
lesions typical of ankylosing spondylitis (‘bone oedema’) are also frequently seen in healthy individuals. MRI is
best used as an adjunct to careful clinical assessment by an experienced clinician. Other imaging modalities,
particularly those that involve ionising radiation such as computed tomography (CT) and radionuclide bone scans,
should not be used because they do not add further diagnostic information.

The following features are predictive of poor prognosis in ankylosing spondylitis:

 hip involvement
age younger than 16 years at the onset of symptoms
presence of three of the following factors within 2 years of the onset of symptoms:
ESR greater than 30 mm/hour or CRP concentration greater than 6 mg/L
limitation of spinal movement
dactylitis (inflammation of a whole finger or toe)
peripheral oligoarthritis
inadequate symptom relief from nonsteroidal anti-inflammatory drugs (NSAIDs).

Refer all patients with suspected ankylosing spondylitis to an appropriate specialist for accurate diagnosis and
initiation of treatment.

General management approach for ankylosing spondylitis

The goal of ankylosing spondylitis management is to maximise long-term health-related quality of life by:

controlling symptoms and inflammation

normalising physical function
enabling participation in social and work-related activities
preventing progressive structural damage
minimising cardiovascular complications.

All patients with ankylosing spondylitis should be advised to stop smoking (see Smoking cessation), exercise and
use nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom control, irrespective of whether other treatments
are used.

Patient education, especially at diagnosis, is important to encourage participation in a long-term exercise program
and to introduce coping strategies to address possible psychosocial impacts of the disease. An integrated
biopsychosocial approach is recommended to address issues such as workforce participation, socialisation, sexual
function, and sleep. Printed or online information is useful to reinforce education [Note 1].

Local corticosteroid injections may be used for peripheral arthritis or enthesitis.

When treatment with the combination of exercise and an NSAID is inadequate to control symptoms, or disease is
severe, disease-modifying therapy is added. The choice of drug depends on the site(s) of disease activity.

Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of axial
inflammation and enthesitis. They are used by specialists to treat patients with severe and/or axial disease.

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have a limited role in the treatment
of ankylosing spondylitis because they have no effect on axial inflammation or enthesitis. They may be used by
specialists in patients with predominantly peripheral arthritis.

Note 1: Patient information on ankylosing spondylitis can be found on the painHEALTH website [URL]. Any
management advice given on this website should be considered in the context of the recommendations in these
guidelines.

Lifestyle management of ankylosing spondylitis

Exercise

Exercise is an essential component of management for all patients with ankylosing spondylitis. The aim is to
maintain and optimise physical function by improving the mobility of the spine and peripheral joints, as well as
improving strength, posture, chest expansion and aerobic fitness. Exercise is also important for mental health.

Consistent participation in exercise is important, particularly for spinal mobility, and patients should be
encouraged to participate in exercise they enjoy. In general, most types of exercise are safe for patients with
ankylosing spondylitis. However, the appropriateness of high-impact exercise, contact sport, jarring activities or
heavy lifting should be considered on a case-by-case basis; particularly in patients who have complications of
ankylosing spondylitis such as spinal ankylosis, impaired balance or mobility, osteoporosis or cardiorespiratory
complications.

Mobility goals should be informed by the patient's disease course. In early, well-controlled disease, an appropriate
goal may be to restore full range of spinal mobility and normal posture. In more advanced disease, however, the
goal may be to maintain the patient's existing movement range.

Referral to a health professional with appropriate expertise (eg physiotherapist) may be beneficial to initiate and
reinforce an exercise program. Some example exercises can be found on the website of the United Kingdom
National Ankylosing Spondylitis Society [URL].

Australian consensus recommendations on the use of exercise for ankylosing spondylitis have recently been
published [Note 2].

Note 2: Millner JR, Barron JS, Beinke KM, Butterworth RH, Chasle BE, Dutton LJ, et al. Exercise for
ankylosing spondylitis: An evidence-based consensus statement. Semin Arthritis Rheum 2015;45(4):411-27.
[URL]

Smoking cessation

All patients with ankylosing spondylitis should be strongly advised to stop smoking because smoking is associated
with a poor disease prognosis. Patient resources and help for smoking cessation are available from the Quitnow
website [URL]. See Smoking cessation for more information on assessment of patients' smoking and advice on
smoking cessation.

Pharmacological management of ankylosing spondylitis

Nonsteroidal anti-inflammatory drug use for ankylosing spondylitis

In combination with exercise, nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of management
of ankylosing spondylitis, with NSAIDs used first line for the treatment of pain and inflammation.

While the symptomatic benefit of NSAIDs is well established, there is conflicting evidence regarding the role of
regular NSAID use in slowing spinal ankylosis. In general, NSAIDs are only used for symptom control in
ankylosing spondylitis.

Use:

an NSAID orally (see Table 12.7 for dosing).

Patients with ankylosing spondylitis often benefit from taking NSAIDs in the evening to minimise night pain and
morning stiffness. It is not unusual to use the upper end of the recommended dosage range.

The risk of harms from NSAID use in patients with ankylosing spondylitis is generally low because the disease
typically affects younger adults; some data show that NSAID-related harms may not differ from placebo in the
short term. Furthermore, the risk of harms is generally outweighed by the benefits of use because of the proven
efficacy of NSAIDs in the treatment of ankylosing spondylitis. NSAIDs are preferred over other analgesics,
particularly opioids, because of their favourable benefit–harm profile in this setting. See Principles of NSAID use
for musculoskeletal conditions in adults for more information.

Biological disease-modifying antirheumatic drug use for ankylosing spondylitis

Biological disease-modifying antirheumatic drugs (bDMARDs) are used by specialists for patients with axial
disease that has not responded adequately to exercise and nonsteroidal anti-inflammatory drugs (NSAIDs). The
tumour necrosis factor (TNF) inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab)
are most commonly used. In most patients bDMARDs are highly effective at decreasing disease activity and
increasing function. However, convincing data about long-term disease modification and prevention of ankylosis
are lacking.

Patients taking bDMARDs are at increased risk of infections and clinicians must always be alert to the possibility
of infection (including opportunistic infection), particularly because the usual symptoms and signs (eg fever) are
often absent. For other considerations in the management of bDMARD therapy (including monitoring, screening
for infection, and vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in
adults.

The TNF inhibitors are generally considered to be equally efficacious in the management of ankylosing
spondylitis, and drug choice is influenced by patient preference regarding route of administration and dosing
frequency. For patients with ankylosing spondylitis and comorbid inflammatory bowel disease, TNF inhibitors
other than etanercept may be preferred because etanercept has been shown to be ineffective in the management of
inflammatory bowel disease. The bDMARD secukinumab, an interleukin-17 inhibitor, is effective in the treatment
of ankylosing spondylitis and is an alternative treatment option.

The usual dosages used for ankylosing spondylitis (listed in alphabetical order) are:

adalimumab 40 mg subcutaneously, every 2 weeks

 OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

thereafter 200 mg every 2 weeks

OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

thereafter every 4 weeks

OR

etanercept 50 mg subcutaneously, once weekly [Note 3]

OR

golimumab 50 mg subcutaneously, every 4 weeks

OR

infliximab 5 mg/kg intravenously, as a single dose at 0, 2 and 6 weeks, and thereafter

every 6 weeks

OR

secukinumab 150 mg subcutaneously, as a single dose at 0, 1, 2, 3 and 4 weeks, and

thereafter every 4 weeks.

Some bDMARDs with other molecular targets (eg the interleukin-12/23 inhibitor, ustekinumab) are effective in the
treatment of ankylosing spondylitis, but are not yet part of standard treatment.

Recent data support the efficacy of bDMARDs in severe nonradiographic axial spondyloarthritis that is
unresponsive to exercise and NSAIDs, particularly in patients with objective markers of inflammation (elevated
erythrocyte sedimentation rate or C-reactive protein concentration, or bone oedema on magnetic resonance
imaging). If used, the dosages are the same as for ankylosing spondylitis [Note 4].

Note 3: An alternative regimen is: etanercept 25 mg subcutaneously, twice weekly.

Note 4: At the time of writing, bDMARDs are not approved by the Australian Therapeutic Goods Administration
(TGA) for treatment of nonradiographic axial spondyloarthritis. See the TGA website for current information
[URL].

Corticosteroid use for ankylosing spondylitis

Oral corticosteroids (eg prednis(ol)one) have a limited role in the management of ankylosing spondylitis.

Intra-articular corticosteroid injections may be used for peripheral arthritis if a small number of accessible joints
are involved. Radiologically guided corticosteroid injections into sacroiliac joints may be beneficial for sacroiliitis.
Peritendinous corticosteroid injections may be beneficial for enthesitis. They should be used with caution in
enthesitis involving major weightbearing tendons such as the Achilles tendons; consider seeking specialist advice
and avoid multiple injections. For principles of use and example doses of local corticosteroid injections, see
Principles of using local corticosteroid injections for musculoskeletal conditions in adults.

Intravenous methylprednisolone is used rarely by specialists for patients with severe systemic disease.

Conventional synthetic disease-modifying antirheumatic drug use for ankylosing spondylitis

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) may be effective for peripheral
arthritis, but should not be used to treat spondylitis because they have no effect on axial inflammation. Since
spondylitis is the predominant symptom of ankylosing spondylitis, csDMARDs are rarely required. They may be
used by specialists in the small number of patients with predominantly peripheral arthritis.

There is limited evidence to guide csDMARD choice in peripheral arthritis in ankylosing spondylitis.
Sulfasalazine is the drug of choice in most patients because of its stronger evidence base and more favourable
adverse effect profile. If sulfasalazine is contraindicated or not tolerated, treatment options include methotrexate or
leflunomide. Methotrexate is preferred over leflunomide because of greater experience with its use.

For considerations in the management of csDMARD therapy (including monitoring, screening for infection, and
vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in adults.

The usual dosage of sulfasalazine is:

sulfasalazine (enteric coated) 500 mg orally, daily, increasing gradually up to 1.5 g twice
daily.

Sulfasalazine doses up to 4 g per day are sometimes used in patients with comorbid inflammatory bowel disease.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

The usual dosage of leflunomide is:

leflunomide 10 to 20 mg orally, daily.

Reactive arthritis
Introduction
Reactive arthritis is an inflammatory, postinfective disease that typically presents 1 to 3 weeks after an infection. It
has an annual incidence of about 30 per 100 000 people. Reactive arthritis following genitourinary infection occurs
predominantly in males, most commonly between 20 and 40 years of age. The most common genitourinary
pathogen associated with reactive arthritis is Chlamydia trachomatis. Reactive arthritis following gastrointestinal
infection affects males and females equally. The most common enteric pathogens are Salmonella typhimurium,
Shigella flexneri, Yersinia enterocolitica and Campylobacter jejuni. Streptococcal infections can also be followed
by reactive arthritis.

In some patients, a history of triggering infection may be absent, but a diagnosis of reactive arthritis can still be
made based on clinical presentation.

In up to 80% of patients with reactive arthritis, the arthropathy settles within 6 months (see Acute reactive
arthritis), while the remaining 20% have chronic reactive arthritis. Some patients will experience recurrent
episodes of acute reactive arthritis, which should be managed as acute reactive arthritis.

See Table 12.10 for comparative features of reactive arthritis and other spondyloarthritides.

Clinical features of reactive arthritis

The clinical presentation of reactive arthritis may include one or more of the triad of arthritis, conjunctivitis and
urethritis.

The arthritis is typically an inflammatory peripheral arthropathy with an asymmetrical oligoarticular distribution,
predominantly affecting the lower limbs. Dactylitis (inflammation of a whole finger or toe) is a common feature,
and enthesitis (inflammation at the sites of tendon and ligament attachment to bone) can occur. The articular
symptoms typically develop at least 1 week after an infective illness; this temporal relationship may help to
distinguish reactive arthritis from joint infection (see Septic arthritis or Viral arthritis). While Streptococcus
pyogenes does not cause reactive arthritis, rheumatic fever is also a postinfective arthritis and should be considered
in high-risk populations (see Acute rheumatic fever).

Extra-articular features of reactive arthritis include:

conjunctivitis in up to 33% of cases. Acute anterior uveitis can occur, although less commonly than with
ankylosing spondylitis (see Clinical features of ankylosing spondylitis for more information on acute
anterior uveitis and its management)
genitourinary inflammation, including urethritis, prostatitis and balanitis
keratoderma blennorrhagica. This is a pustular hyperkeratotic rash typically affecting the palms and soles of
the feet, which is histologically identical to pustular psoriasis.
Management of reactive arthritis

Acute reactive arthritis

Although reactive arthritis typically presents after an infection has resolved, active infection or asymptomatic
infection may still be present at the time of the arthritis diagnosis. Further investigation may be required to
distinguish persistent infection from the inflammatory manifestations of reactive arthritis (eg urethritis). Treat
active infection as indicated. If an asymptomatic sexually transmitted infection is suspected, see Principles of
sexually transmitted infection management for advice on investigation, treatment and contact tracing.

The treatment of acute reactive arthritis (duration of less than 6 months) depends on the extent and severity of joint
involvement, and the nature of any extra-articular involvement.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at treating mild to moderate peripheral arthritis and
spondylitis. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Intra-articular corticosteroid injections are effective for severe peripheral arthritis if a small number of accessible
joints are involved. Peritendinous corticosteroid injections may be beneficial for enthesitis. They should be used
with caution in enthesitis involving major weightbearing tendons such as the Achilles tendons; consider seeking
specialist advice and avoid multiple injections. For principles of use and example doses of local corticosteroid
injections, see Principles of using local corticosteroid injections for musculoskeletal conditions in adults.

Oral corticosteroids may be required for severe articular and extra-articular disease, provided active infection has
been excluded. The usual dosage is:

prednis(ol)one 10 to 50 mg (depending on severity) orally, daily until symptoms improve,

then taper the dose to stop.

See Principles of immunomodulatory drug use for rheumatological diseases in adults for information on adverse
effects associated with long-term corticosteroid therapy (such as bone density loss) and advice on how to minimise
and monitor for such complications.

Topical corticosteroids may be needed for ocular inflammation.

Chronic reactive arthritis

Up to 20% of patients with reactive arthritis may develop chronic arthritis (ie persisting beyond 6 months).

All patients with chronic spondylitis or peripheral arthritis should be advised to exercise (see the advice on
exercise in ankylosing spondylitis). Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for symptom
control. The combination of exercise and NSAIDs is continued throughout the disease course, irrespective of
whether other treatments are used. For more information on the use of NSAIDs, including dosage, see
Nonsteroidal anti-inflammatory drug use for ankylosing spondylitis.

Intra-articular and peritendinous corticosteroid injections may be used for peripheral arthritis and enthesitis,
respectively. Peritendinous injections should be used with caution in enthesitis involving major weightbearing
tendons such as the Achilles tendons; consider seeking specialist advice and avoid multiple injections.
Radiologically guided corticosteroid injections into sacroiliac joints may be beneficial for sacroiliitis. For
principles of use and example doses of local corticosteroid injections, see Principles of using local corticosteroid
injections for musculoskeletal conditions in adults.

When treatment with exercise and an NSAID is inadequate to control symptoms, or disease is severe, disease-
modifying therapy may be added. The choice of drug depends on the site(s) of disease activity. The conventional
synthetic disease-modifying antirheumatic drugs (csDMARDs) are often used by specialists to treat peripheral
arthritis, although strong evidence is lacking. See Conventional synthetic disease-modifying antirheumatic drug
use for ankylosing spondylitis for doses. csDMARDs are relatively ineffective in the treatment of enthesitis.
Biological disease-modifying antirheumatic drugs (bDMARDs) may be effective in refractory cases of chronic
reactive arthritis; however, there is little evidence to support their use. They should only be used by specialists
after persistent infection has been excluded. See Biological disease-modifying antirheumatic drug use in
ankylosing spondylitis for doses.

Enteropathic arthritis
Introduction
Enteropathic arthritis is an inflammatory arthropathy that occurs in conjunction with inflammatory bowel disease,
specifically Crohn disease and ulcerative colitis. Enteropathic arthritis is the most common extra-intestinal feature
of inflammatory bowel disease; up to 20% of patients may develop axial and/or peripheral spondyloarthritis.

See Table 12.10 for comparative characteristics of enteropathic arthritis and other spondyloarthritides.

Clinical features of enteropathic arthritis

In patients with enteropathic arthritis, the clinical features of spondylitis (inflammation of the spine) and sacroiliitis
(inflammation of sacroiliac joints) are indistinguishable from those of ankylosing spondylitis. Like the other
spondyloarthritides, the peripheral arthritis is oligoarticular, asymmetrical and predominantly affects the lower
limbs. Enthesitis (inflammation at the sites of tendon and ligament attachment to bone) may be seen at the Achilles
tendon and plantar fascia insertion.

Other extra-intestinal features of inflammatory bowel disease that can be seen in conjunction with enteropathic
arthritis include:

ocular complications, especially acute anterior uveitis, but also conjunctivitis and episcleritis (see Clinical
features of ankylosing spondylitis for more information on acute anterior uveitis and its management)
cutaneous lesions, such as erythema nodosum (Crohn disease) and pyoderma gangrenosum (ulcerative
colitis).

The spondyloarthritis may precede the clinical presentation of inflammatory bowel disease. As a general rule,
spondylitis disease activity is independent of intestinal disease activity, whereas peripheral arthritis disease activity
is often associated with intestinal inflammation.

Management of enteropathic arthritis

Consideration should be given to the effects of pharmacological therapy used to manage enteropathic arthritis on
the patient's underlying inflammatory bowel disease, as well as the effects of therapy used to manage inflammatory
bowel disease on the patient's arthritis. Whenever possible, a drug that is effective for both indications should be
used to avoid unnecessary polypharmacy. For guidance on the management of inflammatory bowel disease, see
Inflammatory bowel disease.

All patients with spondylitis or peripheral arthritis should be advised to stop smoking (see the advice on smoking
cessation in ankylosing spondylitis), exercise (see the advice on exercise in ankylosing spondylitis) and, if
tolerated, use nonsteroidal anti-inflammatory drugs (NSAIDs) for symptom relief (see Nonsteroidal anti-
inflammatory drug use for ankylosing spondylitis). NSAIDs aggravate inflammatory bowel disease in some
patients.

Intra-articular corticosteroid injections may be used for peripheral arthritis if a small number of accessible joints
are involved. Radiologically guided corticosteroid injections into sacroiliac joints may be beneficial for sacroiliitis.
Peritendinous corticosteroid injections may be beneficial for enthesitis. They should be used with caution in
enthesitis involving major weightbearing tendons such as the Achilles tendons; consider seeking specialist advice
and avoid multiple injections. For principles of use and example doses of local corticosteroid injections, see
Principles of using local corticosteroid injections for musculoskeletal conditions in adults.

When treatment with the combination of exercise and an NSAID is inadequate to control symptoms, or disease is
severe, disease-modifying therapy is added. The choice of drug depends on the site(s) of disease activity. For
patients with peripheral arthritis, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) may
be considered by specialists. Sulfasalazine, azathioprine and methotrexate are preferred because they are widely
used to treat inflammatory bowel disease. Biological disease-modifying antirheumatic drugs (bDMARDs)—
usually tumour necrosis factor (TNF) inhibitors—may be effective in the treatment of enteropathic arthritis;
however, there is no direct evidence to support their use. The choice of bDMARD should take into account the
drug's effect on inflammatory bowel disease—for example, a TNF inhibitor other than etanercept may be preferred
because etanercept has been shown to be ineffective in the management of inflammatory bowel disease.

Psoriatic arthritis
Introduction
Psoriatic arthritis affects 0.04 to 0.1% of the population and typically presents in young to middle-aged adults.
Males and females are affected equally. The reported prevalence of inflammatory arthritis in people with psoriasis
varies widely from 6% up to 42%. In about 67% of patients, psoriasis is present before the onset of the arthropathy,
whereas in approximately 15% of patients the arthritis precedes the skin disease by more than one year.
See Table 12.10 for comparative characteristics of psoriatic arthritis and other spondyloarthritides.

Psoriatic arthritis is associated with an increased risk of cardiovascular disease.

Refer all patients with suspected psoriatic arthritis to an appropriate specialist for accurate diagnosis and initiation
of treatment.

For psoriatic arthritis in children, see Juvenile idiopathic arthritis: psoriatic arthritis.

Clinical features of psoriatic arthritis

In most patients with psoriatic arthritis, the arthropathy affects peripheral joints alone and may present with
dactylitis (inflammation of a single finger or toe) or enthesitis (inflammation at the sites of tendon and ligament
attachment to bone). The following patterns of joint involvement are recognised:

oligoarticular peripheral arthritis—occurs in 50% of patients; involves up to five joints. Over time many
patients with an initially oligoarticular presentation will develop polyarticular disease
polyarticular peripheral arthritis—occurs in 30% of patients; may resemble rheumatoid arthritis
predominant sacroiliitis (inflammation of the sacroiliac joints) and spondylitis (inflammation of the spine)—
occurs in up to 10% of patients. The sacroiliitis is usually asymmetrical. On plain X-ray the syndesmophytes
are typically ‘chunky’, often with noncontiguous involvement of vertebrae
predominant distal interphalangeal joint involvement in both hands and feet—occurs in 5% of patients. The
distal interphalangeal joints involved are usually associated with severe psoriatic nail involvement
arthritis mutilans—occurs in up to 5% of patients. It presents as osteolysis or dissolution of bone affecting
the small joints of the hands and feet and adjacent phalanges, resulting in shortening of digits, and flail
joints. This pattern of involvement is more commonly seen in females.

The extra-articular features common to the spondyloarthritides may occur with psoriatic arthritis (see Box 12.10).
Ocular inflammation most commonly presents as conjunctivitis, although up to 7% of patients can develop iritis.

Markers of poor prognosis in psoriatic arthritis are:

juvenile or young adult onset

extensive psoriatic skin disease
failure to respond to nonsteroidal anti-inflammatory drugs (NSAIDs)
polyarticular presentation.

Management of peripheral psoriatic arthritis

General management approach

Consideration should be given to the effects of pharmacological therapy used to manage psoriatic arthritis on the
patient's underlying psoriatic skin disease, as well as the effects of therapy used to manage psoriatic skin disease
on the patient's arthritis. Whenever possible, a drug that is effective for both indications should be used to avoid
unnecessary polypharmacy. See Psoriasis for guidance on the management of psoriasis (including primary care
treatment and considerations such as psychological health). Ensure good disease control, even in patients with only
one or two joints involved, because the arthritis can be destructive.

In addition to lifestyle management, as recommended for ankylosing spondylitis, the following pharmacological
treatments may be used. In monoarticular or oligoarticular disease, nonsteroidal anti-inflammatory
drugs (NSAIDs) and intra-articular corticosteroid injections are often used first line; disease-modifying
antirheumatic drugs (DMARDs) are used for resistant or progressive cases. In polyarticular disease, DMARD
therapy is required. For more information on DMARD therapy, see Conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs), Biological disease-modifying antirheumatic drugs (bDMARDs) and Targeted
synthetic disease-modifying antirheumatic drugs (tsDMARDs).

As psoriatic arthritis is associated with an increased risk of cardiovascular disease, advise patients about lifestyle
modification, and monitor and actively manage risk factors for cardiovascular disease (see Cardiovascular disease
risk stratification).

Nonsteroidal anti-inflammatory drug use for peripheral psoriatic arthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in managing pain and inflammation in peripheral
psoriatic arthritis. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information). Fish oil
may have an NSAID-sparing effect (see Principles of fish oil use for musculoskeletal conditions in adults for more
information).

Corticosteroid use for peripheral psoriatic arthritis

Intra-articular corticosteroid injections play a significant role in the management of monoarticular or oligoarticular
peripheral arthritis. Intra-articular corticosteroid injections may result in long-term suppression of arthritis in the
injected joint, avoiding the need for disease-modifying antirheumatic drug (DMARD) therapy. For principles of
use and example doses of local corticosteroid injections, see Principles of using local corticosteroid injections for
musculoskeletal conditions in adults.

Avoid using oral corticosteroids in patients with psoriatic arthritis because a flare of skin disease can occur when
the dose is reduced. Topical corticosteroids are often recommended to control skin disease.

Conventional synthetic disease-modifying antirheumatic drug use for peripheral psoriatic arthritis

The conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) methotrexate, sulfasalazine and
leflunomide are established therapies used by specialists for psoriatic arthritis, and may benefit both the arthritis
and skin disease.

There is limited evidence to guide csDMARD choice in peripheral psoriatic arthritis, and comparative efficacy
data are lacking. Drug choice may be influenced by patient factors (including comorbidities), drug interactions,
adverse effects and cost. The risk of abnormalities in liver biochemistry may be higher in patients with psoriatic
arthritis than in other inflammatory arthropathies.

For considerations in the management of csDMARD therapy (including monitoring, screening for infection, and
vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in adults.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

The usual dosage of sulfasalazine is:

sulfasalazine (enteric coated) 500 mg orally, daily, increasing gradually up to 1.5 g twice
daily.

The usual dosage of leflunomide is:

leflunomide 10 to 20 mg orally, daily.

Cyclosporin has been demonstrated in clinical trials to benefit psoriatic arthritis and skin disease. Dose-limiting
adverse effects are significant, especially renal impairment and hypertension.

Other csDMARDs, including azathioprine, gold and hydroxychloroquine, have been used in the treatment of
psoriatic arthritis, with anecdotal evidence of benefit. Caution is recommended with the use of hydroxychloroquine
in psoriatic arthritis because of the risk of inducing a severe flare of skin disease.

Biological disease-modifying antirheumatic drug use for peripheral psoriatic arthritis

The biological disease-modifying antirheumatic drugs (bDMARDs) that inhibit tumour necrosis factor (TNF),
adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, are effective in the treatment of psoriatic
arthritis and psoriatic skin disease. They are used by specialists for psoriatic arthritis when csDMARDs are not
effective or are poorly tolerated.

The TNF inhibitors are generally considered to be equally efficacious in peripheral psoriatic arthritis and drug
choice is influenced by patient preference regarding route of administration and dosing frequency. For patients
with psoriatic arthritis and comorbid inflammatory bowel disease, TNF inhibitors other than etanercept may be
preferred because etanercept has been shown to be ineffective in the management of inflammatory bowel disease.

The usual dosages of the TNF inhibitors used for psoriatic arthritis (listed in alphabetical order) are:
 adalimumab 40 mg subcutaneously, every 2 weeks

OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

thereafter 200 mg every 2 weeks

OR

certolizumab pegol 400 mg subcutaneously, as a single dose at 0, 2 and 4 weeks, and

thereafter every 4 weeks

OR

etanercept 50 mg subcutaneously, once weekly [Note 5]

OR

golimumab 50 mg subcutaneously, every 4 weeks

OR

infliximab 5 mg/kg intravenously, as a single dose at 0, 2 and 6 weeks, and thereafter

every 8 weeks.

Some bDMARDs with molecular targets other than TNF (eg the interleukin-12/23 inhibitor ustekinumab, the
interleukin-17 inhibitor secukinumab) are effective in the treatment of psoriatic arthritis, as well as psoriatic skin
disease. Comparative data to the TNF inhibitors are lacking. Given the longer experience with TNF inhibitors,
bDMARDs with other molecular targets are likely to play a role in the management of patients for whom TNF
inhibitors are ineffective, poorly tolerated, or contraindicated.

The usual dosage of ustekinumab for psoriatic arthritis is:

ustekinumab 45 mg subcutaneously, as a single dose at 0 and 4 weeks, and thereafter

every 12 weeks [Note 6].

The usual dosage of secukinumab for psoriatic arthritis is:

secukinumab 150 mg subcutaneously, as a single dose at 0, 1, 2, 3 and 4 weeks, and

thereafter every 4 weeks [Note 7].

Patients taking bDMARDs are at increased risk of infections and clinicians must always be alert to the possibility
of infection (including opportunistic infection), particularly because the usual symptoms and signs (eg fever) are
often absent. For other considerations in the management of bDMARD therapy (including monitoring, screening
for infection, and vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in
adults.

Note 5: An alternative regimen is: etanercept 25 mg subcutaneously, twice weekly.

Note 6: An increased ustekinumab dose (90 mg rather than 45 mg) can be considered for patients weighing more
than 100 kg; however, it is not clear if this dose is more effective than standard dosing. More frequent
maintenance dosing (up to every 8 weeks) has been used in patients with plaque psoriasis, with or without
comorbid psoriatic arthritis, whose response to treatment was inadequate. At the time of writing, increased doses
of ustekinumab are not available on the Pharmaceutical Benefits Scheme (PBS) for treatment of psoriatic
arthritis. See the PBS website for current information [URL].

Note 7: For patients who have not responded to treatment with a TNF inhibitor or who have comorbid moderate
to severe plaque psoriasis, an increased secukinumab dose (300 mg rather than 150 mg) is used.

Targeted synthetic disease-modifying antirheumatic drug use for peripheral psoriatic arthritis

The targeted synthetic disease-modifying antirheumatic drug (tsDMARD) apremilast is effective in treating
psoriatic arthritis, as well as psoriatic skin disease. While it appears to be well tolerated, there is limited clinical
experience with its use and its place in the treatment of psoriatic arthritis is not yet determined.
Management of psoriatic spondylitis
Spondylitis in psoriatic arthritis is typically milder than in ankylosing spondylitis, but the same management
principles apply; see General management approach for ankylosing spondylitis.

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systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.
Ann Rheum Dis 2009;68(7):1086–93.

Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, et al. Nonsteroidal antiinflammatory drugs reduce
radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum
2005;52(6):1756–65.

Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. American College of Rheumatology/Spondylitis
Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the treatment
of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2016;68(2):282–98.

Reactive arthritis

Kwiatkowska B, Filipowicz-Sosnowska A. Reactive arthritis. Pol Arch Med Wewn 2009;119(1-2):60–5.

Meyer A, Chatelus E, Wendling D, Berthelot JM, Dernis E, Houvenagel E, et al. Safety and efficacy of anti-tumor
necrosis factor alpha therapy in ten patients with recent-onset refractory reactive arthritis. Arthritis Rheum
2011;63(5):1274–80.

Zochling J, Smith EU. Seronegative spondyloarthritis. Best Pract Res Clin Rheumatol 2010;24(6):747–56.

Enteropathic arthritis

Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. Etanercept for active Crohn's disease: a
randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121(5):1088–94.

Psoriatic arthritis

Agca R, Heslinga SC, Rollefstad S, Heslinga M, McInnes IB, Peters MJ, et al. EULAR recommendations for
cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint
disorders: 2015/2016 update. Ann Rheum Dis 2017;76(1):17–28.

Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. European League Against Rheumatism
(EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann
Rheum Dis 2016;75(3):499–510. .

Ogdie A, Yu Y, Haynes K, Love TJ, Maliha S, Jiang Y, et al. Risk of major cardiovascular events in patients with
psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2015;74(2):326–
32.

Ramiro S, Smolen JS, Landewe R, van der Heijde D, Dougados M, Emery P, et al. Pharmacological treatment of
psoriatic arthritis: a systematic literature review for the 2015 update of the EULAR recommendations for the
management of psoriatic arthritis. Ann Rheum Dis 2016;75(3):490–8.

Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. Etanercept for active Crohn's disease: a
randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121(5):1088–94.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Juvenile idiopathic arthritis
Overview of juvenile idiopathic arthritis
Juvenile idiopathic arthritis (JIA) (commonly referred to as juvenile arthritis) is the internationally accepted
nomenclature for inflammatory arthritis beginning before 16 years of age and present for at least 6 weeks, for
which no underlying cause can be found after appropriate investigation. It is the most common rheumatological
disease in childhood, affecting approximately 1 in 1000 children. The spectrum of differential diagnoses of JIA is
broad, ranging from noninflammatory conditions through to malignancy. A thorough assessment by a practitioner
confident with this diagnosis, and its differentials, is recommended before starting long-term therapy (see also
Assessing musculoskeletal symptoms in children and adolescents). For important mimics of JIA in the lower
limbs, see Important mimics of juvenile idiopathic arthritis in the lower limbs.

JIA may present with several patterns of joint involvement and extra-articular disease, which may evolve over the
disease course. Clinical presentations of JIA and their prevalence are given in Table 12.11.

The long-term management of children and adolescents with JIA is best undertaken by, or in conjunction with, a
paediatric rheumatologist. The holistic care of children and adolescents with JIA typically involves a
multidisciplinary team, in which the general practitioner has a key role in providing family support, managing the
general health of the child and monitoring medication. During the transition in late adolescence from paediatric to
adult services, general practitioners are well placed to manage areas of care such as immunisations, starting
contraception and, if relevant, stopping smoking. Input from allied health professionals (eg physiotherapists,
occupational therapists, orthotists, dietitians) when required is also important. Support from social workers and/or
nurse educators can help families come to terms with the diagnosis and its treatment requirements, obtain
disability entitlements, and liaise with schools. For more detailed information about multidisciplinary care of
children with JIA, see the Australian standards of care [Note 1].

Clinical presentations of juvenile idiopathic arthritis and their prevalence (Table 12.11)

Prevalence in patients with juvenile

Clinical presentation
idiopathic arthritis
oligoarthritis—4 or fewer joints affected in the first 6 months of
disease. Two subtypes occur:

persistent oligoarthritis—4 or fewer joints involved

50 to 60%
throughout the disease course
extended oligoarthritis—more than 4 joints involved after the
first 6 months of disease

polyarthritis (rheumatoid factor negative)—more than 4 joints

affected in the first 6 months of disease, in the absence of 10 to 30%
rheumatoid factor
polyarthritis (rheumatoid factor positive)—more than 4 joints
affected in the first 6 months of disease, in the presence of
2 to 7%
rheumatoid factor (detected on at least two occasions 3 months
apart)
systemic arthritis 4 to 17%
enthesitis-related arthritis 3 to 11%
psoriatic arthritis 2 to 11%
undifferentiated arthritis 11 to 21%

Note 1: Munro J, Murray K, Boros C, Chaitow J, Allen RC, Akikusa J, et al. Australian Paediatric
Rheumatology Group standards of care for the management of juvenile idiopathic arthritis. J Paediatr Child
Health 2014;50(9):663-6. [URL]

Investigations in patients with juvenile idiopathic arthritis

In patients with juvenile idiopathic arthritis (JIA), the following tests are useful to classify disease (see Table
12.11) and assess the risk of disease complications:
 antinuclear antibodies (ANA)—ANA is commonly detected in children or adolescents with JIA, but is also
found in up to 15% of healthy children. ANA positivity is a risk factor for the development of asymptomatic
anterior uveitis, particularly in oligoarticular disease
rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (CCP)—a minority of children or
adolescents with polyarthritis are RF positive. Similar to its prognostic role in adults with rheumatoid
arthritis, RF positivity in children and adolescents suggests poor prognosis. Antibodies to CCP are generally
only found in patients who are RF positive; their role in the diagnosis and classification of JIA is yet to be
determined
human leucocyte antigen B27 (HLA-B27)—HLA-B27 is a diagnostic feature of enthesitis-related arthritis,
but it is not useful in isolation because it is also present in about 10% of Caucasians. The significance of a
positive test result is determined by the patient's clinical presentation; in a child or adolescent with
symptoms suggestive of an enthesopathy, a positive result is likely to be significant.

Do not use ANA, RF, antibodies to CCP, or HLA-B27 to screen for juvenile idiopathic arthritis because these tests may be
positive in healthy children.

These tests should not be used to screen for JIA because they may be positive in healthy children.

Juvenile idiopathic arthritis: oligoarthritis

Introduction
Oligoarthritis is most common in girls and typically presents in preschool-aged children, with involvement of large
joints in the lower limb. Leg length discrepancy, as a result of stimulation of the growth plate adjacent to the
affected joint, and flexion contractures may occur in this group if knee arthritis remains poorly controlled.

Screening for asymptomatic anterior uveitis

All patients with juvenile idiopathic arthritis (JIA) are at risk of developing asymptomatic anterior uveitis, with the
exception of patients with enthesitis-related arthritis. Patients with oligoarthritis are at particular risk; up to 30% of
patients will develop uveitis in the first 7 years of disease, particularly those who are positive for antinuclear
antibody (ANA).

Although this form of uveitis is described as ‘asymptomatic’, it is only the ocular pain and redness characteristic of
acute symptomatic anterior uveitis that are absent. Symptoms such as reduced visual acuity and photophobia
occur, but are not reliably reported by younger children. Older children may be able to recognise these symptoms
and, along with their parents, should be instructed to report them. Left undetected or poorly controlled, anterior
uveitis is potentially blinding, so regular slit-lamp screening examinations by an ophthalmologist or, in older
children, an optometrist are essential.

The screening interval and duration vary according to the form of JIA, age at onset of disease and ANA status.
Children with ANA-positive oligoarthritis or ANA-positive polyarthritis with an onset at 6 years of age or younger
have the highest risk of uveitis. These patients should be screened every 3 months for the first 4 years of their
disease course; the frequency of screening is then gradually reduced so that after 7 years of disease screening
occurs yearly. Screening patients with JIA at lower risk of asymptomatic anterior uveitis typically involves reviews
every 6 to 12 months until the age of 10 to 12 years. Patients with enthesitis-related arthritis do not require
screening because they develop acute symptomatic, rather than asymptomatic, anterior uveitis.

Management of oligoarthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used in the initial management of oligoarthritis to
reduce pain and stiffness. They will rarely resolve the arthritis and usually only have a short-term role while more
definitive measures are arranged. For paediatric dosages of oral NSAIDs, see Table 12.12. See also Practical
prescribing considerations for rheumatological diseases in children and adolescents.

The definitive treatment of oligoarthritis is intra-articular corticosteroid therapy, which—in most situations—
should only be initiated on specialist advice. The most effective drug is triamcinolone hexacetonide [Note 2],
which may induce remission in injected joint(s) for 6 to 12 months or longer. Example paediatric doses of
triamcinolone hexacetonide for intra-articular injection are given in Table 12.13. In children younger than 6 years
or in whom multiple joints are being injected, injections should be performed under general anaesthesia. In older
children, sedation and/or analgesia (eg midazolam and/or inhaled nitrous oxide) is generally an acceptable
alternative to general anaesthesia.

Serial casting and/or splinting may be used in conjunction with intra-articular corticosteroid therapy if flexion
contractures are present.
For patients with frequent relapses of oligoarticular disease or who develop extended oligoarticular disease (ie
follow a polyarticular course after the first 6 months of disease), the use of conventional synthetic disease-
modifying antirheumatic drugs (csDMARDs) should be considered (see Management of rheumatoid factor
negative polyarthritis for advice on drug choice and dosing).

Paediatric dosages of oral NSAIDs used for rheumatological diseases (Table 12.12)

Drug Dosage Oral formulations available

5 to 7.5 mg/kg twice daily suspension, tablet (including modified-release formulation)
naproxen [NB1]
[NB2]
(maximum 1000 mg/day)
0.5 to 1 mg/kg 2 to 3 times
indomethacin daily capsule
(maximum 200 mg/day)
0.2 to 0.4 mg/kg once daily
piroxicam capsule, dispersible tablet
(maximum 20 mg/day)
0.15 to 0.3 mg/kg once daily
meloxicam (maximum 15 mg/day) capsule, tablet
[NB3]
10 mg/kg 3 to 4 times daily
ibuprofen capsule, suspension, tablet
(maximum 2400 mg/day)
1 to 1.5 mg/kg twice daily
diclofenac capsule, tablet
(maximum 150 mg/day)
2 to 4 mg/kg twice daily
celecoxib capsule
(maximum 200 mg/day)
NSAIDs = nonsteroidal anti-inflammatory drugs
NB1: Naproxen sodium is used in some preparations; 250 mg of naproxen is equivalent to 275 mg of naproxen sodium.
NB2: Modified-release formulations of naproxen should not be used for acute pain, but can be considered for older children with persistent pain who
have been stabilised on an immediate-release formulation.
NB3: Data indicate that a 0.25 mg/kg once-daily meloxicam dose is not superior to a 0.125 mg/kg once-daily dose.

Example doses of triamcinolone hexacetonide injection for children (Table 12.13) [NB1] [NB2]

Dose of triamcinolone hexacetonide 20 mg/mL

Small joint (eg hand) Medium joint (eg wrist) Large joint (eg knee)
0.03 to 0.05 mL for PIP joints
0.025 mL/kg up to 0.5 mL 0.05 mL/kg up to 1 mL
0.05 to 0.1 mL for MCP and MTP
joints
MCP = metacarpophalangeal; MTP = metatarsophalangeal; PIP = proximal interphalangeal
NB1: These are example doses; the dose should be individualised for each patient depending on the size of the joint, the severity of the condition, the
response obtained, and the patient's tolerance of the corticosteroid.
NB2: Triamcinolone hexacetonide is not registered for use in Australia but is available via the Special Access Scheme.

Note 2: Triamcinolone hexacetonide is not registered for use in Australia but is available via the Special Access
Scheme.

Juvenile idiopathic arthritis: polyarthritis (rheumatoid factor negative)

Introduction
Rheumatoid factor negative polyarthritis may affect both large and small joints, often in a symmetrical pattern.

Although asymptomatic anterior uveitis is less common in rheumatoid factor negative polyarthritis than in
oligoarthritis, regular slit-lamp screening examinations are still required (see Screening for asymptomatic anterior
uveitis for information on screening interval and duration).

Management of rheumatoid factor negative polyarthritis

General management approach

Pharmacological management of polyarthritis aims to induce clinical remission as early as possible and to
maintain disease remission once it is achieved. Conventional synthetic disease-modifying antirheumatic
drugs (csDMARDs) are the mainstay of therapy and should be started early with specialist advice. Biological
disease-modifying antirheumatic drugs (bDMARDs) are used in children and adolescents with inadequate
response to first-line csDMARD therapy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used early in the disease course to manage pain
and stiffness while awaiting a response to csDMARD therapy, which may take up to 12 weeks. For paediatric
dosages of oral NSAIDs, see Table 12.12. Intra-articular corticosteroid therapy may have a role in relieving pain in
specific joints, particularly if joint positioning or mobility is poor (eg subtalar joint). See also Practical prescribing
considerations for rheumatological diseases in children and adolescents.

For children and adolescents with confirmed disease who have significant pain and stiffness despite the use of an
NSAID at an appropriate dose, an oral corticosteroid may be started while awaiting response to csDMARD
therapy. In most situations, this should only be done after seeking specialist advice. If considered appropriate, use:

prednis(ol)one 0.25 to 1 mg/kg up to 60 mg orally, daily.

Patients started on corticosteroids should be reviewed frequently and the dose tapered according to response.

Conventional synthetic disease-modifying antirheumatic drugs

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used by specialists to induce and
then maintain clinical remission of arthritis. Methotrexate is the preferred csDMARD for most patients and may
also be useful for the management of chronic uveitis. Leflunomide has been demonstrated to have similar efficacy
to methotrexate. Sulfasalazine has a limited role in the treatment of patients with polyarthritis; it is most often used
for children with enthesitis-related arthritis. Hydroxychloroquine has been demonstrated not to have the same
efficacy as other csDMARDs, but is sometimes used in milder cases, or in combination with other csDMARDs.

The specialist will determine the appropriate approach to monitoring, screening for infection, and vaccination
based on the adverse effect profile of the immunomodulatory drug(s) used and patient factors (eg disease activity,
comorbidities). See also Practical prescribing considerations for rheumatological diseases in children and
adolescents.

The usual paediatric dosage of methotrexate is:

methotrexate 10 to 20 mg/m2 up to 25 mg orally or subcutaneously, on one specified day

once weekly [Note 3] [Note 4]

PLUS

folic acid 5 mg orally, once weekly (preferably not on the day methotrexate is taken) [Note
5].

The usual paediatric dosage of leflunomide is:

leflunomide:
child less than 20 kg: 10 mg orally, on alternate days
child 20 to 40 kg: 10 mg orally, daily
child more than 40 kg: 20 mg orally, daily.

The usual paediatric dosage of sulfasalazine is:

sulfasalazine 5 mg/kg up to 500 mg orally, twice daily, increasing over 2 to 4 weeks to 15

to 20 mg/kg up to 1.5 g twice daily.

The usual paediatric dosage of hydroxychloroquine is:

hydroxychloroquine 3 to 5 mg/kg up to 400 mg orally, daily.

Note 3: Oral bioavailability of methotrexate plateaus above 15 mg. If doses higher than 15 mg are ineffective,
subcutaneous administration could be considered.
Note 4: Nausea can be reduced by splitting the methotrexate dose over 2 consecutive days (usually 12 hours
apart) or administering methotrexate subcutaneously, as well as by folic acid supplementation.

Note 5: Folic acid can be formulated as a solution by a pharmacist. For formulation details, see the Australian
Pharmaceutical Formulary and Handbook (APF), 23rd edition, 2015.

Biological disease-modifying antirheumatic drugs

Biological disease-modifying antirheumatic drugs (bDMARDs) are used by specialists to treat children and
adolescents with inadequate response to first-line therapy with conventional synthetic disease-modifying
antirheumatic drugs (csDMARDs). In the small group of children and adolescents with difficult-to-control
polyarthritis, treatment with a bDMARD can minimise polypharmacy and reduce the need for prolonged
corticosteroid therapy.

The specialist will determine the appropriate approach to monitoring, screening for infection, and vaccination
based on the adverse effect profile of the immunomodulatory drug(s) used and patient factors (eg disease activity,
comorbidities). See also Practical prescribing considerations for rheumatological diseases in children and
adolescents.

At the time of writing, adalimumab, etanercept and tocilizumab are the only bDMARDs available on the
Pharmaceutical Benefits Scheme (PBS) for polyarticular juvenile idiopathic arthritis (JIA). The usual paediatric
dosages (listed in alphabetical order) are:

adalimumab (child 2 years or older and less than 15 kg: 10 mg; 15 kg to less than 30 kg:
20 mg; 30 kg or more: 40 mg) subcutaneously, every 2 weeks

OR

etanercept (child 2 years or older) 0.8 mg/kg up to 50 mg subcutaneously, once weekly

OR

etanercept (child 2 years or older) 0.4 mg/kg up to 25 mg subcutaneously, twice weekly

OR

tocilizumab (child 2 years or older and less than 30 kg: 10 mg/kg; 30 kg or more: 8
mg/kg) intravenously, every 4 weeks.

Juvenile idiopathic arthritis: polyarthritis (rheumatoid factor positive)

Introduction
Rheumatoid factor positive polyarthritis occurs mainly in older children and adolescents. Similar to rheumatoid
arthritis in adults, it has the potential for early progression to erosive disease, nodules and significant functional
disability.

Children with rheumatoid factor positive polyarthritis are at low risk of developing uveitis; however, regular slit-
lamp screening examinations are still required (see Screening for asymptomatic anterior uveitis for information on
screening interval and duration).

Management of rheumatoid factor positive polyarthritis

Management of rheumatoid factor positive polyarthritis is the same as for patients with rheumatoid factor negative
polyarthritis, particularly in regards to the early initiation of conventional synthetic disease-modifying
antirheumatic drug (csDMARD) therapy with the aim of achieving early disease remission (see Management of
rheumatoid factor negative polyarthritis).

Juvenile idiopathic arthritis: systemic arthritis

Introduction
Systemic arthritis (formerly known as Still disease) shares clinical and laboratory similarities with the rarer adult
equivalent, adult-onset Still disease. The clinical presentation of systemic arthritis is dominated by systemic
features such as:

quotidian fever
evanescent salmon pink rash (Still rash), which is usually nonpruritic
hepatosplenomegaly and/or lymphadenopathy
polyserositis.

Arthritis is necessary for diagnosis but can be preceded by systemic features by weeks or even months. Arthritis
can present with an oligoarticular or polyarticular distribution, but typically progresses to a polyarticular course.
Growth retardation (independent of corticosteroid use) and anaemia of chronic disease commonly coexist with the
arthritis.

A markedly elevated serum ferritin concentration (greater than 1000 micrograms/L) is common. Although not
pathognomonic for systemic arthritis, it suggests the diagnosis.

Macrophage activation syndrome is a well-recognised complication of systemic arthritis. It is characterised by

fever, splenomegaly, abnormal clotting profile (mimicking disseminated intravascular coagulation), cytopenias and
extreme hyperferritinaemia. Urgently refer children or adolescents with this complication to a centre of expertise.

Urgently refer children with macrophage activation syndrome to a centre of expertise.

Children and adolescents with systemic arthritis are at very low risk of developing uveitis; however, regular slit-
lamp screening examinations are still required (see Screening for asymptomatic anterior uveitis for information on
screening interval and duration).

Management of systemic arthritis

Systemic arthritis requires specialist management.

Most children and adolescents with systemic arthritis are treated with nonsteroidal anti-inflammatory drugs
(NSAIDs) for symptom relief (see Table 12.12 for paediatric dosages of oral NSAIDs).

Many children and adolescents will require corticosteroid therapy to control systemic features. To obtain initial
disease control, intravenous methylprednisolone may be used. The usual dosage is:

methylprednisolone sodium succinate 15 to 30 mg/kg up to 1000 mg intravenously, over 1

hour, daily for 3 consecutive days.

A once-monthly dose of methylprednisolone may be given until the disease is controlled.

For ongoing oral therapy, use:

prednis(ol)one 0.5 to 1 mg/kg up to 60 mg orally, daily.

Long-term corticosteroid therapy can cause significant adverse effects; the risk of adverse effects must be balanced
against the risk of disease complications with inadequate treatment. Once disease control is achieved, taper the
dose of oral corticosteroid. Consider tapering to alternate-day dosing to limit adverse effects. Children should be
monitored for the development of adverse effects associated with long-term corticosteroid use and, if appropriate,
measures should be implemented to minimise these adverse effects.

Cyclosporin may have a role in controlling active systemic features, especially in children or adolescents with
subtle features of macrophage activation syndrome. It is used in combination with corticosteroids. The usual
dosage is:

cyclosporin 1.5 to 2.5 mg/kg orally, twice daily.

Children or adolescents who continue to have active polyarthritis despite treatment with a corticosteroid, or in
whom arthritis recurs as the corticosteroid dose is tapered, should be treated with methotrexate in combination
with folic acid. The dosages used are the same as for polyarthritis (see Management of rheumatoid factor negative
polyarthritis).

For patients dependent on corticosteroid therapy (with or without cyclosporin) for control of systemic features, or
those with ongoing active polyarthritis despite the use of methotrexate, biological disease-modifying antirheumatic
drugs (bDMARDs) may be considered. At the time of writing tocilizumab is the only bDMARD available on the
Pharmaceutical Benefits Scheme (PBS) for this indication [Note 6]. The usual dosage is:
 tocilizumab (child less than 30 kg: 12 mg/kg; child 30 kg or more: 8 mg/kg) intravenously,
every 2 weeks.

Alternative bDMARDs for systemic arthritis are anakinra and canakinumab.

In a significant number of patients with systemic arthritis, the systemic features eventually settle and the course of
their disease becomes that of a polyarthritis. In these patients, the disease-modifying antirheumatic drugs
(DMARDs) used for polyarthritis—particularly methotrexate, adalimumab and etanercept—may be used as
alternatives to tocilizumab (see Management of rheumatoid factor negative polyarthritis).

The specialist will determine the appropriate approach to monitoring, screening for infection, and vaccination
based on the adverse effect profile of the immunomodulatory drug(s) used and patient factors (eg disease activity,
comorbidities). See also Practical prescribing considerations for rheumatological diseases in children and
adolescents.

Note 6: See the PBS website for current information [URL].

Juvenile idiopathic arthritis: enthesitis-related arthritis

Introduction
Enthesitis-related arthritis is the only form of juvenile idiopathic arthritis (JIA) that predominantly occurs in males,
typically presenting in late childhood or adolescence. The classic sites for enthesitis (inflammation at the sites of
tendon and ligament attachment to bone) are the Achilles tendon and plantar fascial attachment into the calcaneus,
the poles of the patellae, and the greater trochanters. Hip involvement early in the disease course or isolated severe
disease of the midfoot is relatively common.

Similar to adults with ankylosing spondylitis, children and adolescents with enthesitis-related arthritis may
experience symptomatic acute anterior uveitis; this is distinct from the asymptomatic anterior uveitis of the young
child with oligoarthritis. See Clinical features of ankylosing spondylitis for information on acute anterior uveitis
and its management.

Patients with enthesitis-related arthritis may have extra-articular features. As for other spondyloarthritides,
enthesitis-related arthritis is associated with extra-articular diseases. Consideration should be given to whether
extra-articular symptoms in a patient with enthesitis-related arthritis are due to the disease itself or a comorbid
disease (eg bowel symptoms may warrant consideration of comorbid inflammatory bowel disease) (see
Spondyloarthritides, including psoriatic arthritis for more information).

As in ankylosing spondylitis, human leucocyte antigen B27 (HLA-B27) positivity is typical in children with
enthesitis-related arthritis. Ankylosing spondylitis will develop in a subset of children with enthesitis-related
arthritis.

Management of enthesitis-related arthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) may improve symptoms of peripheral arthritis and enthesitis (see
Table 12.12 for paediatric dosages of oral NSAIDs). In enthesitis-related arthritis, indomethacin is often the
NSAID of choice.

Intra-articular corticosteroid injections can be useful for peripheral arthritis if a small number of accessible joints
are involved; however, the effect may be of shorter duration than in younger children with other forms of JIA.

Early use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) by specialists may be
appropriate, particularly for patients with poor response to NSAIDs and/or intra-articular corticosteroid therapy.
Sulfasalazine is often used initially. Methotrexate may be effective for peripheral arthritis; it should be given in
combination with folic acid. The dosages used are the same as for polyarthritis (see Conventional synthetic
disease-modifying antirheumatic drugs).

The biological disease-modifying antirheumatic drugs (bDMARDs) adalimumab and etanercept are effective for
both joint and entheseal disease; they are used by specialists. The dosages used are the same as for polyarthritis
(see Biological disease-modifying antirheumatic drugs). Infliximab is also effective for treatment of enthesitis-
related arthritis, but at the time of writing it is not available on the Pharmaceutical Benefits Scheme (PBS) for this
indication [Note 7].

Physical therapy is important to maintain flexibility and pelvic girdle strength, and orthoses are used to assist any
subtalar involvement or to cushion painful entheses.

Note 7: See the PBS website for current information [URL].

Juvenile idiopathic arthritis: psoriatic arthritis
Introduction
Psoriatic juvenile idiopathic arthritis (JIA) can present at any age, with either an oligoarticular or polyarticular
distribution. The presence of a psoriatic rash and nail pitting gives a definite diagnosis; dactylitis (inflammation of
a whole finger or toe) is a suggestive feature. A family history in a first-degree relative should be sought, although
family history is not sufficient for diagnosis in the absence of the clinical features.

Regular slit-lamp screening examinations for asymptomatic anterior uveitis should follow the same frequency as
for oligoarthritis (see Screening for asymptomatic anterior uveitis for information on screening interval and
duration).

Management of psoriatic arthritis

Management of psoriatic arthritis depends on the number of actively involved joints. For patients with
oligoarthritis, see Management of oligoarthritis for suggested management. For patients with polyarthritis, see
Management of rheumatoid factor negative polyarthritis for suggested management.

For dactylitis, a corticosteroid injection along the tendon sheath followed by regular physical and occupational
therapy can be helpful, particularly if fingers are involved.

Important mimics of juvenile idiopathic arthritis in the lower limbs

The following conditions are specific to children and may mimic juvenile idiopathic arthritis in the lower limbs. It
is important to recognise and appropriately manage these conditions.

Perthes disease

Perthes disease occurs in children aged 3 to 12 years and is more common in boys. Patients present with hip or
groin pain and limp, but referred pain to the knee may also occur or may be the only symptom. Hip abduction and
internal rotation are limited.

If Perthes disease is suspected, perform a hip X-ray and, if the diagnosis is confirmed, refer the patient to an
orthopaedic surgeon. Pending specialist review, physical activity should be restricted and weightbearing reduced
by the use of crutches if possible.

Slipped capital femoral epiphysis

Slipped capital femoral epiphysis most commonly affects adolescent boys. Patients present with limp and hip or
groin pain that may radiate to the knee. The leg is externally rotated and abducted, with limited internal rotation.

Urgently refer patients with radiographically confirmed slipped capital femoral epiphysis to an orthopaedic surgeon.

If slipped capital femoral epiphysis is suspected, perform a hip X-ray and, if a slip is identified, urgently refer the
patient to an orthopaedic surgeon. Pending specialist review, physical activity should be restricted and
weightbearing reduced by the use of crutches if possible.

Irritable hip
Irritable hip, or transient synovitis of the hip, is a self-limiting, unilateral condition that occurs in children aged 3
to 8 years. Patients present with hip or groin pain and limp, and hip abduction and internal rotation are limited.
Occasionally, patients may refuse to weightbear. Patients are afebrile and appear well; they may have a history of
recent upper respiratory tract infection.

Patients with irritable hip have normal X-ray, full blood count and erythrocyte sedimentation rate (ESR). However,
a hip X-ray may be useful to exclude bony pathology, and ultrasound may be useful to confirm hip effusion.

Symptoms of irritable hip and septic arthritis overlap; if there is any doubt about the diagnosis, seek orthopaedic
review.

Irritable hip is treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (see Table 12.12 for paediatric dosages
of oral NSAIDs). Symptoms usually improve significantly over 24 to 48 hours and generally resolve within a
week.
Key references
Beukelman T, Patkar NM, Saag KG, Tolleson-Rinehart S, Cron RQ, DeWitt EM, et al. 2011 American College of
Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of
therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken) 2011;63(4):465–
82.

Braun J, Kastner P, Flaxenberg P, Wahrisch J, Hanke P, Demary W, et al. Comparison of the clinical efficacy and
safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of
a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008;58(1):73–81.

Brunner HI, Ruperto N, Zuber Z, Keane C, Harari O, Kenwright A, et al. Efficacy and safety of tocilizumab in patients
with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.
Ann Rheum Dis 2015;74(6):1110–7.

Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA 2005;294(13):1671–84.

Hazlewood GS, Thorne JC, Pope JE, Lin D, Tin D, Boire G, et al. The comparative effectiveness of oral versus
subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis 2016;75(6):1003–8.

Munro J, Murray K, Boros C, Chaitow J, Allen RC, Akikusa J, et al. Australian Paediatric Rheumatology Group
standards of care for the management of juvenile idiopathic arthritis. J Paediatr Child Health 2014;50(9):663–6.

Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369(9563):767–78.

Ringold S, Weiss PF, Beukelman T, DeWitt EM, Ilowite NT, Kimura Y, et al. 2013 update of the 2011 American College
of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical
therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving
biologic medications. Arthritis Rheum 2013;65(10):2499–512.

Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G, et al. Two randomized trials of canakinumab
in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367(25):2396–406.

Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous
methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses >/= 15 mg
may be overcome with subcutaneous administration. Ann Rheum Dis 2014;73(8):1549–51.

Yokota S, Tanaka T, Kishimoto T. Efficacy, safety and tolerability of tocilizumab in patients with systemic juvenile
idiopathic arthritis. Ther Adv Musculoskelet Dis 2012;4(6):387–97.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Inflammatory connective tissue diseases
Introduction to inflammatory connective tissue diseases
The connective tissue diseases are a group of chronic diseases characterised by systemic inflammation (probably of
autoimmune pathogenesis) and perpetuated by unknown factors (probably both genetic and environmental). The
connective tissue diseases include:

systemic lupus erythematosus (SLE)

Sjögren syndrome
systemic sclerosis
mixed connective tissue disease
immune-mediated myopathies, including juvenile dermatomyositis and dermatomyositis in adults.

The diagnosis of a connective tissue disease is predominantly based on clinical assessment. The connective tissue
diseases share many clinical features, in particular arthralgia, myalgia, fatigue, Raynaud phenomenon and sicca
symptoms. This makes the diagnosis of a specific connective tissue disease difficult, particularly early in the
course of the disease before specific clinical features develop. Some patients have an illness that remains mild and
poorly defined for many years, or never progresses to a specific connective tissue disease (see Management of the
patient with a positive ANA and mild, nonspecific symptoms for more information).

While identifying the presence of antinuclear antibodies (ANA) is useful to support a diagnosis of a connective
tissue disease in patients with a suggestive clinical presentation, interpretation of the ANA result is complex (see
Antinuclear antibody testing for inflammatory connective tissue diseases for more information).

Antinuclear antibody testing for inflammatory connective tissue

diseases
General information
Antinuclear antibodies (ANA) is a generic term for autoantibodies to nuclear and other cellular elements (known
as autoantigens). Little is known about how autoantigens, or their interaction with ANA, are linked to human
disease; however, the presence of ANA is an important feature of connective tissue diseases.

When to test for antinuclear antibodies

ANA testing should only be undertaken in patients with signs or symptoms suggestive of a connective tissue
disease. While identifying the presence of ANA is useful to support a diagnosis of a connective tissue disease in
patients with a suggestive clinical presentation, ANA may also be present in patients with other autoimmune
diseases (eg thyroid disease) and in healthy individuals—ie ANA testing has a high sensitivity, but a low
specificity, for connective tissue diseases. Therefore, the diagnostic value of a positive ANA result depends on the
pretest probability of a connective tissue disease.

Do not undertake ANA testing in patients without signs or symptoms suggestive of a connective tissue disease.

The presenting symptoms of a connective tissue disease may be commonplace and nonspecific (eg fatigue, pain,
paraesthesia, dry eyes). A thorough patient history is essential to distinguish between symptoms likely due to a
connective tissue disease and those likely due to a busy lifestyle, somatisation or other causes (see also The achey,
tired patient). However, it may still be difficult to determine the need for ANA testing.

Patients whose only symptom is fatigue do not need ANA testing.

The following scenarios are examples of the diagnostic utility of ANA testing based on patient history:

ANA testing is often useful in a young woman who presents with intermittent small joint arthralgia, definite
alopecia, Raynaud phenomenon or serositis (eg pleurisy), or a combination of these features. In this
instance, a positive ANA result is likely to be clinically significant (ie unlikely to be a false positive result)
and a negative ANA result is likely to rule out the diagnosis of a connective tissue disease.
 ANA testing is not useful in a patient with a long history of fatigue, generalised constant pain, and
nonspecific abdominal or neurological symptoms (eg tension headaches, dizziness, paraesthesia). In this
instance, neither a positive nor a negative ANA result changes the likelihood that the patient has a
connective tissue disease sufficiently for ANA testing to be helpful.

The ANA result is unlikely to change over time, so there is no benefit in repeating the test if the patient's clinical
presentation has not changed.

The need for further testing for specific autoantibodies should be guided by the result of the ANA test (ie testing
should occur in a two-step process). See Significance of antinuclear antibody tests for further discussion.

Significance of antinuclear antibody tests

The screening immunoassay for ANA involves the microscopic demonstration of antibody binding to cellular
elements in laboratory cell lines. Results are reported in two components: the quantity of ANA in the serum
(expressed as a titre) and the pattern of antibody binding (staining pattern).

The higher the ANA titre, the higher the likelihood of a connective tissue or other autoimmune disease (eg thyroid
disease). Low ANA titres (up to 1:160) are common in healthy individuals and the frequency increases with age. In
the absence of definite clinical features of a connective tissue disease, a low ANA titre is unlikely to be clinically
significant. The significance of intermediate ANA titres depends on the clinical context, and an intermediate titre
does not necessarily indicate the presence of disease. While the presence of ANA is expressed as a positive result,
low ANA titres may be expressed as a negative result. The cut-off value for a negative result depends on the
laboratory.

Most ANA staining patterns (eg homogeneous or speckled) are subjective and nonspecific for a connective tissue
disease; however, the centromere and nucleolar patterns are linked to systemic sclerosis. The recently described
anti-DFS70 antibodies have a dense fine speckled (DFS) ANA staining pattern and are significantly more common
in healthy individuals than in people with a connective tissue disease. Even when anti-DFS70 antibodies are
present in high titre, provided it is the only antibody, the likelihood of a connective tissue disease is very low in
patients with mild, nonspecific symptoms and long-term follow-up is not required in these individuals. The DFS
pattern can be mistaken for a homogeneous pattern, so it should be specifically looked for if suspected (eg in a
patient with a positive ANA, but mild, nonspecific symptoms).

If there is a high clinical suspicion of a connective tissue disease and the patient has a positive ANA, it is
appropriate to test for specific autoantibodies to aid the diagnosis of a particular connective tissue disease. Table
12.14 lists common tests and the prevalence of specific autoantibodies in connective tissue diseases. Most specific
autoantibody tests have intermediate sensitivity and specificity, and are of limited diagnostic utility if considered in
isolation. Therefore, the tests undertaken should be guided by the patient's clinical presentation. Also consider
assessment for organ involvement and specialist referral in these patients.

For management of patients with a positive ANA and mild, nonspecific symptoms, see Management of the patient
with a positive ANA and mild, nonspecific symptoms.

In patients with a negative ANA or low ANA titre, do not undertake further investigation for connective tissue
diseases (eg testing for antibodies to double-stranded DNA [dsDNA] or extractable nuclear antigens [ENAs])
unless clinical suspicion of systemic lupus erythematosus (SLE) or other connective tissue disease remains high.
The coincidental association of fatigue and lethargy with a low ANA titre is probably the commonest reason for
the misdiagnosis of SLE.

Do not test for antibodies to dsDNA or ENA in patients with a negative ANA or low ANA titre unless clinical suspicion of SLE
or other connective tissue disease remains high.

Common tests and prevalence of specific autoantibodies in connective tissue diseases (Table
12.14) [NB1] [NB2]

Prevalence of autoantibody
Test for autoantibody to
antigen Patients with other
Normal population Patients with SLE
connective tissue diseases
dsDNA 2 to 5% 60% rare
common in
phospholipid [NB3] 5% 5 to 10% antiphospholipid syndrome
[NB4]
ENAs
common in Sjögren
Ro (SS-A) 1 to 2% 40%
syndrome
 La (SS-B) less than 1% 15% common in Sjögren
syndrome
Smith (Sm) less than 1% 10 to 50% rare
U1RNP common in mixed
less than 1% uncommon
connective tissue disease
common in diffuse
Scl-70 (topoisomerase I) less than 1% rare
systemic sclerosis
25% in diffuse systemic
RNA polymerase III less than 1% rare sclerosis (particularly in
scleroderma renal crisis)
common in antisynthetase
Jo1 less than 1% rare
syndrome [NB5]
common in limited
centromere less than 1% rare
systemic sclerosis
ANA = antinuclear antibodies; dsDNA = double-stranded DNA; ENAs = extractable nuclear antigens; SLE = systemic lupus erythematosus
NB1: Do not test for antibodies to dsDNA or ENA in patients with a negative ANA or low ANA titre unless clinical suspicion of SLE or other connective
tissue disease remains high.
NB2: The tests undertaken should be determined by the patient's clinical presentation.
NB3: Antiphospholipid antibodies include lupus anticoagulant, anticardiolipin, and anti-beta-2-glycoprotein 1.
NB4: Antiphospholipid syndrome can occur secondary to connective tissue diseases, or as a primary syndrome.
NB5: Antisynthetase syndrome is an inflammatory myopathy associated with fever, interstitial lung disease, polyarthritis, ‘mechanic's hands’ and
Raynaud phenomenon.

Management of the patient with a positive ANA and mild, nonspecific

symptoms
Some patients have a positive antinuclear antibody (ANA) in intermediate or higher titre (eg titre of 1:640 or
more), but present with mild, nonspecific symptoms (eg arthralgia). Only 10% of these patients will go on to
develop a definable connective tissue disease and this will usually occur within 24 months. The remaining 90% of
patients will continue to have mild, nonspecific symptoms that do not fit a particular diagnosis. In all patients,
avoid inappropriate use of diagnostic labels to limit patient anxiety and inaccurate prognosis.

For patients with mild, nonspecific symptoms, treatment is directed at clinical features (see Management of
common clinical features of inflammatory connective tissue diseases).

Clinically reassess all patients after 12 months. Only repeat ANA testing and specific autoantibody tests (see Table
12.14) if the patient develops new symptoms or signs that are more suggestive of a connective tissue disease. Refer
patients with a suspected connective tissue disease to a specialist. If there has been no change in the patient's
clinical presentation after 12 months, determine the need for ongoing monitoring based on individual patient
factors.

Management of common clinical features of inflammatory connective

tissue diseases
Arthralgia, myalgia and arthritis

Arthralgia and myalgia are more common than arthritis in connective tissue diseases, and erosive joint damage is
rare.

For arthralgia and myalgia, use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

If response to paracetamol is inadequate or for arthritis symptoms, a nonsteroidal anti-inflammatory drug (NSAID)
may be used instead of, or in combination with, paracetamol. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

While there is evidence suggesting that fish oil has a mild anti-inflammatory effect in patients with systemic lupus
erythematosus (SLE), fish oil is a reasonable treatment option for arthritis in any connective tissue disease because
of its low risk of harms. Use:

fish oil at least 2.7 g (omega-3) orally, daily (see Table 12.8 for preparations).

Fish oil may take up to 3 months for maximal effectiveness, so it may be necessary to co-prescribe fish oil with an
NSAID and/or paracetamol initially. See Principles of fish oil use for musculoskeletal conditions in adults for more
information.

If the above drugs are insufficient to control symptoms, refer the patient to a specialist as conventional synthetic
disease-modifying antirheumatic drugs (csDMARDs) may be necessary. csDMARDs can take weeks to months to
become effective. Drugs used include hydroxychloroquine or, for severe arthritis, methotrexate. Dosages are
adjusted depending on clinical response and adverse effects. For considerations in the management of csDMARD
therapy (including monitoring, screening for infection, and vaccination), see Principles of immunomodulatory
drug use for rheumatological diseases in adults.

The usual dosage of hydroxychloroquine is:

hydroxychloroquine 200 to 400 mg orally, daily.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

For patients with severe arthritis, concurrent prednis(ol)one may be necessary to control symptoms until
csDMARDs become effective. The usual dosage is:

prednis(ol)one 5 to 15 mg orally, daily.

Avoid doses of prednis(ol)one greater than 15 mg daily in patients with systemic sclerosis because there is a risk of
precipitating scleroderma renal crisis. See Principles of immunomodulatory drug use for rheumatological diseases
in adults for information on adverse effects associated with long-term corticosteroid therapy (such as bone density
loss) and advice on how to minimise and monitor for such complications. Taper and stop corticosteroids as soon as
symptoms are controlled.

Fatigue

Fatigue is a common problem in patients with a connective tissue disease and is difficult to manage. Consider and
manage other causes of fatigue that may be present in a patient with a connective tissue disease, such as infection,
psychosocial factors or iron deficiency (see Conditions commonly associated with fatigue for more information on
the assessment of patients with fatigue). Patients who have anaemia of chronic disease associated with an elevated
serum ferritin concentration should not be treated with iron supplementation. Iron supplementation is only
indicated in cases of demonstrated iron deficiency (see Iron deficiency for more information).

Fatigue associated with a connective tissue disease can be helped by regular aerobic exercise. Hydroxychloroquine
may be used by specialists. The usual dosage of hydroxychloroquine is:

hydroxychloroquine 200 to 400 mg orally, daily.

For considerations in the management of hydroxychloroquine therapy (including monitoring, screening for
infection, and vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in adults.

Raynaud phenomenon and digital ischaemia

For treatment of Raynaud phenomenon and digital ischaemia, see Raynaud phenomenon and digital ischaemia.

Sicca symptoms
Sicca symptoms (eg dry eyes and/or dry mouth) are due to dry mucosal membranes. Sicca symptoms can be a
feature of any connective tissue disease, but are usually most severe in Sjögren syndrome and systemic sclerosis.
Severe mucosal membrane dryness can cause ulceration and scarring; specialist referral is recommended. Sicca
symptoms can also occur in people without a connective tissue disease, particularly older people; in this case,
symptoms are not usually progressive and are not associated with antinuclear antibody (ANA) positivity.

Advise patients with sicca symptoms to:

wear sunglasses outdoors to avoid wind-drying effects on the eyes

avoid dry and heated air, cigarette smoke, and drugs with anticholinergic effects (eg tricyclic
antidepressants, antiparkinsonian drugs)
ensure adequate oral hydration and good dental hygiene, including regular dental review, to prevent dental
caries (see Management of dental caries)
be aware of the need for extra care to avoid damage to the eyes and mouth if undergoing surgery.

For dry eyes, ocular lubricants (artificial tears) should be used frequently. Multiple preparations are available,
including drops, gels and ointments. Eye drops need to be applied several times a day. Gels and ointments are
retained in the eye for longer and require less frequent administration than drops; however, they are associated
with some blurring of vision and can leave a crust on the eyelashes. Gels and ointments may be most useful at
night because of better tolerance and longer duration of effect. A trial of several different preparations may be
required to determine the most effective and best tolerated preparation for an individual patient. Patients may
become sensitised to the preservatives in multi-use eye drops or gels, especially if they are using them more than
three or four times daily. Switch these patients to preservative-free single-use vials.

In severe cases of dry eyes, cyclosporin eye drops can improve tear flow. Cyclosporin eye drop preparations are
not widely available and must be prescribed by an ophthalmologist. Surgical insertion of punctal plugs into the
lacrimal duct is sometimes tried for symptomatic relief.

Dry mouth is difficult to treat and available preparations are often poorly tolerated. Available preparations include
sprays, mouthwashes and gels, as well as artificial saliva. A trial of several different preparations may be required
to determine the most effective and best tolerated preparation for an individual patient. For more information, see
Dry mouth.

For dry vagina, lubricant jellies are recommended. If the woman is postmenopausal, consider the use of
intravaginal oestrogen (see Intravaginal oestrogen therapy for treatment recommendations).

Systemic lupus erythematosus

Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that has the potential to affect almost any
organ in the body and cause generalised and systemic symptoms. The prevalence of SLE in Australia ranges from
19 to 93 per 100 000 people, with prevalence at the higher end of the range reported in Indigenous Australians.
Females are more commonly affected by SLE than males. SLE may develop at any age, but peak incidence is
during childbearing years (15 to 45 years of age) in women.

The clinical course of SLE is often one of remission and relapse (flare). The prognosis of SLE depends on the
nature and severity of organ involvement. Patients who present with and continue to have mild symptoms in early
disease are generally unlikely to progress to more severe disease. Patients with a younger age of onset and certain
ethnic groups (eg Asians, Indigenous Australians) have an increased risk of more severe disease. Modern
treatments have improved the 5-year survival of SLE to around 95%; however, the mortality rate is still higher in
patients with SLE compared to the general population, with atherosclerotic cardiovascular disease the major cause
of mortality in patients with SLE. Early diagnosis and regular follow-up remain essential to improving outcomes
in patients with SLE.

See also Chronic cutaneous (discoid) lupus erythematosus and Subacute cutaneous lupus erythematosus.

Diagnosis of systemic lupus erythematosus

The American College of Rheumatology developed classification criteria for SLE to identify homogeneous groups
of patients for research purposes; however, these criteria have been adopted internationally to aid the diagnosis of
SLE (see Table 12.15). Four of the eleven criteria are required for classifying a patient as having SLE. These
criteria do not replace clinical judgement in the diagnosis of SLE. For discussion on the role of antinuclear
antibody (ANA) testing in the diagnosis of connective tissue diseases, see Antinuclear antibody testing for
inflammatory connective tissue diseases.

The common presenting symptoms of SLE are musculoskeletal symptoms, fatigue and rash. Patients can also
present with manifestations due to involvement of an organ that is uncommonly affected by SLE, which may delay
the diagnosis. In SLE, organs are often affected sequentially rather than concurrently. SLE can coexist with other
organ-specific autoimmune disease, such as thyroid or liver disease, which can predate the development of
generalised or systemic symptoms.

American College of Rheumatology classification criteria for systemic lupus erythematosus

(Table 12.15)

Criterion Definition
malar rash malar erythema, flat or raised
discoid rash erythematous raised patches with keratotic scaling and follicular plugging
photosensitivity rash as an unusual reaction to sunlight
oral ulcers oral or nasopharyngeal ulcers, usually painless
nonerosive arthritis involving two or more peripheral joints with
arthritis
tenderness, swelling or effusion
serositis pleurisy or pericarditis
renal features proteinuria or cellular casts
neurological and neuropsychiatric
seizures or psychosis
features
haematological features haemolytic anaemia, leucopenia, lymphopenia or thrombocytopenia
presence of anti–double-stranded DNA (dsDNA) antibody, anti–Smith
immunological features
(Sm) antibody, or antiphospholipid antibodies
antinuclear antibody positivity in the absence of drugs known to cause
antinuclear antibody positive
drug-induced lupus
Adapted with permission from the 1997 Update of the 1982 American College of Rheumatology Revised Criteria for Classification of Systemic Lupus
Erythematosus. © [1997] American College of Rheumatology. Available at www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-
Endorsed-Criteria.

General management approach for systemic lupus erythematosus

The management of SLE is best undertaken by a multidisciplinary approach with specialist involvement.
Pharmacological treatment of SLE is determined by the organ involved and the severity of inflammation (see
Management of clinical features of systemic lupus erythematosus).

Urgently refer patients with severe organ- and/or life-threatening disease to a specialist centre for management.
Immunomodulatory drugs are usually required (see Table 12.16 for drugs used and usual dosages). Treatment
choice and dosing are complex and individualised for each patient; combination therapy may be required and
various combinations are used in practice.

Urgently refer patients with severe organ- and/or life-threatening disease to a specialist centre for management.

Hydroxychloroquine has been shown to reduce the risk of flare and is recommended for most patients with SLE.
Hydroxychloroquine can also improve lipid levels, which is beneficial because SLE is a risk factor for premature
atherosclerotic cardiovascular disease. Systemic corticosteroids are commonly used for severe organ- and/or life-
threatening disease in SLE, but they are usually not required for mild disease. The role of biological disease-
modifying antirheumatic drugs (bDMARDs) in SLE is unclear. Studies of rituximab in heterogeneous SLE patient
populations that assessed diverse clinical outcomes did not show a benefit, but rituximab may have a role in certain
patient subgroups (eg refractory lupus nephritis). Belimumab has been shown to be beneficial as an add-on therapy
in SLE. With the exception of systemic corticosteroids, the immunomodulatory drugs can take several months to
become effective.

When immunomodulatory drugs are used in high doses, their adverse effects may complicate assessment of
disease activity (eg hypomania can occur with high-dose corticosteroid therapy, abnormal liver biochemistry can
occur with methotrexate). For more information on drug adverse effects, see Principles of immunomodulatory
drug use for rheumatological diseases in adults.

Another common dilemma is distinguishing between disease flare and infection due to immunosuppression;
inflammatory markers are elevated in both situations. C-reactive protein (CRP) may be more elevated than
erythrocyte sedimentation rate (ESR) in the presence of infection. There is also individual patient variation in the
pattern of elevation of these markers, so knowing each patient's pattern is helpful. Disease flare may be
accompanied by a rise in antibodies to double-stranded DNA (dsDNA) and a reduction in C3 and C4 complement
components; these may be helpful biomarkers for imminent flare in patients with this pattern. However, changes in
treatment based solely on rising disease markers is not recommended.

For reproductive health considerations in women with SLE, see Reproductive health in women with systemic
lupus erythematosus.

For discussion of SLE in children, see Systemic lupus erythematosus in children.

Immunomodulatory drugs used by specialists for severe organ- and/or life-threatening disease
in systemic lupus erythematosus (Table 12.16) [NB1]

Drug Usual dosage [NB2]

Corticosteroids
methylprednisolone sodium succinate various intravenous dosing protocols used
prednis(ol)one 25 to 60 mg orally, daily
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)
azathioprine 1.5 to 2.5 mg/kg orally, daily
50 to 100 mg orally, daily (up to 2 mg/kg orally, daily)
cyclophosphamide
various intravenous dosing protocols used
cyclosporin 1.5 to 3 mg/kg orally, daily in two divided doses
hydroxychloroquine 200 to 400 mg orally, daily
10 mg orally, on one specified day once weekly, increasing up to 25 mg
methotrexate
orally or subcutaneously, on one specified day once weekly [NB3]
mycophenolate mofetil 500 to 3000 mg orally, daily in two divided doses
mycophenolate sodium 180 to 720 mg (mycophenolic acid) orally, twice daily
Biological disease-modifying antirheumatic drugs (bDMARDs)
10 mg/kg intravenously, as a single dose at 0, 2 and 4 weeks, and
belimumab
thereafter every 4 weeks
rituximab two doses of 1 g intravenously, given 2 weeks apart
Other
intravenous immunoglobulin (IVIg) various intravenous dosing protocols used
NB1: For considerations in the management of immunomodulatory therapy (including monitoring, screening for infection, and vaccination), see
Principles of immunomodulatory drug use for rheumatological diseases in adults.
NB2: These are usual dosages; the dosage should be individualised for each patient depending on disease severity and organ damage, clinical response
and adverse effects to treatment, and patient factors (eg renal function).
NB3: Methotrexate should be taken in combination with folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

Management of clinical features of systemic lupus erythematosus

Arthralgia, myalgia and arthritis

For management of arthralgia, myalgia and arthritis, see Arthralgia, myalgia and arthritis.

Raynaud phenomenon and digital ischaemia

For treatment of Raynaud phenomenon and digital ischaemia, see Raynaud phenomenon and digital ischaemia.

Mucosal and cutaneous features

Oral ulcers usually require only topical treatment. Local anaesthetic preparations provide symptomatic relief.
Topical corticosteroids can promote healing if the ulceration is prolonged or severe. For more information, see
Recurrent aphthous ulcerative disease.

For information on specific cutaneous manifestations of SLE, see Cutaneous manifestations of connective tissue
disorders.

Systemic features

For management of fatigue, see Fatigue.

Fever due to active SLE is rare and is associated with changes in inflammatory markers (erythrocyte sedimentation
rate [ESR] and/or C-reactive protein [CRP] elevation, and complement reduction). Coexistent infection must
always be actively excluded.

Weight loss can also occur if SLE remains untreated.

If SLE is associated with significant systemic symptoms, organ involvement is likely. Specific organ involvement
may be identified when appropriate investigations are performed (eg urinalysis on midstream sample, full blood
count, liver biochemistry).

Serosal features

Serositis is common in SLE, both as pleurisy and pericarditis. Rarely, peritoneal inflammation can present as acute
abdominal pain, making the differential diagnosis difficult.

Acute severe serositis requires specialist management; patients with pericardial or pleural effusion respond rapidly
to intravenous methylprednisolone.

In mild serositis, nonsteroidal anti-inflammatory drugs (NSAIDs) may be sufficient to control pain. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

More persistent or recurrent serosal inflammation may require specialist management with prednis(ol)one in
combination with one or more of hydroxychloroquine, methotrexate or azathioprine. Hydroxychloroquine may
also be used to reduce the frequency of flares of serositis.

Haematological features

Immune-mediated cytopenia is well described in SLE and can involve red blood cells, white blood cells and/or
platelets. Minor reductions in blood cell counts do not necessarily require treatment. If cytopenia is progressive, or
the numbers are reduced sufficiently to be of clinical concern, refer patients to a specialist for treatment.

For modest reductions in blood cell counts, options for immunomodulatory therapy include prednis(ol)one,
azathioprine, cyclophosphamide and mycophenolate. Combination therapy may be required. Profound or
progressive cytopenia may require high-dose corticosteroid therapy (intravenous methylprednisolone or high-dose
oral prednis(ol)one), or the removal of the destructive antibody with intravenous immunoglobulin (IVIg),
rituximab or plasma exchange.

Vascular features

Vasculitis of arterioles and/or venules can involve virtually any target organ in SLE and requires specialist
management. When severe it can result in thrombosis within the affected vessel. As the pathogenesis of vasculitis
is inflammatory, treatment is with prednis(ol)one, azathioprine and/or other immunomodulatory drugs.

See also Antiphospholipid syndrome and Neurological and neuropsychiatric features.

SLE is a risk factor for premature atherosclerotic cardiovascular disease, and atherosclerotic cardiovascular disease
is the major cause of mortality in patients with SLE. Other risk factors for cardiovascular disease should therefore
be closely monitored and actively managed in patients with SLE (see Cardiovascular disease risk stratification).

Antiphospholipid syndrome

Some women with SLE and antiphospholipid antibodies (see Table 12.14) will develop features of
antiphospholipid syndrome (APS) (ie arterial thrombosis, venous thrombosis, miscarriage and/or
thrombocytopenia). However, the risks are so low that treatment is not advised in the absence of symptoms.
Routine screening of women with SLE for antiphospholipid antibodies may provoke unnecessary anxiety and is
not recommended. APS can also occur in men with SLE and in patients without SLE (primary APS).

Suspect APS in any patient who presents with apparently unprovoked or resistant venous thrombosis, in patients
less than 50 years of age presenting with stroke, and in women presenting with recurrent first trimester
miscarriages or an unexplained second or third trimester fetal loss.

APS should be managed in consultation with a specialist centre. APS is treated with one or more of low-dose
aspirin, heparin or warfarin. Warfarin should not be used in pregnancy.

Renal features

The histological classification of glomerular involvement in SLE is complex, and both vascular and interstitial
lesions can occur. Mild forms of glomerular disease, indicated by low levels of haematuria (less than 200 000
glomerular red blood cells/mm3), have a good prognosis and generally do not require treatment. Heavier
haematuria and/or significant proteinuria require urgent assessment of renal function and referral to a specialist
centre for consideration of renal biopsy. Treatment choice depends on histological classification and disease
severity, but treatment usually includes high-dose prednis(ol)one plus either mycophenolate or cyclophosphamide.
Other immunomodulatory drugs that may be used include azathioprine, rituximab and cyclosporin.

Aggressive control of associated hypertension and lipid levels improves renal outcomes; for more information, see
Elevated blood pressure and Dyslipidaemia.

Hepatic features

Abnormal liver biochemistry is common in patients with SLE. Exclude organ-specific autoimmune liver disease
associated with specific antibodies (eg smooth muscle antibody) and primary biliary cirrhosis with
antimitochondrial antibody (see Autoimmune hepatitis and Primary biliary cirrhosis). Refer patients with
progressive or persistent abnormal liver biochemistry to a specialist centre for consideration of liver biopsy.

Neurological and neuropsychiatric features

Headache and migraine are the most common neurological symptoms of SLE. Any suspicion of more serious
neurological or neuropsychiatric features of SLE should prompt specialist referral.

Small-vessel cerebral vasculopathy is a common manifestation of central nervous system disease in SLE, and
presents as slow cognitive decline. Depression or thought disorders may be associated with cognitive decline and,
in addition to treatment for SLE, specific treatment for the psychiatric disease is indicated. Small- or large-vessel
cerebral vasculopathy with arterial or venous thrombosis can be associated with antiphospholipid syndrome, and is
treated with anticoagulation.

Seizures can be associated with any cause of cerebral ischaemia.

Cerebral vasculitis is rare and is usually associated with other systemic inflammatory manifestations. It carries a
grave prognosis, even with aggressive treatment.

Transverse myelitis occurs rarely.

Reproductive health in women with systemic lupus erythematosus

The use of oestrogen-containing oral contraceptive pills can induce a flare of SLE in some women. Patients with
SLE who are taking an oestrogen-containing oral contraceptive pill should be monitored clinically. After 3 months
of use of an oestrogen-containing oral contraceptive pill, erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP) and double-stranded DNA (dsDNA) should be measured. If a significant flare occurs, consider alternative
contraceptive options.

Pregnancy can induce a flare of SLE in some women. The strongest predictor of flare is disease activity in the 6
months preceding conception. Therefore, the risk of flare is minimised by ensuring disease inactivity (as assessed
by ESR, CRP and dsDNA) before conception. Antiphospholipid syndrome can cause miscarriage in pregnant
women; see Antiphospholipid syndrome. The treatment of SLE in pregnant women is guided by specialist advice.
Despite hydroxychloroquine being listed as a Therapeutic Goods Administration (TGA) category D drug [Note 1],
it is generally recommended that hydroxychloroquine be continued throughout pregnancy. For more information
on immunomodulatory drug use and reproductive health, see Immunomodulatory drug use and reproductive health
in adults with rheumatological diseases.

Studies of postmenopausal hormone replacement therapy (HRT) indicate that it is not associated with a significant
increase in flares of SLE. However, if the patient still wishes to avoid systemic HRT and their menopausal
symptoms are predominantly genitourinary (eg vaginal atrophy), intravaginal oestrogen treatment may be used
(see Intravaginal oestrogen therapy for treatment recommendations).

Note 1: TGA pregnancy categories are explained in Australian categorisation of drugs in pregnancy.

Systemic lupus erythematosus in children

The criteria for diagnosis of SLE in children are the same as in adults (see Table 12.15); however, multisystem
involvement is more common in children. Renal or central nervous system involvement occurs in approximately
70% and 30% of cases respectively.

The management of SLE in children is best undertaken by, or in conjunction with, a paediatric rheumatologist.
Many children with SLE require treatment with systemic corticosteroids and other immunomodulatory drugs;
treatment choices are similar to those in adults with SLE (see Management of clinical features of systemic lupus
erythematosus). All children with SLE should be started on hydroxychloroquine, which has a role in reducing rates
of disease flare and improving lipid levels. For significant disease manifestations, such as kidney disease,
moderate- to high-dose corticosteroid therapy is usually necessary. Corticosteroids can have an impact on growth
and, importantly, the normal dramatic accrual in bone density that occurs during the preteen and early teen years,
which is when paediatric SLE tends to present. Corticosteroid-induced changes in body habitus (eg Cushingoid
features, hair loss, striae) can also have a profound psychological impact on adolescents. Adherence to therapy can
therefore be difficult (see also Practical prescribing considerations for rheumatological diseases in children and
adolescents).

The peripubertal ovary is more resistant to cyclophosphamide-induced failure than the adult ovary, but testicular
function can be affected in males. Alternative immunomodulatory drugs to cyclophosphamide include
azathioprine, mycophenolate and rituximab; these drugs have an increasing role as first-line treatment for
significant disease manifestations.

Sjögren syndrome
Introduction
Sjögren syndrome is a chronic autoimmune disease associated with lymphoid infiltration of the exocrine glands,
particularly the salivary and lacrimal glands, leading to secretory gland dysfunction and, usually severe, sicca
symptoms. In severe cases, the dryness can cause salivary gland enlargement and calculus formation, and can
affect the trachea causing dry cough and/or hoarse voice. Rarely, loss of gastrointestinal exocrine function can
cause pancreatic dysfunction or pancreatitis, and atrophic gastritis.

Sjögren syndrome may be primary, or secondary when it occurs in association with rheumatoid arthritis or another
connective tissue disease such as systemic lupus erythematosus (SLE) or systemic sclerosis. Primary Sjögren
syndrome predominantly affects females, and the usual age of onset is between 40 and 50 years.

In addition to glandular features, patients with primary Sjögren syndrome often have fatigue, arthralgia and a
nonerosive arthritis, as well as Raynaud phenomenon. A wide spectrum of other extra-glandular features may
occur due to lymphoid infiltration of the kidney, lung, skin, muscle, stomach and liver, and should prompt
specialist referral.

Although Sjögren syndrome is considered a benign disorder, it can very rarely transform into a lymphoid
malignancy, primarily of B cell origin; persistent glandular swelling or abnormal weight loss should prompt further
investigation.

Diagnosis of Sjögren syndrome

A diagnosis of Sjögren syndrome is strongly suggested by significant and persistent sicca symptoms (eg severe dry
eyes necessitating the use of ocular lubricants several times a day), in association with polyclonal
hypergammaglobulinaemia, a positive antinuclear antibody (ANA), and the presence of antibodies to Ro (SS-A)
and La (SS-B). For discussion on the role of ANA testing in the diagnosis of connective tissue diseases, see
Antinuclear antibody testing for inflammatory connective tissue diseases. A raised erythrocyte sedimentation rate
(ESR), a positive rheumatoid factor (RF) and anaemia of chronic disease are common in Sjögren syndrome.

Ocular abnormality due to Sjögren syndrome is confirmed by a Schirmer tear test (to demonstrate reduced tear
production), and rose bengal staining and slit-lamp examination (to show keratitis).

The presence of lymphocytic infiltrate in the minor salivary glands on lip biopsy is diagnostic of Sjögren
syndrome. However, this investigation is usually only undertaken by specialists to confirm the diagnosis of
Sjögren syndrome in the absence of antibodies to Ro and/or La.

Management of Sjögren syndrome

There is no cure for Sjögren syndrome, and treatment largely consists of symptomatic relief and patient education.
For management of common clinical features such as sicca symptoms, arthralgia, arthritis, fatigue and Raynaud
phenomenon, see Management of common clinical features of inflammatory connective tissue diseases.

Systemic sclerosis
Introduction

Scleroderma is an uncommon condition in which excessive collagen deposition leads to fibrosis or thickening of
the skin. The localised form, morphoea, is limited to the skin (see Morphoea). The systemic form, systemic
sclerosis, is characterised by vascular abnormalities, inflammation and fibrosis of the skin, but also a range of other
organs. Raynaud phenomenon (generally the first symptom) and a positive antinuclear antibody (ANA) are usual.
For discussion on the role of ANA testing in the diagnosis of connective tissue diseases, see Antinuclear antibody
testing for inflammatory connective tissue diseases.

Systemic sclerosis is rare in childhood, but morphoea is more common.

Systemic sclerosis has two disease variants defined by the extent of skin involvement:

limited cutaneous disease (limited systemic sclerosis), which is often associated with calcinosis, Raynaud
phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia (previously defined by the acronym
CREST) and a positive anti-centromere antibody
diffuse cutaneous disease (diffuse systemic sclerosis), which is typically more rapidly progressive and
associated with more severe systemic involvement, such as interstitial lung disease and scleroderma renal
crisis. Antibodies to Scl-70 (topoisomerase I) or RNA polymerase III may be present.

The prognosis for patients with systemic sclerosis depends on their age, gender, disease variant and the severity of
systemic involvement. Males have a poorer outcome. Average survival from the first symptom is 30 to 40 years for
limited disease, and 15 to 20 years for diffuse disease. Cardiopulmonary involvement is the leading cause of death.

Common cancers are twice as common in patients with systemic sclerosis compared to the general population, and
occur with increased frequency around the time of diagnosis in patients with the RNA polymerase III antibody. In
a patient with newly diagnosed systemic sclerosis with the RNA polymerase III antibody, clinical vigilance for
malignancy is important.

Management of systemic sclerosis

Management of systemic sclerosis is directed at clinical features, and is best undertaken by a multidisciplinary
approach with specialist involvement. Physiotherapists and other allied health professionals have an important role
in the management of patients with systemic sclerosis.

Arthralgia, myalgia and arthritis

For management of arthralgia, myalgia and arthritis, see Arthralgia, myalgia and arthritis.

Raynaud phenomenon and digital ischaemia

For treatment of Raynaud phenomenon and digital ischaemia, see Raynaud phenomenon and digital ischaemia.

Skin fibrosis

Skin fibrosis is a defining clinical feature of systemic sclerosis. The skin may initially be pruritic, swollen and
oedematous (scleroedematous stage). Thickening of the skin usually follows. In late stages, the skin may become
atrophic with loss of sebaceous glands and hair follicles.

General hand, foot and nail care are important at all stages of skin fibrosis. Regular application of emollients (eg
sorbolene cream) and avoidance of soaps can be useful.

In the scleroedematous stage, pruritus may be helped by oral antihistamines. Low-dose prednis(ol)one may also
provide some symptom relief. Avoid doses of prednis(ol)one greater than 15 mg daily in patients with systemic
sclerosis because there is a risk of precipitating scleroderma renal crisis.

Immunomodulatory drugs used by specialists to treat the underlying disease include oral cyclophosphamide,
mycophenolate and methotrexate. The evidence for these drugs varies. Oral cyclophosphamide reduced the extent
of skin involvement in systemic sclerosis in a randomised controlled trial, and mycophenolate has been beneficial
in case series. Methotrexate is used in practice despite limited evidence to support its use.

Maintaining range of motion of the hand is important from the time of diagnosis, and a simple exercise program is
recommended. Facial exercises, especially mouth opening, are also important and there is some evidence to
suggest facial exercises can improve eating, speaking and dental hygiene. If skin fibrosis is widespread, general
range-of-motion exercises are recommended. These can be in the form of a gym program, hydrotherapy, a walking
program, or a home-based exercise program. Hydrotherapy may not be suitable if skin ulcers are present and may
cause worsening of Raynaud phenomenon. Aerobic exercise can improve lung function and peripheral circulation
in patients with systemic sclerosis.

If foot problems limit mobilisation, consider referral to an orthotist or podiatrist. An orthosis (to reduce pressure
on an overused area of the foot) or custom-made shoes may relieve pain and prevent worsening of ulcers.

Digital calcinosis

The management of painful, extruding digital calcinosis is difficult. Despite reports that warfarin, calcium channel
blockers and colchicine may be effective, there are no drugs of established value. Recurrent surgical excision of
calcinotic deposits may be necessary.

Sicca symptoms

For management of sicca symptoms, see Sicca symptoms.

Fatigue

For management of fatigue, see Fatigue.

Oesophageal dysmotility

Oesophageal dysmotility, with symptoms of gastro-oesophageal reflux, is common in all patients with systemic
sclerosis. If associated with aspiration, it may worsen outcomes of systemic sclerosis–associated interstitial lung
disease.

Management of oesophageal dysmotility is best undertaken in consultation with a gastroenterologist. Proton pump
inhibitors (PPIs) are the mainstay of drug treatment and high doses may be required. There are no effective
prokinetic drugs for oesophageal dysmotility. Nonpharmacological measures include elevating the head of the bed,
eating soft food and small meals, and drinking liquids with meals. Advise patients to avoid smoking, alcohol and
the use of opioids. Repeated endoscopy may be needed for oesophageal dilation for stricture. Severe reflux may
require referral to a surgeon with expertise in antireflux procedures.

Gastric and small bowel involvement

Delayed gastric emptying (with nausea and bloating) and impaired intestinal transit due to systemic sclerosis may
respond to domperidone.

Nonspecific looseness of stools or diarrhoea is frequent in patients with systemic sclerosis. It is best managed with
a trial of avoidance of irritant foods in consultation with a dietitian, or with a trial of an antidiarrhoeal drug such as
loperamide. Use:

loperamide 2 mg orally, 2 to 3 times daily as necessary.

Frequent loose foul-smelling fatty bowel motions suggest malabsorption with bacterial overgrowth; see Small
intestinal bacterial overgrowth for management. Severe malabsorption may eventually require parenteral nutrition
in consultation with a specialist centre.

Repeated endoscopy may be needed for argon laser treatment of bleeding vascular ectatic lesions of the stomach or
intestine.

Large bowel involvement

Involvement of the large bowel in systemic sclerosis may result in altered bowel habits, such as constipation,
faecal impaction with or without faecal overflow, and incontinence with or without rectal prolapse. Symptoms can
be difficult to manage and advice from an incontinence therapist is useful in refractory cases. Regular use of
laxatives or enemas may be necessary for constipation (see Functional constipation). In severe cases, biofeedback
techniques, anal plugs or sacral nerve stimulation may be helpful. Rectal prolapse requires surgical repair.

Interstitial lung disease

Interstitial lung disease, or pulmonary fibrosis, is frequent in systemic sclerosis, but is more likely to be clinically
significant in diffuse disease. Together with pulmonary arterial hypertension, interstitial lung disease is the
commonest cause of death in patients with systemic sclerosis. As there may be few symptoms of pulmonary
involvement, regular monitoring is important; see screening recommendations outlined in Pulmonary arterial
hypertension.

Interstitial lung disease requires management in a specialist centre. The optimal management of interstitial lung
disease in patients with systemic sclerosis is uncertain. Treatment may not be required for patients with indolent
disease, but is indicated for patients who are likely to develop rapidly progressive or life-threatening disease;
however, it can be difficult to identify which patients need treatment. Treatment may be appropriate for patients
with: respiratory symptoms and recent disease onset, restrictive disease on pulmonary function tests or more than
20% lung involvement on high-resolution computed tomography (CT) scan, progressive decline in lung volume or
diffusing capacity of the lungs for carbon monoxide (DLCO) on pulmonary function tests, and/or other disease
manifestations warranting immunomodulatory treatment.
The aim of treatment is to improve respiratory function, but immunomodulatory drugs have only modest benefits.
The nonspecific interstitial pneumonitis (NSIP) pattern of disease can be more responsive to therapy than the usual
interstitial pneumonitis (UIP) pattern of disease more typically seen in idiopathic pulmonary fibrosis. If treatment
is indicated, a trial of immunomodulatory therapy (cyclophosphamide or mycophenolate) with or without low-dose
prednis(ol)one is used. Doses of prednis(ol)one greater than 15 mg daily should be avoided in patients with
systemic sclerosis because there is a risk of precipitating scleroderma renal crisis.

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) occurs in 10 to 15% of patients with systemic sclerosis, regardless of
whether they have diffuse or limited disease. PAH typically develops insidiously in patients without clinically
significant interstitial lung disease, but it may occur secondary to interstitial lung disease with associated
destruction of the pulmonary vascular bed. Initial symptoms of PAH can be subtle and easily misinterpreted as
other manifestations of systemic sclerosis (eg mild breathlessness on exertion, dizziness, palpitations or
generalised weakness).

PAH or interstitial lung disease may be quite advanced when dyspnoea develops; annual screening with
echocardiogram and pulmonary function tests is recommended for early identification. Echocardiogram may
demonstrate changes suggestive of PAH, such as elevated systolic pulmonary arterial pressure, but this is
dependent on obtaining an adequate tricuspid regurgitant jet, which can be absent in up to 25% of people. Right
heart catheterisation and high-resolution computed tomography (CT) scan of the chest should be performed when
clinical suspicion of cardiopulmonary disease is high (eg unexplained deterioration in exercise capacity). Right
heart catheterisation is essential for diagnosis of PAH, and to exclude other causes of elevated pulmonary arterial
pressure (eg left ventricular diastolic dysfunction, shunts).

Refer all patients with suspected PAH to a specialist centre for management. Specific therapies for proven PAH
include endothelin receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase-5 inhibitors
(sildenafil, tadalafil) and prostanoids (iloprost, epoprostenol). These therapies have a symptomatic benefit and may
have a survival benefit. Response to treatment should be assessed every 6 months with a 6-minute walk test and
echocardiogram. For endothelin receptor antagonists, monitor liver biochemistry and full blood count regularly.

Specific therapies for PAH have strict eligibility criteria for access on the Pharmaceutical Benefits Scheme (PBS).
Although only monotherapy is PBS-funded, combinations of these drugs are often used under other funding
arrangements. Selexipag, an oral prostacyclin agonist, and riociguat, a guanylate cyclase stimulator, are newer
drugs for PAH and, at the time of writing, are not available on the PBS [Note 2]. The role of anticoagulation
remains uncertain.

Note 2: See the PBS website for current information [URL].

Scleroderma renal crisis and hypertension

Scleroderma renal crisis (renal failure associated with accelerated hypertension) is a medical emergency. It can
develop over a few days, and was the leading cause of death in patients with diffuse systemic sclerosis before the
widespread use of angiotensin converting enzyme inhibitors (ACEIs). Scleroderma renal crisis usually occurs in
the first 2 years following diagnosis of systemic sclerosis and may be the presenting symptom of the disease. Use
of corticosteroids is a risk factor for scleroderma renal crisis; avoid doses of prednis(ol)one greater than 15 mg
daily in patients with systemic sclerosis.

Check blood pressure in any patient with symptoms of hypertension, such as headache, dizziness or visual
disturbance. Patients may also present with acute pulmonary oedema. Increase in blood pressure may be
asymptomatic so regular screening for hypertension is required. In patients with diffuse disease, especially those
with the RNA polymerase III autoantibody, check blood pressure several times a week in the first 2 years following
diagnosis. Patients may be advised to purchase a home blood pressure monitor to enable self-monitoring.

Increase in blood pressure may be asymptomatic so regular screening for hypertension is required.

Suspect accelerated hypertension and scleroderma renal crisis in any patient with an increase in blood pressure of
30 mmHg or more above baseline. Urgently refer the patient to a specialist and treat immediately with an ACEI
while awaiting specialist review. Captopril is the preferred ACEI because it is short-acting and can be rapidly
titrated. The aim of treatment is to restore blood pressure to baseline as soon as possible. This approach improves
survival, but many patients still require long-term dialysis and renal transplantation.

Any presentation of hypertension, even mild hypertension, should be treated as it can rapidly escalate to
accelerated hypertension in patients with systemic sclerosis. An ACEI is the antihypertensive of choice in these
patients; for principles of use and dosing, see Pharmacological management of hypertension. There is no evidence
that commencing an ACEI before the development of hypertension improves outcomes in patients with systemic
sclerosis.

Mixed connective tissue disease

Mixed connective tissue disease combines features of systemic lupus erythematosus (SLE), systemic sclerosis and
polymyositis, and some features of rheumatoid arthritis. The female to male ratio is high (up to 16:1) and the age
of onset is typically between 20 and 30 years.

Symptoms of mixed connective tissue disease may occur concurrently or, more commonly, evolve sequentially.
The clinical presentation is likely to be oedema of the hands, inflammatory arthritis, Raynaud phenomenon,
sclerodactyly and myositis. The arthritis is usually nonerosive but rheumatoid factor (RF) may be positive in 50 to
70% of patients, making the differentiation of rheumatoid arthritis and mixed connective tissue disease difficult.
Mixed connective tissue disease is defined by clinical features and the presence of antibody to U1RNP, and often to
Ro (SS-A) and La (SS-B) as well (see Table 12.14).

Ten-year survival of mixed connective tissue disease is around 96%. Patients with pulmonary arterial hypertension
(PAH) have a poor prognosis. A high U1RNP titre correlates with a low incidence of renal disease.

Because of small numbers of patients and the diversity of their clinical presentations, there are no controlled trials
of treatments for mixed connective tissue disease. For treatment of PAH, see Pulmonary arterial hypertension.
Angiotensin converting enzyme inhibitors (ACEIs) are indicated for treating hypertension, as in systemic sclerosis
(see Scleroderma renal crisis and hypertension). Standard therapy for SLE and rheumatoid arthritis–like
manifestations includes methotrexate and hydroxychloroquine (see General management approach for systemic
lupus erythematosus).

Juvenile dermatomyositis
Introduction

Juvenile dermatomyositis is a systemic vasculopathy that primarily affects the muscle and skin. The clinical course
is variable. Some children have a monophasic illness; others experience a relapsing pattern, which increases the
potential for morbidity from both the disease and its therapy.

Diagnosis of juvenile dermatomyositis

The cardinal clinical features of juvenile dermatomyositis are proximal weakness and a characteristic heliotrope
rash affecting the face and limbs. Typically, patients also have abnormal nailfold capillaries, reflecting the
vasculopathy underlying this disease.

Investigations for juvenile dermatomyositis include measurement of muscle enzyme levels (which are elevated in
patients with the disease) and magnetic resonance imaging (MRI) of the pelvic girdle musculature (which reveals
diffuse inflammatory changes on T2-weighted images in patients with the disease). Abnormalities on
electromyogram and muscle biopsy are also present in patients with juvenile dermatomyositis, but MRI has
obviated the need for these investigations in patients with typical clinical features. Dermatomyositis in children is
not associated with neoplasia and investigations to exclude occult malignancy are not necessary.

Management of juvenile dermatomyositis

The management of juvenile dermatomyositis is best undertaken by, or in conjunction with, a paediatric
rheumatologist. The goal of management in all patients, including those with relapsing disease, is recovery of
muscle strength and function. Juvenile dermatomyositis is treated with high-dose corticosteroids (intravenous
methylprednisolone or high-dose oral prednis(ol)one) with doses tapered in response to recovery of muscle
strength. Normalisation of muscle enzyme levels tends to occur before clinical response and, in itself, does not
guide therapy. The concurrent use of methotrexate or cyclosporin improves the primary disease and reduces total
exposure to corticosteroids. Other therapies include intravenous immunoglobulin (IVIg) and rituximab. In patients
with severe vasculopathy involving the gastrointestinal tract or skin with severe ulceration and bleeding,
cyclophosphamide is frequently used in combination with high-dose corticosteroids.

Development of subcutaneous calcification is an important complication of juvenile dermatomyositis and may be

more common in poorly controlled disease. No treatment has been consistently reported to be of benefit for
subcutaneous calcification, but spontaneous resolution can occur. Surgical excision may be necessary for
symptomatic localised lesions.

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Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Raynaud phenomenon and digital ischaemia
Raynaud phenomenon
Introduction
Raynaud phenomenon is caused by vasospasm of the digits, usually in response to cold exposure or stress. It
presents as episodic blanching, cyanosis and then erythema of the digits. The condition is often painful. While
Raynaud phenomenon is a common condition, particularly in females, it should be differentiated from the more
common complaint of diffusely cold and/or mottled hands that is not associated with a disease process. In the latter
situation, the hands recover quickly and evenly.

Raynaud phenomenon can be a primary condition or can occur secondary to a connective tissue disease (eg
systemic sclerosis) or other disease (eg arthrosclerosis, malignancy). Suspect an underlying connective tissue
disease in a patient with other common clinical features of a connective tissue disease (eg arthralgia, fatigue), an
elevated erythrocyte sedimentation rate (ESR), a positive antinuclear antibody (ANA), and abnormal nailfold
capillaries on inspection under magnification (eg dilation, capillary dropout, haemorrhage).

Secondary Raynaud phenomenon may cause digital ischaemia (see Digital ischaemia for management).

Management of Raynaud phenomenon

In patients with secondary Raynaud phenomenon, optimise the management of the underlying disease. See
Inflammatory connective tissue diseases for information on the management of connective tissue diseases.

In all cases of Raynaud phenomenon, advise patients to avoid cold exposure. In the absence of an underlying
cause, the use of gloves and warm clothing is often sufficient to control symptoms. Strongly encourage patients to
stop smoking. Avoid the use of beta blockers in patients with Raynaud phenomenon because they can worsen
symptoms.

In more severely affected patients, particularly those with an underlying connective tissue disease, vasodilator
drugs may be used to reduce vasospasm. For first-line therapy, use a dihydropyridine calcium channel blocker:

1 amlodipine 5 to 10 mg orally, daily

OR

1 felodipine modified-release 2.5 to 20 mg orally, daily

OR

1 nifedipine modified-release 30 to 120 mg orally, daily.

Second-line therapy includes topical glyceryl trinitrate (transdermal patches or ointment), angiotensin II receptor
blockers, phosphodiesterase-5 inhibitors, alpha blockers, and selective serotonin reuptake inhibitors (SSRIs).
Combination therapy with drugs from different classes may be used. Sympathectomy is seldom indicated.

Digital ischaemia
Introduction
Digital ischaemia, typically manifesting as digital ulceration, may occur due to secondary Raynaud phenomenon.
In patients with Raynaud phenomenon that is secondary to systemic sclerosis, digital ulcers may occur as a
consequence of the combined effects of severe Raynaud phenomenon and calcinosis. Ulcers occur over the tips of
the digits and also at sites of trauma, such as over the extensor surfaces of contracted digits.

Other causes of digital ischaemia include thromboembolic disease, systemic vasculitis, hyperviscosity, and
Buerger disease.
Management of digital ischaemia
In patients with digital ischaemia, optimising the management of Raynaud phenomenon as well as the underlying
disease is important (see Raynaud phenomenon).

Digital ulcers require protection and regular dressings using preparations such as povidone-iodine. Moisture-
donating dressings to soften dry eschar, followed by debridement to allow healing, may be required. If ulcers fail
to heal, excision of substantial underlying calcinosis may be necessary.

Suspect infection if ulcers become increasingly painful, red and swollen. For management of infected digital
ulcers, see Cellulitis and erysipelas. It is important to remain alert to the possibility of infection spreading to cause
septic arthritis or osteomyelitis. For management of septic arthritis, see Septic arthritis, and for management of
osteomyelitis, see Osteomyelitis.

Adequate analgesia should be given (see Stepwise approach to acute pain management).

If ulcers are refractory to treatment, admission to hospital may be necessary for administration of a potent
vasodilator, such as intravenous alprostadil or iloprost, under the supervision of an experienced clinician.

Critical digital ischaemia or necrosis is a digit-threatening event that can occur in patients with secondary
Raynaud phenomenon due to an underlying connective tissue disease. Critical digital ischaemia is a medical
emergency that always requires urgent specialist assessment, and usually requires hospital admission. Potent
vasodilators, such as intravenous alprostadil or iloprost, are often beneficial. Anticoagulants are used if there is
evidence of recent vascular thrombosis or thromboembolism. Antibiotics are required if there is associated
infection. Patients with digital ischaemia can recover well with adequate therapy, so surgical amputation should be
a last resort.

Key references
Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for
the treatment of systemic sclerosis. Ann Rheum Dis 2016;[epub ahead of print]. doi: 10.1136/annrheumdis-2016-
209909. .

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Polymyalgia rheumatica and giant cell arteritis
Polymyalgia rheumatica
Introduction
Polymyalgia rheumatica is an inflammatory condition characterised by bilateral aching and stiffness of the
shoulders and hip-girdle area caused by low-grade synovitis. Morning stiffness is the hallmark of the disease.
Patients complain of an inability to turn over in bed and of great difficulty getting out of bed. The stiffness tends to
improve after a hot shower, and with activity. The onset of symptoms can be sudden or gradual.

Polymyalgia rheumatica occurs almost exclusively in people older than 50 years; its incidence increases with age.
It is more common in women than men.

Diagnosis of polymyalgia rheumatica

There are no specific diagnostic tests for polymyalgia rheumatica; diagnosis is based on clinical presentation and
elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) concentration. Polymyalgia
rheumatica is unlikely if ESR is normal; however, up to 20% of patients have a normal ESR at diagnosis. If ESR
and/or CRP are not clearly elevated, and onset of symptoms is recent, retest in 1 to 2 weeks. For a summary of
features of polymyalgia rheumatica, see Table 12.17.

Polymyalgia rheumatica is overdiagnosed, particularly in patients younger than 50 years, in whom the diagnosis is
almost always incorrect. Fibromyalgia, myalgias due to drugs such as statins, or Parkinson disease may be
misdiagnosed as polymyalgia rheumatica, especially if ESR is spuriously elevated. Before making a diagnosis,
exclude disorders that can mimic the presentation, such as rotator cuff disease or greater trochanteric pain
syndrome. The features of polymyalgia rheumatica may be vague and nonspecific; in patients with systemic
features such as weight loss, fevers, malaise and generalised pain and stiffness, exclude infection and malignancy
(especially myelodysplasia).

Rapid response to corticosteroid therapy at the usual starting dose (eg prednis(ol)one 15 mg orally, daily) is a good
diagnostic indicator of polymyalgia rheumatica. Reconsider the diagnosis if corticosteroid therapy fails to achieve
prompt symptomatic relief and a decrease in inflammatory markers.

Urgently refer any patient with suspected giant cell arteritis to a specialist.

About 15% of patients with polymyalgia rheumatica also have giant cell arteritis. Urgently refer patients with
suspected giant cell arteritis to a specialist (including patients with polymyalgia rheumatica who have jaw
claudication, severe headache, visual symptoms, scalp tenderness or malaise because these are classic symptoms of
giant cell arteritis); see Giant cell arteritis for more information.

Features of polymyalgia rheumatica (Table 12.17)

age older than 50 years

Features that are usually bilateral shoulder aching
present elevated ESR and/or CRP concentration

clinical

morning stiffness lasting longer than 45 minutes

hip-girdle discomfort or limited range of motion
Supportive features absence of involvement of joints other than the hip and shoulder

laboratory

absence of RF and antibodies to CCP

CCP = cyclic citrullinated peptides; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; RF = rheumatoid factor

Management of polymyalgia rheumatica

General management approach for polymyalgia rheumatica

A long course of a corticosteroid is needed to successfully treat polymyalgia rheumatica and, even with appropriate
treatment, relapse is common. Rapid tapering of the corticosteroid dose significantly increases the risk of relapse,
which often results in higher overall corticosteroid exposure because increased doses and slower tapering are
required to treat relapsed disease. To reduce the risk of relapse, slowly taper the dose of corticosteroid until it can
be stopped; smaller and more frequent dose reductions are more effective at preventing relapse than larger and less
frequent dose reductions. Tapering regimens shown to reduce the risk of relapse use continuous corticosteroid
therapy for 12 months or more; avoid regimens that taper and stop corticosteroid therapy within 9 months. See
Pharmacological management of polymyalgia rheumatica for advice on individualising the corticosteroid regimen.

Avoid regimens that taper and stop corticosteroid therapy within 9 months. Treatment is usually required for 12 months or more.

Long-term corticosteroid therapy can cause significant adverse effects. The risk of adverse effects must be
balanced against the risk of relapse with inadequate treatment. Use the lowest dose and shortest duration of therapy
necessary to control disease and prevent relapse. See Principles of immunomodulatory drug use for
rheumatological diseases in adults for information on adverse effects associated with long-term corticosteroid use
(such as bone density loss) and advice on how to minimise and monitor for such complications.

In specific circumstances, methotrexate is added to corticosteroid therapy for its corticosteroid-sparing effect (see
Pharmacological management of polymyalgia rheumatica).

In addition to drug therapy, patients should be encouraged to stay active and undertake gentle exercise. The goal of
the exercise regimen should be to gradually increase the amount of time spent exercising.

Pharmacological management of polymyalgia rheumatica

Individualise the rate of corticosteroid tapering according to the patient's circumstances, including disease activity
(as indicated by the patient's symptoms and inflammatory markers) and corticosteroid adverse effects.

An example regimen for the treatment of polymyalgia rheumatica is:

prednis(ol)one 15 mg orally, daily for 4 weeks; then reduce daily dose by 2.5 mg every 4
weeks to 10 mg daily; then reduce daily dose by 1 mg every 4 to 8 weeks to stop.

Do not reduce the dose if the patient has signs of active disease, such as recurrence of symptoms or persistently
elevated inflammatory markers.

Although ESR and CRP may help identify deterioration in the patient's condition, they are not specific measures of
disease activity and should always be considered in the context of the patient's symptoms. If an asymptomatic
patient has elevated inflammatory markers, consider alternative pathologies (eg infection) and retest after 4 weeks.
Transient rises in ESR or CRP typically do not indicate relapse. Furthermore, it is normal for these markers to
increase slightly as the corticosteroid dose is reduced. Check ESR and CRP monthly for the first 3 months of
therapy, then every 2 to 3 months thereafter or as clinically indicated.

If the patient has a flare of musculoskeletal or systemic symptoms during tapering, determine if symptoms are due
to relapse; this should include measurement of inflammatory markers. Advise patients that transient symptoms,
such as aching and influenza-like symptoms, are expected as the corticosteroid dose is reduced and, unless advised
otherwise by their doctor, they should persist with planned dose reductions. In the absence of clinician-assessed
relapse, the risks associated with prolonging corticosteroid therapy are likely to outweigh its benefits.

If assessment suggests relapse (eg symptoms for more than a few days, persistently or significantly elevated
inflammatory markers that cannot be explained by another pathology), revert to the previously effective
corticosteroid dose and begin a slower taper; consider referring the patient to a specialist. Specialist referral is also
required if corticosteroid therapy is poorly effective, not tolerated, cannot be tapered, or is needed beyond 18
months.

Although evidence to support the use of methotrexate as a corticosteroid-sparing drug is conflicting, international
guidelines support its use and it is frequently used in practice (particularly in patients who relapse, need prolonged
corticosteroid therapy, or develop early or severe corticosteroid adverse effects). The methotrexate dose is adjusted
on the basis of clinical response and adverse effects. For considerations in the management of methotrexate
therapy (including monitoring, screening for infection, and vaccination), see Principles of immunomodulatory
drug use for rheumatological diseases in adults.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

 orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

The use of tumour necrosis factor (TNF) inhibitors is not recommended; evidence suggests they are not as
effective as methotrexate in allowing the corticosteroid dose to be reduced in patients with polymyalgia
rheumatica.

Giant cell arteritis

Introduction
Giant cell arteritis (formerly known as temporal arteritis or cranial arteritis) is a systemic vasculitis that typically
affects the cranial arteries, including the ophthalmic artery. However, it can affect other large blood vessels,
including the aorta and its major branches. Giant cell arteritis occurs almost exclusively in people older than 50
years, and more commonly in women than men. Its incidence increases with age and peaks in people aged 70 to 79
years.

Diagnosis of giant cell arteritis

The classic symptoms of giant cell arteritis include jaw claudication (which is almost pathognomonic), severe
headache, polymyalgia rheumatica (in about 50% of cases), visual symptoms (commonly diplopia or visual loss),
scalp tenderness and malaise. Physical examination reveals temporal artery abnormality (eg the artery is tender,
enlarged, difficult to compress, nodular or pulseless) in 50% of cases. Elevated erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) concentration are common in giant cell arteritis, but ESR may be normal
initially. The features of giant cell arteritis may be vague and nonspecific; in patients with systemic features such
as weight loss, fevers, malaise and generalised pain and stiffness, exclude infection and malignancy (especially
myelodysplasia).

Urgently refer any patient with suspected giant cell arteritis to a specialist.

Urgently refer any patient with suspected giant cell arteritis to a specialist because a delay in treatment can result
in serious consequences such as blindness or ischaemic events. Giant cell arteritis should be suspected if any of the
classic symptoms (jaw claudication, severe headache, visual symptoms, scalp tenderness, or malaise) develop in a
patient with polymyalgia rheumatica or a history of polymyalgia rheumatica.

Temporal artery biopsy is a specific test for giant cell arteritis, so can help avoid unnecessary long-term treatment
(and its associated toxicities). Diagnostic histological changes persist for at least 1 week after treatment is started,
so—although biopsy must be performed promptly if giant cell arteritis is suspected—treatment should not be
delayed until biopsy is performed.

When a biopsy is performed it is imperative to obtain an adequate sample (at least 2 cm) and to have the sample
comprehensively assessed (multiple sections should be examined), because giant cell arteritis may present with
‘skip’ lesions. However, there is no benefit in performing a contralateral biopsy if the initial biopsy was of
adequate length and comprehensively assessed but did not reveal arteritis; the result is unlikely to be different. Up
to 20% of patients with giant cell arteritis do not have temporal artery involvement. If the diagnosis is strongly
suspected in a patient with a negative temporal artery biopsy result, vascular imaging of the aorta and its major
branches is usually performed to confirm the diagnosis.

Management of giant cell arteritis

Giant cell arteritis requires specialist management. Similar to polymyalgia rheumatica, giant cell arteritis is treated
with a long course of corticosteroid; however, higher initial dosing is required. Corticosteroid therapy often needs
to be continued for 2 years or more, and it would be uncommon to stop therapy before 18 months. Because long-
term corticosteroid therapy can cause significant adverse effects, the lowest dose and shortest duration of therapy
necessary to control disease and prevent relapse should be used. See Principles of immunomodulatory drug use for
rheumatological diseases in adults for information on adverse effects associated with long-term corticosteroid use
(such as bone density loss) and advice on how to minimise and monitor for such complications.

If the diagnosis of giant cell arteritis is strongly suspected, pre-emptive treatment should be started immediately,
without waiting for histological confirmation. The same is true for any patient with, or with a history of,
polymyalgia rheumatica who develops classic symptoms of giant cell arteritis.
 Immediately start treatment, without waiting for histological confirmation, if there is a strong clinical suspicion of giant cell
arteritis.

Patients with evolving visual loss or a recent history of transient visual loss require initial treatment with
intravenous methylprednisolone; the usual dosage is:

methylprednisolone sodium succinate 0.5 to 1 g intravenously, over 1 hour, daily for 3

days, then switch to oral prednis(ol)one as below.

For patients without evolving visual loss or a recent history of transient visual loss, treatment is with oral
prednis(ol)one; the usual dosage is:

prednis(ol)one 40 to 60 mg orally, daily (in two divided doses if necessary for symptom
control) for a minimum of 4 weeks, continue until symptoms and abnormalities in
inflammatory markers resolve; then reduce daily dose by 10 mg every 2 weeks to 20 mg
daily; then reduce daily dose by 2.5 mg every 2 to 4 weeks to 10 mg daily; then reduce
daily dose by 1 mg every 4 to 8 weeks, provided there is no relapse, to stop.

Dose adjustments should be advised by the specialist. Relapse is common during corticosteroid tapering and dose
reductions should not be undertaken if the patient has signs of active disease (such as recurrence of symptoms or
persistently elevated inflammatory markers that cannot be explained by another pathology). ESR and CRP are
usually checked monthly for the first 3 months of therapy, then every 2 to 3 months thereafter or as clinically
indicated.

To prevent ischaemic events, including ophthalmic vascular thrombosis, use aspirin concurrently with
corticosteroid therapy. Use:

aspirin 100 mg orally, daily.

Methotrexate may be used in combination with corticosteroid therapy initially, or as a corticosteroid-sparing drug
in patients who need prolonged high-dose corticosteroid therapy or who develop early or severe corticosteroid
adverse effects. The methotrexate dose is adjusted on the basis of clinical response and adverse effects. For
considerations in the management of methotrexate therapy (including monitoring, screening for infection, and
vaccination), see Principles of immunomodulatory drug use for rheumatological diseases in adults.

The usual dosage of methotrexate is:

methotrexate 10 mg orally, on one specified day once weekly, increasing up to 25 mg

orally or subcutaneously, on one specified day once weekly

PLUS

folic acid 5 to 10 mg orally, per week (preferably not on the day methotrexate is taken).

There is evidence for the efficacy of tocilizumab, in combination with prednis(ol)one, in the treatment of giant cell
arteritis. While its exact place in therapy is not yet clear, tocilizumab is likely to represent a treatment option for
patients with giant cell arteritis refractory to the combination of prednis(ol)one and methotrexate, or who have
intolerable corticosteroid adverse effects [Note 1].

Note 1: At the time of writing, tocilizumab is not approved by the Australian Therapeutic Goods Administration (TGA) for treatment of giant cell
arteritis. See the TGA website for current information [URL].

Key references
Polymyalgia rheumatica

Cantini F, Salvarani C, Olivieri I, Macchioni L, Ranzi A, Niccoli L, et al. Erythrocyte sedimentation rate and C-reactive
protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study.
Semin Arthritis Rheum 2000;30(1):17–24.

Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The lifetime risk of adult-onset
rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63(3):633–9.
 Dasgupta B, Cimmino MA, Kremers HM, Schmidt WA, Schirmer M, Salvarani C, et al. 2012 provisional classification
criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology
collaborative initiative. Arthritis Rheum 2012;64(4):943–54.

Dejaco C, Duftner C, Cimmino MA, Dasgupta B, Salvarani C, Crowson CS, et al. Definition of remission and relapse in
polymyalgia rheumatica: data from a literature search compared with a Delphi-based expert consensus. Ann Rheum
Dis 2011;70(3):447–53.

Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, Mackie S, et al. 2015 recommendations for the management
of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative
initiative. Arthritis Rheumatol 2015;67(10):2569–80.

Gabriel SE, Sunku J, Salvarani C, O'Fallon WM, Hunder GG. Adverse outcomes of antiinflammatory therapy among
patients with polymyalgia rheumatica. Arthritis Rheum 1997;40(10):1873–8.

Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, Miranda-Filloy JA, Gonzalez-Juanatey C, Martin J, et al.
Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009;61(10):1454–61.

Hernandez-Rodriguez J, Cid MC, Lopez-Soto A, Espigol-Frigole G, Bosch X. Treatment of polymyalgia rheumatica: a

systematic review. Arch Intern Med 2009;169(20):1839–50.

Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based
cohort of patients with polymyalgia rheumatica. J Rheumatol 2005;32(1):65–73.

Giant cell arteritis

Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The lifetime risk of adult-onset
rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63(3):633–9.

Dasgupta B, Borg FA, Hassan N, Alexander L, Barraclough K, Bourke B, et al. BSR and BHPR guidelines for the
management of giant cell arteritis. Rheumatology (Oxford) 2010;49(8):1594–7.

Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, Garcia-Porrua C, Sanchez-Andrade A, Llorca J. Giant cell arteritis:
disease patterns of clinical presentation in a series of 240 patients. Medicine (Baltimore) 2005;84(5):269–76.

Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, Miranda-Filloy JA, Gonzalez-Juanatey C, Martin J, et al.
Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009;61(10):1454–61.

Loricera J, Blanco R, Hernandez JL, Castaneda S, Mera A, Perez-Pampin E, et al. Tocilizumab in giant cell arteritis:
Multicenter open-label study of 22 patients. Semin Arthritis Rheum 2015;44(6):717–23.

Mahr A, Saba M, Kambouchner M, Polivka M, Baudrimont M, Brocheriou I, et al. Temporal artery biopsy for diagnosing
giant cell arteritis: the longer, the better? Ann Rheum Dis 2006;65(6):826–8.

Mahr AD, Jover JA, Spiera RF, Hernandez-Garcia C, Fernandez-Gutierrez B, Lavalley MP, et al. Adjunctive
methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum
2007;56(8):2789–97.

Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, et al. Tocilizumab for the treatment
of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res
(Hoboken) 2012;64(11):1720–9.

Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, et al. Tocilizumab for induction and maintenance of
remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet
2016;387(10031):1921–7. .

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Systemic vasculitides
Introduction to systemic vasculitides
Vasculitis is an inflammatory process affecting blood vessel walls. The vasculitides are a heterogeneous group
of uncommon diseases ranging from self-limited cutaneous vasculitides to catastrophic life- and organ-
threatening systemic vasculitides. The systemic vasculitides are addressed here; for information on cutaneous
vasculitides, see Cutaneous vasculitis.

The systemic vasculitides are thought to have an autoimmune pathogenesis. Blood vessel inflammation can
result in occlusion, stenosis or aneurysm, leading to organ damage through haemorrhage or infarction. The
kidneys and/or lungs are often affected and the severity and extent of their involvement is closely related to
the disease prognosis.

The specific systemic vasculitides can be characterised by the size and type of affected blood vessels (see
Table 12.18); however, their classification is evolving. Serology and organ involvement are increasingly
recognised in the classification of these conditions.

Diagnosis of systemic vasculitides

The features of a systemic vasculitis may be nonspecific. Although all vasculitic syndromes are rare, a
systemic vasculitis should be suspected in any patient with an unexplained persistent inflammatory state (eg
fever, weight loss, night sweats, fatigue, malaise, raised inflammatory markers). Specific clinical features may
suggest a particular vasculitic syndrome (see Table 12.18), but diagnosis can be complex and up to 40% of
patients do not fit the classical description for any of the specific vasculitides. Urgently refer any patient with
a suspected systemic vasculitis to a specialist.

Urgently refer any patient with a suspected systemic vasculitis to a specialist.

Some infections (eg sepsis, endocarditis) may have a similar clinical presentation to a systemic vasculitis.
Other differential diagnoses are malignancy, use of illicit drugs such as cocaine and amphetamine, cholesterol
embolisation, cryoglobulinaemia and atrial myxoma.

For most of the systemic vasculitides, diagnosis is confirmed by the identification of vascular inflammation in
a biopsy of affected tissues. The choice of tissue or organ for biopsy is directed by the clinical presentation.
For vasculitis affecting larger blood vessels that cannot be easily accessed for biopsy, such as the aorta or
splanchnic vasculature, imaging may confirm the diagnosis without the need for biopsy.

Serological tests, such as antineutrophil cytoplasmic antibody (ANCA), are helpful in diagnosis but should
only be performed if the patient's clinical presentation suggests a specific vasculitis for which serological
confirmation is needed. For example, ANCA testing should be considered in patients with a vasculitic rash,
acute glomerulonephritis, pulmonary haemorrhage, or refractory ear, nose and throat symptoms.

See also specific considerations in the diagnosis of each systemic vasculitis.

Classification of systemic vasculitides (Table 12.18) [NB1]

Systemic vasculitis Key clinical features

Large-vessel vasculitides (often affect the aorta and/or its major branches)
upper limb claudication
Takayasu arteritis absent pulses, arterial bruits, hypertension

jaw claudication, severe headache, scalp tenderness

diplopia or visual loss
giant cell arteritis [NB2] polymyalgia rheumatica
systemic symptoms such as weight loss, fever and malaise

Medium-vessel vasculitides (predominantly affect the main visceral arteries and their branches)
 palpable purpura, livedo reticularis
peripheral neuropathy
polyarteritis nodosa intestinal and liver ischaemia
renal vasculopathy

occurs almost exclusively in children

Kawasaki disease [NB3] see Criteria for the diagnosis of Kawasaki disease (Box
12.11)

Small-vessel vasculitides (predominantly affect small intraparenchymal arteries, capillaries, venules or

arterioles)
ANCA-associated vasculitides
acute, rapidly progressive glomerulonephritis
microscopic polyangiitis pulmonary haemorrhage
palpable purpura

sinusitis, nasal disease and subglottic stenosis

granulomatosis with polyangiitis otitis media, hearing loss and ear pain
pulmonary infiltrates and nodules, haemoptysis and
(formerly known as Wegener pleuritis
granulomatosis) glomerulonephritis

asthma
pulmonary and blood eosinophilia
eosinophilic granulomatosis with
mononeuritis multiplex
polyangiitis
palpable purpura, skin infarcts, nodules over pressure areas
(formerly known as Churg–Strauss focal, segmental necrotising glomerulonephritis
vasculitis) granulomatous infiltration of the myocardium, coronary
vasculitis

Immune-complex vasculitis
occurs predominantly in children
immunoglobulin A vasculitis nonthrombocytopenic purpura
colicky abdominal pain
(formerly known as Henoch–Schönlein large-joint arthritis
purpura) renal vasculopathy

ANCA = antineutrophil cytoplasmic antibody

NB1: This table only lists the systemic vasculitides discussed in this topic; other specific systemic vasculitides have been defined, including
vasculitis associated with other inflammatory syndromes (eg cryoglobulinaemia, Behçet syndrome).
NB2: Giant cell arteritis typically affects the cranial arteries, including the ophthalmic artery.
NB3: Kawasaki disease typically affects the coronary arteries.

General management approach for systemic vasculitides

Introduction
Systemic vasculitides require specialist management. While a general approach to management can be
described, its application varies for each of the systemic vasculitides. Consider both the following general
management approach and the advice for the specific vasculitis. Immunoglobulin A vasculitis and Kawasaki
disease are exceptions because their management is distinctly different from the general approach outlined
here; see instead Immunoglobulin A vasculitis and Kawasaki disease.

If a systemic vasculitis is strongly suspected, treatment must start immediately, without waiting for diagnostic
confirmation (ie biopsy or other investigations). Systemic vasculitis is treated with corticosteroids and, in
some circumstances, disease-modifying antirheumatic drugs (DMARDs). Corticosteroids are the mainstay of
treatment and must be continued for the duration of treatment. In all cases, the aim of therapy is to induce (see
Inducing remission in systemic vasculitides) and maintain (see Maintaining remission in systemic
vasculitides) remission of disease activity. Remission is defined as:

the absence of clinical features of vasculitis

resolution of organ changes, or stabilisation of organ structure and function
normalisation of inflammatory markers.
Patients taking immunomodulatory drugs are at increased risk of infections. It is important to exclude
infection before starting immunomodulatory therapy, and clinicians must always be alert to the possibility of
infection (including opportunistic infection), particularly because the usual symptoms and signs (eg fever) are
often absent. For other considerations in the management of corticosteroid and DMARD therapy (including
adverse effects associated with long-term therapy, monitoring, screening for infection, and vaccination), see
Principles of immunomodulatory drug use for rheumatological diseases in adults.

For guidance on when to give antimicrobial prophylaxis (eg Pneumocystis jirovecii pneumonia [PJP]
prophylaxis) for patients taking corticosteroids or immunomodulatory drugs, see here.

Inducing remission in systemic vasculitides

Patients with disease affecting a major organ or body system

For patients with disease affecting a major organ or body system (eg glomerulonephritis, pulmonary
haemorrhage, intestinal ischaemia, sight-threatening eye disease, neuropathy), intensive induction therapy is
indicated. The regimens used for intensive induction therapy vary between the specific vasculitides, and
depend on the organ affected and the extent to which it is affected. Regimens include:

high-dose corticosteroids
high-dose corticosteroids plus cyclophosphamide
high-dose corticosteroids plus rituximab.

High-dose corticosteroid therapy is typically intravenous methylprednisolone followed by high-dose oral

prednis(ol)one (usually 1 mg/kg up to 60 mg daily). When intravenous methylprednisolone cannot be started
immediately, start treatment with high-dose oral prednis(ol)one instead and continue until intravenous
methylprednisolone can be started.

If treatment with cyclophosphamide is indicated, see Principles of immunomodulatory drug use for
rheumatological diseases in adults for considerations for use, especially in patients of childbearing potential.

For patients with microscopic polyangiitis or granulomatosis with polyangiitis, rituximab is an alternative to
cyclophosphamide for intensive induction therapy. Rituximab is generally used when these patients have not
responded to cyclophosphamide or have had a major toxicity from cyclophosphamide, or in women who wish
to conceive in the future and are concerned about the effect of cyclophosphamide on fertility.

For patients with rapidly progressive glomerulonephritis or pulmonary haemorrhage, adjunctive plasma
exchange may be used.

Patients with disease not affecting a major organ or body system

For patients with disease not affecting a major organ or body system (eg upper airway, skin or joint
involvement), intensive induction therapy is not required, but treatment must still be started urgently.
Treatment regimens must include high-dose oral prednis(ol)one (usually 1 mg/kg up to 60 mg daily) with or
without another immunomodulatory drug (eg azathioprine, methotrexate or mycophenolate). For patients with
microscopic polyangiitis or granulomatosis with polyangiitis, combination therapy is recommended—high-
dose prednis(ol)one in combination with methotrexate or mycophenolate is preferred.

All patients with disease not affecting a major organ or body system should be frequently monitored for major
organ involvement, particularly kidney disease, because this warrants more intensive treatment.

Maintaining remission in systemic vasculitides

When remission has been achieved, prednis(ol)one is tapered and continued at the lowest effective dose
(usually 5 mg orally, daily). The rate of tapering depends on the clinical and inflammatory marker response,
and the development of corticosteroid adverse effects. Generally the daily prednis(ol)one dose should be
reduced to 5 mg within 6 months of achieving remission. Neither the optimal nor the maximum duration of
therapy is known; however, to reduce the risk of relapse, maintenance therapy should be continued for a
minimum of 2 years once remission is achieved.

Long-term corticosteroid therapy can cause significant adverse effects. The risk of adverse effects must be
balanced against the risk of relapse with inadequate treatment. Use the lowest dose and shortest duration of
therapy necessary to control disease and prevent relapse. See Principles of immunomodulatory drug use for
rheumatological diseases in adults for information on adverse effects associated with long-term corticosteroid
use (such as bone density loss) and advice on how to minimise and monitor for such complications.
To allow lower corticosteroid doses to be used, prednis(ol)one is usually used in combination with another
immunomodulatory drug (eg azathioprine or methotrexate) for maintenance of remission. For patients with
microscopic polyangiitis or granulomatosis with polyangiitis, rituximab or mycophenolate may be used in
combination with prednis(ol)one as an alternative steroid-sparing drug [Note 1]. Rituximab is mainly limited
to use in patients who received it as induction therapy; however, the dosing regimens for induction and
maintenance therapy are different. Cyclophosphamide is not used for maintenance therapy because of toxicity
associated with long-term use.

After remission of disease activity is achieved, monitor all patients with systemic vasculitis for evidence of
disease recurrence.

Note 1: At the time of writing, rituximab is not approved by the Australian Therapeutic Goods
Administration (TGA) for maintenance therapy for microscopic polyangiitis or granulomatosis with
polyangiitis. See the TGA website for current information [URL].

Takayasu arteritis
Takayasu arteritis is a systemic vasculitis that affects large blood vessels, typically the aorta and its major
branches. It typically occurs in early adulthood and females are more commonly affected than males.
Systemic features (eg fever, malaise, weight loss) occur in only 20 to 40% of patients. Most patients present
with features of vascular insufficiency such as upper limb claudication, absent pulses, arterial bruits or
hypertension. Patients with Takayasu arteritis are antineutrophil cytoplasmic antibody (ANCA)–negative.

Takayasu arteritis is thought to have distinct inflammatory and ischaemic phases; however, these can overlap.
The vascular changes seen in the inflammatory phase are potentially reversible with treatment, but it can be
difficult to distinguish active inflammation from irreversible vascular changes (such as stenosis). Specialised
vascular imaging (magnetic resonance imaging or positron emission tomography) can aid this distinction and
may be a useful adjunct to clinical assessment and measurement of inflammatory markers.

If active inflammation is suspected, treatment is recommended (see General management approach for
systemic vasculitides). Patients with Takayasu arteritis generally require treatment with high-dose
corticosteroid therapy; the appropriate route of administration and dosage depends on the disease severity.

Concurrent treatment of hypertension is important (see Elevated blood pressure). It is unclear if antiplatelet
drugs such as aspirin are beneficial. Vascular surgery may be required for irreversible obstructive lesions;
when possible, it is preferable to delay surgery until active inflammation is controlled.

Polyarteritis nodosa
Polyarteritis nodosa is a systemic vasculitis that affects small to medium arteries. It typically occurs in
middle-aged or older adults and males are more commonly affected than females. The clinical presentation of
polyarteritis nodosa includes prominent systemic features, as well as features due to the involvement of
specific organs or tissues. Typical systemic features include fever, anorexia, weight loss, myalgia and
arthralgia. The most commonly affected organs and tissues are the skin, nerves, gastrointestinal tract and
kidneys. Features of skin involvement include cutaneous or subcutaneous nodules, palpable purpura, livedo
reticularis and skin infarction. Neurological involvement is usually restricted to the peripheral nerves, with a
sudden onset of pain and tingling progressing to a motor deficit. The involvement of many nerves evolves into
a pattern of polyneuropathy. Intestinal and liver ischaemia can cause abdominal pain, infarction, haemorrhage
and liver function abnormalities. Kidney impairment can occur due to vascular ischaemic nephropathy, and
malignant hypertension can occur if the renal artery is affected; the glomerulus is rarely affected. End-stage
chronic kidney disease can occur.

About 30% of patients with polyarteritis nodosa are positive for hepatitis B surface antigen, and these patients
should be considered for antiviral therapy before starting, or stopping, immunomodulatory therapy. See
Patients undergoing cancer chemotherapy or immunosuppression for more information, including treatment
recommendations. Classical polyarteritis nodosa is antineutrophil cytoplasmic antibody (ANCA)–negative.

Diagnosis is based on biopsy of affected tissues. Typical sites for biopsy are the sural nerve (particularly if
nerve conduction studies demonstrate involvement), symptomatic muscle, or affected skin. Kidney biopsy
may reveal arteritis (compared to glomerulonephritis in microscopic polyangiitis). Angiography is useful if no
tissue is available for biopsy, and has an increased yield in patients with abdominal symptoms or abnormal
liver biochemistry.

Management should follow the principles outlined in General management approach for systemic
vasculitides. For polyarteritis nodosa without evidence of major organ or body system involvement (eg
disease affecting the skin only, disease characterised by systemic symptoms only) the standard treatment is
high-dose prednis(ol)one as recommended for patients with disease not affecting a major organ or body
system. For disease affecting a major organ or body system (eg patients with polyneuropathy, kidney or
liver involvement) intravenous methylprednisolone is used instead. Cyclophosphamide is added if a visceral
organ is affected or if disease is progressive despite adequate corticosteroid therapy. In the maintenance phase,
combination therapy with prednis(ol)one and another immunomodulatory drug is almost always required (see
Maintaining remission in systemic vasculitides).

Microscopic polyangiitis
Microscopic polyangiitis is a systemic vasculitis that predominantly affects small blood vessels. The mean age
of occurrence is between 65 and 75 years. Microscopic polyangiitis often presents as an acute, rapidly
progressive glomerulonephritis, and may be associated with pulmonary haemorrhage and skin lesions such as
palpable purpura. Systemic features such as fever may be present before more specific symptoms. Nearly all
patients with microscopic polyangiitis are antineutrophil cytoplasmic antibody (ANCA)–positive.

Most patients with microscopic polyangiitis have impaired kidney function and nephritic urinary sediment
(including red cells and red cell casts); however, kidney biopsy is usually required to confirm the diagnosis.
Prognosis is worse in patients with significant kidney impairment, pulmonary haemorrhage or other end-organ
damage, or who have persistently positive ANCA serology despite treatment.

Management of microscopic polyangiitis should follow the principles outlined in General management
approach for systemic vasculitides. Most patients have disease affecting a major organ or body system and
require intensive induction therapy.

Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) is a systemic vasculitis that
predominantly affects small to medium blood vessels and typically occurs in middle-aged adults. It is a
multisystem disease characterised by necrosis, granuloma formation and vasculitis of the ear, nose and throat,
and lower respiratory tract. Involvement of the ear, nose and throat can manifest as sinusitis, nasal disease,
subglottic stenosis (which is almost pathognomonic), otitis media, hearing loss, and ear pain. Oral lesions can
also occur. Lower respiratory tract involvement manifests as pulmonary infiltrates and nodules, haemoptysis
and pleuritis. About 75% of patients develop glomerulonephritis. The onset of kidney involvement can be
acute and can occur at any time in the course of the disease; it can progress to chronic kidney failure.
Uncommonly, an orbital mass (usually an extension of disease affecting the sinus) or necrotising scleritis
occurs; these presentations suggest sight-threatening disease, which requires intensive treatment.

Most patients with granulomatosis with polyangiitis have a positive antineutrophil cytoplasmic antibody
(ANCA) with the cytoplasmic (cANCA) staining pattern and anti-proteinase-3 (PR-3) specificity. The
diagnosis is confirmed by biopsy of affected tissue.

Management of granulomatosis with polyangiitis should follow the principles outlined in General
management approach for systemic vasculitides. Most patients require intensive induction therapy. In rare
cases, patients have limited disease that does not affect a major organ (eg isolated sinus disease) and treatment
can be started with high-dose oral prednis(ol)one in combination with another immunomodulatory drug (eg
methotrexate or mycophenolate). Once remission is achieved, a combination of prednis(ol)one and another
immunomodulatory drug is usually required to maintain remission.

Historically, trimethoprim+sulfamethoxazole monotherapy was used to treat disease limited exclusively to the
upper airway. However, it is not thought to be as effective at achieving or maintaining remission as treatment
with prednis(ol)one, with or without another immunomodulatory drug, and should not be used alone.
Trimethoprim+sulfamethoxazole (160+800 mg orally, twice daily) may be added to the patient's maintenance
regimen; it should be used with caution in patients treated with methotrexate and in patients with renal
impairment because there is an increased risk of toxicity.

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (formerly known as Churg–Strauss vasculitis) is a systemic
vasculitis that predominantly affects small to medium blood vessels and typically occurs in middle-aged
adults. Patients with eosinophilic granulomatosis with polyangiitis often have a history of atopy or asthma.
Systemic features are common and include fever, anorexia and weight loss. Asthma is the most common
respiratory feature, but pulmonary infiltrates and diffuse interstitial changes, including eosinophilic
infiltration, are also common. Mononeuritis multiplex commonly occurs. Skin manifestations include palpable
purpura, skin infarcts and nodules over pressure areas. Coronary vasculitis or granulomatous infiltration of the
myocardium occurs in up to 50% of cases, and myocardial infarction and congestive cardiac failure are major
causes of mortality in eosinophilic granulomatosis with polyangiitis. Focal, segmental necrotising
glomerulonephritis, often with crescent formation, occurs in approximately 20% of patients.

Blood eosinophilia of greater than 1 × 109/L (normal range less than 0.6 × 109/L) is characteristic. A positive
antineutrophil cytoplasmic antibody (ANCA) with a perinuclear (pANCA) staining pattern is seen in
approximately one-third of patients. Diagnosis is based on a suggestive clinical picture, as well as the
identification of small necrotising granulomas or necrotising vasculitis with frequent eosinophils in a biopsy
of affected tissue (such as the lung). Elevated creatinine indicates a poor prognosis.

Management should follow the principles outlined in General management approach for systemic
vasculitides. Eosinophilic granulomatosis with polyangiitis is highly responsive to corticosteroids.

Immunoglobulin A vasculitis
Introduction
Immunoglobulin A (IgA) vasculitis (formerly known as Henoch–Schönlein purpura) is the most common
vasculitis in children, in whom it is predominantly a self-limiting disease. It is not a common vasculitis in
adults; however, if affected, adults are more likely to develop severe and/or progressive kidney disease.

IgA vasculitis affects small blood vessels, producing a leucocytoclastic vasculitis with a classic triad of
nonthrombocytopenic purpura (typically on the lower limbs extending to the buttocks), colicky abdominal
pain and large-joint arthritis. The arthritis can cause significant pain and swelling, but can also resolve
relatively rapidly.

The most significant consequence of IgA vasculitis is nephritis due to IgA immune complex deposits in the
glomerulus (vasculitic IgA nephropathy). It can occur up to 6 months after the initial presentation of IgA
vasculitis, but the majority of cases are seen within 3 months. The nephritis is usually self-limiting and
resolves fully over weeks to months, but severe glomerular inflammation can lead to permanent scarring,
which occasionally progresses to chronic or even end-stage kidney disease. Progression to chronic kidney
disease can occur shortly or even years after an apparent full recovery, and is most likely in patients who
present with a mixed nephritic–nephrotic syndrome or nephrotic syndrome.

General management approach for IgA vasculitis

All patients with immunoglobulin A (IgA) vasculitis (formerly known as Henoch–Schönlein purpura) need to
be monitored for the development of nephritis because even significant kidney involvement can be
subclinical. See Monitoring for vasculitic IgA nephropathy for the recommended monitoring regimen. It is
crucial that early morning urinalysis and blood pressure monitoring are performed regularly so that kidney
involvement is promptly identified and, as necessary, investigated and treated. Kidney biopsy may be
indicated if there is evidence of significant kidney involvement. The severity of nephritis that warrants
intervention is uncertain because of the lack of high-quality randomised controlled trials. However, based on
the available evidence and expert opinion, immunomodulatory therapy is indicated if significant vasculitic or
crescentic changes are seen on kidney biopsy, particularly in the presence of severe clinical manifestations.

Treatment of abdominal and articular manifestations of IgA vasculitis is largely symptomatic; use analgesics
(such as paracetamol) and nonsteroidal anti-inflammatory drugs (NSAIDs). For principles of NSAID use in
children and adolescents, see Practical prescribing considerations for rheumatological diseases in children and
adolescents and for paediatric dosages of oral NSAIDs, see Table 12.12. For principles of use and adult
dosages of oral NSAIDs, see Principles of NSAID use for musculoskeletal conditions in adults.
Corticosteroids can relieve pain and inflammation and can be trialled in patients with severe abdominal or
joint pain. If corticosteroids are indicated, prednis(ol)one is usually used at a dosage of 1 to 2 mg/kg up to 60
mg orally, per day; tapering the dose to stop may be required. See also Practical prescribing considerations for
rheumatological diseases in children and adolescents and Principles of immunomodulatory drug use for
rheumatological diseases in adults.

Well-controlled clinical trials have shown that corticosteroids do not reduce the risk of developing nephritis
and they should not be used for this purpose. However, corticosteroids (including intravenous
methylprednisolone) are sometimes used by nephrologists to treat patients with nephritis depending on
clinical features and changes on kidney biopsy.

Avoid concurrent use of NSAIDs and oral corticosteroids because of the significantly increased risk of
gastrointestinal toxicity, and because NSAIDs are not likely to have additional benefit in patients taking oral
corticosteroids.

Monitoring for vasculitic IgA nephropathy

The monitoring regimen outlined below is based on a clinical pathway developed for use in children with
immunoglobulin A (IgA) vasculitis (formerly known as Henoch–Schönlein purpura) [Note 2], but it is also
likely to represent a reasonable approach for adult patients, who are more likely to have kidney involvement.
Monitoring should continue while there is an increased risk of nephritis, in particular the first 3 months after
presentation and/or a recurrent flare.

For all patients with IgA vasculitis but without evidence of significant nephritis (normotensive patients
either without abnormalities on urinalysis or with isolated microscopic haematuria only), monitor according to
the following schedule:

weekly measurement of blood pressure and early morning urinalysis for the first month
fortnightly measurement of blood pressure and early morning urinalysis for the second and third months
once-off measurement of blood pressure and early morning urinalysis at 6 and 12 months.

If isolated microscopic haematuria persists at 12 months, continue to measure blood pressure and perform
early morning urinalysis once yearly. If there is a flare of cutaneous or gastrointestinal symptoms of IgA
vasculitis, restart the monitoring schedule from the beginning.

For patients with IgA vasculitis who develop hypertension, macroscopic haematuria or proteinuria while
being monitored, or who have these features at baseline, the following approach is suggested:

detailed clinical review, including measurement of height, weight and blood pressure, and the following
investigations:
urine microscopy and protein–creatinine ratio on an early morning sample
blood tests for albumin, creatinine, urea and electrolytes, full blood count, coagulation profile,
anti-deoxyribonuclease B antibodies and antistreptolysin-O titre
particularly if the diagnosis of IgA vasculitis is not certain, measurement of antinuclear antibodies
(ANA), antibodies to double-stranded DNA (dsDNA), antineutrophil cytoplasmic antibodies
(ANCA), immunoglobulins and complement concentration (C3 and C4)
discuss with a nephrologist if any of the following features are present:
acute nephritic syndrome, suggested by the presence of macroscopic haematuria, proteinuria,
oedema, hypertension and oliguria
nephrotic syndrome, suggested by a urinary protein–creatinine ratio greater than 250 mg/mmol, a
serum albumin less than 25 g/L and the presence of oedema
macroscopic haematuria for 5 consecutive days
urinary protein–creatinine ratio greater than 250 mg/mmol for 4 weeks (measured weekly), or
urinary protein–creatinine ratio greater than 250 mg/mmol for less than 4 weeks (measured
weekly) but which has increased on repeat testing
abnormal renal function
confirmed hypertension
if the patient has proteinuria that does not warrant nephrology review based on the features above,
continue to monitor disease activity. Nephrology review is recommended if there is persistent elevation
of urinary protein–creatinine ratio of:
greater than 100 mg/mmol for 3 months
greater than 50 mg/mmol for 6 months.

Note 2: Tizard EJ, Hamilton-Ayres MJ. Henoch Schönlein purpura. Arch Dis Child Educ Pract Ed
2008;93(1):1-8. [URL]

Kawasaki disease
Introduction
Kawasaki disease is a systemic vasculitis that typically affects the coronary arteries. It occurs almost
exclusively in children and is usually seen before 5 years of age. It is the most important cause of acquired
cardiac disease in children in developed countries.

Diagnosis of Kawasaki disease

The diagnosis of Kawasaki disease is based on criteria outlined in Box 12.11. Incomplete cases (ie patients
who do not fulfil the strict criteria for diagnosis of Kawasaki disease but develop coronary artery lesions) are
relatively common, especially under 1 year of age; the diagnosis should be considered in any child with
unexplained fever for 5 or more days associated with any of the cardinal clinical features listed in Box 12.11.
Other disease features may include preceding diarrhoeal illness, aseptic meningitis, sterile pyuria, uveitis, or
hydropic distension of the gallbladder.

Criteria for the diagnosis of Kawasaki disease (Box 12.11)

The diagnosis of Kawasaki disease is based on the presence of fever for 5 or more days, as well as four or
more of the following cardinal clinical features during the course of the illness, or fewer than four cardinal
clinical features plus coronary artery lesions on echocardiogram:

bilateral nonexudative conjunctivitis

cervical lymphadenopathy (greater than 1.5 cm diameter), usually unilateral
polymorphous rash
changes to the lips and oral cavity including erythema, cracked lips and strawberry tongue
changes in the extremities:
in the acute phase, erythema of palms and soles and oedema of hands and feet
in the subacute phase, desquamation of hands and feet.

Management of Kawasaki disease

The risk of coronary aneurysms in patients with Kawasaki disease is reduced (from around 30% to around
3%) by intravenous infusion of immunoglobulin. The usual dosage is:

intravenous immunoglobulin (IVIg) 2 g/kg intravenously, as a single slow infusion

over 10 to 12 hours.

The infusion may be repeated if the fever persists, or recurs 36 hours or more after the completion of the
initial infusion. If fever persists or recurs following a second dose of intravenous immunoglobulin,
intravenous methylprednisolone is used. The usual dosage is:

methylprednisolone sodium succinate 30 mg/kg up to 1000 mg intravenously, over 1

hour, daily for up to 3 consecutive days.

While the patient remains febrile, high-dose aspirin is typically used. In theory, it may have synergistic anti-
inflammatory properties in combination with intravenous immunoglobulin, with a potential benefit on
coronary vascular inflammation. However, direct evidence of a reduction in the risk of coronary artery lesions
is lacking. Various doses of aspirin have been used in febrile patients, ranging from 30 to 100 mg/kg/day,
given in four divided doses over 24 hours. Doses at the higher end of the range are used overseas, whereas
doses at the lower end of the range are usually used locally. High-dose aspirin is generally continued for 48
hours after the fever resolves.

Low-dose aspirin is used once the fever has resolved, when marked thrombocytosis is typical; the usual
dosage is:

aspirin 3 to 5 mg/kg orally, daily.

Low-dose aspirin is continued until follow-up echocardiography has been performed, typically 6 weeks after
the resolution of fever. Aspirin may be stopped if no coronary artery lesions are detected. However, if lesions
are detected, aspirin should be continued, and ongoing surveillance of the coronary arteries is necessary.

Key references
Systemic vasculitides: introduction

Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill
Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65(1):1–11.

General management approach for systemic vasculitides

Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, et al. Rituximab versus azathioprine for
maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371(19):1771–80.

Hiemstra TF, Walsh M, Mahr A, Savage CO, de Groot K, Harper L, et al. Mycophenolate mofetil vs azathioprine
for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled
trial. JAMA 2010;304(21):2381–8.

Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of
maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med
2003;349(1):36–44.

Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in
ANCA-associated renal vasculitis. N Engl J Med 2010;363(3):211–20.

Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, et al. EULAR recommendations for the
management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009;68(3):310–7.

Ntatsaki E, Carruthers D, Chakravarty K, D'Cruz D, Harper L, Jayne D, et al. BSR and BHPR guideline for the
management of adults with ANCA-associated vasculitis. Rheumatology (Oxford) 2014;53(12):2306–9.

Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for
ANCA-associated vasculitis. N Engl J Med 2010;363(3):221–32.

Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, et al. Plasma exchange and glucocorticoid dosing
in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized
controlled trial. Trials 2013;14:73.

Walters G, Willis NS, Craig JC. Interventions for renal vasculitis in adults. Cochrane Database Syst Rev 2015;
(9):CD003232.

Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the
management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75(9):1583–94. .

Takayasu arteritis

Langford CA. Takayasu arteritis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH.
Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 1322–7.

Polyarteritis nodosa

Ntatsaki E, Watts R, Scott DGI. Polyarteritis nodosa and Cogan syndrome. In: Hochberg MC, Silman AJ, Smolen
JS, Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 1290–9.

Pagnoux C, Seror R, Henegar C, Mahr A, Cohen P, Le Guern V, et al. Clinical features and outcomes in 348
patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005
and entered into the French Vasculitis Study Group Database. Arthritis Rheum 2010;62(2):616–26.

Microscopic polyangiitis

Unizony SH, Stone JH. Antineutrophil cytoplasmic antibody–associated vasculitis. In: Hochberg MC, Silman AJ,
Smolen JS, Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 1310–
21.

Eosinophilic granulomatosis with polyangiitis

Unizony SH, Stone JH. Antineutrophil cytoplasmic antibody–associated vasculitis. In: Hochberg MC, Silman AJ,
Smolen JS, Weinblatt ME, Weisman MH. Rheumatology. 6th ed. Philadelphia, PA: Mosby/Elsevier; 2015. p. 1310–
21.

Immunoglobulin A vasculitis

Davin JC, Coppo R. Henoch-Schonlein purpura nephritis in children. Nat Rev Nephrol 2014;10(10):563–73.
Davin JC, Coppo R. Pitfalls in recommending evidence-based guidelines for a protean disease like Henoch-
Schonlein purpura nephritis. Pediatr Nephrol 2013;28(10):1897–903.

Hahn D, Hodson EM, Willis NS, Craig JC. Interventions for preventing and treating kidney disease in Henoch-
Schonlein Purpura (HSP). Cochrane Database Syst Rev 2015;(8):CD005128.

McCarthy HJ, Tizard EJ. Clinical practice: Diagnosis and management of Henoch-Schonlein purpura. Eur J
Pediatr 2010;169(6):643–50.

Tizard EJ, Hamilton-Ayres MJ. Henoch Schonlein purpura. Arch Dis Child Educ Pract Ed 2008;93(1):1–8.

Trnka P. Henoch-Schonlein purpura in children. J Paediatr Child Health 2013;49(12):995–1003.

Kawasaki disease

Baumer JH, Love SJ, Gupta A, Haines LC, Maconochie I, Dua JS. Salicylate for the treatment of Kawasaki
disease in children. Cochrane Database Syst Rev 2006;(4):CD004175.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Miscellaneous inflammatory syndromes
Behçet syndrome
Overview of Behçet syndrome
Behçet syndrome is uncommon in Australia, but the prevalence is high in countries that formed the ancient silk
route (eg Turkey, Iran, Japan). Although Behçet syndrome is often classified as a systemic vasculitis, vasculitis is
only present in up to 25% of patients.

Key clinical features of Behçet syndrome are recurrent oral and genital ulceration, and ocular inflammation. Both
anterior and posterior chambers of the eye can be involved. Severe uveitis occurs relatively commonly and can
lead to blindness, so prompt referral of patients with Behçet eye disease to an ophthalmologist is essential and may
be sight saving.

Promptly refer patients with Behçet eye disease to an ophthalmologist.

Around 5% of patients with Behçet syndrome have neurological involvement, leading to pyramidal, sensory and
cerebellar signs. Patients with Behçet syndrome are also prone to developing superficial venous thrombophlebitis
and more rarely deep vein thrombosis. An episodic oligoarthritis that is mild and nondeforming can occur and
commonly affects the knees; aspiration of affected joints reveals sterile inflammatory fluid. Many other
manifestations occur, including gastrointestinal ulceration causing colicky abdominal pain, diarrhoea and bleeding,
and a pathergy reaction, in which simple trauma causes papule or pustule formation at the site of injury within a
few hours.

There are no specific laboratory or serological findings for Behçet syndrome.

Always consider the diagnosis of herpes simplex infection in patients who present with oral or genital ulceration,
even in patients with an apparent recurrent episode of Behçet syndrome.

Management of Behçet syndrome

Behçet syndrome requires specialist management. The aim of treatment is to suppress inflammation and preserve
organ function while minimising toxicity from immunomodulatory therapy. Various immunomodulatory drug
regimens are used to treat disease affecting major organs or body systems (eg central nervous system disease,
large-vessel disease, gastrointestinal disease). Large-vessel involvement may lead to aneurysms, which may need
surgical repair.

Some manifestations (eg oral and genital ulceration, arthritis) can be managed in primary care.

For treatment of acute oral or genital ulceration, use:

1 triamcinolone acetonide 0.1% paste applied to lesions, 2 to 3 times daily

OR

2 prednis(ol)one 10 to 15 mg orally, daily until pain is controlled (typically 5 days), then

taper the dose over 1 to 2 weeks to stop.

For recurrent episodes of ulceration, the treatment course may be repeated. See Principles of immunomodulatory
drug use for rheumatological diseases in adults for information on adverse effects associated with long-term
corticosteroid use (such as bone density loss) and advice on how to minimise and monitor for such complications.

Topical pimecrolimus has been used to treat recurrent acute genital ulceration (in combination with colchicine for
prevention) [Note 1]. Data suggest it may reduce healing time and pain.

For prevention of oral or genital ulceration, use:

colchicine 500 micrograms orally, once or twice daily. Reduce dosage in renal
impairment.
Full blood count should be monitored in patients taking colchicine long term.

Apremilast is effective in treating and preventing oral ulcers, and can reduce disease activity and improve quality
of life. For resistant cases of oral and genital ulcers, other drugs used include azathioprine, interferon alfa and
infliximab. Azathioprine is used for the prevention of oral and genital ulcers, whereas interferon alfa and
infliximab can be used for both prevention and treatment.

For treatment of arthritis associated with Behçet syndrome, use:

colchicine 500 micrograms orally, once or twice daily. Reduce dosage in renal
impairment.

For resistant arthritis, other drugs used include azathioprine, interferon alfa and infliximab.

Note 1: At the time of writing, topical pimecrolimus is not approved by the Australian Therapeutic Goods Administration (TGA) for treatment of
genital ulcers in Behçet syndrome. See the TGA website for current information [URL].

Adult-onset Still disease

Overview of adult-onset Still disease
Adult-onset Still disease is a rare disease of unknown cause with manifestations in many body systems. It is
characterised by a vigorous systemic inflammatory response. Adult-onset Still disease affects men and women
equally, and typically presents in early adulthood. The equivalent disease in children is known as systemic arthritis.

The most common clinical features of adult-onset Still disease are arthralgia, arthritis, fever, sore throat and rash.
Approximately one-half of patients have abdominal pain and/or enlarged lymph nodes, spleen or liver.
Approximately one-third of patients have pleurisy and/or pericarditis, which can be particularly painful.

The most common laboratory findings in adult-onset Still disease are marked neutrophil leucocytosis, elevated
inflammatory markers, abnormal liver biochemistry and a very high serum ferritin concentration. Serum ferritin
can be extremely elevated (in the tens of thousands compared with the normal range of 15 to 400 micrograms/L)
and may be useful in monitoring disease activity in combination with inflammatory markers.

Adult-onset Still disease is not associated with autoantibodies and the diagnosis is supported by negative
antinuclear antibodies (ANA) and negative rheumatoid factor (RF). Biopsy is nonspecific.

Diagnosis of adult-onset Still disease requires both exclusion of conditions with similar presentations (especially
infection and malignancy, particularly lymphoma) and consistency with clinical criteria (eg spiking fever for 1
week or longer, arthralgia or arthritis for 2 weeks or longer, characteristic transient erythema during febrile
episodes).

A third of patients have an acute, self-limiting disease course lasting less than 1 year. A further third have one or
more flares, with complete symptom resolution between episodes. The final third have chronic disease
characterised by development of persistent, destructive polyarthritis.

Management of adult-onset Still disease

Treatment of adult-onset Still disease depends on the organs involved and disease severity. Urgently refer patients
with life-threatening manifestations, such as cardiac tamponade or pneumonitis, to an emergency department for
specialist review and treatment with intravenous methylprednisolone.

Urgently refer patients with life-threatening manifestations of adult-onset Still disease to an emergency department.

Some manifestations can be managed in primary care.

For musculoskeletal symptoms or fever, use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of a nonsteroidal anti-inflammatory drug (NSAID) should be weighed against its potential
harms, particularly in patients at high risk of harms (see Principles of NSAID use for musculoskeletal conditions in
adults for more information).

If response to NSAIDs is inadequate, use instead:

 prednis(ol)one 10 to 25 mg orally, daily.

Once disease manifestations are controlled, slowly withdraw prednis(ol)one while carefully monitoring disease
activity; however, some patients may require ongoing corticosteroid therapy because the course of adult-onset Still
disease is highly variable. See Principles of immunomodulatory drug use for rheumatological diseases in adults for
information on adverse effects associated with long-term corticosteroid use (such as bone density loss) and advice
on how to minimise and monitor for such complications.

Patients with chronic symptoms that have not responded to an NSAID and corticosteroid require specialist referral;
only anecdotal evidence is available to guide management. Treatment generally involves the addition of a
conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate. In severe
refractory disease, cyclophosphamide or a biological disease-modifying antirheumatic drug (bDMARD) may be
considered.

Periodic fever syndromes

Overview of periodic fever syndromes
Familial Mediterranean fever is the most common of the periodic fever syndromes (also known as
autoinflammatory syndromes). Other periodic fever syndromes include hyperimmunoglobulinaemia D syndrome,
tumour necrosis factor receptor–associated periodic syndrome and familial cold-induced urticaria syndrome. All
involve recurrent fevers in association with other features such as rash, arthritis, serositis, adenitis, conjunctivitis,
changes in hearing and elevated inflammatory markers.

The diagnosis of periodic fever syndromes is complex and often delayed, with the majority of recurrent fevers in
children remaining undiagnosed. Consider the possibility of a periodic fever syndrome in any patient with
recurrent, self-limiting fevers, particularly if they follow a pattern and are accompanied by other recurring features.
The combination of a patient's clinical features and the duration of fever provides clues to the likely periodic fever
syndrome. The diagnosis of some periodic fever syndromes may be confirmed by genetic testing.

Refer any patient with a suspected periodic fever syndrome to a rheumatologist or other specialist experienced in
the diagnosis and management of these conditions.

Familial Mediterranean fever

Familial Mediterranean fever is caused by a genetic mutation and predominantly occurs in Turkish, Armenian and
Arabic ethnic groups. It can occur at any age, although 80% of cases present during childhood, often in children
younger than 5 years.

Common features of familial Mediterranean fever include:

fever—usually lasting 1 to 3 days

arthritis—affecting large joints with a monoarticular or oligoarticular distribution, and of acute onset and
short duration
polyserositis—typically peritoneal or pleuritic
rash—area of erysipelas-like rash on trunk or limbs
marked elevation of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate).

Less common features include headache, microscopic haematuria, and a vasculitic rash similar to that of
immunoglobulin A vasculitis. A small number of patients have a more persistent pattern of arthritis, in a
distribution similar to that of a spondyloarthritis (eg asymmetric, affecting large joints of the lower limbs).

Without therapy, the frequency of attacks varies from weeks to months.

Colchicine is recommended for the treatment of familial Mediterranean fever and should be continued lifelong if
tolerated. It is very effective at both reducing the frequency of attacks and protecting against the development of
amyloidosis, which is the main complication of familial Mediterranean fever. In children and adults, the usual
dosage is:

colchicine 0.5 to 2 mg orally, daily. Reduce dosage in renal impairment.

To limit the occurrence of early adverse effects, start treatment with the lowest dose and slowly titrate up until
disease control is achieved. In young children, the maintenance dose of colchicine is usually at the lower end of the
dose range. Full blood count should be monitored in patients taking colchicine long term.

Cryoglobulinaemia
Overview of cryoglobulinaemia
Cryoglobulins are serum immunoglobulins that reversibly precipitate in the cold. Cryoglobulins most commonly
develop in response to chronic infections with lymphotropic viruses such as HIV or hepatitis C. Other causes are
lymphoproliferative disorders (eg chronic lymphatic leukaemia, multiple myeloma) and connective tissue diseases
(eg Sjögren syndrome). Cryoglobulins can cause disease varying from minor skin manifestations to life-
threatening vasculitic and kidney disease.

Cryoglobulins cause clinical manifestations by forming aggregates that lodge in blood vessels, causing local
ischaemia, or by activating local inflammatory cascades, typically through the complement system. The most
common manifestation of cryoglobulinaemia is a purpuric rash on the lower limbs. Although less common,
arthralgia, weakness and liver disease occur in approximately one-half of patients. About one-third of patients have
kidney involvement. Rarer manifestations are Raynaud syndrome and peripheral neuropathy. Cryoglobulinaemia
can cause an organ-threatening vasculitis.

Testing for cryoglobulins, assessment of kidney function and exclusion of glomerulonephritis are important when
evaluating patients with suspected cryoglobulinaemia. To determine the underlying cause, patients should have
serum electrophoresis (to identify multiple myeloma) and immunoelectrophoresis (to identify chronic lymphatic
leukaemia), and serology for hepatitis C and B, HIV and rheumatoid factor (RF). Inflammatory markers such as
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are usually elevated. The need for other
investigations depends on the underlying disease.

Management of cryoglobulinaemia
Cryoglobulinaemia requires specialist management. Treatment is related to disease severity and involves
management of the underlying disease (eg hepatitis C) as well as the cryoglobulinaemia itself. Managing the
underlying disease controls associated cryoglobulinaemia; however, immediate intensive immunomodulatory
therapy is also required to control cryoglobulinaemia affecting the kidneys, liver or nerves, or other organ-
threatening vasculitic disease. Rituximab is beneficial in severe cryoglobulinaemic vasculitis and can be continued
long term in most patients. Some patients require plasmapheresis.

Immunoglobulin G4–related disease

Immunoglobulin G4 (IgG4)–related disease is a recently described, systemic, immune-mediated disease that affects
multiple organs. The spectrum of IgG4-related disease includes conditions previously thought to be isolated to a
single organ (eg autoimmune cholangitis, autoimmune pancreatitis). Common presentations include aortitis,
retroperitoneal fibrosis and orbital pseudotumour. Diagnosis is usually based on an elevated serum IgG4 and
histopathological analysis of a tissue sample. IgG4-related disease is an important differential diagnosis of many
inflammatory, infectious and malignant diseases (eg granulomatosis with polyangiitis, microscopic polyangiitis,
eosinophilic granulomatosis with polyangiitis, pancreatic cancer, primary sclerosing cholangitis,
cholangiocarcinoma).

In the initial inflammatory phase of IgG4-related disease, corticosteroids are effective and are first-line therapy. If
patients require long-term high-dose corticosteroid therapy to prevent relapse, consider alternative
immunomodulatory therapy (eg azathioprine, mycophenolate). Detailed international guidelines on the
management of IgG4-related disease are available [Note 2].

Note 2: Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International consensus guidance statement on the
management and treatment of IgG4-related disease. Arthritis Rheumatol 2015;67(7):1688-99. [URL]

Key references
Behçet syndrome

Chams-Davatchi C, Barikbin B, Shahram F, Nadji A, Moghaddassi M, Yousefi M, et al. Pimecrolimus versus placebo in
genital aphthous ulcers of Behcet's disease: a randomized double-blind controlled trial. Int J Rheum Dis
2010;13(3):253–8.

Hamuryudan V, Hatemi G, Tascilar K, Yurdakul S, Mat C, Ozyazgan Y, et al. Colchicine in Behcet syndrome: a
longterm survey of patients in a controlled trial. J Rheumatol 2014;41(4):735–8.

Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Turgut Ozturk B, Mat C, et al. Apremilast for Behcet's syndrome--a phase
2, placebo-controlled study. N Engl J Med 2015;372(16):1510–8.
Kose O, Dinc A, Simsek I. Randomized trial of pimecrolimus cream plus colchicine tablets versus colchicine tablets in
the treatment of genital ulcers in Behcet's disease. Dermatology 2009;218(2):140–5.

Yurdakul S, Mat C, Tuzun Y, Ozyazgan Y, Hamuryudan V, Uysal O, et al. A double-blind trial of colchicine in Behcet's
syndrome. Arthritis Rheum 2001;44(11):2686–92.

Familial Mediterranean fever

Barron KS, Kastner DL. Periodic Fever Syndromes and Other Inherited Autoinflammatory Diseases. In: Petty RE,
Laxer RM, Lindsley CB, Wedderburn LR. Textbook of pediatric rheumatology. 7th ed. Philadelphia, PA: Elsevier
Saunders; 2016.

Padeh S, Livneh A, Pras E, Shinar Y, Lidar M, Feld O, et al. Familial Mediterranean Fever in the first two years of life:
a unique phenotype of disease in evolution. J Pediatr 2010;156(6):985–9.

Cryoglobulinaemia

De Vita S, Quartuccio L, Isola M, Mazzaro C, Scaini P, Lenzi M, et al. A randomized controlled trial of rituximab for the
treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012;64(3):843–53.

Immunoglobulin G4–related disease

Kamisawa T, Zen Y, Pillai S, Stone JH. IgG4-related disease. Lancet 2015;385(9976):1460–71.

Khosroshahi A, Wallace ZS, Crowe JL, Akamizu T, Azumi A, Carruthers MN, et al. International Consensus Guidance
Statement on the Management and Treatment of IgG4-Related Disease. Arthritis Rheumatol 2015;67(7):1688–99.

Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366(6):539–51.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Neck pain
Introduction to neck pain
Neck pain is a common condition affecting one in twenty people worldwide at any time. It causes substantial
disability and is the fourth greatest contributor to global disability. It is more common in women than men, and the
prevalence peaks at around 45 years of age.

Pain experienced in the neck region can originate from structures of the cervical spine, or can be referred from
sources in the head, chest, shoulder or arm. Neck pain can also be associated with headaches (see Cervicogenic
headache in Table 7.3).

Most episodes of neck pain cannot be attributed to a specific cause and are acute and self-limiting (see Nonspecific
neck pain). Acute torticollis (also known as ‘wry neck’) is a common form of acute neck pain involving abnormal
muscle contraction and loss of neck rotation; it is managed as for acute nonspecific neck pain. Other causes of
acute neck pain include cervical radiculopathy and acute calcium pyrophosphate crystal arthritis (see Calcium
pyrophosphate deposition). A specific form of neck pain can occur in patients with rheumatoid arthritis (see Neck
pain and rheumatoid arthritis).

Although serious pathology is rare in patients presenting with neck pain in primary care, clinical suspicion of such
pathology should be raised by the presence of alerting features (see Table 12.20).

Assessment of neck pain

In a patient presenting with neck pain, restricted cervical range of movement and local tenderness indicate that the
pain is of local origin, but does not enable a precise anatomical diagnosis. However, a physical examination is still
important to identify alerting features of serious pathologies (see Table 12.20) and neurological signs, and to
exclude nonspinal causes of neck pain.

The prevalence of asymptomatic degenerative changes in the cervical spine is high and increases with age. In
patients with neck pain who do not have neurological symptoms or signs, and who do not have alerting features of
a serious spinal pathology, further investigation is usually not necessary. This represents the vast majority of
patients seen in primary care.

If a serious spinal pathology is suspected clinically, magnetic resonance imaging (MRI) is the preferred
investigation. If MRI is not available, computed tomography (CT) may be useful, but may be associated with
significant radiation exposure.

For assessment of patients with neck pain who have neurological symptoms or signs, see Assessment of cervical
radiculopathy and Cervical myelopathy.

Nonspecific neck pain

Introduction
In patients who present for care for a new episode of nonspecific neck pain, improvement is often rapid,
irrespective of the cause of the episode, and over half of patients fully recover within 3 months. However, half to
two-thirds of patients still report some pain and disability at 1 to 5 years, either in the form of recurrent acute
episodes or chronic pain. The severity of pain and disability at onset are the only well-established prognostic
factors for nonspecific neck pain.

Whiplash-associated disorder refers to nonspecific neck pain caused by an acceleration–deceleration force to the
neck, usually from a motor vehicle collision. In whiplash-associated disorder, most symptom improvement occurs
in the first 3 months and then symptoms plateau; about half of patients still experience some symptoms at 6 to 12
months. The main prognostic factor for whiplash-associated disorder is the severity of initial symptoms, including
sensory, motor and psychological components. Evidence indicates that parameters related to the impact of the
collision (eg direction of impact, seating position, awareness of impending collision, being stationary when hit)
have no effect on outcome.

For assessment of patients with neck pain, see Assessment of neck pain. Imaging has no utility in patients with
nonspecific neck pain, but may be considered if neurological symptoms or signs are present or a serious pathology
is suspected clinically (see Table 12.20).
Acute nonspecific neck pain

General management approach for acute nonspecific neck pain

As most patients with acute nonspecific neck pain improve rapidly, minimal intervention is required beyond
patient education and reassurance of favourable prognosis. Oral analgesia may be required for pain relief (see
Pharmacological management of acute nonspecific neck pain).

Patient education should include an explanation of the nature of the pain, and advice to stay active (see Lifestyle
and nonpharmacological management of acute nonspecific neck pain). Reassure patients that a serious underlying
cause for their pain is very unlikely and the outcome is generally favourable, although some patients experience
persisting symptoms that can still be present at 6 to 12 months. Assess and address any misconceptions the patient
may have about the nature of the pain, as well as fear-avoidance behaviour. Printed or online information that
reinforces these messages is useful to supplement advice provided by the clinician [Note 1].

If there is persisting pain that is not improving by 4 to 6 weeks, reassess the patient for serious pathologies (see
Table 12.20) including cervical myelopathy, as well as cervical radiculopathy and nonspinal causes of neck pain;
see Assessment of neck pain. In patients with persisting nonspecific neck pain, it is important to identify and
manage any psychosocial factors that may be contributing to the persistence of pain.

Note 1: Patient information on neck pain can be found on the painHEALTH website [URL]. Any management advice given on this website should be
considered in the context of the recommendations in these guidelines.

Lifestyle and nonpharmacological management of acute nonspecific neck pain

Staying active: Encourage patients with acute nonspecific neck pain to stay active and to avoid protecting their
neck from movement. Pacing of activities, and/or resuming usual activities and work in a graded manner may be
required. Reassure patients that although some pain with activity is likely, this does not imply damage to the spine
(ie ‘hurt does not mean harm’). Oral analgesia may be required to facilitate staying active (see Pharmacological
management of acute nonspecific neck pain).

Reassure patients and encourage them to maintain usual activities.

Exercise: Neck exercises are commonly recommended for acute nonspecific neck pain; however, there are no
trials evaluating their efficacy and most patients with acute nonspecific neck pain recover rapidly with minimal
intervention.

Passive physical treatments: Passive physical treatments alone have a limited role in the management of acute
nonspecific neck pain, including in whiplash-associated disorder. Although the evidence to support their use is
limited, some patients report temporary pain relief from thermotherapy (application of heat or cold), massage,
spinal mobilisation and upper thoracic spine manipulation. A trial of these treatments may be considered as part of
an overall management approach that includes patient education and re-introduction of physical activity (see
General management approach for acute nonspecific neck pain).

Low-level laser therapy, transcutaneous electrical nerve stimulation (TENS) and cervical spine manipulation are
not recommended for acute nonspecific neck pain because evidence does not support a benefit.

Evidence suggests that collars are ineffective for reducing pain or improving physical function for acute
nonspecific neck pain, including in whiplash-associated disorder.

Pharmacological management of acute nonspecific neck pain

Ensure other components of acute nonspecific neck pain management, in particular patient education and
reassurance (see General management approach for acute nonspecific neck pain), have been implemented before
considering pharmacological management.

Explain to the patient that the goal of pharmacological management is to reduce, rather than abolish, pain so that
physical function can be maintained. Oral analgesia can be useful to facilitate exercise and staying active, but
advise patients that some pain with activity is likely and reassure them that this does not imply damage to the
spine.

A trial of a nonsteroidal anti-inflammatory drug (NSAID) is recommended for short-term pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

The efficacy of paracetamol in neck pain has not been studied in clinical trials. However, because of its favourable
safety profile, a trial of paracetamol may be considered if NSAIDs are contraindicated or not tolerated. Use:

1 paracetamol 1 g orally, 4- to 6-hourly as necessary, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly as necessary.

For patients with pain that persists throughout the day, or if there is inadequate response to ‘as necessary’ dosing,
consider a trial of regular rather than ‘as necessary’ dosing of oral analgesia.

The efficacy of tricyclic antidepressants (TCAs) in neck pain has not been studied in clinical trials. A trial of a
TCA may be considered if pain is not adequately relieved with other measures and is persisting beyond 2 to 3
weeks. TCAs may be particularly useful if pain is interfering with sleep. To reduce the risk of drowsiness during
the day, start at a low dose and increase the dose slowly as tolerated and if needed; an example regimen is:

amitriptyline 10 to 25 mg orally, in the early evening; increasing the daily dose by up to 25

mg every 2 to 4 weeks as tolerated and according to response, up to a maximum
maintenance dose of 50 mg each evening.

If drowsiness during the day is a concern, nortriptyline and doxepin are the preferred TCAs. TCAs should be used
with care in older patients and in patients with cardiovascular disease.

Although commonly prescribed, opioids have a very limited role in the management of acute nonspecific neck
pain. The efficacy of opioids in neck pain has not been studied in clinical trials and they are associated with a
significant risk of harms. Opioids may be considered for patients with severe pain that is not adequately relieved
with other measures and is interfering with their ability to function. If opioids are used, they should be prescribed
on a short-term trial basis, as part of an overall pain management strategy, with clear goals and regular review of
treatment response and adverse effects. Before starting an opioid, a plan for ceasing ineffective therapy should be
in place and discussed with the patient. If treatment response is inadequate, caution should be exercised when
increasing the dose of opioids as there is an increased risk of harm and potentially no added benefit. Prolonged use
of opioids indicates the need for specialist assessment. See Opioids for more information.

Muscle relaxants are not recommended for acute nonspecific neck pain because there is only limited evidence to
support their use, and their potential harms may outweigh any potential benefits. Drowsiness, dizziness, increased
risk of falls and dependency are common adverse effects.

Chronic nonspecific neck pain

General management approach for chronic nonspecific neck pain

Chronic nonspecific neck pain has been poorly studied. Management should follow the same principles as for
other types of noninflammatory chronic pain and should be based on an integrated biopsychosocial approach (see
Chronic pain: overview).

Exercise is recommended for all patients with chronic nonspecific neck pain (see Lifestyle and
nonpharmacological management of chronic nonspecific neck pain). Exercise should be combined with education
about the nature of the pain. Reassure the patient that although some pain with activity is likely, this does not
imply damage to the spine (ie ‘hurt does not mean harm’).

Some patients with chronic nonspecific neck pain require ongoing oral analgesia (see Pharmacological
management of chronic nonspecific neck pain).

Multidisciplinary rehabilitation programs may be considered for patients with chronic nonspecific neck pain.
These programs aim to simultaneously address all components (physical, psychological and social) of the patient's
pain experience. The key psychological intervention is cognitive behavioural therapy (CBT). There is moderate-
quality evidence that CBT is better than other interventions for addressing fear of neck movement, but it may not
provide other benefits. See Cognitive behavioural therapy for more information.

Evidence does not support a role for surgery in chronic nonspecific neck pain. For the specific indication of lateral
atlanto-axial osteoarthritis, observational data suggest that posterior C1-C2 fusion may offer symptom relief if
other measures have failed. Lateral atlanto-axial osteoarthritis is characterised by severe unilateral neck pain, often
radiating into the suboccipital region, and severe unilateral movement restriction.
Lifestyle and nonpharmacological management of chronic nonspecific neck pain

Exercise: Exercise is a central component in the management of chronic nonspecific neck pain, but the optimal
program and mode of exercise has not been defined. Generally, a program that includes stretching, strengthening
and proprioceptive retraining exercises is recommended. Proprioceptive retraining involves slow neck movements
following a moving target. Also consider postural education, postural exercises and ergonomic advice. It is also
important to encourage a general exercise program including walking, gym or water-based exercise.

Collars and pillows: Wearing a soft collar during the day is not useful for chronic nonspecific neck pain. Using
more than one pillow, unless for the management of other medical conditions, is generally not recommended.
Patients who experience neck pain or stiffness on waking may benefit from having a supporting pillow, or a small
towel rolled inside a pillowcase, placed under their neck, or from wearing a soft collar or a thick scarf to bed.
However, none of these strategies has been evaluated in clinical trials.

Other passive physical treatments: Low-level laser therapy, intermittent traction and acupuncture may provide
short-term pain relief for chronic nonspecific neck pain. There is only limited evidence of short-term benefits for
manual therapies (eg spinal manipulation or mobilisation) in chronic nonspecific neck pain, and ongoing manual
therapy is not recommended. These passive physical treatments should only be considered as part of an overall
management approach (see General management approach for chronic nonspecific neck pain).

Ultrasound, infrared light and continuous traction are ineffective for chronic nonspecific neck pain.

Pharmacological management of chronic nonspecific neck pain

Some patients with chronic nonspecific neck pain require ongoing oral analgesia, depending on their degree of
pain. Oral analgesia can be used to facilitate exercise, which is thought to be more effective in the longer-term
control of pain. The drugs and doses used for oral analgesia are as for acute nonspecific neck pain (see
Pharmacological management of acute nonspecific neck pain). Monitor treatment response and adverse effects,
and periodically consider a trial of treatment cessation.

Injection and ablation therapies for chronic nonspecific neck pain

Various types of injections have been used to treat chronic nonspecific neck pain, including trigger point injections
at sites of maximal tenderness with corticosteroid, botulinum toxin or dry needling; however, there is no evidence
that these therapies provide definite benefit.

Injection and ablation techniques targeting putative structural causes of chronic neck pain, such as the cervical
facet joints, are sometimes used. Pain relief from injection of local anaesthetic into the putatively painful joint(s),
or from blocking their nerve supply via medial branch blocks, may identify the source of neck pain and provide the
rationale for percutaneous radiofrequency denervation. The proponents of these techniques assert that meticulous
identification of appropriate patients is required and that these techniques should only be undertaken by skilled
treatment providers in specialist centres. Decisions to investigate chronic nonspecific neck pain for therapeutic
purposes should be coordinated by specialists; current evidence does not justify widespread use of this approach.

Cervical radiculopathy
Introduction

Cervical radiculopathy is due to compression or irritation of nerve roots in the cervical spine. The C7 and C6 nerve
roots are most frequently involved. Most cases of cervical radiculopathy are due to degenerative changes in the
cervical spine and/or lateral disc herniation. Rare noncompressive causes include herpes zoster (shingles),
malignancy, nerve root infarction and demyelination.

Cervical radiculopathy may be associated with spinal cord compromise, so careful neurological examination and
appropriate imaging are required to exclude myelopathy (see Cervical myelopathy).

Cervical radiculopathy is more common in men than women, and the incidence peaks between 50 and 54 years of
age. In general, cervical radiculopathy has a favourable prognosis, with most people starting to improve within 4
weeks and many recovered within 6 months.

Assessment of cervical radiculopathy

Patients with cervical radiculopathy typically describe severe pain radiating from the neck down one arm, but pain
may radiate down both arms. Pain is often accompanied by neurological symptoms or signs (eg paraesthesia,
numbness, weakness). Symptoms and signs may occur in a dermatomal distribution; however, this is often
nonspecific because of the extensive overlap of dermatomes. A full neurological examination of the upper limbs
should be undertaken. Reduced triceps reflex suggests C7 or C8 involvement while reduced biceps and
brachioradialis reflexes suggest C5 or C6 involvement.

Several physical tests have been described for diagnosing cervical radiculopathy. These include the neck
compression test (Spurling manoeuvre) and the shoulder abduction test. The neck compression test is performed
by extending the neck and rotating it to the affected side, then applying downward pressure on the head. The result
is positive if pain is provoked. This test has a high specificity, but a low sensitivity, for cervical radiculopathy. It
should never be performed in patients with rheumatoid arthritis, suspected metastatic disease or myelopathy. The
shoulder abduction test is performed by placing the palm of the affected arm on top of the head while seated. The
result is positive if pain relief is obtained. This test has a low to moderate sensitivity, but a moderate to high
specificity, for cervical radiculopathy.

Early imaging (before 6 to 8 weeks) is usually not required for cervical radiculopathy unless a serious pathology
(see Table 12.20), including cervical myelopathy, is suspected clinically or there is a progressive neurological
deficit or concern about a neurological deficit. Magnetic resonance imaging (MRI) is the preferred imaging
modality.

Management of cervical radiculopathy

If cervical myelopathy has been excluded, the management of cervical radiculopathy is similar to the management
of acute nonspecific neck pain (see General management approach for acute nonspecific neck pain).

Wearing a semi-hard collar during the day combined with rest for 3 to 6 weeks, or a supervised graded exercise
program combined with home exercises for 6 weeks, may be beneficial for acute symptoms (lasting less than 1
month). There is limited evidence that adding cervical traction to exercise is beneficial. Neither cervical spine
manipulation nor foraminal nerve root injections are recommended because the risk of harms outweighs any
potential benefits.

There is limited evidence that a short course of prednis(ol)one reduces pain and improves physical function in
patients with cervical radiculopathy, although the optimal dosage and duration of treatment are not defined. An
example dosage is:

prednis(ol)one 30 mg orally, daily for 5 to 10 days, then taper the dose over 1 to 3 weeks
to stop.

Surgical consultation is indicated for all patients with a progressive neurological deficit, or for any patient if there
is concern about a neurological deficit. Surgical consultation may be considered for patients with severe persisting
arm pain at 6 to 8 weeks despite nonsurgical management, provided imaging identifies nerve root compression that
is concordant with the patient's clinical features and could be corrected with surgery. Limited evidence from open
trials comparing surgery to nonsurgical management suggests surgery results in better short-term outcomes;
longer-term outcomes (up to 2 years) are similar.

Cervical myelopathy
Cervical myelopathy results from a midline disc herniation compressing the spinal cord in the cervical region. This
condition occurs more commonly in the older age group. It requires surgical decompression to prevent progressive
and permanent neurological damage; urgently refer patients with suspected cervical myelopathy for neurosurgical
assessment.

Urgently refer patients with suspected cervical myelopathy for neurosurgical assessment.

Patients with cervical myelopathy present with difficulties walking and have long-tract signs on examination,
including unsteady gait, loss of proprioception and a positive Romberg sign. Lhermitte phenomenon (paraesthesia
occurring with neck flexion) may be present, but is not specific for myelopathy. Patients may also have weakness,
hyperreflexia or hyporeflexia, upgoing plantar responses, and/or sensory loss with a sensory level. Imaging is
required for cervical myelopathy; magnetic resonance imaging (MRI) is the preferred imaging modality.

Neck pain and rheumatoid arthritis

Patients with rheumatoid arthritis can develop neck pain due to cervical spine involvement. This usually occurs in
the context of longstanding disease, but rarely can occur as an early feature of rheumatoid arthritis. Cervical spine
involvement may be associated with atlanto-axial instability, which is important to identify and manage. With the
advent of more effective disease-modifying antirheumatic drugs (DMARDs), the prevalence of atlanto-axial
instability is declining.

Atlanto-axial instability arises through erosive damage to the complex ligament and joint structures that link the
atlas (C1) to the axis (C2). In severe cases, the odontoid peg, normally constrained against the inside of the ring of
C1, moves backwards relative to C1 and compresses the upper spinal cord. Clinically, this is often preceded by
upper neck pain, typically in the suboccipital region and often unilateral. Symptoms and signs of upper motor
neurone deficits occur later and indicate the need for urgent neurosurgical assessment (see Cervical myelopathy).
In patients with concurrent severe peripheral joint disease, detection of subtle neurological deficits, such as
weakness and lower limb reflex changes, may be difficult.

Any clinical suspicion of atlanto-axial instability should prompt further investigation, including lateral plain X-ray
of the cervical spine in flexion and extension. These investigations may reveal an increased distance in the atlanto-
dens interval. Abnormalities on these investigations, or the presence of any neurological symptoms or signs,
require further assessment with magnetic resonance imaging (MRI) or, if unavailable, computed tomography (CT).
MRI or CT should be performed in a specialist centre, ideally with rheumatological and neurosurgical input.

Atlanto-axial instability is an absolute contraindication to cervical spine manipulation. Advise patients with known
atlanto-axial instability to avoid excessive or uncontrolled movements of the neck (eg when having their hair
washed at the hairdresser). Appropriate precautions should be taken in patients with atlanto-axial subluxation who
are receiving general anaesthesia.

Key references
Introduction to neck pain

Global Burden of Disease Study Collaborators. Global, regional, and national incidence, prevalence, and years lived
with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for
the Global Burden of Disease Study 2013. Lancet 2015;386(9995):743–800.

Hoy D, March L, Woolf A, Blyth F, Brooks P, Smith E, et al. The global burden of neck pain: estimates from the global
burden of disease 2010 study. Ann Rheum Dis 2014;73(7):1309–15.

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160
sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
Lancet 2012;380(9859):2163–96.

Introduction to nonspecific neck pain

Carroll LJ, Hogg-Johnson S, van der Velde G, Haldeman S, Holm LW, Carragee EJ, et al. Course and prognostic
factors for neck pain in the general population: results of the Bone and Joint Decade 2000-2010 Task Force on Neck
Pain and Its Associated Disorders. J Manipulative Physiol Ther 2009;32(2 Suppl):S87–96.

Carroll LJ, Holm LW, Hogg-Johnson S, Cote P, Cassidy JD, Haldeman S, et al. Course and prognostic factors for neck
pain in whiplash-associated disorders (WAD): results of the Bone and Joint Decade 2000-2010 Task Force on Neck
Pain and Its Associated Disorders. Spine (Phila Pa 1976) 2008;33(4 Suppl):S83–92.

Hush JM, Lin CC, Michaleff ZA, Verhagen A, Refshauge KM. Prognosis of acute idiopathic neck pain is poor: a
systematic review and meta-analysis. Arch Phys Med Rehabil 2011;92(5):824–9.

Kamper SJ, Rebbeck TJ, Maher CG, McAuley JH, Sterling M. Course and prognostic factors of whiplash: a systematic
review and meta-analysis. Pain 2008;138(3):617–29.

Leaver AM, Maher CG, McAuley JH, Jull G, Latimer J, Refshauge KM. People seeking treatment for a new episode of
neck pain typically have rapid improvement in symptoms: an observational study. J Physiother 2013;59(1):31–7.

Walton DM, Carroll LJ, Kasch H, Sterling M, Verhagen AP, Macdermid JC, et al. An overview of systematic reviews on
prognostic factors in neck pain: results from the International Collaboration on Neck Pain (ICON) project. Open Orthop
J 2013;7:494–505.

Acute nonspecific neck pain

Berry H, Liyanage SP, Durance RA, Goode JD, Swannell AJ. A double-blind study of benorylate and chlormezanone in
musculoskeletal disease. Rheumatol Rehabil 1981;20(1):46–9.

Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle
spasm: results of two placebo-controlled trials. Clin Ther 2003;25(4):1056–73.

Gennis P, Miller L, Gallagher EJ, Giglio J, Carter W, Nathanson N. The effect of soft cervical collars on persistent neck
pain in patients with whiplash injury. Acad Emerg Med 1996;3(6):568–73.

Gross A, Kay TM, Paquin JP, Blanchette S, Lalonde P, Christie T, et al. Exercises for mechanical neck disorders.
Cochrane Database Syst Rev 2015;(1):CD004250.

Gross A, Langevin P, Burnie SJ, Bedard-Brochu MS, Empey B, Dugas E, et al. Manipulation and mobilisation for neck
pain contrasted against an inactive control or another active treatment. Cochrane Database Syst Rev 2015;
(9):CD004249.

Verhagen AP, Scholten-Peeters GG, van Wijngaarden S, de Bie RA, Bierma-Zeinstra SM. Conservative treatments for
whiplash. Cochrane Database Syst Rev 2007;(2):CD003338.

Vincent K, Maigne JY, Fischhoff C, Lanlo O, Dagenais S. Systematic review of manual therapies for nonspecific neck
pain. Joint Bone Spine 2013;80(5):508–15.

Wong JJ, Cote P, Ameis A, Varatharajan S, Varatharajan T, Shearer HM, et al. Are non-steroidal anti-inflammatory
drugs effective for the management of neck pain and associated disorders, whiplash-associated disorders, or non-
specific low back pain? A systematic review of systematic reviews by the Ontario Protocol for Traffic Injury
Management (OPTIMa) Collaboration. Eur Spine J 2016;25(1):34–61.

Chronic nonspecific neck pain

Elliott RE, Tanweer O, Smith ML, Frempong-Boadu A. Outcomes of fusion for lateral atlantoaxial osteoarthritis: meta-
analysis and review of literature. World Neurosurg 2013;80(6):e337–46.

Graham N, Gross AR, Carlesso LC, Santaguida PL, Macdermid JC, Walton D, et al. An ICON overview on physical
modalities for neck pain and associated disorders. Open Orthop J 2013;7:440–60.

Gross A, Kay TM, Paquin JP, Blanchette S, Lalonde P, Christie T, et al. Exercises for mechanical neck disorders.
Cochrane Database Syst Rev 2015;(1):CD004250.

Gross A, Langevin P, Burnie SJ, Bedard-Brochu MS, Empey B, Dugas E, et al. Manipulation and mobilisation for neck
pain contrasted against an inactive control or another active treatment. Cochrane Database Syst Rev 2015;
(9):CD004249.

Gross AR, Dziengo S, Boers O, Goldsmith CH, Graham N, Lilge L, et al. Low level laser therapy (LLLT) for neck pain:
a systematic review and meta-regression. Open Orthop J 2013;7:396–419.

Gross AR, Peloso PM, Galway E, Navasero N, Essen KV, Graham N, et al. Physician-delivered injection therapies for
mechanical neck disorders: a systematic review update (non-oral, non-intravenous pharmacological interventions for
neck pain). Open Orthop J 2013;7:562–81.

Monticone M, Cedraschi C, Ambrosini E, Rocca B, Fiorentini R, Restelli M, et al. Cognitive-behavioural treatment for
subacute and chronic neck pain. Cochrane Database Syst Rev 2015;(5):CD010664.

Trinh K, Graham N, Irnich D, Cameron ID, Forget M. Acupuncture for neck disorders. Cochrane Database Syst Rev
2016;(5):CD004870.

Vincent K, Maigne JY, Fischhoff C, Lanlo O, Dagenais S. Systematic review of manual therapies for nonspecific neck
pain. Joint Bone Spine 2013;80(5):508–15.

Cervical radiculopathy

Engquist M, Lofgren H, Oberg B, Holtz A, Peolsson A, Soderlund A, et al. A 5- to 8-year randomized study on the
treatment of cervical radiculopathy: anterior cervical decompression and fusion plus physiotherapy versus
physiotherapy alone. J Neurosurg Spine 2017;26(1):19–27. .

Engquist M, Lofgren H, Oberg B, Holtz A, Peolsson A, Soderlund A, et al. Surgery versus nonsurgical treatment of
cervical radiculopathy: a prospective, randomized study comparing surgery plus physiotherapy with physiotherapy
alone with a 2-year follow-up. Spine (Phila Pa 1976) 2013;38(20):1715–22.

Fritz JM, Thackeray A, Brennan GP, Childs JD. Exercise only, exercise with mechanical traction, or exercise with over-
door traction for patients with cervical radiculopathy, with or without consideration of status on a previously described
subgrouping rule: a randomized clinical trial. J Orthop Sports Phys Ther 2014;44(2):45–57.

Ghasemi M, Golabchi K, Mousavi SA, Asadi B, Rezvani M, Shaygannejad V, et al. The value of provocative tests in
diagnosis of cervical radiculopathy. J Res Med Sci 2013;18(Suppl 1):S35–8.

Ghasemi M, Masaeli A, Rezvani M, Shaygannejad V, Golabchi K, Norouzi R. Oral prednisolone in the treatment of
cervical radiculopathy: A randomized placebo controlled trial. J Res Med Sci 2013;18(Suppl 1):S43–6.

Kuijper B, Tans JT, Beelen A, Nollet F, de Visser M. Cervical collar or physiotherapy versus wait and see policy for
recent onset cervical radiculopathy: randomised trial. BMJ 2009;339:b3883.

Nikolaidis I, Fouyas IP, Sandercock PA, Statham PF. Surgery for cervical radiculopathy or myelopathy. Cochrane
Database Syst Rev 2010;(1):CD001466.

Radhakrishnan K, Litchy WJ, O'Fallon WM, Kurland LT. Epidemiology of cervical radiculopathy. A population-based
study from Rochester, Minnesota, 1976 through 1990. Brain 1994;117 (Pt 2):325–35.

Rheumatoid arthritis and neck pain

Zhang T, Pope J. Cervical spine involvement in rheumatoid arthritis over time: results from a meta-analysis. Arthritis
Res Ther 2015;17:148.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Low back pain
Introduction to low back pain
Low back pain or lumbar spine pain is defined as pain localised below the costal margin and above the inferior
gluteal folds, with or without leg pain.

Most patients with low back pain seen in primary care will have a nonspecific local musculoskeletal condition with
an acute and self-limited clinical course (see Nonspecific low back pain). Inflammation may occur as part of the
repair process; however, it is a consequence of, rather than the cause of, the presentation. The term ‘mechanical
back pain’ is sometimes used to describe nonspecific low back pain to highlight the exclusion of an underlying
systemic inflammatory disease (eg ankylosing spondylitis) or other serious pathology (eg spinal infection,
malignancy, fracture), but should not be used to infer a reliable relationship between symptoms and anatomical
structures.

Low back pain associated with spinal nerve root involvement is typically due to a herniated lumbar disc (see
Symptomatic lumbar disc herniation), but in older patients is usually due to lumbar canal or foraminal stenosis (see
Symptomatic spinal canal stenosis).

Although serious pathology is rare in patients presenting with low back pain in primary care, clinical suspicion of
such pathology should be raised by the presence of alerting features (see Table 12.20).

Assessment of low back pain

Clinical assessment
Nonspecific low back pain is poorly localised and often influenced by posture and movement. It may be associated
with nonradicular leg pain that is also poorly localised and dull or aching in character; this is described as somatic
referred pain.

Nerve root involvement is suggested by the presence of radicular pain. Lumbar radicular pain is often described by
patients as a sharp, shooting or burning pain that radiates down the lateral or posterior side of one leg, or rarely
both legs, often to the ankle or foot. It is sometimes associated with a ‘pins and needles’ sensation. Pain is often
experienced in a dermatomal distribution and may be aggravated by coughing, sneezing or straining. Radicular leg
pain may be associated with neurological symptoms or signs (eg weakness, dermatomal hyperaesthesia or
hypoaesthesia, absent or reduced reflexes). The presence of radicular leg pain alone is not considered a serious
pathology in the absence of severe or progressive neurological deficits. Radicular pain due to nerve root
involvement in the lumbar spine is commonly referred to as ‘sciatica’, although nerve roots from L1 to L4 may
also be involved. See also Assessment of symptomatic lumbar disc herniation and Assessment of symptomatic
spinal canal stenosis.

In all patients with low back pain, consider and exclude serious pathologies; clinical suspicion of these is raised by
the presence of alerting features (see Table 12.20). Any indication of cauda equina compression is a spinal
emergency; immediately refer the patient to an emergency department for review by a neurosurgeon or spinal
surgeon.

Any indication of cauda equina compression is a spinal emergency.

In patients with nonspecific low back pain, a precise anatomical diagnosis is usually not necessary, or possible with
physical examination. However, a physical examination is still important to identify alerting features of serious
pathologies and neurological signs, and to understand the patient's spinal movement patterns and limitations.
Spinal symmetry, posture and flexibility, and spinal tenderness can be assessed with the patient standing. Firm
digital palpation over spinous processes and paraspinal structures may reproduce the back and referred leg pain.
Abdominal examination, pelvic examination, or assessment of hip irritability and range of movement is indicated
if history suggests pathology in these areas.

Alerting features (‘red flags’) of serious pathologies in patients with spinal pain (Table 12.20)

Serious pathology Alerting features [NB1]

symptoms and signs of infection (eg fever)
 risk factors for infection (eg underlying disease,
spinal infection (eg osteomyelitis, epidural
immunosuppression, penetrating wound, history of injecting
abscess)
drugs)
raised inflammatory markers (eg CRP, ESR) [NB2]

history of significant trauma

vertebral fracture history of minor trauma if: age older than 50 years, history of
osteoporosis or taking corticosteroids

history of malignancy
age older than 50 years
failure to improve with treatment
malignancy unexplained weight loss
pain at multiple sites
pain at rest
symptoms in other body systems (eg cough, dysphagia)

sudden onset of pain

absence of aggravating features (eg pain not aggravated by
visceral disease (eg pancreatitis, aortic spinal movement)
aneurysm [leak or rupture]) associated collapse or hypotension
abdominal pain radiating to the back

altered bladder and/or bowel function (eg urinary retention,

faecal incontinence)
cauda equina compression reduced sensation in the ‘saddle’ area
progressive bilateral foot or leg weakness

a sensory level
weakness
hyperreflexia or hyporeflexia
spinal cord pathology (myelopathy) upgoing plantar responses
sensory loss
see also cervical myelopathy

younger age (onset before 40 years)

symptom duration of longer than 3 months
prolonged morning stiffness and night pain
alternating buttock pain
ankylosing spondylitis
improvement of symptoms with physical activity or exercise,
and failure to improve with rest
response to NSAIDs

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; NSAIDs = nonsteroidal anti-inflammatory drugs
NB1: The presence of a single alerting feature is associated with a small increased likelihood of serious pathology compared with the presence of
multiple alerting features.
NB2: ESR and CRP should only be measured if other alerting features for spinal infection are present.

Imaging

Radiological findings are poorly correlated with symptoms in patients with low back pain. Many commonly
reported abnormalities on lumbar spine imaging are physiological and not related to the experience of pain. For
example, disc abnormalities, facet joint arthropathy, annular tears and spondylolisthesis occur frequently in adults
without back pain. Giving patients a diagnostic label (eg a ruptured, torn, prolapsed or herniated disc) based on
radiological findings is unhelpful and often leads to fear-avoidance behaviour, worsening disability and
unwarranted further investigation and treatment.

Radiological findings are poorly correlated with symptoms in patients with low back pain.

Lumbar spine X-ray and magnetic resonance imaging (MRI) have no utility in patients with nonspecific low back
pain, but may be considered to investigate serious pathologies if suspected clinically (see Table 12.20). Choice of
investigation should be guided by the suspected pathology. MRI is superior to computed tomography (CT) and has
a lower risk of harm because of less radiation exposure, but CT may be considered if MRI is contraindicated or
unavailable. For discussion of imaging in patients with radicular pain, see Assessment of symptomatic lumbar disc
herniation and Symptomatic spinal canal stenosis.
Nonspecific low back pain
Introduction
About 80% of people will experience an episode of nonspecific low back pain at some time in their lives, and it is
most common between the ages of 35 and 55 years. Most episodes are acute and mild, but the prevalence of
chronic severe, disabling pain increases with age (see Prognosis of nonspecific low back pain). Up to half of
patients seek medical care, most in the primary care setting. Adolescents and children also experience nonspecific
low back pain, and unresolved pain in youth is a predictor of pain in adulthood.

For assessment of patients with low back pain, see Assessment of low back pain. Lumbar spine imaging has no
utility in patients with nonspecific low back pain, but may be considered if neurological symptoms or signs are
present or a serious pathology is suspected clinically (see Table 12.20); see Imaging.

Risk factors for developing nonspecific low back pain include heavy physical work; frequent bending, twisting, or
lifting; and prolonged static postures. Symptoms of depression and lifestyle factors (eg smoking, obesity, physical
inactivity) are also associated with nonspecific low back pain. Exercise has a significant protective effect against
nonspecific low back pain.

Prognosis of nonspecific low back pain

Low back pain is designated as acute if it persists for less than 12 weeks or chronic if it persists for longer than 12
weeks. The outcome of a single episode of nonspecific low back pain is generally favourable. Most patients have
an acute course that improves rapidly (usually within 4 weeks) with no ongoing limitation in daily activities, and
patients can resume normal physical function and return to work quickly regardless of whether the pain has fully
resolved. However, many of these patients will have recurrent episodes of low back pain.

A small number of patients develop chronic nonspecific low back pain, which can be severe and disabling. Among
those who present with chronic symptoms, two-thirds are still not fully recovered at 1 to 2 years. Therefore, early
intervention to address risk factors for chronicity is important in patients with acute low back pain.

Risk factors for poor prognosis include a high level of pain and disability at presentation, leg pain, older age, poor
general health, psychosocial factors (eg mental stress, anxiety, depression), and reduced cognition. For work-
related prognostic factors, see Prevention of work-related disability. Misconceptions about the nature of the pain
and unhelpful coping strategies can also contribute to poor prognosis; these include:

belief that back pain is harmful to the spine

belief that there is structural damage to the spine associated with spinal weakness or instability
fear-avoidance behaviour and reduced activity and participation
lowered mood and withdrawal from social interaction
belief that passive treatment(s) alone rather than active participation will help.

Assessment of risk factors for poor prognosis may be aided by the use of validated tools, such as the STarT Back
tool [Note 1] or Örebro Musculoskeletal Pain Questionnaire [Note 2]. Depending on the duration of symptoms at
the time of presentation, some risk factors for poor prognosis may not be assessable initially.

Note 1: The STarT Back tool is available at [URL].

Note 2: Linton SJ, Boersma K. Early identification of patients at risk of developing a persistent back problem:
the predictive validity of the Örebro Musculoskeletal Pain Questionnaire. Clin J Pain 2003;19(2):80-6. [URL]

General management approach for nonspecific low back pain

Acute nonspecific low back pain

In acute nonspecific low back pain, the aims of management are to reduce pain, restore and maintain physical
function, minimise disability and absence from work, and reduce the risk of chronicity.

In most patients with acute nonspecific low back pain, minimal intervention is required and symptoms resolve with
appropriate patient education and reassurance of favourable prognosis. Oral analgesia may be required (see
Pharmacological management of nonspecific low back pain), and massage or thermotherapy may be considered for
pain relief based on patient preference (see Nonpharmacological management of nonspecific low back pain). To
reassure patients and aid confidence in self-management, schedule a review appointment at 4 to 6 weeks and
advise the patient to cancel the appointment in the likely event that their pain improves.

Patient education should include:

 an explanation of the nature of the pain and why imaging is not required—most back pain is caused by a
simple strain of the back and a serious underlying cause is very unlikely; in most patients it is not possible to
make a precise anatomical diagnosis on clinical or radiological grounds, or to identify a specific cause for
the pain
advice to stay active (see Staying active)
encouragement to continue to work or to return to work as soon as possible (see Prevention of work-related
disability)
reassurance that recovery is likely to be quick even though pain may be severe
an assessment and clarification of patient misconceptions about the nature of the pain, including addressing
fear-avoidance behaviour and other unhelpful coping strategies that contribute to poor prognosis.

Printed or online information that reinforces these messages is useful to supplement advice provided by the
clinician [Note 3]. Physiotherapists can have a role in patient education in acute nonspecific low back pain, and
referral should be considered particularly for patients with risk factors for poor prognosis (see Prognosis of
nonspecific low back pain).

If there is persisting pain that is not improving by 4 to 6 weeks, reassess the patient for serious pathologies (see
Table 12.20). In patients with persisting nonspecific low back pain, early intervention to prevent progression to
chronicity is important; use an integrated biopsychosocial approach to management that addresses risk factors for
poor prognosis (see Prognosis of nonspecific low back pain). Components of management include:

patient education and reassurance, including advice to stay active (see Staying active)
support for continuing or returning to work (see Prevention of work-related disability)
identification and management of psychosocial factors; consider cognitive behavioural therapy (see
Nonpharmacological management of nonspecific low back pain) and treat specific diagnoses (eg depression
or anxiety)
exercise
if required, oral analgesia (see Pharmacological management of nonspecific low back pain)
if appropriate, massage or thermotherapy for pain relief (see Nonpharmacological management of
nonspecific low back pain).

Note 3: Patient information on low back pain can be found on the WA Health Networks and painHEALTH
websites. Any management advice given in these sources should be considered in the context of the
recommendations in these guidelines.

Chronic nonspecific low back pain

Management of chronic nonspecific low back pain should follow the same principles as for other types of
noninflammatory chronic pain and should be based on an integrated biopsychosocial approach (see Chronic pain:
overview).

See also the components of management for persisting acute nonspecific low back pain (see Acute nonspecific low
back pain); in particular, exercise is beneficial for chronic nonspecific low back pain and should be encouraged.
Multidisciplinary rehabilitation programs aim to simultaneously address all components (physical, psychological
and social) of the patient's pain experience. They may reduce pain and improve physical function; however, the
ideal content and context for these programs, including the number and duration of sessions, is unclear.

Corticosteroid injections are not recommended for nonspecific low back pain, including putative facet joint pain,
because evidence does not support a benefit.

Anaesthetic blocks or provocation techniques may be used to attempt to identify specific structures that may be
responsible for low back pain. However, currently, there are no proven treatment options for patients with chronic
low back pain in whom such investigations suggest a nociceptive input from discs or sacroiliac joints. There is
limited evidence that percutaneous radiofrequency facet denervation provides pain relief in the small number of
individuals demonstrated to have isolated facet joint pain. The proponents of these techniques assert that
meticulous identification of appropriate patients is required and that these techniques should only be undertaken by
skilled treatment providers in specialist centres. Decisions to investigate chronic nonspecific low back pain for
therapeutic purposes should be coordinated by specialists; current evidence does not justify widespread use of this
approach.

Evidence does not support a role for surgery in chronic nonspecific low back pain.

Lifestyle management of nonspecific low back pain

Staying active

Encourage patients with nonspecific low back pain to stay active, including adopting normal movement and
physical function as much as possible, and continuing or returning to work (see Prevention of work-related
disability). Compared to bed rest, staying active reduces pain, disability and time off work, and increases the rate
of recovery. Prolonged bed rest is harmful and should be discouraged. Adverse effects of bed rest include joint
stiffness, prolonged pain, muscle wasting and bone demineralisation.

Reassure patients that although some pain with activity is likely, this does not imply damage to the spine (ie ‘hurt
does not mean harm’), and that staying active is not associated with recurrent episodes of low back pain. Oral
analgesia may be required to facilitate staying active (see Pharmacological management of nonspecific low back
pain).

Reassure patients and encourage them to maintain usual activities.

To assist patients with staying active, provide advice on techniques to minimise pain when getting out of bed and
moving around; this advice may be provided by a physiotherapist. Encourage pacing of activities, and resuming
usual activities and work in a graded manner.

Prevention of work-related disability

A large proportion of patients with nonspecific low back pain are able to continue their usual work without
modification or restrictions, and work participation is important for recovery from nonspecific low back pain.
Extended initial time off work is associated with prolonged work-related disability; fewer than half of patients who
have been off work for 6 months will return to work and, after 2 years of work absenteeism, the chance of
returning to work is negligible.

The patient's expectation of return to work is the most important predictor of return to work. Other barriers to
returning to work and recovery from nonspecific low back pain include poor relations with colleagues, work-
related mental stress, heavy physical work demands, the presence of compensation claims, and inappropriate work
capacity certification from health professionals. Address work-related prognostic factors early to prevent
prolonged disability; suggested questions for identifying these include:

Have you had time off work in the past with back pain?
What do you understand is the cause of your back pain?
What are you expecting will help?
How are your employers, colleagues, and family responding to your back pain?
What are you doing to cope with back pain?
Do you think that you will return to work? When?

The optimal approach to supporting the patient in returning to work includes:

providing reassurance about returning to work and staying active

understanding the patient's work context and job demands in relation to their physical capacity and beliefs
understanding the employer's ability to accommodate the patient's needs
communicating with the patient's employer to facilitate a prompt return to work; if necessary, return to work
may require modifying the patient's duties and/or hours.

Exercise

Exercise is safe for the majority of patients with nonspecific low back pain. Graded exercise programs can assist in
recovery by improving physical function and normalising central nervous system activity (which is often altered in
people who experience chronic pain). Encouraging patients to exercise also reinforces positive beliefs about
recovery, self-efficacy and physical capacity, and important messages about staying active and resuming usual
activities in a graded manner. Maintaining exercise after the resolution of an acute episode of nonspecific low back
pain may reduce the frequency of recurrent episodes.

Many different exercise programs have been advocated for the treatment of nonspecific low back pain, including
exercises in a specific direction (direction-biased exercise programs, eg flexion or extension), exercises to
strengthen the trunk stabilising muscles, and exercises to improve flexibility or enhance aerobic fitness. Given the
wide range of potentially appropriate exercise modes and dosages, it is difficult to draw definite conclusions about
the comparative effectiveness of specific programs. Data suggest exercise that promotes whole-body, compound
movements (eg squats, lunges, step-ups) and is functionally oriented is more beneficial than non-functional
exercise (eg specific stabilising exercises). Furthermore, isolated non-functional exercise may reinforce
misconceptions about the nature of the pain and fear-avoidance behaviour in the longer term.

In this context, a pragmatic approach to exercise for nonspecific low back pain is recommended based on the
practice points in Box 12.12. Appropriately guided exercise programs can be undertaken independently, in a group,
or as part of an existing fitness program. Consider referral to a physiotherapist particularly for patients with risk
factors for poor prognosis (see Prognosis of nonspecific low back pain). In the short term, some patients may
require specific movement re-education or exercise based on their clinical presentation (eg severity of pain, anxiety
related to pain). This approach may also be needed for patients who do not recover within a clinically reasonable
time frame.

Oral analgesia may be required to facilitate exercise (see Pharmacological management of nonspecific low back
pain).

Practice points for recommending exercise for patients with nonspecific low back pain (Box
12.12)

Emphasise to the patient that it is safe and helpful to move. Bracing and avoiding normal movements is
unhelpful in the long term. Using phrases like ‘hurt does not mean harm’, ‘sore but safe’, and ‘your spine
is strong’ may be helpful. Some patients may benefit from individualised education about their beliefs,
fears and pain experience.
Exercise programs should be individualised, taking into account the patient's physical activity preferences,
beliefs and specific functional impairments.
Exercise programs should include stretching, strengthening and aerobic exercises that are functionally
oriented.
Starting with gentle movements is the first step. These might include water-based walking, land-based
walking, gentle swimming and floor stretches that encourage the spine to move in its normal planes.
Activity should be graded by the duration of time spent exercising, rather than the pain experienced.
As the patient's tolerance to activity over longer periods of time increases, the mode, frequency and/or
intensity of activity can be progressed.
Functional exercises can be introduced to encourage large muscle group activation (eg squats,
lunges, step-ups).
Exercise that patients enjoy (eg yoga, Pilates, walking, cycling) can be gradually introduced (eg start
at 15 to 20 minutes' duration and then increase).
In the later stages of rehabilitation, more dynamic and higher-load exercises can be performed.

Nonpharmacological management of nonspecific low back pain

Passive physical treatments alone have a limited role in the management of nonspecific low back pain. Although
the evidence to support their use is limited, some patients report temporary pain relief from thermotherapy
(application of heat or cold) and massage. A trial of these treatments may be considered as part of an overall
management approach that includes patient education and re-introduction of physical activity (see General
management approach for nonspecific low back pain).

The following passive physical treatments are not recommended for nonspecific low back pain because evidence
does not support a benefit: acupuncture, spinal manipulative therapy, lumbar supports, transcutaneous electrical
nerve stimulation (TENS), laser therapy, traction, electromyographic biofeedback, therapeutic ultrasound or short-
wave diathermy.

Preliminary studies of motion-sensor biofeedback indicate a benefit in low back pain, but further data are required
before this therapy can be recommended.

Cognitive behavioural therapy (CBT) helps patients develop adaptive coping behaviours and strategies to self-
manage their pain. CBT is effective for persisting and chronic nonspecific low back pain and should be considered
early if psychosocial factors are identified. See Cognitive behavioural therapy for more information.

Pharmacological management of nonspecific low back pain

Ensure other components of nonspecific low back pain management, in particular patient education and
reassurance (see General management approach for nonspecific low back pain), have been implemented before
considering pharmacological management.

Explain to the patient that the goal of pharmacological management is to reduce, rather than abolish, pain so that
physical function can be maintained. Oral analgesia can be useful to facilitate exercise and staying active, but
advise patients that some pain with activity is likely and reassure them that this does not imply damage to the
spine.

A trial of a nonsteroidal anti-inflammatory drug (NSAID) is recommended for short-term pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).
Evidence indicates that paracetamol is ineffective for nonspecific low back pain. However, individual patients may
experience a benefit and, because of its favourable safety profile, a trial of paracetamol may be considered if
NSAIDs are contraindicated or not tolerated. Use:

1 paracetamol 1 g orally, 4- to 6-hourly as necessary, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly as necessary.

For patients with pain that persists throughout the day, or if there is inadequate response to ‘as necessary’ dosing,
consider a trial of regular rather than ‘as necessary’ dosing of oral analgesia.

Oral corticosteroids are occasionally used as part of an analgesic strategy for acute nonspecific low back pain, but
evidence does not support a benefit. Given the significant adverse effects of long-term corticosteroid use, oral
corticosteroids should not be used for chronic nonspecific low back pain.

Although commonly prescribed, opioids have a very limited role in the management of nonspecific low back pain.
Evidence for efficacy of opioids in acute low back pain is lacking. In chronic low back pain, opioids provide only
modest short-term pain relief and evidence for long-term efficacy is lacking. Opioids are associated with a
significant risk of harms. Opioids may be considered for patients with severe pain that is not adequately relieved
with other measures and is interfering with their ability to function. If opioids are used, they should be prescribed
on a short-term trial basis, as part of an overall pain management strategy, with clear goals and regular review of
treatment response and adverse effects. Before starting an opioid, a plan for ceasing ineffective therapy should be
in place and discussed with the patient. If treatment response is inadequate, caution should be exercised when
increasing the dose of opioids as there is an increased risk of harm and potentially no added benefit. Prolonged use
of opioids indicates the need for specialist assessment. See Opioids for more information.

Studies up to 1 year in patients with chronic low back pain indicate that tapentadol may have a more favourable
safety profile than oxycodone; however, the long-term safety of tapentadol is not known and the same precautions
as for other opioids should be applied to tapentadol.

There is no evidence that muscle relaxants are effective for persisting or chronic nonspecific low back pain. In the
acute setting (used for less than 4 days), there is evidence that muscle relaxants may reduce pain and muscle
tension, and increase mobility, but their potential harms may outweigh any potential benefits. Drowsiness,
dizziness, increased risk of falls and dependency are common adverse effects.

Symptomatic lumbar disc herniation

Introduction
Lumbar disc herniation is often asymptomatic; up to 36% of people without a history of back pain have a herniated
disc on imaging and this finding is more common in older people. While lumbar disc herniation can cause spinal
nerve root compression, evidence indicates that nerve root compression alone is insufficient to cause symptoms
and that inflammation is also important. The prevalence of symptomatic lumbar disc herniation is between 1 and
3%, with the highest prevalence reported in patients between 30 and 50 years of age. Most herniated discs occur at
the L4 to L5 level; disc herniations above this level are more common in people over 55 years of age.

In symptomatic lumbar disc herniation, the herniated portion of the disc may regress over time. Most patients who
present for care improve rapidly (within 2 weeks); 80% of patients recover within 8 weeks and 95% of patients
recover within a year. Prognostic factors in symptomatic lumbar disc herniation have not been well studied.

Assessment of symptomatic lumbar disc herniation

Nerve root involvement is suggested by the presence of radicular leg pain (see Clinical assessment). Pain may be
worse in certain positions, such as sitting.

A positive straight-leg raise test is highly sensitive (around 91%) for nerve root involvement, but has a low
specificity (around 26%). A positive straight-leg raise test is defined as reproduction of radicular leg pain when the
affected leg is elevated to less than 60 degrees with the ankle dorsiflexed and the knee fully extended. A positive
crossed straight-leg raise test is highly specific (around 88%) for nerve root involvement, but has a low sensitivity
(around 29%). A positive crossed straight-leg raise test is defined as reproduction of radicular leg pain when
performing a straight-leg raise test on the contralateral side. Early referral to a specialist should be considered if
the diagnosis is uncertain.

Neurological symptoms and signs aiding the localisation of possible nerve root involvement are given in Table
12.21. Any indication of cauda equina compression is a spinal emergency; immediately refer the patient to an
emergency department for review by a neurosurgeon or spinal surgeon. Alerting features of other serious
pathologies in patients with spinal pain should also be excluded (see Table 12.20).

Any indication of cauda equina compression is a spinal emergency.

X-rays are not useful for symptomatic lumbar disc herniation. The diagnosis can be confirmed by magnetic
resonance imaging (MRI) or, if not available, computed tomography (CT); however, early imaging (before 6 to 8
weeks) is unnecessary unless there are severe or progressive neurological deficits or there is concern about a
neurological deficit.

Symptoms and signs of nerve root involvement at different spinal levels (Table 12.21)

Reduced muscle Reduced or absent

Level Reduced sensation Other
power reflex
anterior and lateral
L3 or L4 knee extension knee jerk
aspects of thigh
dorsiflexion of big toe particularly dorsum of
L5 ankle jerk
and ankle foot
particularly lateral
plantar flexion of
S1 aspect and sole of ankle jerk
ankle
foot
altered bladder and/or
progressive bilateral bowel function (eg
cauda equina ‘saddle’ area
foot or leg weakness urinary retention,
faecal incontinence)

Management of symptomatic lumbar disc herniation

Conservative management is generally recommended in the first 6 to 8 weeks. Management is essentially the
same as for nonspecific low back pain (see General management approach for nonspecific low back pain). Patients
should be given adequate explanation about the condition including its cause, lack of need for early diagnostic
imaging, and the expected outcome.

Encourage patients to continue with usual activities; however, some activity modification will be necessary to
avoid provoking pain. Physical treatments such as massage, acupuncture, exercise and traction are of unknown
efficacy, and the safety of spinal manipulation in patients with significant radicular symptoms is uncertain.

Translumbar, transsacral or transforaminal (or ‘nerve root’) epidural corticosteroid injections may provide short-
term pain relief in some patients; however, the average improvement in pain is small. A 15-day course of oral
corticosteroids may improve physical function, but has little effect on pain. There is no evidence to support the use
of intradiscal corticosteroid injection or chemonucleolysis of the disc with chymopapain injection. Drugs that are
indicated for neuropathic pain (eg tricyclic antidepressants, gabapentin, pregabalin) may be useful for radicular
pain, which could be considered to be a neuropathic pain; however, evidence from high-quality randomised
controlled trials is lacking.

Surgical consultation is indicated for all patients with severe or progressive neurological deficits, or for any
patient if there is concern about a neurological deficit. Surgical consultation should be considered for patients with
severe persisting leg pain at 6 to 8 weeks despite conservative management, provided there is concordance
between radiological findings and neurological signs. Surgery results in more rapid recovery than conservative
management; however, long-term outcomes are similar in patients who have early surgery and those who have
prolonged conservative management followed by surgery if needed. Potential harms from surgery include
complications from anaesthesia, infection, and neurological damage.

Symptomatic spinal canal stenosis

Introduction
Spinal canal stenosis is the narrowing of the vertebral or intervertebral canal and is often multifactorial. The lower
three lumbar levels are most frequently affected. Spinal canal stenosis can be asymptomatic and is detected on
imaging in over 20% of people older than 60 years of age without a history of back pain.

The clinical course of symptomatic spinal canal stenosis is variable, and can be unpredictable, with flares and
stable periods over time. Approximately 50% of patients remain clinically stable, while 25% deteriorate over time
and the remaining 25% improve over time. Despite the common perception of a progressive course, patients with
mild to moderately symptomatic spinal canal stenosis have a favourable outcome in 30 to 50% of cases.

Assessment of symptomatic spinal canal stenosis

Symptomatic disease generally presents with low back pain radiating to the buttocks and legs, and is usually
bilateral. Patients can also present with leg pain alone and no back pain. Pain may be aggravated by walking or
standing, and relieved by sitting or leaning forward (neurogenic claudication or pseudoclaudication); this must be
distinguished from the similar symptoms of claudication due to arterial insufficiency. Radicular leg pain in a single
dermatomal distribution is more suggestive of single nerve root compression (see Symptomatic lumbar disc
herniation).

Progressive bilateral foot or leg weakness, reduced sensation in the ‘saddle’ area, and altered bladder and/or bowel
function (eg urinary retention, faecal incontinence) indicate the possibility of cauda equina compression. Any
indication of cauda equina compression is a spinal emergency; immediately refer the patient to an emergency
department for review by a neurosurgeon or spinal surgeon. Alerting features of other serious pathologies in
patients with spinal pain should also be excluded (see Table 12.20).

Any indication of cauda equina compression is a spinal emergency.

In patients with suspected symptomatic spinal canal stenosis, the diagnosis can be confirmed by magnetic
resonance imaging (MRI) or, if not available, computed tomography (CT).

Management of symptomatic spinal canal stenosis

Most commonly used treatments for symptomatic spinal canal stenosis are of unproven benefit. Conservative
treatments include physical therapy and exercise. Epidural corticosteroid injection is often considered; however,
recent evidence does not demonstrate a benefit. Oral corticosteroids are not effective for symptomatic spinal canal
stenosis.

Surgical consultation is indicated for all patients with severe or progressive neurological deficits, or for any patient
if there is concern about a neurological deficit. Surgical consultation should be considered for patients with severe
persisting pain despite conservative management. Surgery may have an early benefit compared to conservative
management; however, the long-term effects are uncertain. The risk of harms from surgery increases with
advancing age, comorbidity and concurrent fusion.

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Malmivaara A, Slatis P, Heliovaara M, Sainio P, Kinnunen H, Kankare J, et al. Surgical or nonoperative treatment for
lumbar spinal stenosis? A randomized controlled trial. Spine (Phila Pa 1976) 2007;32(1):1–8.

Weinstein JN, Tosteson TD, Lurie JD, Tosteson AN, Blood E, Hanscom B, et al. Surgical versus nonsurgical therapy
for lumbar spinal stenosis. N Engl J Med 2008;358(8):794–810.

Zaina F, Tomkins-Lane C, Carragee E, Negrini S. Surgical versus non-surgical treatment for lumbar spinal stenosis.
Cochrane Database Syst Rev 2016;(1):CD010264.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Thoracic spine (upper back) pain
Introduction to thoracic spine pain
Pain in the thoracic spine or upper back is defined as pain localised below the neck and above the costal margin.
The thoracic spine is a complex structure with seven joints (one intervertebral joint, two zygapophyseal or facet
joints, two costovertebral joints, two costotransverse joints) at each of 12 levels. Pain experienced in the thoracic
spine can originate from the joints or other structures of the thoracic spine (eg the dura, intervertebral discs,
vertebral bodies, muscles, thoracic nerves), or the underlying mediastinal viscera.

Thoracic spine pain is common, with a 1-year prevalence of 20% in adults. Higher rates are reported in
adolescents, but this may reflect the focus of studies on this group.

Compared with low back pain, pain experienced in the thoracic spine is more commonly due to a serious
underlying pathology (eg myocardial ischaemia, pulmonary embolism, vertebral fracture) (see Assessment of
thoracic spine pain). Pain experienced in the thoracic spine may also be due to a nonspecific local musculoskeletal
condition (see Nonspecific thoracic spine pain) or thoracic radiculopathy. Thoracic spine pain often coexists with
neck pain and low back pain and is common after motor vehicle collisions. Other thoracic spine diagnoses
associated with pain include diffuse idiopathic skeletal hyperostosis and Scheuermann disease.

The prognostic factors for thoracic spine pain have not been well studied, although occupational factors, age and
mental health appear to be important.

Assessment of thoracic spine pain

It is important to exclude serious underlying medical and spinal pathologies in a patient presenting with thoracic
spine pain. Patient history should focus on features that suggest an underlying disease of the heart, great vessels,
lungs or oesophagus. These features include the site of pain, and aggravation of pain on movement, respiration and
eating. Pain aggravated by movement and respiration can occur in both musculoskeletal and visceral (particularly
pleural) causes of thoracic spine pain. Any suspicion of cardiac, pleural or respiratory disease should be fully
evaluated before a diagnosis of nonspecific thoracic spine pain is made. Pain that is constantly present, including at
night, and unrelieved by rest suggests invasion, distortion or inflammation of pain-sensitive structures.
Spondyloarthritides (eg psoriatic arthritis, ankylosing spondylitis) and SAPHO syndrome (characterised by any
combination of synovitis, acne, pustulosis, hyperostosis and osteitis) can affect joints in the upper thoracic region
(eg sternoclavicular joint, manubriosternal joint) and therefore can also present with thoracic spine pain. Alerting
features of serious pathologies in patients with spinal pain are given in Table 12.20.

Thoracic spine pain due to a nonspecific local musculoskeletal condition is suggested by pain that is constant in its
location, dull or aching in character (but may have sharp exacerbations), and often related to specific movements
or postures rather than exertion.

Thoracic radicular pain (pain due to compromise of the thoracic ventral spinal nerve roots) occurs less frequently
than lumbar or cervical radicular pain. Thoracic radicular pain is typically perceived in the back and radiates
around the chest wall and abdomen along the segmental dermatome of the thoracic ventral spinal nerves. The
presence of thoracic radicular pain should alert the clinician to the possibility of systemic pathologies such as
diabetic radiculopathy or, if skin rash is present, herpes zoster (shingles). Thoracic disc herniation is an uncommon
cause of isolated radicular pain but, if present, may compromise the spinal cord (myelopathy). Careful
neurological examination and appropriate imaging is required to exclude myelopathy and the need for urgent
surgical intervention.

Examination of the thoracic spine has limited utility in identifying specific painful structures, but may provide
useful information about the aetiology of the pain. Physical examination should include:

postural assessment for scoliosis and kyphosis, and visible muscle contraction or wasting
assessment of the chest for skin rashes or scars
assessment of range of movement (rotation, flexion and extension) and chest expansion
palpation for tenderness and muscle contraction or spasm
neurological examination, including sensory examination over the chest wall to determine if there is altered
sensation in a dermatomal distribution or there is a sensory level, and assessment of the lower limbs for
long-tract signs (specifically weakness, hyperreflexia or hyporeflexia, upgoing plantar responses and sensory
loss).

The need for and type of investigations are guided by clinical assessment. If fracture is suspected, plain X-ray may
be adequate. If the age of the fracture is uncertain, a bone scan may be useful to determine if the fracture is recent.
For discussion of imaging in patients with radicular pain, see Thoracic radiculopathy. If myelopathy is suspected,
magnetic resonance imaging (MRI) is indicated and should be obtained urgently if there are new or progressive
neurological deficits.

Nonspecific thoracic spine pain

The evidence to guide management of nonspecific thoracic spine pain is limited; the following recommendations
are a reasonable approach.

If analgesia is required, use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

If response to paracetamol is inadequate, a nonsteroidal anti-inflammatory drug (NSAID) may be used instead of,
or in combination with, paracetamol. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Nonpharmacological management of nonspecific thoracic spine pain involves a combination of stretching and
mobilising exercises to restore range of movement (usually rotation and extension). A short course of manual
therapy may assist patients with pain and mobility. There is no evidence to support the use of other physical
treatments, such as electrotherapy and acupuncture, for thoracic spine pain.

Management of chronic nonspecific thoracic spine pain should follow the same principles as for other types of
noninflammatory chronic pain and should be based on an integrated biopsychosocial approach (see Chronic pain:
overview). For patients with persistent pain that is interfering with their ability to function despite conservative
management, consider referral to a pain specialist for targeted techniques.

Thoracic radiculopathy
The evidence base for management of thoracic radiculopathy is sparse.

For management of herpes zoster (shingles), see Shingles for antiviral therapy, and Acute herpes zoster pain.

For management of diabetic radiculopathy, see Atypical diabetic neuropathies.

The clinical course of radiculopathy due to thoracic disc herniation has been poorly studied, but it is thought to
have a more favourable prognosis than cervical or lumbar disc herniation. If myelopathy has been excluded (see
Assessment of thoracic spine pain), initial management should be conservative, including analgesia (as for
nonspecific thoracic spine pain) and local treatments (eg application of heat). Specific treatment for neuropathic
pain is discussed in Neuropathic pain.

The indications for imaging for thoracic radiculopathy are not established; consider magnetic resonance imaging
(MRI) if surgery is being contemplated, such as in patients with persisting or progressive neurological deficits or in
patients with refractory pain.

Diffuse idiopathic skeletal hyperostosis

Diffuse idiopathic skeletal hyperostosis (DISH) (also known as Forestier disease) is characterised by ligamentous
ossification in the spine resulting in progressive stiffness and, sometimes, pain. In some patients, it may be
asymptomatic. DISH typically affects the thoracic spine, but can also affect the cervical and lumbar spine. It can
also cause enthesitis (inflammation at the sites of tendon and ligament attachment to bone) at peripheral sites.
Ankylosing spondylitis is a differential diagnosis, but can be distinguished on the basis of radiographic
appearance. The aetiology of DISH is unknown, but the condition is associated with metabolic disorders such as
hyperuricaemia, dyslipidaemia, obesity, glucose intolerance and diabetes, as well as the use of oral retinoids.

There are no specific treatments for DISH and management is as for nonspecific thoracic spine pain, including
analgesia and exercise. It is prudent to avoid vigorous manipulation of the spine in case this causes fracturing of
ossified ligaments. Metabolic conditions associated with DISH should be managed as indicated; however, it is
uncertain if this affects the progression of DISH. If DISH is associated with the use of an oral retinoid, treatment
should be stopped.

Scheuermann disease
Scheuermann disease is a condition of unknown aetiology that affects the developing intervertebral disc, typically
in the thoracic spine, and is associated with kyphosis of the spine.

In most cases, radiographic findings of Scheuermann disease (endplate irregularity and Schmorl nodes in the
thoracic vertebrae) are identified during investigation for back pain. However, the relationship between these
findings and back pain is uncertain and likely to be weak. There are no specific treatments for Scheuermann
disease and management is as for nonspecific thoracic spine pain. If kyphosis is severe, or associated with
respiratory compromise, surgery may be warranted.

Key references
Thoracic spine (upper back) pain

Atluri S, Singh V, Datta S, Geffert S, Sehgal N, Falco FJ. Diagnostic accuracy of thoracic facet joint nerve blocks: an
update of the assessment of evidence. Pain Physician 2012;15(4):E483–96.

Australian Acute Musculoskeletal Pain Guidelines Group. Evidence-based management of acute musculoskeletal
pain: a guide for clinicians. Bowen Hills, Qld: Australian Academic Press; 2004.
http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/cp95.pdf

Bortsov AV, Platts-Mills TF, Peak DA, Jones JS, Swor RA, Domeier RM, et al. Pain distribution and predictors of
widespread pain in the immediate aftermath of motor vehicle collision. Eur J Pain 2013;17(8):1243–51.

Briggs AM, Smith AJ, Straker LM, Bragge P. Thoracic spine pain in the general population: prevalence, incidence and
associated factors in children, adolescents and adults. A systematic review. BMC Musculoskelet Disord 2009;10:77.

Graf SW, Whittle SL. Isotretinoin-induced skeletal hyperostosis. Springerplus 2014;3:698.

Hincapie CA, Cassidy JD, Cote P, Carroll LJ, Guzman J. Whiplash injury is more than neck pain: a population-based
study of pain localization after traffic injury. J Occup Environ Med 2010;52(4):434–40.

Holm LW, Carroll LJ, Cassidy JD, Skillgate E, Ahlbom A. Widespread pain following whiplash-associated disorders:
incidence, course, and risk factors. J Rheumatol 2007;34(1):193–200.

Johansson MS, Jensen Stochkendahl M, Hartvigsen J, Boyle E, Cassidy JD. Incidence and prognosis of mid-back
pain in the general population: A systematic review. Eur J Pain 2017;21(1):20–8. .

Mader R. Current therapeutic options in the management of diffuse idiopathic skeletal hyperostosis. Expert Opin
Pharmacother 2005;6(8):1313–8.

O'Connor RC, Andary MT, Russo RB, DeLano M. Thoracic radiculopathy. Phys Med Rehabil Clin N Am
2002;13(3):623–44, viii.

Roquelaure Y, Bodin J, Ha C, Le Marec F, Fouquet N, Ramond-Roquin A, et al. Incidence and risk factors for thoracic
spine pain in the working population: the French Pays de la Loire study. Arthritis Care Res (Hoboken)
2014;66(11):1695–702.

Southerst D, Marchand AA, Cote P, Shearer HM, Wong JJ, Varatharajan S, et al. The effectiveness of noninvasive
interventions for musculoskeletal thoracic spine and chest wall pain: a systematic review by the Ontario Protocol for
Traffic Injury Management (OPTIMa) Collaboration. J Manipulative Physiol Ther 2015;38(7):521–31.

van Kleef M, Stolker RJ, Lataster A, Geurts J, Benzon HT, Mekhail N. 10. Thoracic pain. Pain Pract 2010;10(4):327–
38.

van Tulder MW, Assendelft WJ, Koes BW, Bouter LM. Spinal radiographic findings and nonspecific low back pain. A
systematic review of observational studies. Spine (Phila Pa 1976) 1997;22(4):427–34.
Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Low back pain and pelvic pain in pregnancy
Low back pain in pregnancy
Nonspecific low back pain occurs in 50 to 70% of pregnant women. It occurs more commonly in women with
previous back pain, whether associated with pregnancy or not, but is not correlated with maternal weight or fetal
size. The incidence of lumbar disc herniation resulting in radiculopathy in pregnancy is no higher than in the
general population.

Prepregnancy fitness and continuation of a strengthening program throughout pregnancy reduce the likelihood of
low back pain in pregnancy. If exercise is insufficient to control symptoms, use:

1 paracetamol 1 g orally, 4- to 6-hourly as necessary, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly as necessary.

Pelvic pain in pregnancy

Pelvic pain arising from the sacroiliac joints and/or the pubic symphysis can be experienced in pregnancy,
especially in women with high concentrations of relaxin. This pain may occur early in pregnancy. Appropriately
graded strengthening and stabilising exercises, such as the use of a fit ball or water-based exercise, can be helpful
and should be encouraged.

Changes in pubic symphysis width probably occur in most pregnant women, with a gap of up to 1 cm being
considered normal. Rupture of the pubic symphysis (diastasis) can occur; especially in association with precipitate
labour, cephalopelvic disproportion, pre-existing pelvic abnormality or excessive thigh abduction that can occur
during delivery under epidural anaesthesia. The reported incidence of this condition is lessening as the number of
forceps deliveries decreases. Pubic diastasis can be associated with severe suprapubic pain and may take months to
several years to resolve.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Limb conditions
Introduction to limb conditions
In the clinical assessment of any limb condition, consider and exclude features that suggest an underlying systemic
inflammatory disease or other serious pathology (see Assessing peripheral musculoskeletal symptoms in adults and
Assessing musculoskeletal symptoms in children and adolescents).

Soft-tissue conditions of the limbs can be broadly grouped by the affected tissue; management principles are
outlined for the following groups of soft-tissue conditions:

muscle strain or tear

tendinopathy
ligament sprain or tear.

The management of the following specific conditions are also discussed:

rotator cuff disease

adhesive capsulitis (frozen shoulder)
lateral and medial epicondylar tendinopathies (tennis elbow and golfer's elbow)
de Quervain tenosynovitis
carpal tunnel syndrome
flexor tenosynovitis (trigger finger)
hip joint conditions
greater trochanteric pain syndrome
patellofemoral pain syndrome
prepatellar bursitis
chronic exertional compartment syndrome
medial tibial stress syndrome
tear of the Achilles tendon
plantar fasciitis.

Specific radiological findings discussed are femoroacetabular impingement and hip labral tears, and degenerative
meniscal tears.

For common noninflammatory musculoskeletal conditions in children and adolescents, see Noninflammatory
musculoskeletal pain in children and adolescents. Perthes disease, slipped capital femoral epiphysis and irritable
hip are important mimics of juvenile idiopathic arthritis in the lower limbs. For more information on these
conditions, see Important mimics of juvenile idiopathic arthritis in the lower limbs.

Management principles for muscle strain or tear

Muscle strain or tear is an acute injury to muscle caused by excessive tension or lengthening. It is both
aetiologically and mechanistically different from delayed-onset muscle soreness.

The initial management of a muscle strain or tear is RICE therapy (see Table 12.22). Although the benefit of RICE
therapy is supported by widespread use in practice, the effectiveness of this approach has not been proven in
randomised controlled trials.

If analgesia is required, first-line treatment is paracetamol. Nonsteroidal anti-inflammatory drugs (NSAIDs) may
be used in combination with paracetamol. There is a theoretical risk of NSAIDs inhibiting muscle repair through
negative effects on satellite cell populations. For this reason, NSAIDs should not be used for more than 48 hours
for acute muscle injury. See Principles of NSAID use for musculoskeletal conditions in adults for more
information on NSAID use and dosing. Opioids are rarely indicated for acute muscle injury and are associated
with a significant risk of harms.

Exercise is important for rehabilitation of the injured muscle to prevent recurrence of injury, although the optimal
time to start exercise is unclear. Depending on the patient's functional impairments and their expectations for
recovery, referral to an appropriate physical therapist (eg a physiotherapist) may be indicated. A supervised
rehabilitation program is particularly important for patients who participate in significant physical activity or who
have specific functional goals.

To reduce the risk of injury recurrence, advise patients who participate in significant physical activity to avoid
returning to full pre-injury activity until they achieve near-full pre-injury flexibility and 85 to 90% of pre-injury
power in the affected muscle. A gradual return to activity is recommended, with both the duration and intensity of
activity gradually increased over the course of the healing process (usually 5 to 8 weeks).

The following therapies are not recommended because of insufficient evidence of benefit in the management of
acute muscle injury, and inadequate study of treatment harms: autologous conditioned serum, platelet-rich plasma,
platelet-rich fibrin matrix, Traumeel (a homeopathic preparation allegedly containing traces of botanical and
mineral ingredients), Actovegin (extracts of calf blood), and dry needling.

RICE therapy (Table 12.22)

Therapy [NB1] Details

rest so that pain is not provoked, but some physical activity is
Rest
maintained. Continue for up to 48 hours
apply ice packs to the affected area for 10 minutes every 1 to 2
Ice hours. Continue for up to 48 hours. There is a risk of cold burn if
ice is applied directly to the skin
use compression bandaging, if practical. Continue for up to 48
Compression
hours
elevate the limb to reduce swelling. Continue for as long and as
Elevation
often as necessary
NB1: Heat and massage are contraindicated in the first 48 hours following injury.

Management principles for tendinopathy

Tendinopathy is primarily a degenerative condition of the tendon. Tendinopathy can be associated with microtears
of the tendon, but these should be distinguished from acute major tendon tears.

Assess patients with tendinopathy for modifiable predisposing factors and biomechanical abnormalities that may
be amenable to correction (eg posture, motor control). Advise patients to avoid or modify activities that aggravate
discomfort or place high loads on the affected tendon.

For most tendinopathies, rest is not recommended because complete unloading of the tendons is not helpful.
Referral to an appropriate physical therapist (eg a physiotherapist) for a progressive loading program can assist in
treatment and rehabilitation. If undertaken, progressive loading programs should start with isometric loading
followed by eccentric or eccentric-concentric loading. If patients do not respond to a well-supervised 6-month
rehabilitation program, refer to a specialist.

Paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs) are often used for short-term pain relief.
Peritendinous corticosteroid injections are sometimes used for pain relief and the effect usually lasts up to 6 weeks.
They should be used with caution in tendinopathy involving major weightbearing tendons such as the patellar,
tibialis posterior and Achilles tendons. Consider seeking specialist advice and avoid multiple injections. Neither
NSAIDs nor corticosteroids appear to alter the pathology in tendinopathy. See Principles of NSAID use for
musculoskeletal conditions in adults for more information on NSAID use and dosing. See Principles of using local
corticosteroid injections for musculoskeletal conditions in adults for principles of use and example doses of local
corticosteroid injections.

The following therapies are not recommended because of insufficient evidence of benefit in the management of
tendinopathy, and inadequate study of treatment harms: stem cells, autologous conditioned serum, platelet-rich
plasma, platelet-rich fibrin matrix, polidocanol, prolotherapy and dry needling.

Management principles for ligament sprain or tear

Acute ligament injuries are usually caused by distraction forces that lengthen the ligament beyond its normal
elastic limit. They range from virtually asymptomatic minor sprains to complete tears.

The initial management of acute ligament injuries is RICE therapy (see Table 12.22). Although the benefit of RICE
therapy is supported by widespread use in practice, the effectiveness of this approach has not been proven in
randomised controlled trials.

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and shorten time to recovery in acute ligament
sprains, particularly in acute ankle ligament sprain. See Principles of NSAID use for musculoskeletal conditions in
adults for more information on NSAID use and dosing.

Consider referral to an appropriate physical therapist (eg a physiotherapist) for acute ligament injuries, particularly
more severe injuries. Physical therapy includes restoration of range of motion, proprioception training, local
muscle strengthening, and functional exercises. For acute ankle ligament sprains, supportive taping during the
early phase of return to activity is useful.

Prolotherapy is not recommended for the management of acute or chronic ligament sprains because of insufficient
evidence of benefit and inadequate study of treatment harms.

Rotator cuff disease

Introduction
Rotator cuff disease is the most common cause of shoulder pain. The rotator cuff comprises the supraspinatus,
infraspinatus, subscapularis and teres minor muscles and tendons; these muscles and tendons surround the
glenohumeral joint, and facilitate movement and provide stability to the joint. Rotator cuff disease refers to all
symptomatic disorders of the rotator cuff regardless of the anatomical location; it includes rotator cuff tears,
tendinopathy, and impingement (compression) of the rotator cuff. The latter may be associated with subacromial
bursitis.

The aetiology of rotator cuff disease is multifactorial. Risk factors include acromial abnormalities that result in
narrowing of the subacromial space, increasing age, overuse, smoking and obesity. Symptomatic rotator cuff
disease is common in young people who participate in sports involving overhead activity (eg swimming). It is also
common in middle-aged and older people, who are more likely to sustain full-thickness rotator cuff tears.
Asymptomatic rotator cuff tears are present in 4% of people younger than 40 years of age and in over 50% of
people older than 60 years of age. A significant number become symptomatic over time.

The clinical course of rotator cuff disease is not well understood. About 25% of new episodes resolve fully within
1 month and nearly 50% resolve within 3 months; however, persistence of symptoms or recurrence of symptoms
within a year of initial presentation can occur in 40 to 50% of people, and many partial-thickness rotator cuff tears
progress to full-thickness tears over time. Progression of rotator cuff disease can lead to rotator cuff arthropathy, a
form of glenohumeral osteoarthritis.

Diagnosis of rotator cuff disease

The diagnosis of rotator cuff disease is usually made by history and physical examination, without the need for
investigations.

In rotator cuff disease, involvement is usually unilateral and pain is felt in the affected shoulder and/or lateral
aspect of the upper arm. Night pain, interrupted sleep if lying on the affected side, and a painful arc are hallmarks
of the condition. Symptoms may be subacute; painful weakness and atrophy suggest significant rotator cuff tears.
Rapid onset of intense pain suggests calcific tendinitis due to deposition of calcium in the tendon, although
sometimes calcium deposits do not cause symptoms.

Movement loss in rotator cuff disease is isolated and depends on the rotator cuff tendon involved; this can be
identified by stressing specific rotator cuff tendons. Assuming the patient is able to completely relax their shoulder
girdle muscles, the passive range of shoulder movements are generally painless and unrestricted in rotator cuff
disease. This finding can assist in differentiating rotator cuff disease from adhesive capsulitis and glenohumeral
osteoarthritis.

Scapula dysfunction (through malpositioning of the glenoid fossa) and acromioclavicular joint osteoarthritis
(through narrowing of the subacromial space) may contribute to rotator cuff disease, so these pathologies should
also be considered in the diagnosis. In acromioclavicular joint osteoarthritis, pain is typically felt on top of the
shoulder and is worse in full abduction or if reaching across the body. The acromioclavicular joint is tender and an
osteophyte may be palpable.

Plain X-rays are not useful in the majority of cases of rotator cuff disease. They may be considered to demonstrate
calcific deposits if calcific tendinitis is suspected clinically, to identify abnormal acromial morphology or
osteophytes if acromioclavicular joint osteoarthritis is suspected clinically, or to exclude other causes of shoulder
pain (eg glenohumeral osteoarthritis if suspected clinically, fractures and/or dislocations in the setting of trauma).

Although frequently ordered, the diagnostic utility of ultrasound scans for rotator cuff disease is unknown.
Abnormalities reported on ultrasound are common in asymptomatic individuals so, even if identified in a
symptomatic patient, these findings may not explain the patient's symptoms. Furthermore, these findings may lead
to inappropriate management and/or delay correct diagnosis and management. Ultrasound is not recommended for
the diagnosis of shoulder pain suggestive of rotator cuff pathology on clinical assessment.

Do not use ultrasound to investigate shoulder pain if clinical assessment suggests rotator cuff pathology.

Management of rotator cuff disease

The evidence for commonly used treatments for rotator cuff disease is limited; however, a reasonable management
approach includes analgesia if required and exercise. Advise patients to avoid or modify activities that aggravate
discomfort or place high loads on the affected tendon. See also Management principles for tendinopathy.

Analgesia

If analgesia is required, oral analgesia and/or subacromial corticosteroid injection may be considered. If oral
analgesia is indicated, use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

If response to paracetamol is inadequate, a nonsteroidal anti-inflammatory drug (NSAID) may be used instead of,
or in combination with, paracetamol. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Subacromial corticosteroid injection is useful for rapid pain relief, particularly for night pain, but its effect may
only last a few weeks and a repeat injection may be needed. Subacromial corticosteroid injection can be helpful in
alleviating pain in calcific tendinitis, although this has not been proven in randomised controlled trials. Ultrasound
guidance for injection into the subacromial space is not recommended because it provides no additional benefit
compared to non–radiologically guided injection. For principles of use and example doses of local corticosteroid
injections, see Principles of using local corticosteroid injections for musculoskeletal conditions in adults.

Other analgesic therapies that may be considered for rotator cuff disease include suprascapular nerve block and
acupuncture. There is preliminary evidence that suprascapular nerve block relieves pain from rotator cuff disease
for up to 12 weeks. Acupuncture can provide transient pain relief.

Opioids are seldom required for rotator cuff disease. If patients have severe pain that is not adequately relieved
with other measures, reconsider the diagnosis and consider the possibility of rotator cuff arthropathy.

Exercise

Consider referral to an appropriate physical therapist (eg a physiotherapist). A reasonable exercise

recommendation for rotator cuff disease includes range of motion and strengthening exercises for the rotator cuff
and scapular stabilising muscles. The aim of these exercises is to improve shoulder strength and function in the
longer term. Adding manual therapy to exercise is unlikely to provide additional benefit.

Other treatments

Physical treatments other than exercise have a limited role in the management of rotator cuff disease.
Extracorporeal shock wave therapy may reduce pain, improve function, and resolve calcifications in calcific
tendinopathy, but is not beneficial in cases of non-calcific tendinopathy. Based on low-quality evidence,
therapeutic ultrasound may have short-term benefits over placebo in calcific tendinitis, and low-level laser therapy
may have short-term benefits over placebo in rotator cuff disease.

Platelet-rich plasma injections are not recommended for the treatment of rotator cuff disease or as an adjunct to
surgery for rotator cuff disease because of insufficient evidence of benefit and inadequate study of treatment
harms.

Surgery for rotator cuff disease may be considered after 3 to 6 months of appropriate conservative management if
there is progressive weakness suggestive of a full-thickness rotator cuff tear, or if symptoms are severe and
persisting regardless of the presence of a tear. Surgical removal of calcific deposits may relieve persistent pain due
to calcific tendinitis.

Adhesive capsulitis (frozen shoulder)

Introduction
Adhesive capsulitis (frozen shoulder) is the most common cause of shoulder pain after rotator cuff disease. It is
estimated to affect 2 to 5% of the general population and 10 to 20% of patients with diabetes. It is most common in
people between 50 and 60 years of age, and affects women slightly more often than men.

The aetiology and pathophysiology of adhesive capsulitis is poorly understood. Adhesive capsulitis generally has a
self-limiting course that lasts 2 to 3 years. It classically evolves through three overlapping phases:

an initial, painful phase usually lasting between 2 and 9 months. This phase is characterised by the
insidious development of diffuse, severe and disabling shoulder pain. Pain is worse at night and patients are
unable to sleep lying on the affected side
an intermediate, stiff (frozen) phase lasting between 4 and 12 months. In this phase, stiffness and severe
loss of shoulder movement predominate. Pain is less pronounced but still present, particularly at the end of
the free range of shoulder movement
a recovery phase lasting between 5 and 24 months, during which time there is a gradual return of shoulder
movement.

The diagnosis of adhesive capsulitis is predominantly made by history and physical examination. While many
conditions cause shoulder pain, adhesive capsulitis can be distinguished by the presence of severe global passive
movement loss; movement loss occurs in all planes including abduction, flexion, internal rotation and, especially,
external rotation. In the initial, painful phase of adhesive capsulitis, before global passive movement loss is
apparent, differentiating between adhesive capsulitis and rotator cuff disease can be difficult.

Management of adhesive capsulitis

In each phase of adhesive capsulitis, management is directed at symptoms. If pain and stiffness persist despite
conservative management, consider specialist referral.

Initial, painful phase

Advise patients to avoid or modify activities that aggravate discomfort. Avoid manual therapies and high-load
shoulder exercises in the initial, painful phase because they can intensify pain.

In all phases of this condition, but particularly in the initial, painful phase, adequate analgesia is important. For
analgesia, use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

If response to paracetamol is inadequate, a nonsteroidal anti-inflammatory drug (NSAID) may be used instead of,
or in combination with, paracetamol. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).
Limited evidence suggests that topical NSAIDs are ineffective for adhesive capsulitis.

Other options for analgesia in adhesive capsulitis include oral corticosteroid therapy or intra-articular
corticosteroid injection. Oral corticosteroid therapy provides rapid pain relief, and improves function and range of
motion, but the effect may not be maintained beyond 6 weeks. Benefits from oral corticosteroids have been
reported in patients who have had symptoms for up to 6 months. The usual dosage is:

prednis(ol)one 30 mg orally, daily for 3 weeks, then taper the dose over 2 weeks to stop.

In patients with diabetes, monitor blood glucose concentration and adjust diabetes treatment as required. Avoid
concurrent use of NSAIDs and oral corticosteroids because of the significantly increased risk of gastrointestinal
toxicity, and because NSAIDs are not likely to have additional benefit in patients taking oral corticosteroids.

Intra-articular corticosteroid injection may be useful for rapid pain relief, but may have a short duration of effect.
Limited evidence suggests that a second or third injection may be useful for recurrence of pain. Local
corticosteroid injection may cause a transient increase in blood glucose concentration, but usually no adjustment to
diabetes treatment is necessary. For principles of use and example doses of local corticosteroid injections, see
Principles of using local corticosteroid injections for musculoskeletal conditions in adults.
Opioids have a very limited role in the management of adhesive capsulitis because of a lack of evidence for
efficacy and a significant risk of harms. Opioids may be considered for patients with severe pain that is not
adequately relieved with other measures and is interfering with their ability to function. If opioids are used, they
should be prescribed on a short-term trial basis, as part of an overall pain management strategy, with clear goals
and regular review of treatment response and adverse effects. Before starting an opioid, a plan for ceasing
ineffective therapy should be in place and discussed with the patient. If treatment response is inadequate, caution
should be exercised when increasing the dose of opioids as there is an increased risk of harm and potentially no
added benefit. Prolonged use of opioids indicates the need for specialist assessment. See Opioids for more
information.

Intermediate, stiff (frozen) and recovery phases

In the intermediate, stiff (frozen) and recovery phases, continue activity modification and analgesia as required
(see Initial, painful phase). A reasonable exercise recommendation includes strengthening and active range-of-
motion exercises. The aim is to gradually increase range of motion.

Arthrographic distension (hydrodilation) of the glenohumeral joint may provide sustained pain relief, and improve
function and range of motion in the intermediate, stiff phase. It involves injection of a combination of local
anaesthetic, corticosteroid and saline into the joint under radiological guidance. The procedure can be performed
with minimal sedation and may be repeated if needed. Following arthrographic joint distension, the combination of
manual therapy and exercise may improve patient-reported treatment success and active range of motion, but does
not provide additional benefit over arthrographic distension alone in terms of pain or function.

Arthroscopic capsular release may be considered in refractory cases.

Lateral and medial epicondylar tendinopathies (tennis elbow and

golfer's elbow)
Lateral epicondylar tendinopathy (tennis elbow) is a common condition, particularly in patients between 40 and 50
years of age. It is thought to be an overload injury of the common extensor tendons at their origin at the lateral
epicondyle. In spite of the title ’tennis elbow’, tennis is a direct cause in only 5% of cases. Medial epicondylar
tendinopathy (golfer's elbow) is a similar, but less common condition, involving the common flexor tendons at
their origin at the medial epicondyle.

Both conditions are characterised by pain and tenderness over the epicondyle, and pain on resisted movements. In
lateral epicondylar tendinopathy, pain occurs on resisted dorsiflexion of the wrist and/or middle finger. In medial
epicondylar tendinopathy, pain occurs on resisted volar flexion of the wrist. Pain at night and stiffness, particularly
in the morning and after periods of inactivity, may occur.

The diagnosis of these conditions is usually made by history and physical examination, without the need for
investigations. Myriad changes in the tendons on ultrasound scans and magnetic resonance imaging (MRI) may be
present in asymptomatic individuals so, even if identified in a symptomatic patient, these findings may not explain
the patient's symptoms.

Both conditions are generally self-limiting and many patients recover within 1 year; however, symptoms can
persist beyond 2 years in some patients.

Management of lateral and medial epicondylar tendinopathies

Reassure patients about the generally favourable prognosis of these conditions. Consider the impact of the
condition on the patient's ability to perform daily activities (eg participation in social, recreational and
occupational activities) and on their mental health.

A reasonable management approach includes analgesia if required and exercise. Advise patients to avoid or modify
activities that aggravate discomfort or place high loads on the affected tendon. See also Management principles for
tendinopathy.

Analgesia

If analgesia is required, topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs) may provide short-term
pain relief. Use:

1 an NSAID orally (see Table 12.7 for dosing)

OR
 1 a topical NSAID applied directly to the painful area, up to 4 times daily (see Table 12.7
for available topical preparations).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Local corticosteroid injection may be considered instead of, or in combination with, an NSAID. Local
corticosteroid injection can provide pain relief for 6 to 12 weeks. The injection may be repeated if needed. A
rebound effect or worsening of symptoms after initial favourable response may occur. For principles of use and
example doses of local corticosteroid injections, see Principles of using local corticosteroid injections for
musculoskeletal conditions in adults.

Exercise

A reasonable exercise recommendation for lateral and medial epicondylar tendinopathies is a progressive loading
program for the affected tendon incorporating functional upper limb exercise. Stretching and strengthening
exercises at the elbow are commonly used and are not harmful; they may be considered as a self-management
strategy.

Other treatments

There is limited evidence to support the use of a range of physical treatments other than exercise in the
management of lateral and medial epicondylar tendinopathies. These treatments include the application of ice or
heat; the use of an elbow brace, strap or taping; the use of a wrist splint; manual therapy; laser therapy; and
acupuncture.

Evidence does not support the use of ultrasound or extracorporeal shock wave therapy for lateral and medial
epicondylar tendinopathies.

Surgery may be considered in the small subset of patients with persisting symptoms despite conservative
management, but well-conducted trials comparing surgery with placebo or a nonsurgical control group are lacking.

De Quervain tenosynovitis
De Quervain tenosynovitis affects the abductor pollicis longus and extensor pollicis brevis tendons at the distal end
of the radius. Pain and swelling occur over the radial aspect of the wrist, extending to the thumb. De Quervain
tenosynovitis often occurs in people who perform repetitive manual tasks. It can occur in pregnancy or, more
commonly, in the postpartum period. In the postpartum period, it is probably caused by repeated radial and ulnar
deviation of the wrist during gripping movements (eg during breastfeeding).

The diagnosis of de Quervain tenosynovitis is usually made by history and physical examination, but an ultrasound
scan may be useful if there is uncertainty about the diagnosis.

Treatment options for de Quervain tenosynovitis include local corticosteroid injection, splinting and/or
nonsteroidal anti-inflammatory drugs (NSAIDs). The choice of treatment(s) depends on patient factors, including
patient preference.

Local corticosteroid injection is very effective in relieving pain and is more effective than NSAIDs or splinting.
Injection can be repeated if symptoms recur. Give the injection into the tendon sheath along the radial aspect of the
wrist. For principles of use and example doses of local corticosteroid injections, see Principles of using local
corticosteroid injections for musculoskeletal conditions in adults. Local corticosteroid injection can be used in
women who are pregnant or breastfeeding.

Resting the thumb is considered an effective treatment; however, this can be difficult for patients to implement,
especially in the postpartum period, so splinting to immobilise the base of the thumb is often recommended.
Splinting is usually used continuously for 6 weeks and then use is slowly reduced.

NSAIDs may provide pain relief, but should not be given in late pregnancy (beyond 32 weeks' gestation). If
treatment with an NSAID is appropriate, use:

1 an NSAID orally (see Table 12.7 for dosing)

OR

1 a topical NSAID applied directly to the painful area, up to 4 times daily (see Table 12.7
for available topical preparations).
The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information). For
advice on the use of NSAIDs in women who are pregnant or breastfeeding, see NSAIDs and reproductive health in
women.

NSAIDs should not be used in pregnant women beyond 32 weeks' gestation.

Surgical release of tendons may be effective for refractory de Quervain tenosynovitis, but is rarely required.

Carpal tunnel syndrome

Introduction
Carpal tunnel syndrome refers to entrapment of the median nerve in the carpal tunnel at the wrist. It presents with
paraesthesia, pain, and numbness in the fingers and thumb, in the distribution of the median nerve. Carpal tunnel
syndrome is generally idiopathic, but can be associated with pregnancy, diabetes, hypothyroidism, rheumatoid
arthritis, and overuse of the forearm muscles.

Carpal tunnel syndrome in pregnant women mostly occurs in the second and third trimesters. Symptoms
commonly recur in subsequent pregnancies and later in life, especially around menopause. It is thought to be
associated with the fluid retention that occurs in pregnancy.

The clinical course of carpal tunnel syndrome is not well understood. The condition resolves spontaneously in up
to one-third of patients and may resolve with treatment of the underlying medical condition, if present. If
associated with pregnancy, it usually resolves within 4 weeks of delivery.

Suspect carpal tunnel syndrome in any patient with persistent hand pain, particularly if it is nocturnal and
dysaesthetic in quality. Nerve conduction studies can confirm an entrapment median neuropathy at the wrist,
thereby excluding alternative diagnoses such as C6 radiculopathy.

Management of carpal tunnel syndrome

Management of carpal tunnel syndrome includes treatment of the underlying medical condition, if present.
Treatment choice for symptomatic relief depends on patient factors, including patient preference.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide pain relief, but should not be given in late pregnancy
(beyond 32 weeks' gestation). If treatment with an NSAID is appropriate, use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information). For
advice on the use of NSAIDs in women who are pregnant or breastfeeding, see NSAIDs and reproductive health in
women.

NSAIDs should not be used in pregnant women beyond 32 weeks' gestation.

Injection of corticosteroid into the carpal tunnel provides symptomatic relief, especially if inflammatory arthritis is
also present. Benefit has been demonstrated for at least 1 month after injection. A second injection may be
appropriate. Local corticosteroid injection can be used in women who are pregnant or breastfeeding, and is
preferred over the use of NSAIDs if pharmacological management for pain relief is required in pregnant women.
For principles of use and example doses of local corticosteroid injections, see Principles of using local
corticosteroid injections for musculoskeletal conditions in adults.

Splinting and hand braces may provide short-term symptomatic relief for patients with carpal tunnel syndrome.
Elevating the forearm on a pillow at night can also give symptomatic relief.

Evidence indicates that diuretics (including in pregnancy-induced carpal tunnel syndrome), magnets, laser
acupuncture and chiropractic treatment have no benefit. There is insufficient evidence to support the use of
gabapentin, amitriptyline, therapeutic ultrasound, exercise or mobilisation for carpal tunnel syndrome.

Do not use diuretics for carpal tunnel syndrome.

Patients should be referred for surgery if they do not respond to conservative management, or if they have
progressive sensory or motor deficits or moderate to severe electrodiagnostic abnormalities. However, surgery
should be avoided in pregnant women if possible because symptoms almost always resolve following delivery.

Flexor tenosynovitis (trigger finger)

Introduction
Flexor tenosynovitis (trigger finger, including the thumb) is most common in patients between 50 and 60 years of
age. Gradually, or in some cases acutely, abnormality of the flexor tendon causes a painful click as the patient
flexes and extends the digit. The patient may present with locking of the affected digit in a flexed position, and this
may require gentle passive manipulation to release the digit into extension. Crepitus and/or a nodule may be
palpable. Differential diagnoses include Dupuytren contracture and, in patients with multiple digit involvement,
underlying systemic inflammatory disease (eg spondyloarthritides, rheumatoid arthritis) and chronic infection (eg
mycobacterial infection).

A variety of causes for flexor tenosynovitis have been suggested, including repetitive finger movements,
compressive forces at the A1 pulley (an annular ligament near the metacarpal head), and repetitive trauma. The
incidence of flexor tenosynovitis is higher in patients with diabetes; patients with type 1 diabetes are more likely to
have multiple digit involvement and treatment is difficult in these patients.

The clinical course of flexor tenosynovitis is not well understood. In idiopathic cases, the condition may resolve
spontaneously.

Management of flexor tenosynovitis

Management of flexor tenosynovitis includes treatment of the underlying medical condition, if present.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Splinting aims to reduce or remove tendon excursion through the A1 pulley for long enough to allow the
tenosynovitis to resolve. Various methods of splinting may be beneficial, but none of these has been studied in
randomised controlled trials.

Local corticosteroid injection in the region around the A1 pulley is a highly effective treatment, with reported
success rates of 50 to 70% in randomised controlled trials. Injection may be particularly effective if a well-defined
nodule is palpable, or if symptoms have been present for less than 6 months. For principles of use and example
doses of local corticosteroid injections, see Principles of using local corticosteroid injections for musculoskeletal
conditions in adults.

Surgery may be considered for patients with persisting symptoms despite conservative management. Success rates
of over 90% have been reported, with a low complication rate.

Hip joint conditions

Patients use the word ‘hip’ to refer to a number of anatomical structures, so when patients complain of hip pain,
care must be taken to define the precise anatomical location of their pain. Patients with true hip joint pathology
usually present with groin and/or anterior thigh pain, which may extend down to the knee. Occasionally, patients
may present with referred knee pain only. Hip joint pathology rarely refers pain to the lateral thigh; other
diagnoses, such as greater trochanteric pain syndrome, back pain and diabetic amyotrophy (see Atypical diabetic
neuropathies), should be considered in patients presenting with isolated pain in this area. In patients with hip joint
pathology, passive movements of the hip are often painful and/or limited.

Acute pain secondary to hip joint pathology in an adult could be osteoarthritis or inflammatory arthritis (see
Assessing peripheral musculoskeletal symptoms in adults). Consider the possibility of osteoarthritis in patients
with risk factors for osteoarthritis (see Risk factors for osteoarthritis). In patients presenting with hip-girdle pain
and stiffness, consider the possibility of polymyalgia rheumatica.

In patients with severe groin and/or anterior thigh pain but normal hip movements, consider the possibility of
avascular necrosis or stress fracture. Avascular necrosis of the head of the femur is relatively uncommon, but the
atraumatic form should be suspected in patients with recognised risk factors, such as the use of systemic
corticosteroids or excessive alcohol consumption. Post-traumatic cases are associated with fracture of the head or
the neck of the femur. Stress fractures may be seen in patients with risk factors for osteoporosis (see Risk factors
for osteoporosis and fractures) or patients who participate in recurrent, vigorous physical activity.

In older patients, consider the possibility of a fracture of the neck of the femur. This is usually due to trauma.
Patients have an inability to weightbear and present with an externally rotated, shortened leg.

Femoroacetabular impingement and hip labral tears

Femoroacetabular impingement (FAI) and hip labral tears are primarily radiological findings and are poorly
correlated with symptoms. FAI is characterised by abnormal contact between the proximal femur and the
acetabulum. Two types of FAI have been described—pincer impingement (caused by an overcovered acetabulum)
and cam impingement (caused by an aspherical femoral head). The prevalence of FAI in the general population is
uncertain; the prevalence estimates of cam hip shape morphology ranged from 5 to 75% across three studies that
included nonrepresentative subgroups of the general population, 19 studies of different clinical populations and
eight studies in professional athletes. Higher prevalence was not demonstrated in athletes or symptomatic patients.
Hip labral tears are also seen in high prevalence in asymptomatic people.

The clinical and long-term significance of these radiological findings, including the relationship between FAI and
osteoarthritis, is unclear. There are no proven effective treatments for FAI and hip labral tears, and any
interventions should be undertaken with caution.

Greater trochanteric pain syndrome

Lateral thigh pain is often given the name ‘trochanteric bursitis’, but many cases involve pathology of the gluteus
medius and/or minimus tendons (with or without bursal pathology); these are collectively referred to as greater
trochanteric pain syndrome. A differential diagnosis is pain referred from the low back along the L2 and L3
dermatomes (see Low back pain).

There are few randomised controlled trials to guide the management of greater trochanteric pain syndrome. Initial
management is usually exercises to improve the tensile strength of the gluteus medius and minimus tendons. Some
patients may benefit from a specific exercise program to address muscle imbalance contributing to compression
loading of the gluteal tendons. Encourage patients to persist with exercise even if symptom relief is achieved with
analgesia because exercise is important to prevent recurrence of symptoms. Advise the patient to avoid
compression of the gluteal tendons over the greater trochanter (eg avoid leg-crossing, hip-hanging, and side-lying
in bed). If necessary, a pillow can be placed between the knees when sitting or lying down to reduce compression.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide pain relief in early cases. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

For patients with more severe symptoms (night pain, impaired physical function, inability to lie on the side),
consider local corticosteroid injection. Local corticosteroid injection can relieve pain and improve the patient's
ability to undertake an exercise program; local corticosteroid injection may be considered instead of, or in
combination with, an NSAID. Give the corticosteroid injection at the point of maximum tenderness. Ultrasound
guidance for injection into the trochanteric bursa is not recommended because it provides no additional benefit
compared to non–radiologically guided injection. A repeat injection may be given if needed but, in general, local
corticosteroid injections should not be performed more than twice per year. For principles of use and example
doses of local corticosteroid injections, see Principles of using local corticosteroid injections for musculoskeletal
conditions in adults. Failure to have any response to local corticosteroid injection should raise suspicion of a
gluteal tear or alternative diagnosis.

Degenerative meniscal tears

Most people aged 50 years and older will have some radiological findings of osteoarthritis in their knees, and
roughly a quarter will have some degenerative changes in the menisci; the prevalence of these findings increases
with age. These findings are common in both people with and without knee pain. Therefore, in people aged 50
years and older with knee pain, abnormalities reported on magnetic resonance imaging (MRI) may not necessarily
explain their symptoms and MRI is not recommended. Management of knee pain in people aged 50 years and
older with degenerative meniscal tears is the same as for those without this finding (see General management
approach for osteoarthritis).

Patellofemoral pain syndrome

Patellofemoral pain syndrome refers to idiopathic pain arising from the anterior knee or patellofemoral region. The
pain has an insidious onset and is generally felt anteriorly. Running, walking up or down stairs, and prolonged
sitting may aggravate the pain. An effusion is uncommon. Risk factors for patellofemoral pain syndrome include
female gender, obesity, and joint laxity. Biomechanical abnormalities that may be associated with patellofemoral
pain syndrome include excessive pronation of the subtalar joint, weak quadriceps and tight hamstrings, tight lateral
patellar retinaculum, and a laterally placed tibial tuberosity.

Patellofemoral osteoarthritis is often clinically identical to the patellofemoral pain syndrome and is the most
common cause of retropatellar pain in the older patient.

Individually tailored conservative care, with a focus on graduated functional lower limb exercise and reduction of
aggravating activities, is the mainstay for management of patellofemoral pain syndrome. The evidence to support
the use of other physical treatments is limited; these include patellofemoral joint mobilisation, medial patellar
taping, external patellar bracing and the use of foot orthoses.

If analgesia is required, paracetamol may provide pain relief. Use:

1 paracetamol 1 g orally, 4- to 6-hourly, up to a maximum of 4 g daily

OR

1 paracetamol modified-release 1.33 g orally, 8-hourly.

If response to paracetamol is inadequate, a nonsteroidal anti-inflammatory drug (NSAID) may be used instead of,
or in combination with, paracetamol. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Prepatellar bursitis
The prepatellar bursa is located anterior to the patella and is the most frequently symptomatic bursa around the
knee joint. Prepatellar bursitis presents as a painful, tender superficial swelling over the patella, often after acute or
chronic trauma. Gout and septic bursitis are differential diagnoses.

Kneepads should be used by those who kneel frequently to prevent prepatellar bursitis.

Mild cases of traumatic prepatellar bursitis can be managed with rest, application of ice, compression bandaging,
and nonsteroidal anti-inflammatory drugs (NSAIDs). Advise patients to avoid traumatic compression.

If NSAIDs are indicated, use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

In more severe or refractory cases, or if inflammatory or septic bursitis is suspected, aspiration of bursal fluid for
analysis and culture is required. For management of gout, see Gout. Management of septic bursitis requires urgent
hospital referral (see Septic bursitis). If infection has been excluded, local corticosteroid injection is appropriate.
For principles of use and example doses of local corticosteroid injections, see Principles of using local
corticosteroid injections for musculoskeletal conditions in adults.

Chronic exertional compartment syndrome

Pain originating in the anterior or deep posterior muscle compartment of the lower leg is common in those who
exercise, and may be caused by a chronic exertional compartment syndrome. If examined immediately after
activity, the area is tender and firm to touch.

Initial management of chronic exertional compartment syndrome is conservative. Nonsteroidal anti-inflammatory

drugs (NSAIDs) may provide short-term pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Other conservative measures include reducing or stopping activities that lead to pain, changing the exercise
program, stretching, and correction of foot biomechanical abnormalities if appropriate. These measures should be
tried for 2 to 3 months, but are usually only successful if accompanied by stopping or significantly reducing
athletic activity. Many patients with chronic exertional compartment syndrome are not willing to give up athletic
activity, so fasciotomy may be required.

Medial tibial stress syndrome

Medial tibial stress syndrome (formerly known as shin splints) presents as exercise-related pain at the lower third
to half of the medial tibial border. It is most likely due to a stress lesion at the fascial insertion of the medial soleus,
tibialis posterior or flexor digitorum longus at the medial tibial border.

Medial tibial stress syndrome is difficult to treat and there is no strong evidence for any intervention. Rest is an
important component of management, but can be difficult for patients to implement. There is little evidence for the
use of nonsteroidal anti-inflammatory drugs (NSAIDs), but they may provide short-term pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).

Evidence indicates that low-energy laser treatment, stretching and strengthening exercises, sports compression
stockings, leg braces and pulsed electromagnetic fields have no benefit in medial tibial stress syndrome. There is
insufficient evidence to recommend the use of iontophoresis, phonophoresis, ice massage, ultrasound, periosteal
pecking and extracorporeal shockwave therapy for medial tibial stress syndrome.

Tear of the Achilles tendon

Complete tear of the Achilles tendon typically occurs in males older than 40 years of age, usually during rapid
acceleration (eg while playing tennis). It has also been described as an adverse effect of fluoroquinolone antibiotics
(eg ciprofloxacin), generally in patients older than 60 years of age. It presents with acute pain and/or loss of
function in the posterior aspect of the lower leg.

All complete tendon ruptures merit immediate surgical consultation. In acute tendon ruptures, conservative
management (casting or functional brace with a heel lift for 6 to 8 weeks) or surgery may be considered. Surgery
followed by intensive rehabilitation may reduce the rate of re-rupture when compared with conservative
management, but has a higher risk of other complications. If conservative management is used, it should include
functional rehabilitation.

Partial tear of the Achilles tendon presents with acute pain, often with a history of Achilles tendinopathy.
Management is as for tendinopathy; see Management principles for tendinopathy.

Plantar fasciitis
Plantar fasciitis presents with pain at the anteromedial aspect of the calcaneus; the pain is worst during the first
steps taken in the morning and improves during the day. Plantar fasciitis may represent an enthesopathy associated
with one of the spondyloarthritides. Most cases that are not associated with a spondyloarthritis resolve within 1
year with conservative management. Heel spurs are a common incidental X-ray finding and are not related to the
experience of pain.

Advise patients with plantar fasciitis to avoid or modify aggravating activities, and to avoid walking in flat shoes
or barefoot. Conservative management of plantar fasciitis involves stretching and strengthening the calf muscles,
stretching the fascia, use of a heel cup or cushion, and ice massage after aggravating activity that cannot be
avoided or modified. The evidence to support the use of these interventions is limited, but they are reasonable low-
cost approaches. Orthoses, night splints and Low-Dye taping also have limited evidence for efficacy.
Extracorporeal shock wave therapy has not been proven to be of benefit in the management of plantar fasciitis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide pain relief. Use:

an NSAID orally (see Table 12.7 for dosing).

The potential benefits of an NSAID should be weighed against its potential harms, particularly in patients at high
risk of harms (see Principles of NSAID use for musculoskeletal conditions in adults for more information).
Corticosteroid injection into the region of the attachment may provide short-term pain relief. For principles of use
and example doses of local corticosteroid injections, see Principles of using local corticosteroid injections for
musculoskeletal conditions in adults.

If patients do not respond to a well-supervised 6-month rehabilitation program, refer to a specialist.

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Management principles for ligament sprain or tear

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Adhesive capsulitis (frozen shoulder)

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Lateral and medial epicondylar tendinopathies

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Bisset LM, Vicenzino B. Physiotherapy management of lateral epicondylalgia. J Physiother 2015;61(4):174–81.

Buchbinder R, Green SE, Youd JM, Assendelft WJ, Barnsley L, Smidt N. Shock wave therapy for lateral elbow pain.
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Green S, Buchbinder R, Barnsley L, Hall S, White M, Smidt N, et al. Acupuncture for lateral elbow pain. Cochrane
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Pattanittum P, Turner T, Green S, Buchbinder R. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral
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Smidt N, van der Windt DA, Assendelft WJ, Deville WL, Korthals-de Bos IB, Bouter LM. Corticosteroid injections,
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Peters-Veluthamaningal C, van der Windt DA, Winters JC, Meyboom-de Jong B. Corticosteroid injection for trigger
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Femoroacetabular impingement and hip labral tears

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Medial tibial stress syndrome

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Tear of the Achilles tendon

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tendon rupture: A PRISMA-compliant systematic review of overlapping meta-analyses. Medicine (Baltimore)
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Thomson CE, Crawford F, Murray GD. The effectiveness of extra corporeal shock wave therapy for plantar heel pain:
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Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Fibromyalgia
Introduction to fibromyalgia
In contrast to inflammatory connective tissue syndromes, chronic diffuse noninflammatory soft-tissue pain is very
common. No consistent measurable investigational abnormality has yet been found and the best way to define this
problem is still debated. Fibromyalgia is the current preferred term for the common and well-defined clinical
syndrome of chronic widespread noninflammatory musculoskeletal pain accompanied by a variety of typical
symptoms including fatigue, sleep disturbance and cognitive clouding.

The pathophysiology of fibromyalgia is complex and remains poorly understood. Altered levels of
neurotransmitters in the cerebrospinal fluid (CSF), as well as various abnormalities on functional imaging studies,
have been demonstrated in patients with fibromyalgia. These findings suggest that central nervous system
mechanisms (including central sensitisation) are fundamental to the development of the multiple symptoms of
fibromyalgia.

The absence of laboratory or imaging abnormalities can be challenging for both patients and practitioners,
particularly if a simple biomedical causal model to explain the patient's symptoms has been sought. A more
nuanced biopsychosocial understanding of fibromyalgia is preferred; however, it should be understood that this
does not imply that symptoms are a direct consequence of psychological distress.

See Diffuse amplified musculoskeletal pain for information on paediatric fibromyalgia.

Assessment of fibromyalgia
Pain in fibromyalgia is typically widespread and may be experienced in both soft tissues and joints. While pain
severity often fluctuates, it rarely follows the consistent diurnal pattern seen in inflammatory disorders. Patients
may present with regionalised pain related to a recent event, but a detailed history often reveals a more extensive
pain history. Some individuals may be genetically predisposed to widespread pain, and a history of ‘growing pains’
or other painful disorders in childhood is not uncommon.

While chronic widespread musculoskeletal pain is the hallmark of fibromyalgia, patients typically experience a
variety of other symptoms including cognitive clouding (known as ‘fibrofog’), fatigue, impaired concentration,
sleep dysfunction, depression, and gastrointestinal and urogenital dysfunction and discomfort (irritable bowel and
irritable bladder). Sleep dysfunction may be both a consequence of widespread pain and a contributor to its
persistence. Practitioner time and patience are required to thoroughly evaluate the patient's fibromyalgia symptoms
in the context of their individual life-course and sociocultural setting.

A thorough general physical and musculoskeletal examination should be performed in all patients. There are no
physical examination findings specific to fibromyalgia; however, soft-tissue tenderness to pressure is typically
diffuse. While the location and severity of tenderness varies between patients, some anatomical locations (eg
lateral epicondyles, trapezius muscles, anserine bursae) are tender in the majority of patients with fibromyalgia.
The presence of allodynia (pain induced by normal touch) should be sought in both history and examination; pain
induced by inflation of a sphygmomanometer cuff is a useful screening tool. Dermographism is seen in some
patients.

Diagnostic criteria have been developed that incorporate both widespread pain and other symptoms typical of
fibromyalgia; a formal tender point count is not required.

The diagnosis of fibromyalgia is not confirmed by the results of investigations, although normal C-reactive protein
(CRP) and erythrocyte sedimentation rate (ESR) reassure both patient and doctor that significant inflammatory
disease is unlikely to be the cause of symptoms.

Since fibromyalgia frequently coexists with other rheumatological diseases, a complete clinical evaluation of a
patient with musculoskeletal pain should seek evidence of joint inflammation as well as the more diffuse soft-
tissue tenderness typical of fibromyalgia.

Any change in the nature or pattern of symptoms needs a thorough assessment to avoid missing the onset of a
comorbid illness.

Thoroughly assess any change in the nature or pattern of symptoms.

Consider referral to a rheumatologist if the diagnosis is uncertain or the patient's presentation is atypical (see When
to refer a patient with fibromyalgia to a specialist).

Management of fibromyalgia
General management approach
Effective management of fibromyalgia requires a clear diagnosis, thorough patient education informed by a
contemporary understanding of pain neuroscience, and an individualised management plan developed
collaboratively by the patient and their treating clinician(s).

Patient education regarding the concept of chronic pain and principles of self-management is an effective
component of overall management. It is often helpful to include people who are significant in the patient's life (eg
a partner, relative or friend) in the process of education and self-management. The patient should be reassured that
the condition is not damaging to joints or soft tissues and will not be associated with significant morbidity.
Fibromyalgia can be likened to an alarm system that has become oversensitive and is generating its alarm under
conditions that offer no threat to the tissues. Interventions in fibromyalgia aim to muffle the alarm so that it is less
intrusive upon other activities (see Lifestyle and nonpharmacological management of fibromyalgia and
Pharmacological management of fibromyalgia). Helpful points to discuss with a newly diagnosed patient may
include:

The pain experienced by the patient is real but is not caused by tissue damage.
Fibromyalgia is not a progressive or deforming disease.
Fibromyalgia is frustrating and, because symptoms fluctuate, the patient may feel like they are taking two
steps forward and one step back.
The chronic pain experienced in fibromyalgia can affect the way the patient feels, but this does not
necessarily indicate a problem with their mental health.
The overarching goal of management is not to achieve a pain-free state but rather to enable the patient to
manage their pain so that it does not limit their function.

Printed or online information is useful to reinforce education provided by the clinician [Note 1].

Some patients may need specialist referral (see When to refer a patient with fibromyalgia to a specialist).

Comorbid rheumatological conditions (eg osteoarthritis, rheumatoid arthritis or inflammatory connective tissue
disease) need appropriate management.

Note 1: Patient information on fibromyalgia can be found on the painHEALTH website. Any management advice given on this website should be
considered in the context of the recommendations in these guidelines.

Lifestyle and nonpharmacological management of fibromyalgia

Regular graded aerobic exercise has been shown to reduce pain and fatigue and improve quality of life scores in
patients with fibromyalgia. Patients are often physically deconditioned at presentation and may have tried and
failed a previous exercise regimen. A graded exercise program should be advised, beginning with very light
aerobic exercise, for example walking or exercise in water. The program should prescribe a slow incremental
increase in exercise duration and intensity over a realistic time frame of several months. Importantly, the program
should be graded by the duration of time spent exercising rather than the pain experienced, to reduce the risk of
unhelpful cycles of overexertion followed by inactivity.

The practitioner may also help to design strategies to reduce situational stresses, identify coping strategies that
help the individual manage their pain, and provide guidance and support for goal setting. Cognitive behavioural
therapy (CBT) may improve pain and function in patients with fibromyalgia. Attention to good sleep practices is
also of value. There are some data to suggest that mindfulness-based approaches may also be beneficial in
fibromyalgia.

Mutual support from those similarly affected can have a positive effect. The state affiliate organisations of Arthritis
Australia maintain fibromyalgia support groups (see the Arthritis Australia website for contact details).

Pharmacological management of fibromyalgia

Drug therapy is a component of fibromyalgia management; however, it may yield only modest benefits, so is best
employed in conjunction with lifestyle and nonpharmacological management. Multiple drugs may need to be
trialled sequentially because patients with fibromyalgia commonly experience unpleasant adverse effects or may
have an inadequate response to treatment. The tolerability of drug therapy in fibromyalgia is often improved by
starting treatment at a low dose and slowly increasing the dose in small increments. As with nonpharmacological
interventions, realistic goal setting is recommended, focusing on functional improvement rather than abolition of
pain.

Tricyclic antidepressants (TCAs), gabapentinoids, and some serotonin and noradrenaline reuptake inhibitors
(SNRIs) have been shown to reduce pain in fibromyalgia; however, at the time of writing these drugs (with the
exception of milnacipran) are not approved by the Australian Therapeutic Goods Administration (TGA) for this
indication.

Low-dose TCAs are often used as first-line therapy because they have few major adverse effects and, in addition to
reducing pain, may improve sleep. The goal of therapy is to achieve a dose that is beneficial without causing
daytime drowsiness; this is best achieved with the use of a low starting dose, with small incremental dose
increases. Dose adjustments should not usually be made more frequently than monthly; however, if treatment is
well tolerated but response is poor, more frequent dose increases (eg fortnightly) can be considered. Amitriptyline
and dothiepin are the most commonly used TCAs for the treatment of fibromyalgia; suitable regimens are:

1 amitriptyline 10 to 25 mg orally, in the early evening; increasing the daily dose by up to

25 mg every 2 to 4 weeks as tolerated and according to response, up to a maximum
maintenance dose of 50 mg each evening

OR

1 dothiepin 25 mg orally, in the early evening; increasing the daily dose by up to 25 mg

every 2 to 4 weeks as tolerated and according to response, up to a maximum maintenance
dose of 75 mg each evening.

If low-dose TCAs are ineffective or poorly tolerated, consider a gabapentinoid or SNRI. Drug choice is influenced
by patient factors (including comorbidities; eg an SNRI may be preferred in patients with comorbid depression),
potential drug interactions and adverse effects (eg an SNRI may be preferable in obese patients), and drug cost.

If a gabapentinoid is preferred, use:

1 gabapentin 100 to 300 mg orally, in the early evening; increasing to 3 times daily as
tolerated and according to response, up to a maximum maintenance dose of 2400 mg
daily in 3 divided doses. Do not increase the dose more frequently than every 4 days

OR

1 pregabalin 25 to 75 mg orally, in the early evening; increasing to twice daily after 3 to 7

days and then increasing slowly as tolerated and according to response, up to a maximum
maintenance dose of 450 mg daily in 2 divided doses.

Individual patient responses to gabapentin and pregabalin can differ; it is reasonable to switch between them if
response to one is inadequate.

If an SNRI is preferred, use:

duloxetine 30 mg orally, daily; increasing after 1 month to 60 mg daily and then increasing
as tolerated and according to response, up to a maximum maintenance dose of 60 mg
twice daily.

Evidence also supports the use of milnacipran for the treatment of fibromyalgia. However, evidence for the
effectiveness of other SNRIs (eg desvenlafaxine, venlafaxine) in fibromyalgia is lacking.

Combination therapy can be used but should be employed with caution. The need for combination therapy should
flag consideration for specialist referral.

Analgesia with paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) is generally only moderately
helpful, if at all. Opioids should not be used because they have a significant risk of harm and are rarely of overall
benefit.

When to refer a patient with fibromyalgia to a specialist

While fibromyalgia does not cause tissue damage, it is a chronic condition that is often difficult to bear. It is
sufficiently common that general practitioners need to be equipped with strategies for assessment and
management. Rheumatological assessment can help confirm the diagnosis, exclude alternative diagnoses, and
assist the patient to understand and deal with their condition; however, it is not necessary for every patient.
Referral should be considered if the patient has an atypical presentation or refractory symptoms. When abnormal
mood or adjustment disorders are a feature, psychological or psychiatric assessment may be advisable.
Key references
Bawa FL, Mercer SW, Atherton RJ, Clague F, Keen A, Scott NW, et al. Does mindfulness improve outcomes in
patients with chronic pain? Systematic review and meta-analysis. Br J Gen Pract 2015;65(635):e387–400.

Busch AJ, Webber SC, Richards RS, Bidonde J, Schachter CL, Schafer LA, et al. Resistance exercise training for
fibromyalgia. Cochrane Database Syst Rev 2013;(12):CD010884.

Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311(15):1547–55.

Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for pain in fibromyalgia in adults. Cochrane Database
Syst Rev 2015;(10):CD008244.

Crowe M, Jordan J, Burrell B, Jones V, Gillon D, Harris S. Mindfulness-based stress reduction for long-term physical
conditions: A systematic review. Aust N Z J Psychiatry 2016;50(1):21–32.

Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. Pregabalin for pain in fibromyalgia in adults. Cochrane
Database Syst Rev 2016;9:CD011790.

Hauser W, Klose P, Langhorst J, Moradi B, Steinbach M, Schiltenwolf M, et al. Efficacy of different types of aerobic
exercise in fibromyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials. Arthritis Res
Ther 2010;12(3):R79.

Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane
Database Syst Rev 2014;(1):CD007115.

Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for fibromyalgia in adults. Cochrane Database Syst
Rev 2015;(7):CD011824.

Moore RA, Wiffen PJ, Derry S, Toelle T, Rice AS. Gabapentin for chronic neuropathic pain and fibromyalgia in adults.
Cochrane Database Syst Rev 2014;(4):CD007938.

Theadom A, Cropley M, Smith HE, Feigin VL, McPherson K. Mind and body therapy for fibromyalgia. Cochrane
Database Syst Rev 2015;(4):CD001980.

Wiffen PJ, Derry S, Moore RA, Aldington D, Cole P, Rice AS, et al. Antiepileptic drugs for neuropathic pain and
fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev 2013;(11):CD010567.

Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, et al. 2016 Revisions to the 2010/2011
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Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RS, et al. Fibromyalgia criteria and severity
scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for
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Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, et al. The American College of Rheumatology
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Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Noninflammatory musculoskeletal pain in children
and adolescents
Introduction to noninflammatory musculoskeletal pain in children
and adolescents
In the majority of cases, careful evaluation of children and adolescents presenting with musculoskeletal
symptoms (see Assessing musculoskeletal symptoms in children and adolescents) fails to identify a
pathological basis for their symptoms; their pain is considered to be noninflammatory in origin. Important
noninflammatory musculoskeletal conditions include postactivity musculoskeletal pain, benign nocturnal
limb pain, diffuse amplified musculoskeletal pain and complex regional pain syndrome type I.

Postactivity musculoskeletal pain in children and adolescents

Postactivity musculoskeletal pain typically occurs in the limbs after strenuous activity. It is not associated
with limitation of function and the child or adolescent is otherwise healthy and has a normal musculoskeletal
examination. Pain tends to settle over time.

Benign nocturnal limb pain in children

Benign nocturnal limb pain (sometimes referred to as ‘growing pains’) presents in children between the ages
of 3 and 8 years. Patients have a characteristic history of night-time waking in distress, complaining of lower
limb pain. It is common for the child to want the affected area to be rubbed or squeezed. The child usually
falls asleep within an hour of waking and symptoms will have resolved when they wake the following
morning. Physical examination is normal. Symptoms wax and wane in frequency over time and eventually
resolve spontaneously.

Diffuse amplified musculoskeletal pain in children and adolescents

Diffuse amplified musculoskeletal pain (also known as paediatric fibromyalgia) is typically seen in
adolescents. It is characterised by generalised pain that is not specifically articular, does not exhibit the
diurnal variation typical of inflammatory joint disease, and may be associated with excessive fatigue.
Features may overlap with chronic fatigue syndrome. Physical examination is normal, with the exception of
multiple nonarticular tender points.

Initial management of diffuse amplified musculoskeletal pain involves a detailed explanation of the diagnosis
and reassurance that serious pathology has been excluded. Other important aspects of management include
reducing school absence because school attendance is frequently impacted; good sleep practices; exercise;
and support for the adolescent as they resume their regular routine. Cognitive behavioural therapy (CBT) and
pharmacological therapy may benefit some patients.

Complex regional pain syndrome type I in children and adolescents

Complex regional pain syndrome type I (also known as reflex sympathetic dystrophy) is characterised by
severe pain in a limb, typically in the setting of recent trivial trauma. Allodynia of the affected area is usual,
as is reduced temperature and pallor. Oedema of the limb may develop.

As with other pain amplification syndromes (including diffuse amplified musculoskeletal pain), management
involves a detailed explanation of the diagnosis and reassurance that serious pathology has been excluded;
this may require carefully selected investigations to exclude relevant differential diagnoses. Treatment
involves desensitisation of the affected area by repeated gentle tactile stimulation and an intensive
physiotherapy program.

Published March 2017. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Hormonal contraception
Overview of hormonal contraception
Hormonal contraception is an effective and safe option for women and may contain oestrogen and progestin, or
progestin alone. Combined preparations are the:

combined oral contraceptive pill (COCP; commonly referred to as ‘the pill’)

vaginal ring.

Progestin-only preparations are the:

progestin-only pill (POP; commonly referred to as ‘the minipill’)

long-acting progestin-only reversible methods (injections, subdermal implants, progestin-bearing
intrauterine devices).

Discussion of contraceptive options should prioritise the woman's choice and safety, and be evidence-based.

Failure rates for a range of contraception methods are shown in Table 5.29.

Breastfeeding is as reliable as hormonal methods of contraception if the baby is younger than 6 months and the
mother is fully breastfeeding and has not yet had a period. Lactation is not a reliable contraceptive method once
any of these criteria is not met—if the mother is still breastfeeding, a progestin-only method is advised.

Several forms of hormonal contraception (eg COCP, vaginal contraceptive ring, POP, etonogestrel implant) may
be unreliable when taken with some antiepileptic drugs. See advice on reliable contraception for women with
epilepsy.

Contraceptive failure rates (Table 5.29) [NB1]

Failure rate (%) during first year of use [NB2]

Contraceptive method Perfect use (consistent and
Typical use
correct)
no method 85 85
fertility awareness-based methods 24 0.4 to 5
spermicide only 28 18
withdrawal 22 4
barrier
female

diaphragm with spermicide

12 6
condom
21 5
sponge
–
parous women 24 20
– 12 9
nulliparous women

male
condom
18 2

intrauterine contraceptive device

copper 0.8 0.6

levonorgestrel 0.2 0.2

dermal patch 9 0.3

vaginal ring 9 0.3
oral contraception 9 0.3
injection (medroxyprogesterone acetate) 6 0.2
implant (etonogestrel) 0.05 0.05
sterilisation
female 0.5 0.5
male 0.15 0.1
NB1: Adapted with permission from Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar M.
Contraceptive technology. 20th rev ed. New York, NY: Ardent Media; 2011.
NB2: Failure rate is the percentage of women who have an unintended pregnancy during the first year of use of the contraceptive method. United States
data.

Combined hormonal contraception

Selecting a combined hormonal contraceptive method

Overview

The combined hormonal contraceptive preparation of choice:

has the lowest effective dose of oestrogen and progestin

is well tolerated
provides acceptable cycle control.

Levonorgestrel is slightly more androgenic than norethisterone. It is significantly more androgenic than more
recent progestins that are antiandrogenic (cyproterone, drospirenone [less so]) or have low androgenic activity
(desogestrel, gestodene). Levonorgestrel gives good cycle control, but may be associated with a higher risk of
androgenic adverse effects (eg weight gain, acne).

The vaginal contraceptive ring contains ethinyloestradiol and etonogestrel. It may be a good choice in women who
have:

difficulty adhering to daily therapy

inflammatory bowel disease or other malabsorption syndromes
breakthrough bleeding when taking the COCP.

Most women with acne find that it improves when they take the COCP, particularly if they take a pill containing
cyproterone, desogestrel, drospirenone or gestodene.

Women over 35 years

A strategy for healthy nonsmoking menstruating women older than 35 years is to continue taking combined
hormonal contraceptives up to the age of 50 years. As well as receiving a contraceptive benefit, these women have
a reduced risk of fracture and reduced incidence of ovarian, endometrial and colorectal cancer. However, these
benefits of combined hormonal contraceptives are outweighed by increased cardiovascular risk if the women:

are obese
smoke
have diabetes
have elevated blood pressure
have migraines with aura (classical migraine, associated with focal neurological symptoms).

Women with these cardiovascular risks should consider the POP, intrauterine contraceptive methods, barrier
contraceptives or sterilisation (if childbearing is completed).

Both the Faculty of Sexual and Reproductive Health Care [Note 1] and Australian guidance [Note 2] suggest that
women should stop combined hormonal contraception at the age of 50 years. Options after this are to:

switch to a nonhormonal or progestin-only method of contraception

use a barrier method until they have been amenorrhoeic for 1 year and therefore no longer require
contraception.

Note 1: Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Contraception for
women aged over 40 years: Royal College of Obstetricians and Gynaecologists FSRH; 2010. [URL]
Note 2: Contraception: an Australian clinical practice handbook. 3rd ed. Ashfield, NSW: Sexual Health and
Family Planning Australia; 2012. Chapter 11. Contraception in specific circumstances (pp 190-3).

Combined oral contraception

Starting combined oral contraception

A thorough medical history should be taken before prescribing a COCP to ensure it is not contraindicated. Choice
of preparation depends on the woman's medical history and preference.

Counselling before starting oral contraception is essential to address concerns and encourage the woman to take
the tablets correctly. It is important to highlight that bioavailability of the COCP may be reduced in certain
situations (eg during episodes of vomiting or diarrhoea, when taking antibiotics that induce liver enzymes).
Women should be:

shown how to use their particular COCP (since packaging varies between brands)
given instructions on what to do if they miss a pill.

The oral contraceptive pills available in Australia are shown in Table 5.30.

Missed combined oral contraceptive pills

A missed pill is defined as one that is more than 24 hours overdue (ie more than 48 hours since the last pill was
taken). If a pill is up to 24 hours overdue, two pills can be taken on the same day. See the advice in Figure 5.3.

Extended use, tricycling or continuous pack use

Some women prefer to avoid a withdrawal bleed by taking 3 consecutive months of active treatment, without a
pill-free interval. They start the active tablets in the new packet as soon as they finish the active tablets in the
previous packet. This regimen may be useful for women who experience:

withdrawal headaches in the hormone-free interval

premenstrual syndrome
heavy or painful menstrual periods.

It may also be useful to reduce the chance of ovulation in women who:

forget to take their pills

are taking drugs that may reduce the efficacy of the pill.

Finally, women may follow this regimen for convenience (eg travel, sporting events, social reasons).

Managing adverse effects of combined oral contraceptives

To determine whether a COCP is suitable, it should be taken for three cycles to allow time for common early
adverse effects (eg breakthrough bleeding, breast tenderness, nausea) to disappear. For advice on managing
persistent or severe adverse effects, see Table 5.31. Evidence is limited on managing adverse effects or the benefit
of one combined hormonal contraceptive method over another. The strategies in Table 5.31 are based on expert
opinion. [Note 3]

Breakthrough bleeding in women taking the COCP may be due to:

reduced endometrial thickness and increased endometrial fragility (from relative oestrogen deficiency)
irregular concordance with treatment
drug interactions (eg phenytoin)
a sexually transmitted infection (particularly Chlamydia trachomatis), in a woman with new onset of
bleeding who was previously stable on her COCP
cervical abnormalities (check Papanicolaou [Pap] smear is up to date).

If no pathological cause for the bleeding is found, readjusting the balance between the oestrogen and progestin
may solve the problem. This can be achieved by changing to a COCP with a less androgenic progestin (eg
drospirenone) or higher dose of oestrogen. After 6 months of regular cycles, returning to the lower oestrogen dose
is reasonable. If breakthrough bleeding is erratic, further gynaecological investigation is required.

Note 3: Contraception: an Australian clinical practice handbook. 3rd ed. Ashfield, NSW: Sexual Health and
Family Planning Australia; 2012.
Vaginal contraceptive ring
The vaginal contraceptive ring is a soft plastic ring containing oestrogen and progestin. The woman inserts the ring
high in the vagina and wears it for 3 weeks. Then she removes the ring and has a withdrawal bleed a few days
later. Seven days after removal, she inserts a new ring. Use:

etonogestrel+ethinyloestradiol 11.7 mg + 2.7 mg ring, intravaginally. Leave ring in place

for 3 consecutive weeks then remove. After 7 days, insert new ring.

It is recommended that the vaginal ring is not removed for sexual intercourse. For advice on what to do if vaginal
ring insertion or removal deviates from the schedule, see Figure 5.4.

Contraindications to combined hormonal contraception

Overview

Combined hormonal contraceptive methods should not be prescribed for women with:

current or previous venous thromboembolism (VTE)

a genetic thrombophilia
coronary artery disease
cerebrovascular disease
uncontrolled hypertension
severely impaired liver function
malignancy of the breast or genital tract
migraine with aura (classical migraine, associated with focal neurological symptoms), because the risk of
stroke is increased.

If the COCP is contraindicated, alternative contraception to consider is a progestin-only method or a nonhormonal

method (eg copper intrauterine device).

Smokers should be strongly encouraged to stop smoking, especially if they are older than 35 years. The risk of
thromboembolic and cardiovascular events is much greater in smokers using combined hormonal contraceptive
methods.

COCPs can be used in women who are HIV positive. However, antiretroviral drugs may decrease or increase the
bioavailability of steroid hormones in hormonal contraceptives. COCPs with ethinyloestradiol 30 micrograms can
be used with nucleoside reverse transcriptase inhibitors, but they are not recommended with ritonavir-boosted
protease inhibitors—in the latter case, women can use depot medroxyprogesterone acetate or the etonogestrel
implant.

Venous thromboembolism

All combined hormonal contraceptives increase the relative risk of VTE, but the absolute risk is still low. Studies
have shown that COCPs containing cyproterone, desogestrel, drospirenone or gestodene have a higher risk of VTE
than COCPs containing levonorgestrel or other progestins. Venous thromboembolism associated with the COCP
usually occurs in the first year of use, and is most common in women with a genetic thrombophilia.

COCPs are contraindicated in women with a current or past history of VTE or a known thrombogenic mutation.
Other risk factors to exclude before prescribing a COCP include:

a family history of VTE or thrombophilia in a first degree relative

obesity (body mass index [BMI] 35 kg/m2 or greater)
prolonged immobilisation
being under 21 days post partum.

Screening all women for a thrombophilia before they start taking a COCP is not cost effective. In a woman with a
VTE history in a first degree relative, screening should be considered before prescribing a COCP. However, a
negative thrombophilia screen does not necessarily exclude all thrombogenic mutations. COCP use by women
with a first degree relative who had a VTE when younger than 45 years is not recommended, regardless of
screening.

Women taking COCPs should be taught to recognise the signs and symptoms of VTE.

Drug interactions with combined hormonal contraceptives

Combined hormonal contraceptives are metabolised by the cytochrome P450 system. Drugs that upregulate this
enzyme system can reduce concentrations of relevant contraceptive hormones, resulting in pregnancies.
Interactions with St John's wort, griseofulvin, protease inhibitors and older antiepileptic drugs (eg phenytoin,
carbamazepine, primidone) are commonly reported.

Current evidence suggests that most antibiotics do not interact with combined hormonal contraceptives. The only
exception is for those that induce liver enzymes (ie rifabutin, rifampicin). When taking either of these antibiotics,
no combined hormonal contraceptive at any dose can be considered effective—alternative methods (eg intrauterine
contraception) need to be considered.

Whenever a woman taking a combined hormonal contraceptive is started on another drug, their clinician should
check for interactions.

Combined hormonal contraceptive preparations available in Australia (Table 5.30)

Print-friendly PDF

Oestrogen dose Progestin dose

Brand name examples [NB1]
(micrograms) (micrograms)
monophasic preparation (oral): low dose
oestradiol
nomogestrol acetate 2500 Zoely [NB2]
(hemihydrate) 1500
ethinyloestradiol 20 drospirenone 3000 Yaz [NB2]
Femme-Tab ED 20/100, Loette [NB2], Microgynon 20
ethinyloestradiol 20 levonorgestrel 100
[NB2], Microlevlen [NB2]
monophasic preparation (oral): standard dose
ethinyloestradiol 30 desogestrel 150 Marvelon [NB2]
ethinyloestradiol 30 dienogest 2000 Valette [NB2]
ethinyloestradiol 30 drospirenone 3000 Yasmin [NB2]
ethinyloestradiol 30 gestodene 75 Minulet [NB2]
Femme-Tab ED 30/150, Levlen, Microgynon 30,
ethinyloestradiol 30 levonorgestrel 150
Monofeme, Nordette
Brenda-35 [NB2], Diane-35 [NB2], Estelle-35 [NB2],
ethinyloestradiol 35 cyproterone 2000
Juliet-35 [NB2]
ethinyloestradiol 35 norethisterone 500 Brevinor, Norimin
ethinyloestradiol 35 norethisterone 1000 Brevinor-1, Norimin-1
monophasic preparation (oral): high dose
ethinyloestradiol 50 levonorgestrel 125 Microgynon 50
multiphasic preparation (oral)
ethinyloestradiol 30 to
levonorgestrel 50 to 125 Logynon, Trifeme, Triphasil, Triquilar
40
ethinyloestradiol 35 norethisterone 500 to 1000 Improvil
oestradiol valerate
dienogest 2000 to 3000 Qlaira [NB2]
1000 to 3000
monophasic preparation (vaginal)
ethinyloestradiol 2700
etonogestrel 11 700 (120 per
(15 per 24 hours over 3 NuvaRing [NB2]
24 hours over 3 weeks)
weeks)
NB1: List may not be complete.
NB2: Not available on the Pharmaceutical Benefits Scheme (PBS) at the time of writing. See the PBS website for current information [URL].

Managing common problems associated with the combined oral contraceptive pill (Table 5.31)

Problem Management strategies

reduce oestrogen dose

nausea [NB1] take the pills at night

change to progestin-only pill

reduce oestrogen and/or progestin dose
breast tenderness
consider using pill containing drospirenone
reduce oestrogen dose
bloating and fluid retention
change to progestin with mild diuretic effect (eg drospirenone)
 reduce oestrogen dose
dysmenorrhoea
increase progestin dose
reduce oestrogen dose

if headache occurs in hormone-free week, consider:

headache extended use [NB2]
giving oestradiol 50 micrograms transdermal patch in this week
[NB3]

decreased libido no evidence of a difference between oral contraceptive hormones

increase oestrogen dose if taking a pill with oestradiol 20 micrograms
breakthrough bleeding [NB4] change progestin if already taking a pill with oestradiol 30 to 35
micrograms
NB1: A woman with persistent nausea should have a pregnancy test.
NB2: See advice on extended use
NB3: See Table 5.35 for oestrogen preparations
NB4: See causes of breakthrough bleeding

Missed combined oral contraceptive pill (Figure 5.3) [NB1] [NB2]

Patient information sheet

NB1: Adapted from Contraception: an Australian clinical practice handbook and reproduced with permission ©2012. Family Planning NSW, Family
Planning Victoria and Family Planning Queensland.

NB2: These instructions do not apply to the quadriphasic combined oral contraceptive pill that contains oestradiol valerate 1000 to 3000 micrograms
and dienogest 2000 to 3000 micrograms. See the product information for advice.

Deviations from schedule for inserting or removing the vaginal contraceptive ring (Figure 5.4)
[NB1]

Patient information sheet

 NB1: Adapted from Contraception: an Australian clinical practice handbook and reproduced with permission ©2012. Family Planning NSW, Family
Planning Victoria and Family Planning Queensland.

Progestin-only contraception
Progestin-only contraception is available as an oral pill or a long-acting reversible form (ie intramuscular injection,
subdermal implant, intrauterine system). These methods are safe in women who are breast feeding or have a
contraindication to taking oestrogen. Progestin-only preparations are shown in Table 5.32.

Progestin-only contraceptive preparations available in Australia (Table 5.32)

Print-friendly PDF

Route Progestin Brand name examples [NB1]

levonorgestrel 30 micrograms Microlut
oral
norethisterone 350 micrograms Locilan 28 Day, Micronor, Noriday 28
subdermal implant etonogestrel 68 mg over 3 years Implanon NXT
medroxyprogesterone acetate 150
deep intramuscular injection Depo-Provera, Depo-Ralovera
mg/mL
intrauterine levonorgestrel 52 mg over 5 years Mirena
NB1: List may not be complete.

Contraindications to progestin-only contraception

Progestin-only contraception is contraindicated in women with active breast cancer within the last 5 years, but has
relatively few other contraindications. The harms outweigh the benefits in the following conditions:
antiphospholipid antibodies with systemic lupus erythematosus, unexplained vaginal bleeding, ischaemic heart
disease or stroke, severe cirrhosis or hepatocellular carcinoma.

The product information warns of the risk of VTE. However, with the possible exception of injectable progestins
(on which more studies are needed), use of progestin-only contraception is not associated with an increased risk of
VTE.

Progestin-only oral contraception

Overview

The POP (see Table 5.32 for preparations) is another type of oral contraception. It is suitable for women who:

cannot tolerate a combined hormonal contraceptive

do not want to take a combined hormonal contraceptive
are breastfeeding.

Strict concordance with therapy when taking the POP is essential, because:

its efficacy relies on its effect on vaginal mucus, which can be lost if the POP is delayed for even a few
hours
it doesn't reliably suppress ovulation.
Women who elect to take the POP need to be meticulous about taking it at the same time each day, and some hours
before sexual intercourse. In some women the effect of the POP only lasts about 21 hours. If she has intercourse 24
or 25 hours later, the effect may have worn off. A woman who is more likely to have intercourse in the morning
should take her POP at night.

If the time of day when this pill is taken varies by more than 3 hours, contraceptive protection may be reduced.
Following a missed or delayed pill, the woman should:

continue to take the pill at the normal time

use additional protection (eg condom, diaphragm) for the next 48 hours (ie until she has taken 3 consecutive
daily pills).

No evidence shows that the POP is less effective in women whose BMI is in the overweight or obese range. The
main adverse effect of the POP is unpredictable bleeding patterns. A small percentage of women develop
amenorrhoea. Other adverse effects are rare.

Irregular bleeding while breastfeeding

When taking the POP while breastfeeding, irregular bleeding may signify the return of ovulation and fluctuating
hormone concentrations. Other causes (eg pregnancy, Chlamydia trachomatis infection) need to be excluded. As
long as the POP is being taken correctly, this method of contraception can be continued. If a woman finds the
bleeding unacceptable, she can switch to another progestin-only contraception method (eg etonogestrel implant,
intrauterine system). Changing to a combined hormonal contraceptive method is only advised when the woman
wants to stop breastfeeding.

Long-acting reversible progestin-only contraception

For reliable and cost-effective contraception, the long-acting reversible methods (LARC) are best. These methods
require administration less than once a month. They include a progestin-only (etonogestrel) implant, hormonal
(levonorgestrel) intrauterine system and depot medroxyprogesterone acetate (DMPA). The nonhormonal (copper)
intrauterine device is not discussed.

Etonogestrel implant

The etonogestrel implant rarely fails. It:

provides immediate contraceptive cover when inserted subdermally (most commonly on the inside upper
arm) during the first 5 days of the menstrual cycle, or immediately following an induced or spontaneous
abortion
is effective for up to 3 years.

Fertility returns rapidly after the implant is removed. The etonogestrel implant should only be inserted and
removed under local anaesthetic by trained practitioners. Use:

etonogestrel 68 mg implant subdermally. Replace every 3 years.

The main adverse effect of the etonogestrel implant is unpredictable bleeding patterns. Amenorrhoea occurs in
22% of women. Infrequent, frequent or prolonged bleeding episodes are common. Several treatments (eg cyclical
use of a COCP; mefenamic acid; tranexamic acid) reduce this bleeding in the short term, but none increases the
likelihood of continuing this method long term. If considered appropriate, use:

1 combined oral contraceptive pill (see Table 5.30 for preparations)

OR

1 mefenamic acid 500 mg orally, 3 times daily for 5 days

OR

1 tranexamic acid 500 mg orally, twice daily for 5 days.

If the bleeding pattern is unacceptable, the implant should be removed. Approximately 20% to 25% of women
request that the implant be removed within 12 months.

Other adverse effects (eg acne, breast pain, headaches, abdominal pain, dizziness, mood changes) are less common
and are similar to those for other progestin-only hormonal methods of contraception.

Levonorgestrel-releasing intrauterine system

Introduction

The levonorgestrel-releasing intrauterine system (LNG-IUS) releases levonorgestrel at an initial rate of 20

micrograms daily, and provides effective contraception for 5 years. An LNG-IUS should only be inserted by a
trained practitioner, and can be inserted:

during the first 7 days of the menstrual cycle

immediately after an induced or spontaneous abortion
from 6 weeks post partum
at any time in the menstrual cycle, as long as the clinician is sure the woman is not pregnant.

The LNG-IUS is suitable for women of all ages and women who have never given birth. Before its insertion, a
woman needs counselling about its harms and benefits. Harms include:

perforation of the uterus (rare) and infection around the time of insertion (uncommon)
the long-term risk of irregular bleeding.

Use:

levonorgestrel-releasing intrauterine system 52 mg. Replace every 5 years.

The LNG-IUS is one of the most effective methods of contraception. But if the woman has symptoms of
pregnancy and her menses are delayed by more than 6 weeks, pregnancy should be excluded.

Adverse effects

An LNG-IUS often causes erratic bleeding and spotting, especially in the first 3 to 5 months, but blood loss
decreases dramatically over 6 months. Amenorrhoea or light bleeding occurs in up to 65% of women after 12
months of use.

Pelvic pain occurs in some women for a few days after insertion, but usually eases with time.

Over 5 years, the LNG-IUS has a cumulative expulsion rate of 2.2 to 5.8 per 100 women-years, but the rate may be
slightly higher in women experiencing heavy menstrual bleeding.

Other adverse effects are rare and include acne, breast tenderness, weight gain, headache, nausea and mood
changes.

Follow-up after insertion

Women should be reviewed 4 to 6 weeks after the LNG-IUS has been inserted, to:

exclude post-insertion pelvic inflammatory disease (rare)

ensure the strings attached to the LNG-IUS have not lengthened (suggesting partial expulsion).

Women should be reviewed annually after that. They should be told to return immediately if they develop:

pelvic pain
pain during intercourse
a dramatic change in bleeding patterns, after initial changes settle.

If the strings of the LNG-IUS can't be seen at follow-up, the LNG-IUS may have been expelled or have perforated
the uterus. Pelvic ultrasound can usually show the position of the LNG-IUS or confirm its absence.

Removal

Any medical practitioner can remove an LNG-IUS, as long as the device's strings are visible at the cervical os. The
LNG-IUS is removed by applying gentle traction on its strings with a pair of long-handled forceps. At the same
time, the cervix may be held steady by countertraction with a swab on the end of sponge forceps. If the strings of
the LNG-IUS can't be seen, referral is advised to a practitioner experienced in difficult LNG-IUS removals.

Depot medroxyprogesterone acetate

Depot medroxyprogesterone acetate (DMPA) is administered by deep intramuscular injection every 12 weeks (plus
or minus 14 days). It is effective as long as the woman returns regularly for the injections. The first injection
should be given during the first 5 days of the menstrual cycle, because this provides immediate contraceptive
protection. DMPA may also be given at other times in the cycle, including:

when a woman hasn't returned at the correct interval for her injection, if pregnancy can be excluded (extra
precautions should be used for 7 days)
immediately following an induced or spontaneous abortion
within 5 days post partum (if the woman is not breastfeeding).

Use:

medroxyprogesterone 150 mg deep IM, every 12 weeks.

After stopping DMPA the time for fertility to return varies, due to persisting anovulation. The effect on fertility is
not permanent. The median conception time is 8 to 10 months after the last injection. Seventy-eight per cent of
women wanting to conceive do so within 12 months of their most recent injection, and 95% within 2 years.

Some women have erratic and prolonged bleeding as DMPA wears off after their last injection. A COCP can be
used to maintain regular cycles during DMPA withdrawal, if pregnancy is not desired.

As with all progestin-only forms of contraception, the main adverse effect of DMPA is unpredictable bleeding
patterns. Other possible adverse effects are weight gain, acne, mood changes, depression and increased risk of
bone loss (with prolonged use). The decline in bone mineral density associated with DMPA is reversible, but its
use in two populations has potential concern. These populations are:

adolescents who have not yet reached peak bone mass

women older than 45 years who are approaching menopause.

Therefore, DMPA is not advised as first-line therapy at the extremes of reproductive life.

After the first injection of DMPA many women have a delay before their next period, often for 8 weeks or more.
Menstrual bleeding may last for 10 days but is not usually heavy. After using DMPA for 12 months, 50% to 70%
of women are amenorrhoeic.

Emergency (postcoital) contraception

The sooner emergency contraception methods are started after unprotected sexual intercourse, the more effective
they are. A hormonal method using levonorgestrel has two forms. Use:

1 levonorgestrel 1.5 mg orally, as a single dose within 72 hours of unprotected sexual

intercourse

OR

2 levonorgestrel 750 micrograms orally, as an initial dose within 72 hours of unprotected

sexual intercourse, repeating the same dose 12 hours later.

In Australia, this emergency contraception is available from a pharmacy without a prescription. A single
levonorgestrel 1.5 mg tablet is sold as Levonelle-1, NorLevo-1 and Postinor-1. Two levonorgestrel 750 microgram
tablets are sold as Levonelle-2, NorLevo and Postinor-2.

An equivalent to these over-the-counter measures is 25 tablets of a levonorgestrel progestin-only minipill

(levonorgestrel 30 micrograms per pill; see Table 5.32), followed by another 25 tablets 12 hours later.

This progestin-only method of emergency contraception has efficacy for up to 120 hours (5 days) after unprotected
sexual intercourse, but this reduces with time. If taken correctly, it prevents 80% to 85% of expected pregnancies.
A nonhormonal method of emergency contraception, the copper intrauterine device, can be used up to 5 days after
unprotected sexual intercourse and prevents 99% of pregnancies.

Key references
Hormonal contraception: introduction

Contraception: an Australian clinical practice handbook. 3rd ed. Ashfield, NSW: Sexual Health &​ Family Planning
Australia; 2012.

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Postnatal sexual and reproductive
health. London: RCOG; 2009. [URL]
Tang JH, Lopez LM, Mody S, Grimes DA. Hormonal and intrauterine methods for contraception for women aged 25
years and younger. Cochrane Database Syst Rev 2012;(11):CD009805. [ ]

Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar M. Contraceptive
technology. 20th rev ed. New York, NY: Ardent Media; 2011. [URL]

Combined hormonal contraception

Increased risk of thromboembolism in newer oral contraceptives. NPS Health News and Evidence 2013;(Feb 14).
[URL]

Update to CDC's U.S. medical eligibility criteria for contraceptive use, 2010: revised recommendations for the use of
hormonal contraception among women at high risk for HIV infection or infected with HIV. MMWR Morb Mortal Wkly Rep
2012;61(24):449–52. [ ]

Women over the age of 40. In: Contraception: an Australian clinical practice handbook. 3rd ed. Ashfield, NSW: Sexual
Health &​ Family Planning Australia; 2012. p. 190–3.

Faculty of Sexual and Reproductive Healthcare (FSRH). UK medical eligibility criteria for contraceptive use (UKMEC).
London: FSRH; 2009. [URL]

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Contraception for women aged
over 40 years. London: RCOG; 2010. [URL]

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Combined hormonal
contraception: Royal College of Obstetricians and Gynaecologists FSRH; 2011, updated 2012. [URL]

Kaunitz AM. Clinical practice. Hormonal contraception in women of older reproductive age. N Engl J Med
2008;358(12):1262–70. [ ]

Manzoli L, De Vito C, Marzuillo C, Boccia A, Villari P. Oral contraceptives and venous thromboembolism: a systematic
review and meta-analysis. Drug Saf 2012;35(3):191–205. [ ]

Royal College of Obstetricians and Gynaecologists (RCOG). Venous thromboembolism and hormonal contraception
(Green-top Guideline no. 40). 2nd ed. London: RCOG; 2010. [URL]

US Food and Drug Administration (FDA). Updated information about the risk of blood clots in women taking birth
control pills containing drospirenone (FDA Drug Safety Communication). [URL]

Progestin-only contraception

Canto De Cetina TE, Canto P, Ordonez Luna M. Effect of counseling to improve compliance in Mexican women
receiving depot-medroxyprogesterone acetate. Contraception 2001;63(3):143–6. [ ]

Crosignani PG, Vercellini P, Mosconi P, Oldani S, Cortesi I, De Giorgi O. Levonorgestrel-releasing intrauterine device
versus hysteroscopic endometrial resection in the treatment of dysfunctional uterine bleeding. Obstet Gynecol
1997;90(2):257–63. [ ]

Faculty of Sexual and Reproductive Health (FSRH) Clinical Effectiveness Unit. Intrauterine contraception. London:
RCOG; 2007. [URL]

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Progestogen-only pills. London:
RCOG; 2008, updated 2009. [URL]

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Progestogen-only implants.
London: RCOG; 2008, updated 2009. [URL]

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Progestogen-only injectable
contraception. London: RCOG; 2008, updated 2009. [URL]

Harvey C, Seib C, Lucke J. Continuation rates and reasons for removal among Implanon users accessing two family
planning clinics in Queensland, Australia. Contraception 2009;80(6):527–32. [ ]

Lanza LL, McQuay LJ, Rothman KJ, Bone HG, Kaunitz AM, Harel Z, et al. Use of depot medroxyprogesterone acetate
contraception and incidence of bone fracture. Obstet Gynecol 2013;121(3):593–600. [ ]
Lopez LM, Chen M, Mullins S, Curtis KM, Helmerhorst FM. Steroidal contraceptives and bone fractures in women:
evidence from observational studies. Cochrane Database Syst Rev 2012;(8):CD009849. [ ]

Mansour D, Korver T, Marintcheva-Petrova M, Fraser IS. The effects of Implanon on menstrual bleeding patterns. Eur
J Contracept Reprod Health Care 2008;13(Suppl 1):13–28. [ ]

Mantha S, Karp R, Raghavan V, Terrin N, Bauer KA, Zwicker JI. Assessing the risk of venous thromboembolic events
in women taking progestin-only contraception: a meta-analysis. BMJ 2012;345e4944. [ ]

McNicholas C, Zhao Q, Secura G, Allsworth JE, Madden T, Peipert JF. Contraceptive failures in overweight and obese
combined hormonal contraceptive users. Obstet Gynecol 2013;121(3):585–92. [ ]

Said S, Omar K, Koetsawang S, Kiriwat O, Srisatayapan Y, Kazi A, et al. A multicentered phase III comparative clinical
trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100 mg or 150 mg: II. The comparison of
bleeding patterns. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation
Special Programme of Research, Development and Research Training in Human Reproduction. Contraception
1987;35(6):591–610. [ ]

Schwallie PC, Assenzo JR. The effect of depo-medroxyprogesterone acetate on pituitary and ovarian function, and the
return of fertility following its discontinuation: a review. Contraception 1974;10(2):181–202. [ ]

Emergency (postcoital) contraception

Faculty of Sexual and Reproductive Healthcare (FSRH) Clinical Effectiveness Unit. Emergency contraception. London:
RCOG; 2011, updated 2012. [URL]

von Hertzen H, Piaggio G, Ding J, Chen J, Song S, Bartfai G, et al. Low dose mifepristone and two regimens of
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Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Menstrual disorders
The menstrual cycle
Menstrual disorders are common during a woman's reproductive years, causing significant social and personal
health problems. Population studies suggest that up to 30% of women consider their periods to be heavy, but only
5% seek medical assistance. Uterine bleeding may be abnormal in volume, duration and/or frequency, with
management linked to whether cycles are regular (ovulatory) or irregular (anovulatory). Pelvic pain can be a
disabling component, irrespective of the periodicity of the cycle.

For advice on managing anovulatory cycles resulting in amenorrhoea (absent bleeding for more than 3 cycles) or
oligomenorrhoea (intermenstrual interval longer than 35 days), see secondary amenorrhoea.

In general terms, a normal menstrual cycle is characterised by:

an intermenstrual length of 24 to 35 days

a luteal (secretory) phase of 14 ± 1 days
vaginal mucus that changes at ovulation to become more copious, clear, sticky and stretchy
breast and abdominal swelling in the late luteal phase
menstrual bleeding of less than 80 mL over 4 to 7 days.

The endometrium proliferates and thickens during the follicular phase, under the influence of oestrogen. A normal
endometrial thickness (measured by ultrasound) is from 6 to 12 mm. After ovulation, the secretory phase is
induced by endometrial exposure to progesterone (produced by the corpus luteum). Biochemically, the cycle is
considered ovulatory if the serum progesterone concentration is above 20 nmol/L during the midluteal phase (5 to
10 days before menses).

Heavy menstrual bleeding (menorrhagia)

Introduction

Heavy menstrual bleeding (menorrhagia) may be defined by:

blood loss of more than 80 mL per menstrual cycle

bleeding that persists for more than 7 days
bleeding that is unacceptable to the woman.

Heavy menstrual bleeding is caused by excessive fibrinolytic activity and/or increased prostaglandin production
within the endometrium and myometrium. In turn, this results in delayed or ineffective local haemostasis.

Heavy menstrual bleeding is more commonly associated with cycles that are ovulatory (regular) rather than
anovulatory (irregular). Anovulation results from excessive oestrogen stimulation in the absence of progesterone.
This produces proliferation of the endometrium, which then bleeds erratically. Anovulatory cycles often occur with
menarche, at perimenopause or in polycystic ovary syndrome (PCOS). While not uncommon at the beginning and
end of reproductive life, anovulatory cycles are abnormal at other times. Recurring anovulation is a risk factor for
endometrial hyperplasia and endometrial carcinoma.

Causes of heavy menstrual bleeding, regardless of whether cycles are ovulatory or anovulatory, include:

uterine pathology (eg uterine fibroids, endometrial or endocervical polyps, endometrial hyperplasia,
adenomyosis)
the presence of an intrauterine contraceptive device.

Heavy menstrual bleeding may also be associated with comorbidities (eg hypothyroidism, bleeding disorders [in
particular von Willebrand disease], PCOS). However, often no pathology can be shown, and then the heavy
menstrual bleeding is assumed to be due to hormonal dysfunction.

Heavy menstrual bleeding is a common cause of iron deficiency anaemia in women in Australia.

Investigating heavy menstrual bleeding

A thorough history and examination is essential when investigating heavy menstrual bleeding, to establish:
 age
parity
last normal menstrual period and likelihood of pregnancy
frequency, volume and pattern (regular or irregular) of menstrual bleeding
perception of the impact of the bleeding on quality of life
symptoms, signs or past history of comorbidities (eg diabetes, obesity, thyroid disease, PCOS, bleeding
disorders)
experience of pelvic pain or pressure
family history of endometriosis, endometrial cancer or bowel cancer.

A full blood examination and a pregnancy test are needed. Additional blood tests that may be indicated based on
clinical assessment, include a:

coagulation profile, especially in adolescent girls with irregular bleeding and a family history of clotting
disorders
serum ferritin or thyroid stimulating hormone concentration.

If a woman is sexually active, she should have a Papanicolaou (Pap) smear.

Uterine pathology should be suspected when heavy menstrual bleeding is:

regular, in women who are:

–
older than 40 years
–
younger than 40 years and whose heavy bleeding does not respond to a trial of medical therapy
irregular, in women who are in their reproductive years or perimenopausal.

Investigations for uterine pathology include transvaginal ultrasound, saline-infused sonography or hysteroscopy.

An endometrial biopsy to exclude endometrial hyperplasia may be considered in women:

whose bleeding does not respond to medical therapy

whose endometrium is thickened (12 mm or more)
who have intermenstrual bleeding.

Note that endometrial cancer is not excluded by a normal Pap smear.

Postcoital bleeding needs further investigation.

Treating heavy menstrual bleeding

Introduction

If no pathology has been found, choice of medical treatment for heavy menstrual bleeding depends on several
factors. These include the woman's age, parity, coexisting medical conditions, preference and need for
contraception. If cycles are anovulatory, management must include a hormonal treatment, but otherwise
management options for ovulatory and anovulatory heavy menstrual bleeding are the same. Nonhormonal and
hormonal treatments are summarised in Table 5.33. See also advice on treating acute emergency heavy menstrual
bleeding.

Medical options for treating heavy menstrual bleeding (Table 5.33)

Drug Reduction in blood loss

nonhormonal options
tranexamic acid 47%
nonsteroidal anti-inflammatory drugs 29% to 49%
hormonal options
levonorgestrel-releasing intrauterine system 71% to 90%
combined oral contraceptive pill 43%
oral progestins (norethisterone or
83%
medroxyprogesterone)

Nonhormonal drug treatment

Tranexamic acid and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat heavy menstrual bleeding.
Unless the woman also has dysmenorrhoea, tranexamic acid is preferred because it is more effective than NSAIDs.
When cycles are anovulatory, these drugs must be used with a progestin, to prevent the bleeding from recurring.

Tranexamic acid

Tranexamic acid is an antifibrinolytic drug that inhibits clot breakdown by preventing activation of plasminogen
and plasmin. It effectively reduces blood loss. Dosage varies, according to the heaviness and duration of bleeding.
Use:

tranexamic acid 1 to 1.5 g orally, 6- to 8-hourly for the first 3 to 5 days of menstruation.

Tranexamic acid is tolerated well. Limited studies suggest it reduces flooding, leakage and sexual difficulties. The
main adverse effects are nausea and gastrointestinal upset. Caution is suggested in women predisposed to
thromboembolic events, although large-scale studies have not shown an increased risk of venous
thromboembolism.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs decrease the prostaglandin concentration in the endometrium, thereby
reducing menstrual blood loss. If hormonal treatment is undesirable or unacceptable and dysmenorrhoea is also
present, NSAIDs are an acceptable option. However, NSAIDs should be avoided in women with bleeding or
clotting disorders, or those at risk of peptic ulcers. Ibuprofen, mefenamic acid and naproxen are commonly used.
NSAIDs can be combined with hormonal treatment or tranexamic acid. Treatment needs to start just before, or
with the onset of, menstrual bleeding and continue for up to 5 days. Use:

1 ibuprofen 200 to 400 mg orally, 3 to 4 times daily. Maximum daily dose 1600 mg

OR

1 mefenamic acid 500 mg orally, 3 times daily

OR

1 naproxen 500 mg orally initially, then 250 mg every 6 to 8 hours. Maximum daily dose
1250 mg.

Choice of drug is based on patient preference and cost.

Hormonal drug treatment

Choosing a hormonal over a nonhormonal option to treat heavy menstrual bleeding is guided by the woman's
preference and her need for contraception. Counselling helps establish which delivery system is more acceptable
and whether contraception is needed (short- or long-term).

Levonorgestrel-releasing intrauterine system

The levonorgestrel-releasing intrauterine system (LNG-IUS) can be used to treat heavy menstrual bleeding
associated with ovulatory or anovulatory cycles. The LNG-IUS avoids the systemic adverse effects of oral
progestins, has higher patient satisfaction rates and reduces bleeding more effectively than a 21-day course of
norethisterone. Use:

levonorgestrel-releasing intrauterine system 52 mg. Replace every 5 years.

Combined oral contraceptive pill

The combined oral contraceptive pill (COCP) produces a thinner endometrium, and has a high degree of patient
acceptability and convenience. It is the most widely used first-line drug in primary care for controlling heavy
menstrual bleeding, whether cycles are ovulatory or anovulatory. However, a meta-analysis [Note 1] concluded
that only one properly randomised crossover trial has examined how effectively the COCP reduces menstrual
bleeding. This trial showed a 43% reduction in mean menstrual loss using a COCP containing 30 micrograms of
ethinyloestradiol, but it is not known if this formulation is optimal. Use:

combined oral contraceptive pill (see Table 5.30 for preparations).

Note 1: Farquhar C, Brown J. Oral contraceptive pill for heavy menstrual bleeding. Cochrane Database Syst
 Rev 2009;(4):CD000154. [URL]

Oral progestins

Cyclical progestins reduce endometrial thickness, and are often used to control heavy bleeding in ovulatory and
anovulatory cycles. These are an alternative oral therapy to a COCP.

Ovulatory cycles

To be effective in ovulatory heavy menstrual bleeding, progestins must be given for 21 days of the menstrual
cycle. Shorter courses (from days 15 to 25) do not reduce mean menstrual blood loss. A common regimen is:

1 medroxyprogesterone 10 mg orally, 1 to 3 times daily (depending on heaviness of

bleeding) on days 1 to 21 of a 28-day cycle, for up to 6 months

OR

1 norethisterone 5 mg orally, 2 to 3 times daily on days 1 to 21 of a 28-day cycle, for up to 6

months.

Although bleeding control is similar to that of the LNG-IUS, patient acceptability is poor due to the adverse effects
of oral progestins. Treatment should not usually continue for longer than 6 months due to the risk of hypo-
oestrogenism.

Anovulatory cycles

Cyclical progestins for the same 12 days of each, or every second, calendar month usually control anovulatory
bleeding. Evidence for a preferred treatment is limited. A common regimen is:

1 medroxyprogesterone 10 mg orally, once daily for the same 12 days of each calendar
month

OR

1 norethisterone 5 mg orally, once daily for the same 12 days of each calendar month.

If long-term treatment is needed, the LNG-IUS may be used.

Surgical treatment

Endometrial ablation or hysterectomy may be preferred to drug therapy in women who:

no longer wish to be able to conceive

are perimenopausal
have poorly controlled symptoms
have adverse effects from the drugs
have significant uterine pathology.

Hysterectomy is preferred to drug therapy for women with endometrial hyperplasia with atypia—endometrial
ablation is not appropriate.

Acute emergency heavy menstrual bleeding

Occasionally, acute heavy menstrual bleeding may cause severe anaemia and clinical features of reduced
circulatory volume. Pregnancy-related haemorrhage must be excluded. Adolescent girls with severe menstrual
bleeding, especially if it occurs from menarche, should be investigated for coagulation disorders. In adolescent
girls who are otherwise healthy, this bleeding usually reflects an immature hypothalamic–pituitary–ovarian axis
that is causing anovulatory cycles. This pattern results in prolonged endometrial stimulation by oestrogen, without
luteinisation by progesterone. In older women with established cycles, investigations are required once they are
stabilised. This is particularly so in women for whom this is a new symptom, in women with a background of
PCOS, and when malignancy needs to be excluded.

In addition to restoring blood volume, management includes stopping the uterine bleeding, but evidence for how
best to achieve this is lacking. Using the lowest effective drug dose is important, especially in adolescents, but high
doses may be necessary short term to control bleeding.
In an acute setting, tranexamic acid is considered first-line treatment. Choice of intravenous or oral therapy
depends on clinical assessment of the patient, clinical preference and availability of preparations. Use:

1 tranexamic acid 10 mg/kg IV, every 8 hours until bleeding stops

OR

1 tranexamic acid 1 to 1.5 g orally, 6- to 8-hourly until bleeding stops.

If tranexamic acid is unavailable or not tolerated, hormonal treatments are also effective. Options include:

1 ethinyloestradiol 30 to 35 micrograms combined oral contraceptive pill (see Table 5.30

for preparations) orally, every 6 hours until bleeding stops. Re-evaluate after 48 hours

OR

1 medroxyprogesterone 10 mg orally, every 4 hours until bleeding stops. Maximum daily

dose 80 mg

OR

1 norethisterone 5 to 10 mg orally, every 4 hours until bleeding stops.

Occasionally if the bleeding doesn't stop, high dose oestrogen may be required, but this usually has limited
concordance due to nausea. Use:

ethinyloestradiol 50 micrograms combined oral contraceptive pill (see Table 5.30 for
preparations) orally, every 6 hours until bleeding stops. Re-evaluate after 48 hours.

Caution is advised with high doses of oestrogen and progestin in women at risk of venous thromboembolism.

An antiemetic is recommended with hormonal therapy. Once acute bleeding has been controlled, the dose of
hormonal drugs should be reduced using a tapering regimen (tranexamic acid does not need this). A suitable
reducing regimen is to take a COCP:

three times daily for 2 days, then

twice daily for 2 days, then
daily for 3 weeks.

After this, stop the COCP for 1 week to allow a withdrawal bleed.

To prevent heavy menstrual bleeding from recurring in subsequent months, options include the COCP, cyclical
progestin for 21 days of each month or the LNG-IUS (see hormonal drug treatment).

Dysmenorrhoea
Dysmenorrhoea (painful menstrual bleeding) is one of the most common gynaecological problems. Despite the
psychosocial impact of this condition, women seem reluctant to seek medical help. The condition is classified
according to the absence (primary) or presence (secondary) of an identified underlying disease.

Primary dysmenorrhoea

Prostaglandins released by endometrial cells at the start of menstruation cause vasoconstriction, muscle contraction
and compression of the spiral arteries, leading to myometrial ischaemia. The severity of primary dysmenorrhoea is
directly related to the prostaglandin concentration in the menstrual fluid.

Risk factors for primary dysmenorrhoea include early onset of menarche, long duration of menstrual flow,
smoking, obesity and alcohol consumption. Period pain that starts within 6 to 12 months of menarche is a strong
diagnostic indicator of primary dysmenorrhoea.

Treatment aims to suppress ovulation and/or inhibit prostaglandin production, using a COCP or an NSAID. These
approaches may be combined for persistent pain.

Good quality clinical trials showing that the COCP reduces pain compared with placebo are lacking. A meta-
analysis [Note 2] concluded on limited evidence that the preparation of choice was a COCP containing fewer than
35 micrograms of oestrogen. Use:

ethinyloestradiol 30 micrograms combined oral contraceptive pill (see Table 5.30 for
preparations).

The LNG-IUS may have benefits in managing primary dysmenorrhoea, but evidence is scant.

NSAIDs relieve primary dysmenorrhoea by suppressing prostaglandins in menstrual fluid. Ideally these drugs are
given 48 hours before menstruation is expected, or with onset of pain. Treatment should continue for the first 48 to
72 hours of menses when prostaglandin release is maximal. There is insufficient evidence to favour one NSAID
over another. In women at risk of gastrointestinal adverse effects from NSAIDs, a proton pump inhibitor may be
prescribed concurrently. Suitable NSAID regimens include:

1 ibuprofen 200 to 400 mg orally, 3 to 4 times daily. Maximum daily dose 1600 mg

OR

1 mefenamic acid 500 mg orally, 3 times daily

OR

1 naproxen 500 mg orally initially, then 250 mg every 6 to 8 hours. Maximum daily dose
1250 mg.

Other options for treating primary dysmenorrhoea, assessed by small randomised controlled trials (RCTs), include
local heat, transcutaneous electrical nerve stimulation (TENS), acupressure, acupuncture, spinal manipulation and
herbal and dietary preparations (eg vitamin E, thiamine, pyridoxine, magnesium, fish oil). Pain reduction was
demonstrated but the studies were limited in size and quality. Chinese herbal medication, exercise and
psychological behavioural interventions have shown benefit in small trials.

Note 2: Wong CL, Farquhar C, Roberts H, Proctor M. Oral contraceptive pill for primary dysmenorrhoea.
Cochrane Database Syst Rev 2009;(4):CD002120. [URL]

Secondary dysmenorrhoea

Overview

Causes of secondary dysmenorrhoea include endometriosis, pelvic inflammatory disease, fibroids, adenomyosis,
endometrial polyps, nonhormonal intrauterine devices, pelvic actinomycosis and congenital abnormalities.

Aspects of the medical history that suggest dysmenorrhoea is secondary include:

the time of onset of dysmenorrhoea (often in the third decade or later, although may be from the onset of
menses)
a change in the pattern of period pain
the presence of dyspareunia, heavy menstrual bleeding, intermenstrual bleeding or postcoital bleeding
irregular periods
a poor response to a trial of treatment
family history.

Treatment of secondary dysmenorrhoea is directed to its cause.

Endometriosis

Laparoscopy is required for diagnosing endometriosis but not before treating pelvic pain. A diagnosis of
endometriosis should be considered in any woman or postpubertal girl with pelvic pain and/or infertility. Physical
examination and ultrasound aid diagnosis. In adolescents, pain may be acyclical and surgical findings may be
atypical. Surgery with excision or ablation of endometriotic lesions is indicated in women with severe pain or
endometriomas 3 cm or more. See also discussion of endometriosis and infertility.

Empirical medical therapy is indicated in women and girls with suspected endometriosis who:

have not had a laparoscopy

present in a low-resource setting.

Drug treatment may halt or regress the growth of endometriotic lesions.

NSAIDs are first-line management, and regimens as for primary dysmenorrhoea are appropriate. Paracetamol
(standard doses, 4- to 6-hourly) can be added to the NSAID if analgesia is inadequate, or used as an alternative if
NSAIDs are not tolerated or contraindicated. Dosing of NSAIDs and/or paracetamol must be regular during the
time of pain.

A short trial of the COCP to inhibit ovulation is indicated before using drugs with more significant adverse effects.
However, the COCP may be ineffective in some women. If symptoms of endometriosis occur in the 7-day pill-free
interval, active tablets may be used continuously to prevent this. If prolonged breakthrough bleeding occurs on
continuous use, the COCP should be stopped for 1 week before restarting. In adolescent girls, treatment should be
individualised according to their age and the adverse effects of the drugs.

Other drugs that may be used are a:

progestin, to directly suppress endometriosis (eg LNG-IUS, medroxyprogesterone, norethisterone)

gonadotrophin releasing hormone (GnRH) analogue (eg goserelin), to reduce the activity of the
hypothalamic–pituitary axis.

Oral progestins and GnRH analogues are only used short term, but have a place in managing some patients. Oral
progestins (eg medroxyprogesterone, norethisterone) are used in women with a contraindication to the COCP,
while waiting for surgery or for LNG-IUS insertion, or in very young girls. GnRH analogues may be used after
surgery, especially if endometriotic lesions were not completely excised. The goserelin implant may also be used
short-term when other treatments have failed. Depot medroxyprogesterone acetate may be used if other treatments
have been unsuccessful or are contraindicated. If appropriate, use:

1 combined oral contraceptive pill (see Table 5.30 for preparations)

OR

2 levonorgestrel-releasing intrauterine system 52 mg, until fertility is desired or for 5 years

OR

2 medroxyprogesterone 10 mg orally, twice daily for up to 6 months

OR

2 norethisterone 5 mg orally, twice daily for at least 4 to 6 months

OR

3 goserelin 3.6 mg SC implant, every 28 days for up to 6 months.

Significant adverse effects are associated with progestins and GnRH analogues. Progestins are associated with
bloating, mood change and weight gain. GnRH analogues are associated with symptoms of oestrogen deficiency
(eg flushing, vaginal dryness, bone loss), but these may be alleviated by adding back oestrogen.

Use of the synthetic steroid, danazol, is limited by its significant adverse effects. These include moderate
virilisation (eg hirsutism, acne, voice change), liver toxicity, adverse effects on the serum lipid profile and a small
increase in the risk of ovarian cancer. Danazol may be considered appropriate in women who have used it
successfully in the past and do not tolerate other options.

Progestins, GnRH analogues and danazol are associated with menstrual cycle disturbance (usually amenorrhoea),
and are contraindicated when a woman is trying to conceive.

Premenstrual syndrome
Diagnosis
Premenstrual syndrome (PMS) is characterised by somatic and psychological symptoms during the luteal phase of
the menstrual cycle. These symptoms remit within a few days of menstruation and are absent in the follicular
phase of the cycle. Typically, they recur in subsequent cycles.

Psychological symptoms of PMS include irritability, mood swings, anxiety, depression and general dysphoria,
associated with a sense of loss of control and inability to cope. Physical symptoms include bloating, headaches and
breast discomfort. Chronic conditions (eg epilepsy, migraine, asthma) may be exacerbated in PMS. It is estimated
that up to 80% of women experience some form of PMS. Symptoms are moderately severe in 20% to 40% of
women and disabling in 2% to 9%. The latter group may satisfy Diagnostic and Statistical Manual of Mental
Disorders (fifth edition; DSM-5) diagnostic criteria for premenstrual dysphoric disorder.

As there is no diagnostic test, prospective daily charting of symptoms over two menstrual cycles is highly
desirable for assessment. Charting [Note 3] also helps to differentiate PMS from premenstrual exacerbation of
concurrent depression or anxiety. Use of a premenstrual screening tool [Note 4] before charting is advised, to
ensure management for any concurrent condition (eg depression) is not delayed.

Note 3: Johnson SR. Clinician's approach to the diagnosis and management of premenstrual syndrome. Clin
Obstet Gynecol 1992;35(3):637-57. [URL]

Note 4: Steiner M, Macdougall M, Brown E. The premenstrual symptoms screening tool (PSST) for clinicians.
Arch Womens Ment Health 2003;6(3):203-9. [URL]

Treatment

Overview

The cause and pathophysiology of PMS remains unclear—this makes it difficult to target and evaluate treatment.
Diagnostic criteria have varied, but a classification system from the International Society for Premenstrual
Disorders [Note 5] may change this. Treatment choice is guided by the severity of the woman's symptoms, her
preference and intercurrent conditions or lifestyle factors.

Note 5: O'Brien S, Rapkin A, Dennerstein L, Nevatte T. Diagnosis and management of premenstrual disorders.
BMJ 2011;342:d2994. [URL]

Nonpharmacological treatment

Nonpharmacological treatment (eg lifestyle modification, exercise, relaxation techniques, cognitive behavioural
therapy [CBT]) can help relieve the symptoms of PMS. CBT for PMS and premenstrual dysphoric disorder has
been shown to have some effect in several RCTs.

Pharmacological treatment

If a woman has severe PMS or premenstrual dysphoric disorder, and nonpharmacological treatment is
unsuccessful, pharmacological treatment may help.

Combined oral contraceptive pill

Hormonal therapy aims to suppress ovulation. Progestins used alone are ineffective and may even aggravate
symptoms, but can be used in conjunction with oestrogen to protect the endometrium.

An oral contraceptive that combines ethinyloestradiol and drospirenone is the only COCP that has been subjected
to a RCT for treating PMS. Drospirenone is a progestin derived from spironolactone (other more widely used
COCP preparations contain 19-nortestosterone derivatives). Use:

ethinyloestradiol+drospirenone 20 micrograms + 3 mg orally, daily on days 1 to 24 of a

28-day cycle (see Table 5.30 for preparations).

Variations on this regimen include an extended use regimen or a shortened hormone-free pill interval.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs; eg fluoxetine, paroxetine, citalopram, sertraline) are effective
treatment for the physical and psychological symptoms of PMS. Fluoxetine and sertraline are most commonly
used, but other SSRIs are also effective. No difference in efficacy between SSRIs has been shown. The most
common adverse effects reported from trials using SSRIs to treat PMS were insomnia, gastrointestinal disturbance
and fatigue. Anorgasmia with secondary decreased libido was not reported commonly.

Intermittent dosing of SSRIs, limited to the 2 weeks before menses (ie the luteal phase), may have fewer adverse
effects and be more acceptable to patients. However, if the woman's pattern of symptoms suggests premenstrual
exacerbation of a comorbid depressive or anxiety disorder, a continuous regimen is usually more appropriate.
Generally, treatment should be stopped for a trial period after 12 months. Symptoms usually recur after women
stop taking SSRIs and these drugs may be required long term. Use:

1 fluoxetine 20 mg orally, once daily in the morning or intermittently (14 days before
anticipated onset of menstruation through to the first day of menses for each cycle)

OR

1 sertraline 50 mg orally, once daily in the morning or intermittently (14 days before
anticipated onset of menstruation through to the first day of menses for each cycle).

Other drugs

A single RCT suggested that spironolactone may help relieve the physical (eg abdominal bloating, swelling, breast
discomfort) and psychological symptoms of PMS.

Limited evidence from RCTs supports treating PMS with calcium, pyridoxine or the fruit extract of Vitex agnus
castus (chasteberry).

Key references
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Shapley M, Jordan K, Croft PR. Increased vaginal bleeding and psychological distress: a longitudinal study of their
relationship in the community. BJOG 2003;110(6):548–54. [ ]

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Farquhar C, Brown J. Oral contraceptive pill for heavy menstrual bleeding. Cochrane Database Syst Rev 2009;
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Fraser IS, McCarron G. Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a
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Gupta J, Kai J, Middleton L, Pattison H, Gray R, Daniels J. Levonorgestrel intrauterine system versus medical therapy
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Hickey M, Farquhar CM. Update on treatment of menstrual disorders. Med J Aust 2003;178(12):625–9. [ ]

Hickey M, Higham J, Fraser IS. Progestogens versus oestrogens and progestogens for irregular uterine bleeding
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James AH, Kouides PA, Abdul-Kadir R, Dietrich JE, Edlund M, Federici AB, et al. Evaluation and management of
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Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Female hypogonadism
Overview of management of female hypogonadism
Oestrogen deficiency has physiological and pathological causes. Lack of gonadal hormone secretion in a female
may result from pituitary or ovarian deficiency. In either case, replacement is given as oestrogen. If the uterus is
intact, progestin is added to prevent endometrial hyperplasia or cancer from unopposed oestrogen action.
Gonadotrophins must be stimulated or replaced when fertility needs to be restored in the presence of pituitary
dysfunction.

Delayed puberty in girls

Puberty is considered to be delayed in girls with no signs of sexual maturation (eg breast development) by the age
of 13 years. Constitutional delay may be the cause in approximately 30% of cases. Underlying conditions (eg other
endocrinopathies, poor nutrition, other chronic medical conditions) may lead to delayed puberty in approximately
20% of cases. The remaining 50% have no known cause.

Before considering treatment for delayed puberty, underlying causes should be excluded (and managed, if
necessary). Constitutional delay is considered in the context of the girl's family history and her medical and
developmental history. An appropriate review period is 6 months; if there is no development, treatment may be
initiated. The benefits of inducing puberty (eg breast development, growth of genital tract [including uterus],
psychosexual development) must be balanced against the harm of reducing final height.

Growth hormone treatment must be completed before oestrogen therapy begins.

The initial oestrogen dosage is much lower than standard adult replacement dosages. A progestin should not be
added until breast growth is well advanced, since progestins may impair normal breast development. Use:

oestrogen ultra-low dose orally, on alternate days, increasing gradually after 6 to 12

months to oestrogen medium dose orally, daily (see Table 5.34 for doses and Table 5.35
for preparations).

Once the medium dose of oestrogen has been reached, and the girl has good glandular development in her breasts,
vaginal secretion and first onset of vaginal bleeding (this may take up to 2 years), add:

progestin low to medium dose orally, once daily for the same 12 days of each calendar
month (see Table 5.34 for doses and Table 5.36 for preparations).

If no cause of permanent pubertal failure has been diagnosed, it is reasonable to withdraw treatment after 2 years
to:

assess endogenous hormonal status

see whether spontaneous periods occur.

If permanent pubertal failure is confirmed, ongoing hormone replacement is required. In young women,
appropriate therapy is medium to high dose, rather than low dose (see Table 5.34 for doses).

Primary amenorrhoea
Introduction
Primary amenorrhoea is defined as normal secondary sex characteristics but no menstrual period by the age of 16
years. It accompanies delayed puberty in girls, but should also be considered when menstrual periods have not
begun more than 5 years after the first physical signs of puberty. Possible causes for this delay are:

reproductive tract abnormalities (eg imperforate hymen) in the presence of normal endocrinology
sexual differentiation abnormalities (eg androgen insensitivity)
an endocrine abnormality (eg hyperprolactinaemia, consequence of anorexia nervosa) developing between
puberty and the onset of menses, leading to hypogonadism.

After the cause has been found, primary amenorrhoea accompanied by hypogonadism can be treated in the same
way as delayed puberty.
Turner syndrome
Most girls with Turner syndrome (missing one X chromosome) or Turner mosaic (missing one X chromosome in
some of their cells) present with failed pubertal development and primary amenorrhoea. However, up to 30% may
go through spontaneous, but delayed, puberty. Even fewer begin menstruating before developing secondary
amenorrhoea.

In Turner syndrome, inducing puberty with oestrogen theoretically could limit the final height achieved with
growth hormone treatment. Using oestrogen at an ultra-low dose allows normal growth as well as age-equivalent
pubertal development. Use:

oestrogen ultra-low dose orally, on alternate days, increasing gradually after 6 to 12

months to oestrogen medium dose orally or transdermally (see Table 5.34 for doses and
Table 5.35 for preparations).

Once the medium dose of oestrogen has been reached, a cyclical progestin may be added to induce menses.
Occasionally, progestin is given in alternate months, if the:

girl has a strong aversion to menstrual bleeding

progestin causes adverse effects (eg headaches, mood changes, premenstrual syndrome).

Use:

progestin low to medium dose orally, once daily for the same 12 days of each calendar
month (see Table 5.34 for doses and Table 5.36 for preparations).

After menses have been induced, therapy should continue with continuous oestrogen and cyclical progestin as
separate preparations or as a cyclical combined hormone replacement preparation (see Table 5.37 for cyclical
combined hormone replacement preparations). This is preferred to the combined oral contraceptive pill, because:

it avoids an oestrogen-free interval

progestin is given in a more physiological pattern
replacement oestrogen preparations are less likely to elevate blood pressure.

Oestradiol 2 mg daily (medium dose) is usually recommended for most women with Turner syndrome, but up to 4
mg daily (high dose) may be needed. From late adolescence, monitor for disorders that accompany Turner
syndrome (eg thyroid dysfunction, hearing loss, heart defects, abnormal glucose metabolism, dyslipidaemia,
diminished bone density).

Secondary amenorrhoea
Introduction

Secondary amenorrhoea and oligomenorrhoea may be caused by pituitary or hypothalamus disorders, primary
ovarian failure or hyperandrogenic states (eg polycystic ovary syndrome). The cause should be diagnosed before
beginning therapy.

Hypogonadotrophic amenorrhoea
Oestrogen therapy is recommended for hypogonadotrophic amenorrhoea, including when it is secondary to low
percentage body fat, weight loss and/or stress. This partially addresses the effect of long-term oestrogen deficiency
on bone density. However, to reverse the substantial deficit in bone density that is secondary to poor nutrition,
weight recovery may be needed as well.

It has not been established that women with hypogonadotrophic amenorrhoea are at increased risk of
cardiovascular disease, but women who have an early menopause (spontaneous or iatrogenic) are at increased risk
of ischaemic heart disease. Use:

1 oestrogen medium to high dose orally or transdermally, plus the corresponding cyclical
progestin dose orally (see Table 5.34 for doses, Table 5.35 for oestrogen preparations and
Table 5.36 for progestin preparations)

OR

1 equivalent cyclical combined preparation (see Table 5.37 for preparations).

If pituitary and ovarian function return, note that hormone replacement therapy (HRT) does not provide
contraception.

Premature menopause and early menopause

Premature menopause (in women younger than 40 years) and early menopause (in women aged 40 to 45 years)
may be induced or spontaneous. Causes include bilateral oophorectomy, exposure to cytotoxic drugs, idiopathic
early menopause and autoimmune ovarian failure. Unless contraindicated, women with premature or early
menopause should be treated with HRT. The current recommendation is to continue HRT at least until the median
age of natural menopause (ie 51 years). [Note 1]

Note 1: The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause
2012;19(3):257-71. [URL]

Menopause
Introduction
Women usually undergo menopause from the age of 45 to 55 years. Symptoms may include hot flushes, night
sweats, vaginal dryness, mood swings, sleep disturbance and loss of self-confidence. Symptoms often begin in the
perimenopausal period in women who still have a regular bleeding pattern. Symptoms can also occur in women
with menstrual cycle disturbance or amenorrhoea. Abnormal (eg heavy, infrequent, irregular) uterine bleeding is
common, in response to wide fluctuations of oestradiol production in perimenopause. Ongoing significant bleeding
should be investigated before starting HRT.

HRT is the most effective treatment for the vasomotor symptoms of menopause (eg hot flushes, night sweats) in
women of all ages. In contrast, the use of HRT for the sole purpose of preventing chronic disease is not
recommended. When initiating or continuing HRT, the woman and her clinician should weigh up the evidence for
long-term harms and benefits.

Unless contraindicated, all women with premature or early menopause should be treated with HRT.

The appropriate HRT regimen depends on many factors (eg time since last menstrual period, menopausal
symptoms, medical conditions, response to previous HRT). The most common regimens contain oestrogen, with or
without a progestin. Tibolone is a synthetic steroid that is also used for HRT. None of the alternative therapies (eg
black cohosh, red clover isoflavones, compounding pharmacy products) has evidence of benefit, and they may be
harmful.

When a woman is using the oral contraceptive pill, it can be difficult to know when she is menopausal and whether
a change to HRT is appropriate. HRT does not provide contraception, so a woman who continues to ovulate must
use nonhormonal contraception.

At menopause many cardiovascular risks emerge (eg central adiposity, increased insulin resistance, dyslipidaemia).
Absolute risk for cardiovascular disease should be assessed in all women aged 45 years or older, and addressed if
necessary. This applies whether or not a woman decides to start HRT.

Oestrogen/progestin hormone replacement

Introduction

Unopposed oestrogen replacement therapy (ie continuous daily oestrogen without progestin) is appropriate for
women who have had a hysterectomy. Oestrogen taken alone increases the risk of endometrial cancer, so women
with an intact uterus should take a progestin as well. See also contraindications to HRT.

HRT regimens containing oestrogen plus progestin are called combined HRT, and can be:

cyclical (oestrogen daily and progestin for 10 to 14 days of the month)

continuous (oestrogen and progestin throughout the month).

Combined HRT can be given as separate hormone preparations or a combined preparation. Separate oestrogen and
progestin preparations simplify dose titration to ease menopausal symptoms and minimise adverse effects.
Alternatively, combined preparations are easier to take and improve concordance with progestin therapy.

Oestrogen/progestin HRT is available as oral, transdermal (eg patch, gel) or intravaginal (eg cream, pessary)
preparations. If one preparation is ineffective or not tolerated, a different drug or route of administration should be
tried. The levonorgestrel-releasing intrauterine system can be used to deliver progestin in combination with oral or
topical oestrogen. Endometrial protection delivered in this manner may be particularly suitable for women with
heavy menstrual bleeding leading up to the menopause (once pathology has been excluded).

Initiating therapy at a low or ultra-low dose (see Table 5.34 for doses) reduces the incidence of oestrogenic adverse
effects (eg breast tenderness, nausea). The dose should be adjusted according to symptoms. Women who have been
oestrogen deficient for a significant time (eg older women) should start on an ultra-low dose.

In the short term (ie for 6 months), vaginal oestrogen preparations can be used alone in all women, whether or not
they have a uterus. Women with an intact uterus on this regimen should be given progestin after 6 months to see if
a withdrawal bleed occurs.

Women who become amenorrhoeic after an endometrial ablation need progestin as well as oestrogen, because
endometrial regeneration can occur.

Combined hormone replacement therapy

Cyclical combined HRT

Cyclical combined HRT is continuous daily oestrogen with cyclical progestin and can be used in women who:

are still having some spontaneous menses

had their last menstrual period under 2 years ago, as they might get breakthrough bleeding on a continuous
regimen.

Use:

oestrogen low to high dose (according to symptoms) orally or transdermally (see Table
5.34 for doses and Table 5.35 for preparations)

PLUS
corresponding cyclical progestin dose orally (see Table 5.34 for doses and Table 5.36
for preparations)

OR

cyclical combined hormone preparation (see Table 5.37 for preparations).

Some women prefer to change from a cyclical progestin to a continuous combined regimen when they are 2 or
more years post menopause.

Continuous combined HRT

Continuous combined HRT is continuous oestrogen and progestin and can be used in women:

whose menstrual periods stopped more than 2 years ago

who have been taking cyclical combined HRT, and their withdrawal bleeding is becoming lighter.

Use:

oestrogen low to medium dose orally or transdermally (see Table 5.34 for doses and Table
5.35 for preparations)

PLUS
corresponding continuous progestin dose orally (see Table 5.34 for doses and Table
5.36 for preparations)

OR

continuous combined hormone preparation (see Table 5.38 for preparations).

Oestrogen therapy

Unopposed oestrogen replacement therapy (ie continuous daily oestrogen without progestin) is appropriate for
women who have had a hysterectomy (see Table 5.34 for doses and Table 5.35 for oestrogen preparations). The
dose depends on the woman's symptoms.

Transdermal oestrogen therapy

Transdermal oestrogen has been associated with lower risks of venous thromboembolism (VTE) and stroke,
compared with standard doses of oral oestrogen—evidence from randomised controlled trials is not yet available.
Transdermal oestrogen therapy is preferred in women with a history of VTE. It is also useful for women whose
symptoms are not adequately controlled by oral therapy. Transdermal oestrogen is favoured over oral therapy, but
should be used with caution, in women who:

have elevated blood pressure that is difficult to control

have significant liver disease
are smokers.

Use:

1 oestradiol 1 mg/g gel 1 g transdermally, once daily (see Table 5.35 for preparations)

OR

1 oestradiol patch 25 to 100 micrograms (release rate per 24 hours) transdermally, once or
twice weekly depending on the brand (see Table 5.35 for preparations).

Women with an intact uterus should use transdermal oestrogen with cyclical or continuous progestin.

Intravaginal oestrogen therapy

Local oestrogen therapy (intravaginal pessaries or creams) can be used in women whose symptoms are
predominantly genitourinary (eg urinary frequency, dysuria, vaginal atrophy). It can also be used in women for
whom systemic oestrogen therapy is contraindicated or ineffective. Women with vaginal dryness who have a
history of breast cancer should try nonhormonal preparations (eg Replens, Sylk) before using oestrogen
intravaginally. Some systemic absorption of oestrogen can occur and safety cannot be assured. Oestradiol has a
more significant effect on serum oestrogen concentration than oestriol. Use:

1 oestriol 1 mg/g cream 500 micrograms intravaginally, daily at bedtime for 2 to 3 weeks,
then once or twice weekly (see Table 5.35 for preparations)

OR

1 oestriol pessary 500 micrograms intravaginally, daily at bedtime for 2 to 3 weeks, then
once or twice weekly (see Table 5.35 for preparations)

OR

2 oestradiol pessary 25 micrograms intravaginally, daily for 2 weeks, then twice weekly
(see Table 5.35 for preparations).

Intravaginal oestrogen may be required long term if symptoms persist. If used long term in women with an intact
uterus, a 12-day course of progestin every 6 or 12 months may be used. This is in case sufficient oestrogen has
been absorbed to stimulate the endometrium.

Contraindications to oestrogen therapy

A history of a hormone-dependent cancer or the presence of an active hormone-dependent cancer contraindicates

HRT. See advice on nonhormonal treatment for menopausal symptoms.

A past history of thromboembolic disease is a relative contraindication for oral HRT. Transdermal oestrogen
therapy is preferred in these women, but their additional risk factors for thrombosis should be assessed.

Combined oral HRT is relatively contraindicated in cardiovascular and cerebrovascular disease.

Monitoring oestrogen/progestin HRT

In the past, the serum oestradiol concentration was sometimes monitored when oestradiol implants (no longer
available) were used for HRT. However, laboratory assays do not reliably assess the efficacy of oral therapy with
conjugated equine oestrogens. Measuring follicle stimulating hormone (FSH) may be useful if severe symptoms
attributed to menopause do not respond to HRT. If FSH is suppressed, other causes for the symptoms should be
excluded.

Stopping oestrogen/progestin HRT

The decision to stop HRT should be based on informed choice, weighing up the benefits of ongoing treatment
versus its harms. In terms of preventing vasomotor symptoms from recurring, a randomised controlled trial found
that tapering the dose was no better than stopping suddenly.

Special situations in oestrogen/progestin HRT

Older women

HRT is sometimes used in older women (more than 10 years post menopause) to manage menopausal symptoms.
Therapy should begin with an ultra-low dose of oestrogen, which is slowly increased as adverse effects resolve or
are tolerated. Women who have been oestrogen deficient for many years should be warned that breast pain and
tenderness are common adverse effects when they begin oestrogen therapy.

Evidence suggests that initiating, but not continuing, combined HRT in older women is associated with an increase
in cardiovascular events. If an older woman needs HRT, other cardiovascular risks should be addressed
concurrently. See further discussion of the cardiovascular effects of HRT.

If the woman has an intact uterus, use:

oestrogen ultra-low dose orally, increasing to oestrogen low dose orally or transdermally
as tolerated or required (see Table 5.34 for doses and Table 5.35 for preparations)

PLUS
corresponding progestin dose orally, either cyclical or continuous (see Table 5.34 for
doses and Table 5.36 for preparations)

OR

equivalent cyclical combined or continuous combined hormone preparation (see Table

5.37 and Table 5.38, respectively, for preparations).

Osteoporosis

See advice on the role of HRT in preventing and treating osteoporosis.

New bleeding in women using continuous combined HRT

The following recommendations for treating postmenopausal bleeding assume that, before starting HRT, the
woman had:

no history of unexplained postmenopausal bleeding

normal findings on speculum and pelvic examinations
a negative Papanicolaou smear.

Management of breakthrough bleeding within the first 3 to 6 months of continuous combined HRT is expectant or
to change the progestin dosage (eg increase dose, change formulation) or change to cyclical combined HRT.
Bleeding that is heavy, persistent or unresponsive to an alteration in therapy should be investigated.

Bleeding that occurs more than 6 months after starting continuous combined HRT should be investigated by
endometrial ultrasound, with or without a hysteroscopy.

Progestin intolerance

Progestin intolerance may be a problem when taking combined HRT. Symptoms include bloating and flatus,
irritability, depression and breast tenderness. Management options include:

using an alternative oral progestin

reducing the progestin dose, keeping in mind the need for endometrial protection
trying a different route of administration (eg transdermal combined HRT patches or intrauterine progestin).

Harms and benefits of long-term oestrogen/progestin HRT

Introduction

Long-term use of HRT should be based on an informed discussion between the woman and the clinician of the
harms and benefits. The balance of benefits versus harms is likely to be more favourable in women younger than
60 years. However, the baseline risks for the woman must be considered.
Observational studies found an association between HRT and a reduced risk of coronary heart disease (CHD), but
the Women's Health Initiative (WHI) randomised clinical trials did not clearly support this. [Note 2] A
nonsignificant trend in the WHI data suggested that HRT, when started in younger women, protected against CHD.
In contrast, HRT started in older women, distant from menopause onset, appeared to increase the risk of CHD.
However, the WHI trials were not powered to allow definitive analysis of subgroups.

The absolute harms and benefits of long-term HRT are likely to vary with the regimen (eg hormone/s, dose, route
of administration). The following data from the US Preventive Services Task Force indicate the likely magnitude
of excess harms and benefits. [Note 3]

Note 2: Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal
hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's
Health Initiative randomized trials. JAMA 2013;310(13):1353-68. [URL]

Note 3: Moyer VA, U.S. Preventive Services Task Force. Menopausal hormone therapy for the primary
prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. Ann Intern
Med 2013;158(1):47-54. [URL]

Combined oestrogen/progestin HRT

Combined HRT reduces the risk for fractures in postmenopausal women, with:

46 fewer fractures of all types per 10 000 woman years

6 fewer hip fractures per 10 000 woman years.

However, combined HRT increases the risk of:

invasive breast cancer (8 additional cases per 10 000 woman years)

stroke (9 additional cases per 10 000 woman years)
deep vein thrombosis (12 additional cases per 10 000 woman years)
pulmonary embolism (9 additional cases per 10 000 woman years)
gallbladder disease (20 additional cases per 10 000 woman years)
dementia (22 additional cases per 10 000 woman years)
self-reported urinary incontinence (872 additional cases per 10 000 woman years).

When discussing whether to continue combined HRT long term, the severity of menopausal symptoms and the risk
factors for chronic disease should be considered. Because of the increased risk of breast cancer, combined HRT
should not normally be used for more than 5 years.

Unopposed oestrogen HRT

Unopposed oestrogen therapy (in women without a uterus) has a more favourable harm/benefit profile than
combined HRT. It reduces the risk of:

invasive breast cancer (8 fewer cases per 10 000 woman years)

fractures of all types (56 fewer per 10 000 woman years)
hip fractures (6 fewer per 10 000 woman years).

However, unopposed oestrogen therapy increases the risk of:

stroke (11 additional cases per 10 000 woman years)

deep vein thrombosis (7 additional cases per 10 000 woman years)
gallbladder disease (33 additional cases per 10 000 woman years)
self-reported urinary incontinence (872 additional cases per 10 000 woman years).

When discussing whether to continue unopposed oestrogen therapy long term, the severity of menopausal
symptoms and the risk factors for chronic disease should be considered.

Oestrogens and progestins for hormone replacement therapy

The following tables list doses and preparations of oestrogen/progestin hormone replacement therapy.

Oestrogen and progestin dosages for hormone replacement therapy (Table 5.34) [NB1]

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Ultra-low dose Low dose Medium dose High dose

Oestrogen
oral
1 mg on alternate
oestradiol 1 mg 2 mg 4 mg
days
1 mg on alternate
oestradiol valerate 1 mg 2 mg
days
conjugated oestrogens 0.3 mg on alternate
0.3 mg 0.625 mg 1.25 mg
days
transdermal patch (dose released daily)
25 to 37.5
oestradiol 50 to 75 micrograms 100 micrograms
micrograms
transdermal gel
oestradiol 1 mg/g 1 mg
Progestin: cyclical
5 to 10 mg for the 5 to 10 mg for the 10 mg for the same
medroxyprogesterone 5 mg for the same 12
same 12 days of each same 12 days of each 12 days of each
days of each month
month month month
0.7 mg for the same 0.7 mg for the same 0.7 to 2.5 mg for the 2.5 mg for the same
norethisterone 12 days of each 12 days of each same 12 days of each 12 days of each
month month month month
Progestin: continuous
medroxyprogesterone
2.5 mg 2.5 mg 2.5 to 5 mg 5 mg
350 to 700
norethisterone 350 micrograms 350 micrograms 700 micrograms
micrograms
NB1: All doses are once daily unless specified.

Oestrogen hormone replacement preparations (Table 5.35) [NB1]

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Oestrogen Brand name examples

oral
oestradiol 1 mg, 2 mg Estrofem [NB2], Zumenon
oestradiol valerate 1 mg, 2 mg Progynova
conjugated oestrogens 0.3 mg, 0.625 mg Premarin [NB2]
transdermal patch (dose released daily)
oestradiol 25 micrograms, 37.5 micrograms, 50 Climara, Estraderm [NB2], Estradot, Estraderm MX, Femtran
micrograms, 75 micrograms, 100 micrograms [NB2]
transdermal gel
oestradiol 1 mg/g Sandrena
vaginal cream
oestriol 1 mg/g Ovestin
vaginal pessary
oestradiol 25 micrograms Vagifem
oestriol 500 micrograms Ovestin Ovula
NB1: This list may not be complete, and some brands are not available in all the listed doses.
NB2: Not available on the Pharmaceutical Benefits Scheme (PBS) at the time of writing. See the PBS website [URL] for current information.

Progestin hormone replacement preparations (Table 5.36) [NB1]

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Progestin Brand name examples

oral
medroxyprogesterone acetate 2.5 mg, 5 mg, 10
Provera, Ralovera, Medroxyprogesterone Sandoz
mg
norethisterone 350 micrograms Micronor
norethisterone 5 mg Primolut N
intrauterine
levonorgestrel 52 mg over 5 years Mirena
NB1: This list may not be complete, and some brands are not available in all the listed doses.

Cyclical combined hormone replacement preparations (Table 5.37) [NB1] [NB2]

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Oestrogen-only phase Oestrogen + progestin phase Brand name examples

oral
oestradiol 2 mg + dydrogesterone 10
oestradiol 2 mg Femoston 2/10
mg
oestradiol 2 mg + norethisterone
oestradiol 2 mg, 1 mg Trisequens [NB3]
acetate 1 mg
transdermal (dose released daily)
oestradiol 50 micrograms +
oestradiol 50 micrograms Estalis Sequi 50/140
norethisterone acetate 140 micrograms
oestradiol 50 micrograms +
oestradiol 50 micrograms Estalis Sequi 50/250
norethisterone acetate 250 micrograms
NB1: Continuous oestrogen combined with cyclical progestin
NB2: This list may not be complete.
NB3: Not available on the Pharmaceutical Benefits Scheme (PBS) at the time of writing. See the PBS website [URL] for current information.

Continuous combined hormone replacement preparations (Table 5.38) [NB1] [NB2]

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Oestrogen (continuous) Progestin (continuous) Brand name examples

oral
oestradiol 1 mg drospirenone 2 mg Angeliq 1/2 [NB3]
conjugated oestrogens 0.625 mg medroxyprogesterone acetate 2.5 mg Premia 2.5 Continuous [NB3]
conjugated oestrogens 0.625 mg medroxyprogesterone acetate 5 mg Premia 5 Continuous [NB3]
oestradiol 1 mg norethisterone acetate 0.5 mg Kliovance [NB3]
oestradiol 2 mg norethisterone acetate 1 mg Kliogest [NB3]
transdermal (dose released daily)
oestradiol 50 micrograms norethisterone acetate 140 micrograms Estalis Continuous 50/140
oestradiol 50 micrograms norethisterone acetate 250 micrograms Estalis Continuous 50/250
NB1: Continuous oestrogen combined with continuous progestin
NB2: This list may not be complete.
NB3: Not available on the Pharmaceutical Benefits Scheme (PBS) at the time of writing. See the PBS website [URL] for current information.

Tibolone for menopausal symptoms

Tibolone is a synthetic steroid that is used as an alternative to combined HRT in postmenopausal women. It has
combined oestrogenic, progestogenic and androgenic actions, and does not need concurrent therapy with
progestins. When compared with equipotent doses of combined HRT, tibolone is less effective in relieving
menopausal symptoms. Tibolone is unsuitable for perimenopausal women because of an increased risk of
breakthrough bleeding. Its use is also limited because it increases the risk of breast cancer recurring, and doubles
the risk of stroke in women older than 60 years.

In women who are surgically postmenopausal or who have not had a natural menstrual bleed for at least 12
months, if considered appropriate, use:

tibolone 2.5 mg orally, daily.

Testosterone for menopausal symptoms

Testosterone production declines throughout adult life in women, but this decline does not accelerate at
menopause. Studies of premenopausal and postmenopausal women did not show a correlation between sexual
interest and function and circulating serum testosterone concentrations. Although some are advocates for
testosterone therapy to improve sexual function, this is largely based on studies that used supraphysiological
testosterone doses. In addition, exogenous testosterone can be aromatised to oestrogen, and oestrogen
concentration has been shown to correlate with sexual function in menopausal women.

No preparations of testosterone that are registered and available in Australia have been shown to deliver
physiological and effective therapy for postmenopausal women. Studies using testosterone patches have been
conducted with variable results in women who are postmenopausal as a result of age or surgery. Doses producing
effects superior to placebo were associated with supraphysiological circulating testosterone concentrations, even in
oophorectomised women who have low basal testosterone concentrations. No relationship between dose and effect
was observed.

Pharmacological testosterone doses may be effective, but virilisation is a risk. Also, the long-term adverse effects
of supraphysiological concentrations of testosterone are uncertain, particularly in relation to their effects on breast
cancer risk, endometrial stimulation and blood lipids (especially high-density lipoprotein cholesterol).

Nonhormonal treatment for menopausal symptoms

Introduction

Nonhormonal treatment for menopausal symptoms may be suitable for some women (eg when hormone therapy is
not tolerated or is contraindicated, personal choice). Postmenopausal women with a history of hormone-dependent
cancer, most commonly breast cancer, need special consideration. Menopausal symptoms can arise because:

cancer treatments induce menopause

HRT is stopped with the diagnosis of cancer
endocrine therapies (eg tamoxifen, aromatase inhibitors) are started.

Symptoms are similar to those of natural menopause, with the added psychological component of the woman's
response to her cancer diagnosis.

Hot flushes

Several drugs have some efficacy in treating hot flushes. In short-term studies, serotonin noradrenaline reuptake
inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) were more effective than placebo in treating
hot flushes. Use:

1 venlafaxine 37.5 mg orally, daily; increase to 75 mg daily after 1 week if needed

OR

2 paroxetine 10 mg orally, daily; increase to 20 mg daily after 1 week if needed

OR

3 gabapentin 100 to 300 mg orally, daily; increase as tolerated and according to response
every 4 days from once daily to 3 times daily

OR

4 clonidine 25 micrograms orally, twice daily; increase to 50 micrograms twice daily after 2
weeks if needed.

Sexual dysfunction may be an adverse effect of SNRIs and SSRIs. Paroxetine should be avoided in patients taking
tamoxifen. Gabapentin has shown efficacy in treating hot flushes and appears to be well tolerated. Adverse effects
of gabapentin include dizziness, unsteadiness and drowsiness, but generally abate with time. Clonidine has modest
efficacy in treating hot flushes, and its adverse effects include dry mouth and drowsiness.

Vaginal dryness

For vaginal dryness, first-line therapy is a nonhormonal preparation (eg Replens, Sylk). If these nonhormonal
preparations are ineffective, low-dose vaginal oestrogen preparations can be considered.

Alternative therapies for menopausal symptoms

Because of concern about the safety of conventional HRT, interest arose in:

alternative therapies (eg so-called ‘bioidentical hormones’)

complementary medicines (eg phytoestrogens, black cohosh).

Compounded ‘bioidentical hormones’ (particularly oestrogens and progesterone) have been promoted as safer and
more effective than traditional hormone therapies. Little or no clinical evidence supports these claims. In addition,
compounded ‘bioidentical hormone’ preparations are not subject to oversight by regulatory bodies and the strength
and purity can be inconsistent.

Placebo-controlled clinical studies of phytoestrogens to treat menopausal hot flushes found:

no evidence for efficacy of red clover isoflavones

inconsistent evidence for efficacy of soy extracts.

The Therapeutic Goods Administration has issued a warning about liver toxicity associated with black
cohosh. [Note 4]

Note 4: Therapeutic Goods Administration. Black cohosh (Cimicifuga racemosa): new labelling requirements
and consumer information for medicines containing Black cohosh. Canberra: TGA ; 29 May, 2007
[update]. [URL]

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Primary amenorrhoea

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Elsheikh M, Dunger DB, Conway GS, Wass JA. Turner's syndrome in adulthood. Endocr Rev 2002;23(1):120–40. [
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Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician 2006;73(8):1374–82. [
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Secondary amenorrhoea

The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause
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Lokkegaard E, Jovanovic Z, Heitmann BL, Keiding N, Ottesen B, Pedersen AT. The association between early
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The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause
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de Villiers TJ, Gass ML, Haines CJ, Hall JE, Lobo RA, Pierroz DD, et al. Global Consensus Statement on menopausal
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Hickey M, Elliott J, Davison SL. Hormone replacement therapy. BMJ 2012;344e763. [ ]

Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast
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Panay N, Hamoda H, Arya R, Savvas M, British Menopause S, Women's Health C. The 2013 British Menopause
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Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, et al. Postmenopausal hormone therapy: an
Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(7 Suppl 1):s1–s66. [ ]

Oestrogen/progestin hormone replacement

The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause
2012;19(3):257–71. [ ]

Antoine C, Liebens F, Carly B, Pastijn A, Rozenberg S, Women's Health I. Influence of HRT on prognostic factors for
breast cancer: a systematic review after the Women's Health Initiative trial. Hum Reprod 2004;19(3):741–56. [
]

Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362(9382):419–
27. [ ]

Bergkvist L, Adami HO, Persson I, Bergstrom R, Krusemo UB. Prognosis after breast cancer diagnosis in women
exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol 1989;130(2):221–8. [ ]

Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Levesque H, et al. Hormone therapy and venous
thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens:
the ESTHER study. Circulation 2007;115(7):840–5. [ ]

Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous
thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336(7655):1227–31. [
]

Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, et al. Unopposed estrogen therapy and the
risk of invasive breast cancer. Arch Intern Med 2006;166(9):1027–32. [ ]

Chen W, Petitti DB, Geiger AM. Mortality following development of breast cancer while using oestrogen or oestrogen
plus progestin: a computer record-linkage study. Br J Cancer 2005;93(4):392–8. [ ]

Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of estrogen plus progestin on
breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.
JAMA 2003;289(24):3243–53. [ ]

Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, et al. The effects of tibolone in older
postmenopausal women. N Engl J Med 2008;359(7):697–708. [ ]

de Villiers TJ, Gass ML, Haines CJ, Hall JE, Lobo RA, Pierroz DD, et al. Global Consensus Statement on menopausal
hormone therapy. Maturitas 2013;74(4):391–2. [ ]

Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal
hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol
2008;26(8):1260–8. [ ]

Gramling R, Eaton CB, Rothman KJ, Cabral H, Silliman RA, Lash TL. Hormone replacement therapy, family history,
and breast cancer risk among postmenopausal women. Epidemiology 2009;20(5):752–6. [ ]

Henderson VW, Lobo RA. Hormone therapy and the risk of stroke: perspectives 10 years after the Women's Health
Initiative trials. Climacteric 2012;15(3):229–34. [ ]

Hendrix SL, Wassertheil-Smoller S, Johnson KC, Howard BV, Kooperberg C, Rossouw JE, et al. Effects of conjugated
equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113(20):2425–34. [ ]

Herrington DM, Vittinghoff E, Lin F, Fong J, Harris F, Hunninghake D, et al. Statin therapy, cardiovascular events, and
total mortality in the Heart and Estrogen/Progestin Replacement Study (HERS). Circulation 2002;105(25):2962–7. [
]

Hickey M, Elliott J, Davison SL. Hormone replacement therapy. BMJ 2012;344e763. [ ]

Hsia J, Langer RD, Manson JE, Kuller L, Johnson KC, Hendrix SL, et al. Conjugated equine estrogens and coronary
heart disease: the Women's Health Initiative. Arch Intern Med 2006;166(3):357–65. [ ]

Lindh-Astrand L, Bixo M, Hirschberg AL, Sundstrom-Poromaa I, Hammar M. A randomized controlled study of taper-
down or abrupt discontinuation of hormone therapy in women treated for vasomotor symptoms. Menopause
2010;17(1):72–9. [ ]

Lobo RA. The risk of stroke in postmenopausal women receiving hormonal therapy. Climacteric 2009;12 Suppl 181–5.
[ ]

Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast
cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer 2010;126(2):483–9. [ ]

Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy
and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative
randomized trials. JAMA 2013;310(13):1353–68. [ ]

Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of
coronary heart disease. N Engl J Med 2003;349(6):523–34. [ ]

Moyer VA, U. S. Preventive Services Task Force. Menopausal hormone therapy for the primary prevention of chronic
conditions: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013;158(1):47–54. [
]

Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Langer RD, Pettinger M, et al. Conjugated equine estrogens
and breast cancer risk in the Women's Health Initiative clinical trial and observational study. Am J Epidemiol
2008;167(12):1407–15. [ ]

Rosenberg LU, Granath F, Dickman PW, Einarsdottir K, Wedren S, Persson I, et al. Menopausal hormone therapy in
relation to breast cancer characteristics and prognosis: a cohort study. Breast Cancer Res 2008;10(5):R78. [ ]

Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of
estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative
randomized controlled trial. JAMA 2002;288(3):321–33. [ ]

Rossouw JE, Manson JE, Kaunitz AM, Anderson GL. Lessons learned from the Women's Health Initiative trials of
menopausal hormone therapy. Obstet Gynecol 2013;121(1):172–6. [ ]

Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk
of cardiovascular disease by age and years since menopause. JAMA 2007;297(13):1465–77. [ ]

Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus
progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA
2003;289(20):2673–84. [ ]

Tibolone for menopausal symptoms

Cummings SR, Ettinger B, Delmas PD, Kenemans P, Stathopoulos V, Verweij P, et al. The effects of tibolone in older
postmenopausal women. N Engl J Med 2008;359(7):697–708. [ ]

Hendrix SL, Wassertheil-Smoller S, Johnson KC, Howard BV, Kooperberg C, Rossouw JE, et al. Effects of conjugated
equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113(20):2425–34. [ ]

Kenemans P, Bundred NJ, Foidart JM, Kubista E, von Schoultz B, Sismondi P, et al. Safety and efficacy of tibolone in
breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. Lancet Oncol
2009;10(2):135–46. [ ]

Vassalle C, Cicinelli E, Lello S, Mercuri A, Battaglia D, Maffei S. Effects of menopause and tibolone on different
cardiovascular biomarkers in healthy women. Gynecol Endocrinol 2011;27(3):163–9. [ ]

Wassertheil-Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, et al. Effect of estrogen plus
progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA
2003;289(20):2673–84. [ ]

Testosterone for menopausal symptoms

Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone,
dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin
Endocrinol Metab 2000;85(8):2832–8. [ ]

Davis SR, Braunstein GD. Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder
in postmenopausal women. J Sex Med 2012;9(4):1134–48. [ ]

Davis SR, Davison SL, Donath S, Bell RJ. Circulating androgen levels and self-reported sexual function in women.
JAMA 2005;294(1):91–6. [ ]

Dennerstein L, Randolph J, Taffe J, Dudley E, Burger H. Hormones, mood, sexuality, and the menopausal transition.
Fertil Steril 2002;77 Suppl 4S 42–8. [ ]

Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women. Cochrane Database
Syst Rev 2005;(4):CD004509. [ ]

Wierman ME, Basson R, Davis SR, Khosla S, Miller KK, Rosner W, et al. Androgen therapy in women: an Endocrine
Society Clinical Practice guideline. J Clin Endocrinol Metab 2006;91(10):3697–710. [ ]

Nonhormonal treatment for menopausal symptoms

Hickey M, Saunders CM, Stuckey BG. Management of menopausal symptoms in patients with breast cancer: an
evidence-based approach. Lancet Oncol 2005;6(9):687–95. [ ]

Rada G, Capurro D, Pantoja T, Corbalan J, Moreno G, Letelier LM, et al. Non-hormonal interventions for hot flushes in
women with a history of breast cancer. Cochrane Database Syst Rev 2010;(9):CD004923. [ ]

Alternative therapies for menopausal symptoms

Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J. Phytoestrogens for vasomotor menopausal
symptoms. Cochrane Database Syst Rev 2007;(4):CD001395. [ ]

Stuckey B. [How to treat]: sex hormones in menopause. Australian Doctor 2006;(September 8):27–34. [URL]

The Endocrine Society. Bioidentical hormones [position statement]. Maryland, USA: The Endocrine Society; October,
2006.

Therapeutic Goods Administration. Black cohosh (Cimicifuga racemosa): new labelling requirements and consumer
information for medicines containing Black cohosh. Canberra: TGA; 29 May, 2007 [update]. [URL]

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Male hypogonadism
Causes of male hypogonadism
Pathologically based hypogonadism in men can result from diseases of the:

testes (high luteinising hormone [LH] and low testosterone, ie primary or hypergonadotrophic
hypogonadism)
hypothalamus or pituitary gland (low LH and low testosterone, ie secondary or hypogonadotrophic
hypogonadism).

Causes of hypergonadotrophic hypogonadism include Klinefelter syndrome, cryptorchidism, orchidectomy,

orchitis, postcytotoxic or radiation damage, trauma and testicular torsion.

Causes of hypogonadotrophic hypogonadism include hypothalamic lesions, pituitary tumours, haemochromatosis

and idiopathic hypogonadotrophic hypogonadism (including Kallmann syndrome). The hypothalamic–pituitary–
gonadal axis can be disrupted by nonfunctioning macroadenomas that may result in hypopituitarism, and
prolactinomas.

Other causes of reduced serum testosterone concentration include systemic nongonadal disease (eg type 2
diabetes), obesity, depression, prescribed medication (eg opioids, high dose glucocorticoids) and recreational drugs
(eg marijuana, amphetamines, opioids).

Older men (aged 65 years or more) have lower testosterone concentrations than younger men. In ageing men, a
lower testosterone concentration predicts poorer health outcomes (eg frailty, cardiovascular events, mortality).
However, randomised trial evidence that testosterone therapy improves cardiovascular and mortality outcomes is
lacking.

For treatment of infertility in gonadotrophin-deficient men, see gonadotrophin therapy.

Diagnosing androgen deficiency

For a diagnosis of androgen deficiency, a man must have both the following factors. These are:

consistent symptoms and signs of androgen deficiency

an unequivocally low early morning plasma testosterone concentration, confirmed by repeat measurement.

Men who should be investigated for androgen deficiency are those with reduced libido, decreased spontaneous
erections, hot flushes or sweats, reduced facial hair growth, breast discomfort or gynaecomastia, loss of axillary
and pubic hair, small testes (especially volume under 5 mL) or osteoporosis. Less specific symptoms and signs
include: decreased energy, motivation, concentration or memory; lower mood; diminished physical work or work
performance; disturbed sleep or increased sleepiness; reduced muscle bulk and strength; increased body fat or
body mass index; mild anaemia.

Androgen deficiency should not be evaluated during an acute illness. Systemic illness can confound assessment of
symptoms and be associated with lower testosterone concentration.

Biochemical investigations for androgen deficiency include measuring early morning plasma concentrations of
total testosterone, sex hormone–binding globulin (SHBG) and LH. Total testosterone may be low in men with low
SHBG, without a reduction in bioavailable testosterone. A low testosterone concentration must be confirmed by
repeating the measurement in an early morning blood sample. Some laboratories report a free testosterone
concentration, calculated using the testosterone and SHBG concentrations. In most cases, measuring the total
testosterone concentration is sufficient. Calculated free testosterone may be helpful in men with low SHBG
concentration. Follicle stimulating hormone (FSH) does not need to be measured unless spermatogenesis is a
concern.

Mass spectrometry-based assays for total testosterone are more accurate than immunoassays. However, at the time
of writing most pathology laboratories in Australia use immunoassays, each with its own assay-dependent
reference range. Furthermore, serum androgen concentration decreases by 1% to 2% per year from the third
decade. Therefore, reference intervals for testosterone must take into account assay characteristics and the man's
age. When assayed by mass spectrometry, the lower limit in men:

aged 21 to 35 years with normal sexual and reproductive function was 10.4 nmol/L
 aged 70 to 89 years and healthy was 6.4 nmol/L.

Reference ranges using mass spectrometry are less well defined for men aged 35 to 70 years.

Androgen replacement therapy

Introduction
Reduced serum testosterone concentration can recover after treating a reversible cause (eg correcting
hyperprolactinaemia with a dopamine agonist, losing excess weight).

If the disorder that causes male hypogonadism is irreversible, lifelong androgen replacement therapy is required.
Treatment aims to relieve the symptoms and signs of androgen deficiency. Standard androgen replacement therapy
is not appropriate for boys with delayed puberty (see advice).

In the absence of pathologically based hypogonadism, older men should only be considered for testosterone
therapy if they meet both criteria for a diagnosis of androgen deficiency. In general, men older than 60 years with
serum testosterone concentration higher than 12 nmol/L are unlikely to benefit from testosterone therapy.

At the time of writing, the Pharmaceutical Benefits Scheme criteria for androgen replacement in males older than
18 years [Note 1] are:

androgen deficiency in males with established pituitary or testicular disorders

androgen deficiency in males 40 years and older who do not have established pituitary or testicular disorders
other than aging, confirmed by at least two morning blood samples taken on different mornings. Androgen
deficiency is confirmed by testosterone lower than 8 nmol/L, or 8 to 15 nmol/L with high LH (greater than
1.5 times the upper limit of the eugonadal reference range for young men).

Therapy can be initiated with injectable, transdermal or oral testosterone preparations. These modes of delivery
can continue to be used when moving to long-term treatment. Changing from one mode to another may improve
treatment acceptability. If parenteral therapy is contraindicated (eg bleeding disorders, anticoagulation treatment),
transdermal or oral testosterone should be used. The choice of treatment modality is based on treatment efficacy,
patient preference, convenience and adverse effects.

Note 1: To check current advice on criteria for androgen replacement, see the Pharmaceutical Benefits
Scheme [URL].

Standard androgen replacement therapy

Androgen replacement therapy should be initiated with greater caution in older men, particularly those who are
frail or have medical comorbidities. Standard androgen replacement therapy is:

1 testosterone 50 mg transdermal gel, every morning on the trunk or proximally on the

limbs

OR

1 testosterone undecanoate 1000 mg by deep IM injection, repeat after 6 weeks and then
every 10 to 14 weeks, according to clinical response and serum testosterone
concentration. For more gradual supplementation, give the second dose after 10 to 14
weeks

OR

2 testosterone enanthate 250 mg by deep IM injection, every 2 weeks

OR

2 testosterone esters 250 mg by deep IM injection, every 2 weeks

OR

2 testosterone 5 mg transdermal patch, every night applied on the trunk or proximally on

the limbs for 24 hours
 OR

3 testosterone undecanoate 80 mg orally, 2 or 3 times daily.

Care must be taken when using testosterone gel or liquid to avoid transferring active drug by skin to skin contact.
Repeated inadvertent transfer to others could increase their serum testosterone concentration with consequent
adverse effects (eg growth of facial and/or body hair, deepening of the voice and menstrual irregularities in
women; premature puberty and genital enlargement in children). This transfer can be minimised by:

washing hands thoroughly after applying the gel or liquid

wearing clothing that covers the application area
showering before direct skin contact with others.

Deep intramuscular injections are given slowly to minimise discomfort.

Testosterone enanthate or testosterone ester injections may be associated with variation in energy, wellbeing and
libido, associated with marked fluctuation in testosterone concentration. Experience using testosterone liquid is
limited at the time of writing. The main limitation of transdermal testosterone patches is skin irritation, which is
common (about 50% of patients) and can be severe. Pretreating the application site with hydrocortisone cream may
help.

Oral testosterone undecanoate has low (under 10%) and variable bioavailability. It also has a short duration of
action, so multiple daily doses are required. These features (and the consequent high daily androgen load,
gastrointestinal intolerance and higher cost) make it a lower ranked formulation for routine androgen replacement
therapy.

Adverse effects of androgen replacement therapy

Serious adverse effects from testosterone are uncommon. Truncal seborrhoea and acne are common during
treatment with testosterone ester injections. These can be managed with topical measures and/or intermittent
broad-spectrum antibiotics without discontinuing therapy. Modest weight gain (under 3 kg) is common, reflecting
anabolic effects on muscle and/or fluid retention. Increased truncal hair and temporal hair loss or balding may
occur in susceptible men. Gynaecomastia may also occur. Adverse effects generally reverse on cessation of
therapy.

Monitoring androgen replacement therapy

Androgen replacement therapy should be monitored by:

assessing improvement in clinical symptoms and signs of androgen deficiency

measuring serum or plasma testosterone concentration during treatment, the target being the middle of the
normal range.

The clinical features of androgen deficiency usually respond within 1 to 2 months of starting treatment. Changes in
body composition can occur within 3 to 6 months. Bone mineral density should be assessed at intervals of 12
months or longer, to check that the androgen dose is adequate for bone maintenance.

Adverse effects of androgen replacement therapy should be monitored (before and during therapy) by prostate
examination and assessing:

age-appropriate prostate-specific antigen (PSA) concentration

haemoglobin and/or haematocrit
cardiovascular risk factors (including lipids)
idiosyncratic effects (eg sleep apnoea).

The reduced prostate volume and PSA concentration that occur in androgen deficiency are restored to normal by
testosterone. Polycythaemia is uncommon (approximately 1%) and occurs most often in men receiving short-
acting injectable testosterone. It is treated by interrupting therapy. Occasionally, venesection is required. After this,
treatment may resume using a testosterone formulation with a more even delivery profile. Rarely, testosterone
treatment may precipitate overt sleep apnoea from subclinical. This results in poorer quality of sleep, snoring and
increased daytime sleepiness. If sleep apnoea is confirmed by a sleep study and treated with nasal continuous
positive airway pressure, testosterone treatment may continue.

Contraindications and precautions for androgen replacement therapy

Prostate or breast cancer is a contraindication to androgen therapy.

Testosterone treatment is also contraindicated in men desiring fertility.

Precautions and/or careful monitoring are required in:

all older men starting androgen treatment

–
some older men may not tolerate unfamiliar increases in libido (replacement should be gradual)
men with bleeding disorders or having anticoagulation treatment, as parenteral testosterone administration
may cause severe bruising or bleeding (oral or transdermal therapy are suitable alternatives)
elite athletes, who may be disqualified from competition
men with androgen-sensitive epilepsy, migraine or sleep apnoea
men with heart failure, kidney failure or severe hypertension, who are susceptible to fluid overload from
sodium and fluid retention
men with primary or secondary polycythaemia (haemoglobin more than 170 g/L or haematocrit more than
50%).

Delayed puberty in boys

Delayed puberty has several causes, including:

constitutional delay (ie delay in completing spontaneous puberty)

a chronic medical condition, where puberty progresses slowly unless the underlying disorder is corrected
hypogonadotrophic hypogonadism, either idiopathic (including Kallmann syndrome) or due to
hypopituitarism.

Boys with permanent hypogonadotrophic hypogonadism need lifelong androgen replacement therapy to induce
and maintain virilisation. Boys with constitutional delay or a chronic medical condition may only need temporary
androgen replacement. Clear distinction between these states during adolescence is difficult, and they may
represent a spectrum rather than discrete disorders.

A decision to start androgen replacement therapy is based on chronological delay in virilisation and its physical
and psychological effects. Therapy should be considered in boys with no evidence of testicular growth (ie no
indication of entering puberty; testicular volume under 4 mL) by the age of 14 years.

Be cautious starting androgen replacement therapy in boys with delayed puberty and monitor carefully.

When starting androgen replacement therapy in boys with pubertal failure, precautions and/or careful monitoring
are required. This is because:

excessive androgen may accelerate epiphyseal maturation leading to premature closure

a full adult dose of testosterone in previously untreated males can cause priapism.

Androgen treatment should be given in 6- to 12-month periods, with breaks of 3 months to check for spontaneous
pubertal development. When constitutional delay is suspected, initial treatment should be limited to 3 months. Use:

1 testosterone enanthate 50 mg by deep IM injection for the first dose, then 100 mg monthly
for subsequent doses

OR

1 testosterone undecanoate 40 mg orally, on alternate days initially, increasing gradually to

40 mg 3 times daily.

If prolonged treatment is required, the testosterone dose can be gradually increased to the full adult replacement
dose at a rate that produces the desired speed of maturation. The physical and psychological effects of treatment
must be monitored.

Preliminary data show that fertility outcomes for males with hypogonadotrophic hypogonadism may be improved
by early exposure to gonadotrophin therapy (human chorionic gonadotrophin [hCG]/FSH) during puberty. Referral
to a specialist centre is needed for this treatment.

Key references
Causes of male hypogonadism

Bhasin S. Testicular disorders. In: Kronenberg F, Williams RH, editors. Williams textbook of endocrinology. 11th ed.
Philadelphia: Saunders Elsevier; 2008. p. 645–99.

Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men
with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab
2010;95(6):2536–59. [ ]

Cunningham GR, Toma SM. Why is androgen replacement in males controversial? J Clin Endocrinol Metab
2011;96(1):38–52. [ ]

Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, et al. Age trends in the level of serum
testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J
Clin Endocrinol Metab 2002;87(2):589–98. [ ]

Fronczak CM, Kim ED, Barqawi AB. The insults of illicit drug use on male fertility. J Androl 2012;33(4):515–28. [
]

Grossmann M, Thomas MC, Panagiotopoulos S, Sharpe K, Macisaac RJ, Clarke S, et al. Low testosterone levels are
common and associated with insulin resistance in men with diabetes. J Clin Endocrinol Metab 2008;93(5):1834–40. [
]

Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of A. Longitudinal effects of
aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin
Endocrinol Metab 2001;86(2):724–31. [ ]

Liu PY, Beilin J, Meier C, Nguyen TV, Center JR, Leedman PJ, et al. Age-related changes in serum testosterone and
sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts.
J Clin Endocrinol Metab 2007;92(9):3599–603. [ ]

Sikaris K, McLachlan RI, Kazlauskas R, de Kretser D, Holden CA, Handelsman DJ. Reproductive hormone reference
intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab
2005;90(11):5928–36. [ ]

Wang C, Catlin DH, Demers LM, Starcevic B, Swerdloff RS. Measurement of total serum testosterone in adult men:
comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol
Metab 2004;89(2):534–43. [ ]

Yeap BB, Alfonso H, Chubb SA, Handelsman DJ, Hankey GJ, Norman PE, et al. Reference ranges and determinants
of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass
spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab 2012;97(11):4030–9. [ ]

Yeap BB, Araujo AB, Wittert GA. Do low testosterone levels contribute to ill-health during male ageing? Crit Rev Clin
Lab Sci 2012;49(5–6):168–82. [ ]

Androgen replacement therapy

Pharmaceutical benefits scheme (PBS) [website]. Canberra: Australian Department of Health. [URL]

Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al. Adverse events associated with
testosterone administration. N Engl J Med 2010;363(2):109–22. [ ]

Behre HM, Bohmeyer J, Nieschlag E. Prostate volume in testosterone-treated and untreated hypogonadal men in
comparison to age-matched normal controls. Clin Endocrinol (Oxf) 1994;40(3):341–9. [ ]

Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Adverse effects of
testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95(6):2560–
75. [ ]

Giannoulis MG, Martin FC, Nair KS, Umpleby AM, Sonksen P. Hormone replacement therapy and physical function in
healthy older men. Time to talk hormones? Endocr Rev 2012;33(3):314–77. [ ]

Isidori AM, Giannetta E, Gianfrilli D, Greco EA, Bonifacio V, Aversa A, et al. Effects of testosterone on sexual function
in men: results of a meta-analysis. Clin Endocrinol (Oxf) 2005;63(4):381–94. [ ]

Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al. Effects of testosterone on body
composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf)
2005;63(3):280–93. [ ]
Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, et al. Investigation, treatment, and
monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. J Androl 2006;27(2):135–7.
[ ]

Wang C, Ilani N, Arver S, McLachlan RI, Soulis T, Watkinson A. Efficacy and safety of the 2% formulation of
testosterone topical solution applied to the axillae in androgen-deficient men. Clin Endocrinol (Oxf) 2011;75(6):836–43.
[ ]

Delayed puberty in boys

Zacharin M, Sabin MA, Nair VV, Dabadghao P. Addition of recombinant follicle-stimulating hormone to human
chorionic gonadotropin treatment in adolescents and young adults with hypogonadotropic hypogonadism promotes
normal testicular growth and may promote early spermatogenesis. Fertil Steril 2012;98(4):836–42. [ ]

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Female sexual dysfunction
Overview of female sexual dysfunction
Many factors can contribute to female sexual dysfunction (eg psychological factors, interpersonal
relationships, gynaecological disorders, chronic medical conditions, certain drugs [eg selective serotonin
reuptake inhibitors]). A consensus classification of female sexual dysfunction lists:

sexual desire disorders (ie hypoactive sexual desire disorder, sexual aversion disorder)
sexual arousal disorders
orgasmic disorder
sexual pain disorders (ie dyspareunia, vaginismus, other sexual pain disorders).

The woman should have a full medical (including current medication), social and psychiatric history and
physical examination. Menopausal status should be determined. Dermatological conditions that need to be
excluded in a woman with a sexual pain disorder include lichen sclerosus, candidiasis and atrophic vaginitis.
The clinician should also check for persisting thick hymenal tissue or other vaginal structural anomaly. When
a woman has pain before, during or after intercourse (dyspareunia), medical conditions such as deep
infiltration endometriosis and pelvic inflammatory disease must be excluded.

Treatment for sexual dysfunction may include psychotherapy, physical therapies and medication. Evidence-
based treatment is lacking. If sexual dysfunction is suspected to be secondary to menopause, a trial of
hormone replacement therapy may be useful. When postmenopausal atrophic vaginitis is the cause of sexual
pain, treatment for vaginal dryness may be beneficial. Although some advocate testosterone therapy to
improve female sexual function, this recommendation is largely based on studies that used supraphysiological
testosterone doses. Conclusive evidence in support of other drug therapies is lacking.

Key references
Female sexual dysfunction

American College of Obstetricians and Gynecologists (ACOG). Female sexual dysfunction. Washington, DC:
ACOG; 2011. [URL]

Basson R, Berman J, Burnett A, Derogatis L, Ferguson D, Fourcroy J, et al. Report of the international
consensus development conference on female sexual dysfunction: definitions and classifications. J Urol
2000;163(3):888–93. [ ]

Brotto LA, Bitzer J, Laan E, Leiblum S, Luria M. Women's sexual desire and arousal disorders. J Sex Med
2010;7(1 Pt 2):586–614. [ ]

Fooladi E, Davis SR. An update on the pharmacological management of female sexual dysfunction. Expert Opin
Pharmacother 2012;13(15):2131–42. [ ]

Nastri CO, Lara LA, Ferriani RA, Rosa ESAC, Figueiredo JB, Martins WP. Hormone therapy for sexual function in
perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2013;(6):CD009672. [ ]

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Male sexual dysfunction
Erectile dysfunction
Introduction
Erectile dysfunction is the inability to achieve or maintain an erection sufficient for satisfactory sexual
performance. It affects up to 50% of men aged 40 to 70 years. A 2013 survey of 101 674 Australian men aged 45
years or more and without prostate cancer, found that 39% did not have erectile dysfunction, 25% had it
sometimes, 19% usually had it and 17% had complete erectile dysfunction.

Risk factors for erectile dysfunction are increasing age, some clinical conditions (eg depression, obesity, diabetes,
dyslipidaemia, elevated blood pressure, neurovascular disease, obstructive sleep apnoea), smoking and medication
(eg antihypertensive, anticholinergic, antidepressant and antipsychotic drugs). About 80% of cases of erectile
dysfunction have an organic cause (mainly neurovascular disease, diabetes or medication). Fewer than 20% of
cases are due to primary psychogenic erectile failure—these are clustered in men at the beginning of their sexual
experience. Erectile dysfunction can arise after therapy for prostate cancer.

Psychological reactions to organic erectile dysfunction are common and complicate diagnosis and management.
Supportive counselling and realistic treatment goals for both partners should be part of management. Expert
psychological counselling may be needed for primary psychogenic erectile dysfunction or when medical therapy is
not successful.

Endocrine disorders other than diabetes are rare causes of erectile failure (about 4%). Androgen deficiency and
erectile dysfunction may coexist in a small proportion of middle-aged and older men. Testosterone therapy should
not be used unless the man has an overt androgen deficiency. A 2012 randomised trial showed that when erectile
dysfunction treatment with phosphodiesterase type 5 (PDE5) inhibitors was optimised, adding testosterone did not
further improve erectile function.

All men with erectile dysfunction need thorough medical evaluation for its cause. This should include a history,
physical examination and appropriate laboratory tests (see Figure 5.5). The practitioner can then make a functional
and aetiological diagnosis. The man should also be assessed for his fitness to resume sexual intercourse (eg able to
exercise at a level equivalent to climbing 20 stairs in 15 seconds). Erectile dysfunction is a risk marker for
cardiovascular disease. Cardiovascular risk factors or pre-existing cardiovascular conditions should be addressed
before the man begins therapy for erectile dysfunction.

Erectile dysfunction is a risk marker for cardiovascular disease.

Erectile dysfunction can be treated using PDE5 inhibitors, intracavernosal therapy, vacuum erection devices or
penile implants.

Diagnosing and managing erectile dysfunction (Figure 5.5)

Phosphodiesterase type 5 inhibitors

If a man with erectile dysfunction is fit for sexual activity and is not taking nitrates, phosphodiesterase type 5
(PDE5) inhibitors are first-line therapy. These drugs are likely to be effective for organic and psychogenic erectile
dysfunction.

Use:

1 sildenafil 50 mg orally, 1 hour before sexual activity. Maximum of one dose per 24 hours.
Increase dose to 100 mg or reduce dose to 25 mg according to efficacy and tolerability

OR

1 tadalafil 10 mg orally, at a time before sexual activity that the patient has determined is
optimal. Maximum of one dose per 24 hours. Increase dose to 20 mg according to
efficacy and tolerability

OR

1 vardenafil 10 mg orally, 0.5 to 1 hour before sexual activity. Maximum of one dose per 24
hours. Increase dose to 20 mg or reduce dose to 5 mg according to efficacy and
tolerability.

For pharmacokinetic properties and doses of PDE5 inhibitors, see Table 5.39. Although the pharmacology and
clinical efficacy of PDE5 inhibitors are similar, the half-lives are different.

When frequent use (at least twice weekly) of tadalafil is anticipated and tolerated, some men prefer to take a lower
dose every day. Use:

tadalafil 2.5 mg to 5 mg orally, once daily.

PDE5 inhibitors are less effective in the presence of:

occlusive pelvic vascular disease

peripheral autonomic nerve damage (caused by total prostatectomy or other pelvic surgery)
autonomic neuropathy (especially in people with long-term diabetes).

Men with these conditions may need a higher dose of PDE5 inhibitor.

PDE5 inhibitors do not produce an erection without sexual stimulation and activity. The dose should be adjusted
according to response and adverse effects. Common adverse effects are dose-related. They include facial flushing,
headache, dyspepsia, nasal congestion, dizziness, disturbance in colour vision (with sildenafil and vardenafil) and
back pain (with tadalafil).

Phosphodiesterase type 5 inhibitors interact with nitrates to produce a profound hypotensive response that may be fatal.

The most serious adverse effect of PDE5 inhibitors results from their interaction with nitrates. This produces a
profound hypotensive response that may be fatal. Therefore, PDE5 inhibitors must not be used in men taking long-
acting nitrates.

Short-acting and long-acting nitrates should not be administered within 24 hours after sildenafil and vardenafil, or
within 5 days after tadalafil. Special precautions against hypotensive episodes are needed for men taking complex
antihypertensive therapy, particularly alpha blockers. Clearance of PDE5 inhibitors may be delayed in men who:

are older
have liver and kidney impairment (see dose adjustments in Table 5.39)
are taking drugs that inhibit cytochrome P450 3A4 (eg erythromycin).

Pharmacokinetic properties and doses of phosphodiesterase type 5 inhibitors (Table 5.39)

Property Sildenafil Tadalafil Vardenafil

peak effect 1 hour 2 hours 1 hour
duration of clinical effect 4 to 6 hours 24 to 36 hours 4 hours
half-life 3 to 5 hours 17.5 hours 4 to 5 hours
metabolism hepatic hepatic hepatic
starting dose 50 mg 10 mg 10 mg
dose range 25 to 100 mg 5 to 20 mg 5 to 20 mg
dose in kidney initial dose 25 mg if severe 10 mg maximum if severe
do not use if on dialysis
impairment impairment impairment
initial dose 5 mg if mild to
10 mg maximum if mild to moderate impairment (10
moderate impairment mg maximum if moderate
dose in liver impairment initial dose 25 mg impairment)
consider harms/benefits if
severe impairment do not use if severe
impairment

Intracavernosal therapy

Introduction

Intracavernosal vasodilator injections are second-line therapy for erectile dysfunction when PDE5 inhibitors are
ineffective or contraindicated. Monotherapy with prostaglandin E1 (alprostadil) is the treatment of choice. Some
other vasodilators (eg phentolamine, papaverine) have been used (but are not approved) for this indication.
Alprostadil has a lower risk of priapism or long-term cavernosal fibrosis compared with these drugs.

Intracavernosal therapy should be under the supervision of an experienced practitioner with arrangements for
managing priapism after hours. Men must be given written, clear, practical instructions on how to manage
prolonged erections, including an after-hours contact number and information about appropriate 24-hour medical
facilities. These instructions may be shown to a pharmacist if pseudoephedrine is needed. Men should be advised
to keep pseudoephedrine at home in case of emergency.
Dosage and self-injection technique for alprostadil

All men starting treatment with alprostadil need titration to determine the optimal dose (ie the minimum dose that
produces an adequate erection lasting under 60 minutes). They should be taught to inject themselves (see Box 5.9
for technique) under the direct supervision of an experienced practitioner. The time to onset of effect is 5 to 20
minutes, and the duration is dose-dependent.

In men with idiopathic, neurogenic or psychogenic erectile dysfunction, use:

alprostadil 2.5 micrograms intracavernosally (see Box 5.9 for technique), initially.
Increase each subsequent dose by 2.5 micrograms until an adequate erection is achieved
(maximum dose 60 micrograms). Maximum of one dose per 24 hours.

In men with vascular erectile dysfunction or erectile dysfunction from other organic causes, use:

alprostadil 5 micrograms intracavernosally (see Box 5.9 for technique), initially. Increase
each subsequent dose by 5 micrograms until an adequate erection is achieved (maximum
dose 60 micrograms). Maximum of one dose per 24 hours.

Once the optimal dose of alprostadil has been determined under supervision, most men can inject themselves.

Continuation rates on intracavernosal self-injection programs are approximately 50% within 6 to 24 months of
starting treatment. Alprostadil should be titrated up to 60 micrograms as monotherapy before considering referral
for intracavernosal therapy with vasodilator combinations.

Self-injection technique for alprostadil (Box 5.9)

Advice on the correct technique for self-injecting alprostadil

This technique delivers the drug to one or the other corpus cavernosum, avoiding the neurovascular bundle on
the dorsum of the penis.

The penis is held and extended with the non-injecting hand, and the penile shaft is steadied against the thigh.

The optimal sites for injection are between the 8 and 10 o'clock, or the 2 and 4 o'clock, positions of the shaft
cross-section.

Drawing back on the needle is important, to ensure it has not entered a blood vessel. Usually a small drop of
blood is consistent with entry into the corpus.

The drug should be injected slowly using a fine 25G needle, holding the syringe perpendicular to the skin.
Subcutaneous veins should be avoided.

Complications of intracavernosal therapy

Introduction

The main complications of intracavernosal therapy are local pain, bruising or haematoma (especially in men on
anticoagulant therapy), priapism (the most serious complication) and cavernosal fibrosis. Severe local pain is more
common in men who have:

had a prostatectomy
injected incorrectly, so the needle has not entered the cavernosal space.

Systemic complications (eg hypotension) are rare unless large doses are used.

Priapism

Priapism is a medical emergency occurring in 5% to 10% of men during supervised dose titration of alprostadil.
Priapism is less frequent (1% of men) when men are self-injecting after the optimal dose has been established.
Early presentation determines the success of medical therapy and whether surgery can be avoided. Delay in
treating priapism can result in permanent damage to the cavernosal tissue and complete loss of erectile capacity.

If an erection has lasted for 2 hours, the man should have a hot shower and take:
 pseudoephedrine immediate-release 120 mg orally, as a single dose.

If the erection has not subsided in 4 hours, the shower and the dose of pseudoephedrine should be repeated. The
man should also phone his treating practitioner or after-hours contact number.

If the erection is still present after 6 hours, the man must attend a suitable clinic for aspiration and drainage of the
corpora cavernosa.

The man should inform his practitioner even if the priapism resolves with a hot shower and pseudoephedrine. Any
episode of priapism should prompt review of the dose of intracavernosal drug.

Intracavernosal therapy is the most common cause of priapism. Treatment of priapism due to other causes may
differ, according to the underlying pathology (eg sickle cell disease, chronic myeloid leukaemia).

Vacuum erection devices and penile implants

Vacuum erection devices are second-line therapy for erectile dysfunction in selected patients. Some dexterity is
required to use them, but generally they are safe, relatively inexpensive and a one-off cost.

When all other treatments are unsuccessful, penile implants (semirigid or inflatable) can be used in carefully
selected patients. Penile implants are expensive, require surgery, implant foreign materials and destroy the
cavernosal tissue.

Premature ejaculation
Introduction
Premature ejaculation is persistent or recurrent ejaculation before, on, or shortly after penetration, associated with
significant personal distress. In most cases this occurs within 1 minute of vaginal penetration, and in a minority
within 1 to 2 minutes. Premature ejaculation may be:

primary (lifelong), when the man has had this condition since the beginning of his sexual experience
acquired, secondary to other factors (eg situational factors, erectile dysfunction in older men).

The main aims of therapy are control over ejaculation and satisfactory sexual intercourse for the man and his
partner.

Appropriate management of acquired premature ejaculation is to treat the underlying condition.

Primary premature ejaculation is usually treated with:

topical preparations that reduce glans penis sensitivity

certain selective serotonin reuptake inhibitors, which delay ejaculation.

Choice of treatment depends on the couple's preference.

Topical preparations

Topical application of a local anaesthetic can delay premature ejaculation. Use:

lidocaine+prilocaine 2.5% + 2.5% cream topically thinly to glans and distal shaft of penis,
10 to 20 minutes before intercourse. Wash off residual cream before contact with partner.

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) may be used to treat premature ejaculation. A single dose before
sexual activity is less likely to be associated with adverse effects (eg anorexia, reduced libido and/or anejaculation)
than continuous dosing. Use:

1 dapoxetine 30 mg orally, 1 to 3 hours before sexual activity. Maximum of one dose per 24
hours. Review patient after 4 weeks or 6 doses, whichever is first

OR

1 paroxetine 20 mg orally, 3 to 5 hours before sexual activity

 OR

1 sertraline 50 mg orally, 3 to 5 hours before sexual activity.

Most men prefer to take SSRIs daily, despite the associated increase in adverse effects. Use:

1 paroxetine 10 mg orally, once daily. Slowly increase the dose as needed, up to a

maximum of 40 mg daily

OR

1 sertraline 25 mg orally, once daily. Slowly increase the dose as needed, up to a maximum
of 200 mg daily.

Intracavernosal therapy is not appropriate for premature ejaculation.

Key references
Erectile dysfunction

Banks E, Joshy G, Abhayaratna WP, Kritharides L, Macdonald PS, Korda RJ, et al. Erectile dysfunction severity as a
risk marker for cardiovascular disease hospitalisation and all-cause mortality: a prospective cohort study. PLoS Med
2013;10(1):e1001372. [ ]

Bhasin S, Basson R. Sexual dysfunction in men and women. In: Kronenberg F, Williams RH, editors. Williams textbook
of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008. p. 701–37.

Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F, et al. Guidelines on male sexual
dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010;57(5):804–14. [ ]

Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil
Study Group. N Engl J Med 1996;334(14):873–7. [ ]

Matsumoto AM. Erectile dysfunction: who, when and what treament (chapter 20). In: Anawalt BD, editor. Endocrine
essentials. Chevy Chase, MD: The Endocrine Society; 2012. p. [155–66].

Olujohungbe A, Burnett AL. How I manage priapism due to sickle cell disease. Br J Haematol 2013;160(6):754–65. [
]

Pryor J, Akkus E, Alter G, Jordan G, Lebret T, Levine L, et al. Priapism. J Sex Med 2004;1(1):116–20. [ ]

Qaseem A, Snow V, Denberg TD, Casey DE, Jr., Forciea MA, Owens DK, et al. Hormonal testing and pharmacologic
treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians. Ann Intern Med
2009;151(9):639–49. [ ]

Rodgers R, Latif Z, Copland M. How I manage priapism in chronic myeloid leukaemia patients. Br J Haematol
2012;158(2):155–64. [ ]

Rowland D, McMahon CG, Abdo C, Chen J, Jannini E, Waldinger MD, et al. Disorders of orgasm and ejaculation in
men. J Sex Med 2010;7(4 Pt 2):1668–86. [ ]

Sadeghi-Nejad H, Seftel AD. The etiology, diagnosis, and treatment of priapism: review of the American Foundation
for Urologic Disease Consensus Panel Report. Curr Urol Rep 2002;3(6):492–8. [ ]

Spitzer M, Basaria S, Travison TG, Davda MN, Paley A, Cohen B, et al. Effect of testosterone replacement on
response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med
2012;157(10):681–91. [ ]

Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, et al. Oral phosphodiesterase-5 inhibitors and
hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med 2009;151(9):650–
61. [ ]

Weber MF, Smith DP, O'Connell DL, Patel MI, de Souza PL, Sitas F, et al. Risk factors for erectile dysfunction in a
cohort of 108 477 Australian men. Med J Aust 2013;199(2):107–11. [ ]
Premature ejaculation

Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F, et al. Guidelines on male sexual
dysfunction: erectile dysfunction and premature ejaculation. Eur Urol 2010;57(5):804–14. [ ]

McMahon CG, Jannini E, Waldinger M, Rowland D. Standard operating procedures in the disorders of orgasm and
ejaculation. J Sex Med 2013;10(1):204–29. [ ]

Palmer NR, Stuckey BG. Premature ejaculation: a clinical update. Med J Aust 2008;188(11):662–6. [ ]

Waldinger MD, Zwinderman AH, Olivier B, Schweitzer DH. The majority of men with lifelong premature ejaculation
prefer daily drug treatment: an observation study in a consecutive group of Dutch men. J Sex Med 2007;4(4 Pt
1):1028–37. [ ]

Published March 2014. Amended March 2020. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Infertility
Introduction to infertility
It is estimated that one in seven couples are infertile. The cause of infertility may be female, male or mixed.
10% to 20% of infertile couples have unexplained infertility.

Human fertility depends on a complex series of events including:

production of gametes (sperm and oocytes) capable of fertilisation

release of the oocyte into the fallopian tube after ovulation
timely deposition and migration of sufficient fertile sperm in the female reproductive tract
implantation and development of the embryo in the hormonally primed uterine mucosa
maintenance of the growing fetus in the uterus until pregnancy is full term.

Defects in one or more of these steps can be the basis for infertility. Both partners should be investigated
systematically so noninvasive investigations are completed before beginning invasive tests. Fertility in women
and men declines naturally with age. Couples should be referred for expert advice after trying to conceive for:

1 year, if the woman is 36 years or younger

6 months, if the woman is older than 36 years.

Anovulatory infertility
Introduction

In approximately 10% to 20% of infertile couples, infertility is largely due to lack of ovulation. Anovulation is
suspected if menstrual cycles are irregular or absent. Its cause should be determined before starting treatment.
Polycystic ovary syndrome (PCOS) is the most common cause. Anovulation may also result from a:

hypothalamic abnormality
pituitary disorder causing a lack of, or uncoordinated, gonadotrophin secretion.

Premature ovarian dysfunction can present with anovulation. Women with premature ovarian dysfunction
should be investigated because the cause of oocyte depletion may affect their general health. Appropriate
hormone replacement therapy (HRT) should be offered to these women (see Premature menopause and early
menopause).

Anovulation should be thoroughly investigated to determine its cause, before treatment.

Causes of ovulation failure can be classified as shown in Table 5.40.

Causes and treatment of anovulation (Table 5.40)

Type of anovulation Cause Characteristics Treatment Prognosis

weight loss/eating
disorder clomiphene
low serum
oestradiol combined
systemic illness
gonadotrophins (LH
possible lack of
extreme exercise and FSH)
progestin
hypothalamic/pituitary good
stress withdrawal bleed FSH alone

hypopituitarism low FSH and LH dopamine agonists

for
prolactinoma normal/high AMH
hyperprolactinaemia
(micro- or macro-)
 unopposed
oestrogen secretion

progestin diet and exercise

unknown, but withdrawal bleed
associated with
clomiphene varies, depending
polycystic ovary hyperandrogenism low FSH on severity of
syndrome and insulin
metformin PCOS
resistance high LH
syndromes FSH
high AMH

low SHBG

high FAI
low serum
oestradiol HRT [NB1]
possible lack of
donor oocyte or
absent or progestin
premature ovarian embryo
unresponsive withdrawal bleed poor
failure
follicles in the ovary spontaneous
elevated FSH and
ovulation occurs
LH sometimes
low AMH
AMH = anti-Mullerian hormone; FAI = free androgen index; FSH = follicle stimulating hormone; LH = luteinising hormone; PCOS = polycystic
ovary syndrome; SHBG = sex hormone–binding globulin
NB1: HRT is not contraceptive.

Ovulation induction

Lifestyle modification and counselling

All couples need lifestyle advice before pharmacological treatment. Lifestyle modification and counselling
could include:

advice about appropriate body weight and exercise

discussion of the normal fertile period
advice to avoid tobacco and other recreational drugs and minimise alcohol intake.

Folate must be prescribed for all women before and during pregnancy, to minimise the risk of neural tube
disorders.

When possible, the woman should modify her lifestyle (including diet and exercise) before pharmacotherapy
to induce ovulation (see advice in Overweight and obesity). These modifications may be beneficial even if
they do not improve ovulation frequency. Evidence shows that a reduction in body mass index (BMI) may
improve the response to ovulation induction and reduce the risk of gestational diabetes.

A BMI above 30 kg/m2 usually contraindicates assisted reproductive technology (ART), but the woman's age
and time remaining for fertility treatment should be considered.

Pharmacotherapy

General information

The cause of anovulation determines its treatment (see Table 5.40). Hyperprolactinaemia is treated with a
dopamine agonist (cabergoline or bromocriptine). Ovarian failure rarely responds to drug treatment and is best
managed by ART, with a donor oocyte or embryo. Hormone replacement therapy should be encouraged while
the couple consider their options.

Other forms of anovulation respond to ovulation induction using clomiphene or gonadotrophins. The risk that
multiple follicles will develop with either treatment is substantial, which may result in multiple pregnancies or
ovarian hyperstimulation syndrome (OHSS). Therefore, clinicians with experience in reproductive medicine
must monitor this treatment carefully. Treatment aims to develop a single ovarian follicle. With proper
monitoring, this is usually possible. If multiple follicles do develop, cancelling the treatment cycle and
avoiding intercourse usually avoids adverse effects.

Ovulation induction must not begin before excluding pregnancy and confirming semen is normal. Fallopian
tube patency should be tested:

before ovulation induction, if the woman has a past history of pelvic infection or surgery
if the woman does not conceive after 3 to 6 cycles where ovulation has been documented.

Amenorrhoeic women usually begin with a short course of progestin to induce uterine bleeding. Use:

medroxyprogesterone 10 mg orally, once daily for 12 days.

Metformin can be used to treat subfertility in women with PCOS.

Clomiphene

Clomiphene increases endogenous gonadotrophin secretion by blocking negative feedback to the pituitary
gland. Clomiphene must be prescribed by a specialist. To initiate therapy, the normal dose is:

clomiphene 50 mg (25 mg may be sufficient when body mass index is lower) orally,
once daily for 5 consecutive days. Start between days 2 to 5 of the menstrual cycle.

Follicular development is monitored by biochemistry and ultrasound, to detect a single dominant follicle and
exclude multifollicular development. Ovulation is confirmed by measuring the serum progesterone
concentration in the midluteal phase (5 to 10 days before menses).

If ovulation does not occur, usual practice is to start another cycle a month later, using clomiphene 100 mg
daily for 5 days. If this is ineffective, a maximum dose of clomiphene 150 mg daily for 5 days can be used
another month later. If the plasma oestrogen concentration does not rise or ovarian follicles do not develop,
gonadotrophin therapy is needed.

If ovulation is confirmed but pregnancy fails to occur after six cycles of treatment, other causes of infertility
should be excluded.

Clomiphene results in ovulation in 80% of women, but only 35% to 40% become pregnant, possibly because
clomiphene thins the endometrium. Clomiphene is associated with a 6% incidence of multiple pregnancy (the
background risk is 1 in 80). Serious adverse effects (eg visual disturbance) are uncommon. Ovarian
hyperstimulation syndrome is rare. An association has been reported between ovarian cancer and long-term
(more than 12 months) treatment with clomiphene. However, a 2013 meta-analysis found no evidence to
support this. Current practice is to limit clomiphene use to less than 12 months.

Gonadotrophins

Overview

Ovulation induction with gonadotrophins involves sequential use of:

follicle stimulating hormone (FSH), which recruits and matures follicles, then
human chorionic gonadotrophin (hCG), which acts like luteinising hormone (LH) to induce ovulation of
a single dominant mature follicle.

Follicle recruitment and maturation occur during the first days of treatment. The oestrogen increase in
response to FSH may not be adequate in women who lack LH (eg as a result of severe hypothalamic or
pituitary disorders). They may need a small amount of recombinant LH or hCG at this time. Injection with
hCG is usually required to facilitate release of the oocyte from the follicle.

For in-vitro fertilisation or intracytoplasmic sperm injection (IVF/ICSI), gonadotrophins are used in higher
doses and in combination with other drugs. Drugs used include:

gonadotrophin-releasing hormone (GnRH) analogues or antagonists, to prevent premature oocyte

release
hCG, to trigger release of the oocytes
vaginal progestin or hCG, to support the luteal phase.

Adverse effects of gonadotrophins

The main hazards of ovulation induction with gonadotrophins are multifollicular development (leading to
multiple pregnancy) and ovarian hyperstimulation syndrome (OHSS). OHSS presents with severe abdominal
discomfort (due to massive ovarian enlargement and ascites), vomiting, dehydration and depletion of
intravascular volume. It is a medical emergency and early detection and management is important. Serious
complications can occur (eg acute kidney failure, venous and arterial thrombosis, and even death). OHSS
cannot always be predicted and is more common in patients having IVF than in those having ovulation
induction. It is important that gonadotrophin treatment is monitored by practitioners with:

experience in recognising OHSS

access to facilities for admitting and treating women with OHSS.

Metformin

See advice on using metformin in women with subfertility associated with PCOS.

Endometriosis
Endometriosis can cause infertility by producing adhesions around fallopian tubes and ovaries, and
endometriomas in the ovaries. Deep dyspareunia may reduce the frequency of intercourse in couples trying to
conceive. Endometriosis may also cause infertility by interfering with the fertilisation or implantation of
embryos, but there is less evidence for this. When endometriosis is associated with infertility, evidence
suggests that laparoscopic surgery is preferred to drug therapy. Surgery may involve excising and ablating
endometriotic deposits and dividing adhesions. See also advice on drug therapy for endometriosis. Note that
hormonal therapies are not suitable for women trying to conceive.

Male infertility
Introduction
Male infertility is a major factor for 30% to 50% of couples who experience reduced fertility. The identifiable
causes are:

failed spermatogenesis (origin may be primary [testicular] or secondary [pituitary or hypothalamic])

failed delivery of sperm (due to obstruction of the vas deferens, or erectile or ejaculatory failure)
reduced numbers or motility, or changed morphology of the sperm
sperm autoimmunity.

Optimal management of male infertility depends on recognising those conditions for which non–assisted
reproductive technology treatment is available (10% to 15% of patients). For the rest of these men, if their
sperm number or quality precludes natural fertility, IVF/ICSI procedures are available. Using donated sperm
is also an option, as it is for men with a complete lack of spermatogenesis. Men with erectile dysfunction need
investigation for underlying medical conditions before beginning treatment.

A range of therapies has been used to treat unexplained male infertility. These include hormones and hormone
antagonists (gonadotrophins, androgens, antioestrogens), nutritional supplements, anti-inflammatory drugs,
antibiotics and physical therapies (testicular cooling, varicocele ablation). Systematic reviews (using
conception rate as a measure) have shown that none of these therapies consistently improves fertility.

Sperm autoantibodies can be identified in the blood and/or semen of 10% of infertile men, and are common in
men who have had a vasectomy reversal. The presence of sperm autoantibodies does not necessarily make a
man infertile. In-vitro fertilisation and ICSI are preferred treatments. Immunosuppressive doses of
glucocorticoids do not have a role in managing sperm autoantibodies because the risk of adverse effects is
high.

Gonadotrophin therapy
Gonadotrophin therapy is used in gonadotrophin-deficient men (hypogonadotrophic hypogonadism) to induce
spermatogenesis and fertility. Before treatment, secondary treatable causes of hypogonadotrophic
hypogonadism should be excluded. These include pituitary tumours, hyperprolactinaemia, use of exogenous
testosterone, and syndromes associated with iron overload (eg haemochromatosis, thalassaemia).

Treatment with human chorionic gonadotrophin (hCG) may be successful. An initial testis size of over 4 mL
and previous treatment with gonadotrophins are associated with a better prognosis. Before a man starts
treatment with gonadotrophins, his female partner must be assessed for conditions that may alter treatment (eg
anovulation, tubal obstruction). Gonadotrophin therapy begins with hCG alone for up to 6 months. Use:

human chorionic gonadotrophin 1500 international units SC, 2 or 3 times weekly.

The response is monitored by:

the trough blood testosterone concentration immediately before an injection, 3 months after starting
therapy
clinical evaluation of sexual function.

If a trial (usually 6 months) of hCG alone is not adequately spermatogenic, FSH is usually added. Most
gonadotrophin-deficient infertile men need this. Use:

follicle stimulating hormone (follitropin alfa or follitropin beta) 50 to 75 international

units SC, 3 times weekly. If sperm are not present after at least 3 to 6 months of
treatment, increase the dose to 100 to 150 international units 3 times weekly.

Treatment with FSH is monitored by semen analysis every 3 months.

Despite prolonged gonadotrophin therapy (typically longer than 12 months), normal testis size (over 15 mL)
and normal sperm output are rarely achieved. However, pregnancy may occur when the sperm count is still
low but greater than 5 000 000 per mL. When the sperm count reaches 5 000 000 per mL, the option of
freezing semen for future use should be offered. Even when this sperm concentration is not achieved,
gonadotrophin therapy may allow sufficient sperm to be collected (from semen or a testicular biopsy) for
ICSI.

Key references
Infertility: introduction

Fields E, Chard J, James D, Treasure T, Guideline Development G. Fertility (update): summary of NICE
guidance. BMJ 2013;346f650. [ ]

National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people
with fertility problems [CG156]. London: RCOG; 2013. [URL]

Anovulatory infertility

Amer SA, Li TC, Metwally M, Emarh M, Ledger WL. Randomized controlled trial comparing laparoscopic ovarian
diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary
syndrome. Hum Reprod 2009;24(1):219–25. [ ]

Costello MF, Misso ML, Wong J, Hart R, Rombauts L, Melder A, et al. The treatment of infertility in polycystic
ovary syndrome: a brief update. Aust N Z J Obstet Gynaecol 2012;52(4):400–3. [ ]

Homburg R, Insler V. Ovulation induction in perspective. Hum Reprod Update 2002;8(5):449–62. [ ]

Jensen A, Sharif H, Frederiksen K, Kjaer SK. Use of fertility drugs and risk of ovarian cancer: Danish Population
Based Cohort Study. BMJ 2009;338b249. [ ]

Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for
infertility in the polycystic ovary syndrome. N Engl J Med 2007;356(6):551–66. [ ]

PCOS Australian Alliance. Evidence-based guideline for the assessment and management of polycystic ovary
syndrome. Melbourne: Jean Hailes Foundation for Women's Health; 2011. [URL]

Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated with ovarian stimulating drugs for
infertility. Cochrane Database Syst Rev 2013;(8):CD008215. [ ]

Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG. Ovarian tumors in a cohort of infertile women. N Engl J
Med 1994;331(12):771–6. [ ]

Sommer C, Morkrid K, Jenum AK, Sletner L, Mosdol A, Birkeland KI. Weight gain, total fat gain and regional fat
gain during pregnancy and the association with gestational diabetes: a population-based cohort study. Int J Obes
(Lond) 2014;38(1):76–81. [ ]

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone,
pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility.
Cochrane Database Syst Rev 2012;(5):CD003053. [ ]

Teede HJ, Misso ML, Deeks AA, Moran LJ, Stuckey BG, Wong JL, et al. Assessment and management of
polycystic ovary syndrome: summary of an evidence-based guideline. Med J Aust 2011;195(6):S65–112. [
]

Endometriosis

Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier C. Consensus on current management of
endometriosis. Hum Reprod 2013;28(6):1552–68. [ ]

Leyland N, Casper R, Laberge P, Singh SS. Endometriosis: diagnosis and management. J Obstet Gynaecol Can
2010;32(7 Suppl 2):S1–32. [ ]

Male infertility

Burgues S, Calderon MD. Subcutaneous self-administration of highly purified follicle stimulating hormone and
human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Spanish
Collaborative Group on Male Hypogonadotropic Hypogonadism. Hum Reprod 1997;12(5):980–6. [ ]

National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people
with fertility problems [CG156]. London: RCOG; 2013. [URL]

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Androgenisation in women
Signs and causes of androgenisation in women
Signs of androgenisation in women include hirsutism, androgenetic alopecia and acne. More common and
relatively benign causes (eg idiopathic hirsutism, polycystic ovary syndrome [PCOS]) must be distinguished from
adrenal and ovarian tumours (these need surgery). An androgen-producing tumour should be considered if a
woman has:

recent or abrupt onset of androgenisation

virilisation (eg deepening voice, clitoromegaly)
raised plasma androgen (testosterone, dehydroepiandrosterone sulfate) concentrations, at least twice the
upper limit of the normal range.

Milder forms of nonclassical (late onset) congenital adrenal hyperplasia may manifest similarly to PCOS, but are
relatively uncommon.

For a discussion of androgenetic alopecia, see Hair loss disorders.

Hirsutism
Introduction

The two types of hair are terminal hair (coarse and pigmented) and vellus hair (fine, soft and relatively
unpigmented). In hirsutism, androgens induce vellus follicles in sex-specific areas to develop into terminal hairs.
Hirsutism in women is defined as excessive terminal hair that is distributed in a male pattern. This hair may be in
one region only (eg lower face) or widespread (eg including limbs, chest, and midline of trunk).

Hirsutism should be differentiated from hypertrichosis, a widespread overgrowth of non–androgen-dependent hair

in areas like the forehead and forearms. Occasionally, hypertrichosis is an adverse effect of drugs (eg cyclosporin,
minoxidil, penicillamine, phenytoin, diazoxide).

Hirsutism usually results from:

minor androgen excess of adrenocortical or ovarian origin

an increased responsiveness of the hair follicles to normal circulating androgens (idiopathic hirsutism).

Most commonly hirsutism is idiopathic or related to PCOS. Less commonly it results from excessive adrenal
androgen production (eg Cushing syndrome, classical or nonclassical congenital adrenal hyperplasia). Morning
blood testosterone concentration should be measured when hirsutism is:

severe
combined with menstrual irregularities
of recent onset
combined with virilisation.

Treating hirsutism

Introduction

Hirsutism management is long term. When treatment is sought, the options are:

physical removal of unwanted hair

topical therapy
oral therapy (if the woman has no immediate wish for fertility).

If signs of androgenisation persist after simple therapies, antiandrogen therapy and specialist referral need to be
considered.

Physical measures

Physical measures have a major role in managing hirsutism. Their effect is more immediate than drug therapy,
where prolonged treatment is required.

Simple measures include waxing, plucking, shaving or depilatory creams. These are suitable:

when drug therapy is contraindicated (eg for a woman planning a pregnancy)

for a woman who is reluctant to use drug therapy
as an adjunct to drug therapy.

Contrary to common belief, shaving does not accelerate hair growth. Bleaching may make hirsutism less obvious
in women with fair skin.

Epilation by laser or electrolysis is more intensive, and can be time consuming and expensive. Laser epilation can
produce results that last 6 to 9 months, but these are not permanent. It is most suitable for women with fair skin
and dark hairs. Drug therapy during and after laser epilation helps prevent regrowth. Electrolysis, performed by a
skilled operator, may have a more permanent benefit. It destroys hair follicles, but some regrowth occurs.

Topical therapy

Eflornithine inhibits ornithine decarboxylase, an enzyme necessary for hair growth. It does not remove hair, but
slows regrowth. It can be used with any physical measure. Noticeable effect takes 6 to 8 weeks. Apply:

eflornithine hydrochloride 11.5% cream topically thinly, twice daily.

Oral therapy

Introduction

Hirsutism can be treated with oral therapy if the woman has no immediate wish for fertility. Control of the hair
growth cycle should be apparent within 6 months. In premenopausal women, the combined oral contraceptive pill
(COCP) is the basis of therapy. In postmenopausal women, oestrogen may be beneficial in doses commonly
prescribed for combined hormone replacement therapy (HRT) (see Table 5.37 for cyclical combined HRT
preparations and Table 5.38 for continuous combined HRT preparations). A combined HRT preparation with a less
androgenic progestin should be selected. If the COCP or combined HRT is not satisfactory, an antiandrogen can be
added. Oestrogen should not be used unopposed because of the risk of endometrial hyperplasia, leading to
carcinoma.

Combined oral contraceptive pill

The COCP reduces gonadotrophin-driven androgen production. It is the preferred hirsutism treatment in women
with menstrual irregularity or amenorrhoea, since a major benefit is cycle control. The COCP also reduces
bioavailable testosterone by increasing sex hormone–binding globulin (SHBG). A COCP containing the
antiandrogenic progestin, cyproterone, has added benefit (see Table 5.30 for COCP preparations). Drospirenone is
also antiandrogenic, but less so than cyproterone. Less evidence supports the use of a COCP containing
drospirenone to treat hirsutism, but it is sometimes used. Use:

1 ethinyloestradiol+cyproterone 35 micrograms + 2 mg orally, daily on days 1 to 21 of a 28-

day cycle (see Table 5.30 for preparations)

OR

2 ethinyloestradiol+drospirenone 30 micrograms + 3 mg orally, daily on days 1 to 21 of a

28-day cycle (see Table 5.30 for preparations).

Levonorgestrel and norethisterone (to a lesser extent) have androgenic properties. However, COCPs containing
these progestins are still useful for treating hirsutism because they increase SHBG production and reduce ovarian
androgen production. See also advice on choosing a COCP and its contraindications.

Antiandrogen therapy

Introduction

Antiandrogens are contraindicated in pregnancy.

Antiandrogen drugs are contraindicated in pregnancy because of the risk of defective virilisation of the male fetus.
Cyproterone should be suspended a few months before a woman attempts to conceive. Spironolactone should be
stopped when planning pregnancy or when pregnancy is suspected or confirmed.

Women of reproductive age must not conceive while taking antiandrogen therapy. The COCP provides reliable
contraception and has the added benefit of suppressing ovarian androgen production.

Spironolactone

Spironolactone is an androgen receptor antagonist at the hair follicle, and slightly reduces testosterone
biosynthesis. It has a weak progestogenic effect, and if used alone can lead to irregular uterine bleeding or
amenorrhoea. This can be avoided by combining it with the COCP. Use:

spironolactone 100 mg orally, once daily, increasing to 200 mg daily if no benefit is

apparent after 6 months.

Spironolactone should be used with care in patients with kidney impairment or taking angiotensin converting
enzyme inhibitors or angiotensin II receptor blockers. In older patients, kidney and potassium status should be
assessed before starting therapy, and again after 3 months. Patients should be advised to avoid potassium
supplements while taking spironolactone.

Spironolactone is well tolerated in young women, but patients may notice polyuria and postural hypotension when
starting therapy.

Cyproterone

Cyproterone has a similar antiandrogen action to spironolactone, but has a more pronounced progestogenic action
and suppresses gonadotrophins. When used alone, it usually leads to oligomenorrhoea or amenorrhoea and hypo-
oestrogenism. Therefore, it should be combined with oestrogen unless this is contraindicated (eg migraine with
aura [classical migraine, associated with focal neurological symptoms]).

Cyproterone has a long half-life. When prescribed with oestrogen, it is given in a ‘reverse sequential’ regimen for
10 days that coincide with the first 10 days of a course of a COCP. This allows the effect of cyproterone to wear
off by the end of 21 days of active tablets.

For women who are premenopausal or perimenopausal, use:

cyproterone 50 mg orally, once daily for 10 days per month, coinciding with the first 10
days of a course of a combined oral contraceptive pill (see Table 5.30 for preparations).
According to response after 3 months, dose may be increased to 100 mg daily.

A withdrawal bleed usually occurs in the week after the 21 days of active COCP tablets. But this may be delayed
due to the long half-life of cyproterone. If the withdrawal bleed is delayed for more than a week, a pregnancy test
should be considered. Adverse effects of cyproterone include fatigue, weight gain, breast tenderness and reduced
libido.

For younger postmenopausal women (aged 50 to 55 years), cyproterone is the preferred treatment for severe
hirsutism. If considered appropriate, use:

cyproterone 50 mg orally, once daily for the first 10 days of each calendar month.
According to response after 3 months, dose may be increased to 100 mg daily

PLUS

1 oestradiol 2 mg orally, once daily (see Table 5.35 for preparations)

OR

1 oestradiol 1 mg/g gel 1 g transdermally, once daily (see Table 5.35 for preparations)

OR

1 oestradiol patch 50 to 100 micrograms (release rate per 24 hours) transdermally, once or
twice weekly depending on the brand (see Table 5.35 for preparations)

OR

oestradiol valerate 2 mg orally, once daily (see Table 5.35 for preparations)
 1

OR

1 conjugated oestrogens 0.625 to 1.25 mg orally, once daily (see Table 5.35 for
preparations).

A withdrawal bleed usually occurs before the next cycle of cyproterone, but may be delayed or absent. Sometimes
the woman may wish to eliminate the withdrawal bleed. A lower dose of cyproterone (25 to 50 mg orally daily)
may be used continuously, with continuous oestrogen as above.

Adrenocortical suppressive therapy

Adrenocortical suppressive therapy may be indicated in nonclassical congenital adrenal hyperplasia. Standard
antiandrogen therapy can also be used in milder cases.

Polycystic ovary syndrome

Introduction

Polycystic ovary syndrome is a common condition associated with:

menstrual irregularity
clinical (acne and/or hirsutism) or biochemical hyperandrogenism
obesity and insulin resistance (with a tendency to develop type 2 diabetes)
subfertility.

Cystic structures may not always be evident on ovarian ultrasound. For a diagnosis of PCOS, two of the following
criteria must apply—menstrual irregularity, hyperandrogenism and polycystic appearance of the ovaries.

Management should address the presenting complaint and its long-term sequelae (eg type 2 diabetes, an increase in
other cardiovascular risk factors, increased endometrial cancer).

Appropriate treatment depends on each woman's goals and symptoms.

All women with PCOS should be given advice on healthy eating and exercise.

See also advice on treating:

acne
hirsutism. Note that metformin has minimal effect in reducing androgens and improving hirsutism,
compared with the COCP
androgenetic alopecia.

Menstrual irregularity or amenorrhoea

The menstrual disturbance of PCOS is treated to provide:

predictable uterine bleeding

effective endometrial shedding.

The COCP is the most effective way to regulate menses in PCOS, and has the added benefit of suppressing ovarian
androgen production. Although some small studies show an effect, a meta-analysis of the COCP's metabolic
effects did not find that it causes insulin resistance in women with PCOS. The woman should take the lowest
possible dose that is sufficient to control her cycles. Use:

combined oral contraceptive pill (see Table 5.30 for preparations).

When the COCP is contraindicated (eg thromboembolic disease), regular endometrial shedding can be induced
with cyclical progestin. Use:

1 medroxyprogesterone 10 mg orally, once daily for the same 12 days of each calendar
month

OR

norethisterone 5 mg orally, daily for the same 12 days of each calendar month.
 1

Alternatively, a levonorgestrel-releasing intrauterine system can provide protection from endometrial hyperplasia.

Some women do not tolerate hormonal treatment. Metformin can improve menstrual frequency, but oral
contraceptives achieve better cycle control. If metformin is considered appropriate, use:

metformin immediate-release 250 mg orally, twice daily with food as an initial dose,
increasing the daily dose slowly by 500 mg per week, up to a maximum of 1 g twice daily.

If the immediate-release formulation is not tolerated, the extended-release formulation may be useful. If
considered appropriate, use:

metformin extended-release 500 mg orally, daily with evening meal as an initial dose,
increasing the daily dose slowly by 500 mg per week, up to a maximum of 2 g daily.

See additional information on metformin, including its mode of action and adverse effects.

Obesity

Many women with PCOS are overweight, obese or centrally obese, but the exact prevalence is not known. Women
with PCOS who are obese have more severe metabolic and fertility problems. A modified diet and increased
exercise:

reduce waist circumference, insulin resistance and hyperandrogenism

improve ovulatory function, fertility and psychological wellbeing.

It is reasonable to recommend weight reduction and exercise as a long-term strategy. However, minimal long-term
data on the efficacy of lifestyle measures in PCOS have been reported.

A low glycaemic index diet is supported by randomised controlled trial data. Compared with a conventional diet, it
improves menstrual cycles and insulin sensitivity.

Insulin resistance, impaired glucose tolerance and type 2 diabetes

Polycystic ovary syndrome is typically associated with insulin resistance. Insulin resistance and hyperinsulinaemia
drive ovarian androgen production and suppress sex hormone–binding globulin (SHBG), leading to greater
bioavailability of androgens.

A significant proportion of women with PCOS progress to impaired glucose tolerance or type 2 diabetes.
Australian guidelines recommend screening all women with PCOS for impaired glucose tolerance or diabetes,
using an oral glucose tolerance test. Women most likely to benefit from screening include those who:

are overweight
have a family history of diabetes
are over 30 years old
are contemplating pregnancy.

Successful diet and exercise measures aimed at weight loss are likely to improve insulin sensitivity and reduce the
risk of developing diabetes. For women with PCOS and either impaired glucose tolerance or type 2 diabetes,
metformin may be appropriate. Dosage is the same as for menstrual irregularity or amenorrhoea. See additional
information on metformin, including its mode of action and adverse effects.

Subfertility

Infertility is not absolute in PCOS. Some women with PCOS ovulate spontaneously, and may conceive without
needing ovulation induction. Time to conception is usually longer than in women with normal cycles. The risk of
early miscarriage is increased in women who are obese or have impaired glucose tolerance. Some women may
become more fertile in response to modifying their lifestyle (including diet), and this is first-line therapy. After
lifestyle changes, clomiphene is the treatment with most evidence, and may give the greatest chance of live birth.
If clomiphene is unsuitable or contraindicated, treatment options include:

gonadotrophins
metformin alone or with clomiphene
laparoscopic ovarian drilling.

Therapy with clomiphene or gonadotrophins requires specialist referral and should be in the care of clinicians
experienced in reproductive medicine. Women with PCOS have an unpredictable response to fertility drugs and
may develop multiple follicles. Cycle monitoring should be available whenever fertility drugs are prescribed.

Metformin has been used, with or without clomiphene, to improve the frequency of ovulation and rate of
pregnancy. It may be added to clomiphene in women who have not responded to clomiphene alone. Using
metformin alone to induce ovulation has a place in women:

with a contraindication to clomiphene or gonadotrophins

who do not have access to cycle monitoring.

Metformin alone has most benefit in women with a body mass index under 30 kg/m2. While waiting for specialist
referral for clomiphene or gonadotrophin therapy, a trial of metformin in these women may be considered. Dosage
is the same as for menstrual irregularity or amenorrhoea. Clinical review after 3 months should be considered.

See additional information on metformin, including its mode of action and adverse effects.

Insufficient evidence supports using aromatase inhibitors in preference to clomiphene to induce ovulation in
women with PCOS.

In-vitro fertilisation or intracytoplasmic sperm injection is indicated for infertile women with PCOS if
conservative treatments are unsuccessful or the male partner is also infertile.

Cardiovascular risk

Many studies show women with PCOS have increased cardiovascular risk factors. However, evidence for
increased cardiovascular mortality in women with PCOS is inconclusive. Cardiovascular risk factors should be
treated (eg with diet, exercise, lipid-lowering and antihypertensive drugs).

Key references
Hirsutism

Arowojolu AO, Gallo MF, Lopez LM, Grimes DA. Combined oral contraceptive pills for treatment of acne. Cochrane
Database Syst Rev 2012;(7):CD004425. [ ]

Bhattacharya SM, Jha A. Comparative study of the therapeutic effects of oral contraceptive pills containing
desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Fertil Steril
2012;98(4):1053–9. [ ]

Elger W, Beier S, Pollow K, Garfield R, Shi SQ, Hillisch A. Conception and pharmacodynamic profile of drospirenone.
Steroids 2003;68(10–13):891–905. [ ]

Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, et al. Evaluation and treatment of hirsutism in
premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93(4):1105–20. [
]

Muhn P, Fuhrmann U, Fritzemeier KH, Krattenmacher R, Schillinger E. Drospirenone: a novel progestogen with
antimineralocorticoid and antiandrogenic activity. Ann N Y Acad Sci 1995;761311–35. [ ]

Androgenetic alopecia

Shapiro J. Hair loss in women. N Engl J Med 2007;357(16):1620–30. [ ]

Sinclair R, Patel M, Dawson TL, Jr., Yazdabadi A, Yip L, Perez A, et al. Hair loss in women: medical and cosmetic
approaches to increase scalp hair fullness. Br J Dermatol 2011;165 Suppl 312–8. [ ]

Polycystic ovary syndrome

Amer SA, Li TC, Metwally M, Emarh M, Ledger WL. Randomized controlled trial comparing laparoscopic ovarian
diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary
syndrome. Hum Reprod 2009;24(1):219–25. [ ]

Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Consensus on women's health
aspects of polycystic ovary syndrome (PCOS). Hum Reprod 2012;27(1):14–24. [ ]

Cosma M, Swiglo BA, Flynn DN, Kurtz DM, Labella ML, Mullan RJ, et al. Clinical review: Insulin sensitizers for the
treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab
2008;93(4):1135–42. [ ]

Costello MF, Misso ML, Wong J, Hart R, Rombauts L, Melder A, et al. The treatment of infertility in polycystic ovary
syndrome: a brief update. Aust N Z J Obstet Gynaecol 2012;52(4):400–3. [ ]

Halperin IJ, Kumar SS, Stroup DF, Laredo SE. The association between the combined oral contraceptive pill and
insulin resistance, dysglycemia and dyslipidemia in women with polycystic ovary syndrome: a systematic review and
meta-analysis of observational studies. Hum Reprod 2011;26(1):191–201. [ ]

Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review
and meta-analysis. Obes Rev 2013;14(2):95–109. [ ]

Marsh KA, Steinbeck KS, Atkinson FS, Petocz P, Brand-Miller JC. Effect of a low glycemic index compared with a
conventional healthy diet on polycystic ovary syndrome. Am J Clin Nutr 2010;92(1):83–92. [ ]

Mehrabani HH, Salehpour S, Amiri Z, Farahani SJ, Meyer BJ, Tahbaz F. Beneficial effects of a high-protein, low-
glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized
controlled intervention study. J Am Coll Nutr 2012;31(2):117–25. [ ]

Moran LJ, Hutchison SK, Norman RJ, Teede HJ. Lifestyle changes in women with polycystic ovary syndrome.
Cochrane Database Syst Rev 2011;(7):CD007506. [ ]

PCOS Australian Alliance. Evidence-based guideline for the assessment and management of polycystic ovary
syndrome. Clayton South, Vic: Jean Hailes Foundation; 2011. [URL]

Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-
chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst
Rev 2012;(5):CD003053. [ ]

Teede HJ, Misso ML, Deeks AA, Moran LJ, Stuckey BG, Wong JL, et al. Assessment and management of polycystic
ovary syndrome: summary of an evidence-based guideline. Med J Aust 2011;195(6):S65–112. [ ]

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Lactation suppression
Lactation suppression
Drugs are only used to suppress lactation when this is medically indicated (eg for women with major
postpartum mastitis or other significant medical problems that are complicated by lactation). Cabergoline is
the drug of choice, as it is taken as a single dose and has a lower rate of rebound breast activity and adverse
effects than bromocriptine. Use:

cabergoline 1 mg orally, as a single dose.

If a single dose of cabergoline does not adequately suppress lactation after the first week, an additional short
course may be required. Use:

cabergoline 250 micrograms orally, 12-hourly for 4 doses.

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Gonadal disorders in children
Introduction
This topic considers treating gonadal disorders that are specific to children, as well as treating children with
gonadal disorders that occur at all ages. Gonadal disorders in children should be managed by, or in consultation
with, experienced paediatricians or paediatric endocrinologists.

When treating children, the factors that must be considered include:

growth and pubertal development

size, including body weight and surface area
the child's level of communication and understanding
the need to manage the child within the family.

In the neonate, systems for drug biotransformation take some months to mature. In childhood, body weight or
surface area [Note 1] are the major determinants of dosage.

Note 1: Click here for body surface area calculator and formula.

Delayed puberty
Delayed puberty is defined as the absence of pubertal changes in girls older than 13 years (no breast development)
and in boys older than 14 years (no testicular enlargement [ie testicular volume less than 4 mL]). Acne, body odour
and body hair may be due to adrenarche alone. For further information and management advice, see Delayed
puberty in girls and Delayed puberty in boys.

Precocious puberty
Precocious puberty is defined as signs of puberty in girls younger than 8 years and in boys younger than 9 years.
Precocious puberty may be gonadotrophin-dependent (central) or gonadotrophin-independent, and must be
distinguished from premature thelarche, premature adrenarche and pseudopuberty (eg severe hypothyroidism).

It is more common in girls, in whom it is usually central/idiopathic, although a pathological cause still needs to be
carefully considered. In boys the cause is more likely to be pathological, due to a central nervous system lesion,
congenital adrenal hyperplasia, or other such serious pathology. Active treatment is not always required and should
only be initiated after referral, assessment, and counselling of the child and their family.

Although not registered in Australia for this indication, gonadotrophin releasing hormone analogues are used to
treat precocious puberty. The aims of treatment are to delay pubertal progress (eg delay menstruation in girls) until
an appropriate age and social time, and to achieve optimal height. A usual dosage regimen is:

1 goserelin 3.6 mg SC implant in the anterior abdominal wall or buttocks, monthly

OR

1 goserelin 10.8 mg SC implant in the anterior abdominal wall or buttocks, 3-monthly

OR

1 leuprorelin depot 7.5 mg by deep IM injection, monthly

OR

1 leuprorelin depot 22.5 mg by deep IM injection, 3-monthly.

In children with gonadotrophin-independent precocious puberty, such as McCune Albright syndrome or

testotoxicosis, analogue therapy is not effective unless the condition has triggered concurrent central puberty.
These rare conditions warrant specialist referral.

In McCune Albright syndrome, ovarian hyperfunction is often intermittent and other endocrine organs may be
affected. Aromatase inhibitor therapy (with letrozole or anastrozole) is sometimes used to block autonomous
oestrogen production.

Pubertal gynaecomastia
A degree of gynaecomastia is common and physiological in pubertal boys (up to 40%) in Tanner Stage 3 or 4
(testicular volume 10 to 15 mL). However, Klinefelter syndrome or other causes of hypogonadism should be
considered, especially if gynaecomastia occurs in Tanner Stage 1 or 2 (discordant with normal physiology). A
pathological cause is rare. Observation and reassurance are required.

There is no medical therapy shown to be successful. Plastic surgery may be required for persistent significant
breast enlargement, but should be delayed until late puberty due to the risk of recurrence. Surgery may particularly
be important in Klinefelter syndrome where there is an increased risk of breast malignancy.

Published March 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: general approach
General approach to risk assessment and poisons information
Risk assessment is the most important step in managing the poisoned patient after the initial resuscitation. It allows
informed decisions to be made regarding all subsequent aspects of management of the poisoned patient. Under
most circumstances, risk assessment reassures the clinician that good supportive care is all that is required to
produce a good outcome, preventing unnecessary interventions. However, in some situations, it alerts healthcare
staff to the potential for severe toxicity, directs timely institution of specific interventions and informs appropriate
disposition. Risk assessment requires specific knowledge and, where questions remain, specialist consultation is
advised through clinical toxicology services or a poisons information centre.

Risk assessment is based on the following information:

agent
–
toxin or drug (intrinsic toxicity)
–
dose
–
route of exposure (ingestion, contact, inhalation, parenteral)
time since exposure
patient-specific vulnerabilities
–
age
–
sex
–
comorbidities
–
co-ingestants
action since exposure
evident clinical effects and laboratory results (see Screening tests).

It is essential to get a good patient history as well as corroborating history (eg from relatives or the ambulance
officer). The history of ingestion should not be neglected and, where absent, a worst case scenario may need to be
formulated.

The management of common acute poisonings are discussed in this guideline. Note that these do not represent a
comprehensive list. Also see Box 17.1, below for some other highly toxic drugs and chemicals that require expert
toxicological advice.
Some other highly toxic drugs and toxins (Box 17.1) [NB1]

acrylolnitrile

aluminium phosphide

Amanita mushrooms

aniline dyes

benzenes

bromine gas

chlorine gas

chloropicrin

fluoroacetamide

fluoroacetic acid

isoniazid

mercury

methyl bromide

organochlorines

1080 (sodium monofluoroacetate)

strychnine

thallium

NB1: Seek expert toxicological advice for patients presenting with any of these poisonings.

For a list of drugs and toxins that are minimally toxic, see Box 17.4.

Poisons information centres

Poisons information centres in Australia are staffed by specialist pharmacists 24 hours a day, who are able to refer
to clinical toxicologists for medical advice. Telephone 13 11 26 (Australia).

In New Zealand, the National Poisons Centre is in Dunedin. Telephone 0800 POISON / 0800 764 766.

When calling a poisons information centre, have available the following useful information:

name of the toxin or drug—the exact name and spelling of the product makes finding information about it
easier—if possible, keep the product at hand. Active constituents can be useful if there is no record of the
product name
patient details—age, weight, sex and comorbidities
exposure details—time since exposure, route of exposure, dose (eg amount swallowed, licked container lid)
immediate action taken by the parents or carers
clinical effects—symptoms influence what treatment is recommended.

Key investigations in poisoning

Screening tests

The most common tests that change management in acute poisoning are:

Serum electrolyte (bicarbonate and potassium) concentrations.

Serum paracetamol concentration.
 Blood glucose concentration.
Electrocardiography.

These tests should be considered in patients with suspected overdose as a routine screen to pick up potentially
lethal occult disease (eg paracetamol poisoning, hyperkalaemia).

The majority of patients with deliberate self-poisoning take more than one substance. Alcohol is commonly co-
ingested. A high serum ethanol concentration does not exclude other causes of intoxication.

Electrocardiography
A 12-lead electrocardiogram (ECG) should be done as a diagnostic test to detect QRS widening, QT prolongation
and other ECG changes that occur in poisonings. The decision for continuous ECG monitoring or repeated 12-lead
ECG is determined on a case-by-case treatment protocol.

In addition to QRS widening and QT prolongation, poisoning may also affect the ECG through the following
mechanisms:

Na+/K+ ATPase blockade (eg digoxin)

calcium channel blockade
adrenoreceptor stimulation/blockade
toxin mediated myocardial ischaemia.

QRS widening

QRS widening on ECG is an effect of sodium channel blockade seen with overdose of a number of drugs (see
Table 17.1). A QRS complex wider than 120 msec (0.12 seconds) is generally regarded as abnormal. The degree of
QRS widening has been linked prognostically in tricyclic antidepressant poisoning (see Toxicology: tricyclic
antidepressants). Minor QT prolongation is often seen on an ECG with QRS widening.

For the treatment of QRS widening in poisoning, see QRS widening and sodium channel blockade.

Drugs highly associated with QRS widening and sodium channel blockade (Table 17.1)

tricyclic antidepressants (see Toxicology: tricyclic antidepressants)

antidepressants venlafaxine (see Toxicology: serotonin and noradrenaline reuptake inhibitors)

antiepileptic drugs carbamazepine (see Toxicology: carbamazepine)

antihistamines diphenhydramine (see Toxicology: sedating antihistamines)

antipsychotics [NB1] chlorpromazine (see Toxicology: antipsychotics)

flecainide (see Toxicology: flecainide)

cardiovascular drugs propranolol (see Toxicology: beta blockers)

bupivacaine
local anaesthetics ropivacaine

bupropion (see Toxicology: bupropion)

chloroquine, hydroxychloroquine and quinine (see Toxicology: chloroquine,
hydroxychloroquine and quinine)
cocaine (see Toxicology: stimulant drugs)
others
dextropropoxyphene (see Toxicology: opioids)
dolasetron
orphenadrine (see Anticholinergic (antimuscarinic) agents)

NB1: Antipsychotic drugs are not highly associated with QRS widening, but are commonly taken in overdose.

QT prolongation

Drug-induced QT prolongation on ECG is a potassium channel effect associated with torsades de pointes and, less
commonly, other arrhythmias. The assessment of the QT interval remains problematic, but a QT nomogram (see
Figure 17.1) has been suggested as a useful way to determine if the QT/heart rate pair is abnormal (at risk of
torsades de pointes). The use of QTc as a method of rate correction is problematic.

Drugs highly associated with QT prolongation and torsades de pointes are listed in Table 17.2. For the treatment of
QT prolongation in poisoning, see QT prolongation and torsades de pointes.

In some cases the QT interval may be prolonged due to QRS widening, but this is not a risk factor for torsades de
pointes (eg bupropion poisoning). It is important to always manually measure the QT interval, and not rely on the
automatically generated measurement on the ECG.

Drugs highly associated with QT prolongation and torsades de pointes (Table 17.2) [NB2]

amiodarone
antiarrhythmics disopyramide
sotalol (see Toxicology: beta blockers)

other cardiovascular propranolol (see Toxicology: beta blockers)

drugs
citalopram (see Toxicology: selective serotonin reuptake inhibitors)
escitalopram (see Toxicology: selective serotonin reuptake inhibitors)
antidepressants fluoxetine (see Toxicology: selective serotonin reuptake inhibitors)
moclobemide
tricyclic antidepressants (see Toxicology: tricyclic antidepressants) [NB3]

antihistamines loratadine (see Toxicology: antihistamines, less sedating)

ciprofloxacin
clarithromycin
erythromycin
fluconazole
antimicrobials
moxifloxacin
pentamidine
voriconazole

amisulpride
antipsychotics (see chlorpromazine
Toxicology: antipsychotics) haloperidol
ziprasidone

arsenic (see Toxicology: arsenic)

chemotherapeutic agents
chloroquine (see Toxicology: chloroquine, hydroxychloroquine and quinine)
cisapride
other drugs cocaine (see Toxicology: stimulant drugs)
methadone (see Toxicology: opioids)

NB2: A full list with continuing updates can be found at the CredibleMeds website
NB3: QT prolongation is usually due to QRS widening and there is no true lengthening of the JT interval (defined as the QT interval minus the QRS
duration)

QT interval nomogram to assess risk of drug-induced torsades de pointes (Figure 17.1)

 The QT interval should be measured manually on a 12-lead ECG from the beginning of the Q wave to the end of the T wave in multiple leads (six
leads including limb and chest leads) and the median QT calculated. The median QT interval is plotted on the nomogram against the heart rate
recorded on the ECG. If the point is above the line, then the QT-HR combination implies a risk of torsades de pointes.
Adapted by permission of Oxford University Press from: Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-
induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007;100(10):609-15, Fig
1.

Drug concentrations

Serum concentrations of drugs taken in overdose are rarely available in a timely fashion for the clinical
management of patients. However, they are necessary in a number of notable exceptions, namely:

paracetamol
most common anticonvulsants (eg phenytoin, carbamazepine, phenobarbitone, sodium valproate)
aspirin
digoxin
iron
lithium
potassium
theophylline
toxic alcohols—methanol, ethylene glycol.

Serum ethanol concentrations are readily measured, but easily misinterpreted. Even in the setting of a high serum
ethanol concentration, possible co-ingestants should always be considered.

There is virtually no indication for urine drug screens in toxicology patients.

Pathology tests

In general, patients with poisoning do not require routine blood tests and testing is required only for particular
drugs or toxins. Specific blood tests are listed as key investigations for individual drugs.

Electrolyte, blood glucose and paracetamol concentrations should be considered as screening tests in patients with
suspected overdose. Venous blood gases are useful to quickly assess electrolytes, pH, bicarbonate and lactate. Full
blood count and international normalised ratio (INR) are appropriate in some circumstances, but are rarely
necessary.

Kidney function tests may be useful in patients who have ingested drugs that may cause kidney impairment (eg
nonsteroidal anti-inflammatory drugs [NSAIDs]) or, more importantly, drugs that are eliminated by the kidneys (eg
lithium, digoxin). Creatine kinase should be measured in any patient with prolonged coma and with
sympathomimetic toxicity to detect rhabdomyolysis.

Arterial blood gases

Arterial bloods gases are not routine investigations in poisoning. They allow for a more accurate evaluation of
metabolic and respiratory disturbances. Poisoned patients who are sedated require close respiratory monitoring and
care, with regular assessment of oxygen saturation and respiratory rate.

Arterial blood gases can be used to determine whether the cause of hypoxia is resulting from impaired ventilation
or a direct respiratory complication. When impaired ventilation is the cause of hypoxia, (eg opioid overdose),
oxygen therapy does not treat this deficit and may mask its presence.

Radiological imaging

Chest X-ray is not a routine investigation in poisoning. It is used to diagnose aspiration pneumonitis, acute
respiratory distress syndrome (ARDS) and atelectasis in patients with hypoxia or significant oxygen requirement.

A brain computerised tomography (CT) scan may be occasionally required to exclude other diagnoses in patients
with central nervous system (CNS) depression or coma where there is diagnostic doubt, or in patients with a
suspected hypoxic brain injury following an overdose.

Resuscitation of poisoned patients

The vast majority of poisoned patients have a good outcome with excellent supportive care. Standard advanced life
support (ALS) protocols should be followed for cardiac arrest (see flowcharts developed by the Australian
Resuscitation Council); however, treatment may differ in certain circumstances and require specific resuscitative
antidotes (see Circulation and individual drugs in this guideline for details).
Prolonged cardiopulmonary resuscitation (CPR) is essential because, unlike arrests due to cardiovascular disease,
the majority of patients are healthy before the overdose and the cause is reversible. Prolonged CPR allows for the
rapid redistribution of drugs and for other therapies to have effect. Survival with normal neurological function after
long periods (hours) of CPR is well documented. CPR should be continued until the situation has been discussed
with a clinical toxicologist.

CPR should be continued for much longer periods in patients with toxicity-related cardiorespiratory arrest.

Airway and breathing

Usual ALS principles for airways assessment and intervention apply in poisoned patients. Direct airway injury in
caustic ingestions requires a heightened awareness with an appreciation of the potential for extreme difficulty (see
Toxicology: caustic ingestions). CNS depression is a common effect of drugs, so regular and careful assessment of
airway protection and patency is important.

The commonest problem in toxicology patients is hypoventilation secondary to respiratory depression. Toxicology
patients rarely have hypoxia unless they develop aspiration pneumonitis. Deficits in ventilation and oxygenation
should be supported appropriately.

Oxygen therapy can mask respiratory depression in poisoned patients.

Circulation

Deficits in circulation in poisoning can be multiple and include disturbances to heart rate, blood pressure and
cardiac conduction. Standard care includes support with intravenous fluids and inotropes (selected according to
specific toxin or drug). In patients with hypotension, use:

sodium chloride 0.9% 20 mL/kg IV over 10 to 30 minutes.

In selected cases, circulation cannot be satisfactorily resuscitated without the use of appropriate antidotal therapy
—for example, sodium bicarbonate in poisoning with sodium channel blocking agents and digoxin immune Fab in
digoxin poisoning (see Toxicology: digoxin).

Inotropic support

Inotropic support is rarely required in toxicology—initiation of inotropes and choice of drug should ideally be after
consultation with a clinical toxicologist.

For specific advice on inotropic support, see the individual drug or toxin. For drugs or toxins that mainly cause
peripheral vasodilation, noradrenaline should be considered first-line. For drugs that cause cardiogenic shock,
other inotropes can be used.

See Box 17.2 for doses of inotropes that may be recommended by a clinical toxicologist. High-dose insulin
euglycaemia therapy (HIET) may be recommended by a clinical toxicologist in the setting of severe calcium
channel blocker or beta-blocker poisoning. This is a complex treatment regimen requiring intensive monitoring,
and should only be commenced under specialist advice.
Doses of inotropes that may be recommended by a clinical toxicologist (Box 17.2)

Adrenaline

adrenaline 1 to 20 micrograms/minute (child: 0.05 to 0.1 microgram/kg/minute) IV

infusion (see Box 17.7), titrated to response.

Noradrenaline

noradrenaline 1 to 20 micrograms/minute (child: 0.02 to 0.1 microgram/kg/minute) IV

infusion (see Box 17.7), titrated to response.

Isoprenaline

isoprenaline 20 micrograms IV, repeat according to clinical response up to a maximum

of 100 micrograms, followed by an infusion at 2 to 4 micrograms/minute. The rate may
need to be rapidly increased to give double, quadruple or higher doses as required to
overcome beta blockade. Isoprenaline can be given via a peripheral line (see Box 17.8).

Dobutamine

dobutamine 2.5 to 10 micrograms/kg/minute (child: 5 to 20 micrograms/kg/minute) IV

infusion.

Milrinone (phosphodiesterase inhibitor)

In adults, use:

milrinone 50 micrograms/kg IV slowly over 10 minutes, followed by an infusion of

0.375 to 0.75 micrograms/kg/minute, adjusting according to clinical and haemodynamic
response, up to a maximum of 1.13 mg/kg daily.

In children, use:

milrinone (child 30 kg or less) 1.5 mg/kg in 50 mL, 2.5 mL (= 75 micrograms/kg) IV

over 1 hour, then 1 to 1.5 mL/hour (0.5 to 0.75 micrograms/kg/minute)

or milrinone (child more than 30 kg) 1.5 mg/kg in 100 mL, 5 mL (= 75 micrograms/kg) IV over 1 hour, then 2 to
3 mL/hour (0.5 to 0.75 micrograms/kg/minute).

QRS widening and sodium channel blockade

QRS widening is highly significant in toxicology. A widened QRS complex (wider than 120 msec [0.12 seconds])
should be monitored closely with continuous ECG monitoring and regular 12-lead ECGs. When QRS widening is
associated with any deterioration in mental status or decompensation in airway, breathing or circulation (eg
arrhythmias, hypotension), therapy should be instituted in a timely fashion.

In this setting patients with QRS widening require serum alkalinisation with intravenous sodium bicarbonate and
mechanical ventilation to control partial pressure of carbon dioxide (PaCO2). Sodium bicarbonate and serum
alkalinisation has been extensively evaluated, particularly in tricyclic antidepressant poisoning. Intravenous
boluses of sodium bicarbonate produce transient changes in pH, but they are very difficult to maintain without
controlling PaCO2 with mechanical ventilation. Bicarbonate infusions do not overcome this problem because
physiological reflex changes in PaCO2 and renal bicarbonate excretion buffer the change in pH.

When QRS widening is progressive, intravenous boluses of sodium bicarbonate and concurrent hyperventilation
therapy (by intubation and mechanical ventilation) should be used to increase the pH to a target range of 7.45 to
7.55. Use:

sodium bicarbonate 8.4% (= 1 mmol/mL) 1 to 2 mmol/kg IV bolus, every 3 to 5 minutes,

titrated to a narrowing of the QRS complex. If no response, urgently seek advice from a
poisons information centre. Maximum total dose 10 mmol/kg

PLUS
 hyperventilation following intubation and mechanical ventilation (where indicated).

QT prolongation and torsades de pointes

Continuous ECG monitoring and regular 12-lead ECGs are required to assess the QT interval.

Electrolyte replacement

QT prolongation should be monitored and any other precipitating factors should be determined and treated if
possible. Electrolytes, including magnesium, potassium and calcium, should be checked and deficiencies
corrected.

Patients with hypomagnesaemia should have magnesium replacement [Note 1].

In adults, use:

magnesium sulfate 50% 5 to 10 mL (= 2.5 to 5 g or 10 to 20 mmol) IV over 30 to 60

minutes.

In children, use:

magnesium sulfate 50% 0.1 mL/kg (= 50 mg/kg or 0.2 mmol/kg) IV over 20 minutes
[Note 2], followed by an infusion of 0.06 mL/kg/hour (= 30 mg/kg/hour or 0.12
mmol/kg/hour).

Patients with hypokalaemia should have potassium replaced. Use:

1 potassium chloride 14 to 16 mmol orally, up to 3 times daily as required (child: 1

mmol/kg/day in 2 to 4 divided doses) [Note 3]

OR

1 potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV over 1 to 2 hours (child: 0.6

mmol/kg IV over 3 hours), preferably as a premixed solution of the appropriate
intravenous fluid [Note 4].

Patients with hypocalcaemia should have calcium replaced. In adults, use:

calcium gluconate 10% 10 to 20 mL (= 1 to 2 g or 2.2 to 4.4 mmol) IV over 10 to 30

minutes.

In children, use:

calcium gluconate 10% 0.5 mL/kg (0.11 mmol/kg; maximum dose 20 mL) IV infusion
over 10 to 30 minutes.
Note 1: In toxicology patients, the correction of magnesium deficiency, if required, needs to be done rapidly
while the patient has a prolonged QT interval and is at risk of torsades de pointes.

Note 2: Magnesium can be given intramuscularly in infants or children if urgent IV access not possible.

Note 3: Effervescent immediate-release tablets of potassium contain 14 mmol potassium per tablet, and slow-
release tablets contain 8 mmol potassium per tablet. The slow-release formulations of potassium are almost
completely absorbed within one hour.

Note 4: Extemporaneous addition of ampoules of potassium chloride to intravenous fluids is no longer regarded
as safe, because inadequate mixing may result in delivery of potassium at a lethal concentration. If premixed IV
solution is unavailable, potassium chloride concentrate injection must be added to a large volume of parenteral
fluid and mixed thoroughly before infusion. The usual maximum concentration is 40 mmol/L.

Torsades de pointes

Magnesium sulfate or chronotropy (using transvenous pacing or isoprenaline) should be considered in patients
with a prolonged QT interval and an episode of torsades de pointes. In adults, use:
 1 magnesium sulfate 50% 2 to 4 mL (= 1 to 2 g or 4 to 8 mmol) IV as a slow injection over
10 to 15 minutes

OR

2 isoprenaline 20 micrograms IV, repeated according to clinical response, followed by an

infusion of 1 to 4 micrograms/minute (see Box 17.8), with a target heart rate above 90
beats per minute. The infusion rate may need to be rapidly increased to give higher doses
if there is beta blockade.

If torsades de pointes is associated with haemodynamic collapse, treat as ventricular fibrillation with standard
advanced life support protocols (see flowcharts developed by the Australian Resuscitation Council).

Gastrointestinal decontamination of poisons

Single-dose activated charcoal
Activated charcoal reduces the systemic absorption of drugs and toxins by binding the substance in the
gastrointestinal tract. It can also increase the clearance of some drugs and toxins by interrupting enterohepatic
circulation, or by gastrointestinal dialysis (ie drawing already absorbed drugs or toxins back into the
gastrointestinal tract down a concentration gradient).

The effectiveness of activated charcoal in adsorbing a drug or toxin is dependent on:

how well the drug or toxin binds to activated charcoal

the normal absorption properties of the drug or toxin
any effect of the drug or toxin on gastrointestinal activity (eg ileus).

Activated charcoal has been shown to not be effective when used routinely, but may be used in specific
circumstances. It has its own inherent risks; in particular, charcoal aspiration can be fatal. Activated charcoal
should not be used when it is expected that supportive care would deliver a good outcome. Use should be
cautioned when rapid deterioration in conscious state is expected or there is a significant chance of seizures.

The current consensus is to use activated charcoal in significant poisonings when it is expected there is drug still in
the upper gastrointestinal tract, so long as the risk versus benefit is considered. For most overdoses this is within 1
hour of the estimated time of ingestion. Patients must be able to protect their airway or be intubated. In this
situation, use:

activated charcoal 50 g (child: 1 g/kg up to 50 g) orally or via nasogastric tube, within 1

hour of the estimated time of ingestion. Patients must be able to protect their airway or be
intubated.

There are good theoretical reasons and some recent evidence for using activated charcoal later than 1 hour after
ingestion. Therefore, the recommendation to use activated charcoal and the timing of its use varies for some
agents. This is described under each drug or toxin.

For slow-release preparations, consider using activated charcoal within 4 hours of the estimated time of ingestion
or discuss with a clinical toxicologist. Activated charcoal may be used later in intubated patients.

Activated charcoal in children

Decontamination with activated charcoal is rarely indicated in children. Activated charcoal should only be
considered in children when risk assessment suggests that a good outcome is unlikely with supportive care.

Activated charcoal should never be administered in children with altered conscious state without airway
protection. The use of activated charcoal requires a careful assessment of the risks and benefits because a general
anaesthetic is often required to protect the airway.

Young children rarely drink activated charcoal slurries, but may if mixed with ice cream. If a nasogastric tube is
required, verification of the correct placement is essential before administration of charcoal. If used, the
nasogastric tube should be one size larger than the 'feeding-tube' range because activated charcoal is a thick
suspension.

Whole bowel irrigation

Whole bowel irrigation should be considered within the first few hours for ingestions of metals or slow-release
preparations. Specific examples include patients who have ingested iron (greater than 60 mg/kg), lead, lithium,
slow-release metformin, slow-release potassium chloride (greater than 2.5 mmol/kg), slow-release verapamil or
life-threatening doses of slow-release diltiazem (see Toxicology: calcium channel blockers). Another group in
whom whole bowel irrigation may be considered is body packers [Note 5].

Although there are good theoretical reasons for using whole bowel irrigation in these situations, there is little
evidence to support its use. It is essential to carefully balance the possible benefits against the significant risk of
aspiration and practical difficulties of administering whole bowel irrigation. In particular, vomiting and profuse
diarrhoea can interfere with timely retrieval and life-saving interventions.

Whole bowel irrigation is contraindicated in patients with gastrointestinal ileus. Development of ileus must,
therefore, be carefully monitored by listening for bowel sounds, particularly in intubated patients and patients
taking anticholinergic drugs.

It is reasonable to discuss the use of whole bowel irrigation for individual patients with a clinical toxicologist. Use:

macrogol 3350 powder with electrolytes (ColonLYTELY) 2 sachets dissolved in 2 L of

water, 1 to 1.5 L (child: 20 to 30 mL/kg) in the first hour, then 1 L/hour (child: 20 to 30
mL/kg/hour) orally or via orogastric or nasogastric tube, if given within 2 hours of
ingestion. Patients must be able to protect their airway or be intubated [Note 6].
Note 5: Body packing refers to the swallowing of plastic- or latex-wrapped packages of illicit drugs for
concealment from inspection. Presentation to the emergency department is often long after swallowing the
packages, which have therefore usually entered the small or large intestine.

Note 6: Macrogol is the recommended International Nonproprietary Name for polyethylene glycol.

Gastric lavage
Gastric lavage is no longer recommended, except in rare circumstances where a single aspiration of the stomach
contents may be attempted early in potentially life-threatening poisoning and only if the airway is protected. A safe
option is to simply suction out the contents of the stomach if the patient has been intubated, but instillation of fluid
in the stomach is not recommended.

Induced emesis
Inducing emesis by any means is not recommended due to the risks of aspiration. Ipecac syrup is not
recommended at all and is no longer available in Australia. This is due to lack of effectiveness and the risks of
aspiration if the patient becomes sedated and then begins to vomit.

Skin decontamination of poisons

Patients who have had skin exposure to hazardous materials should have all of their clothes removed, and then be
washed in a shower with soapy water. Once this has been done there is no risk of secondary contamination or
poisoning by toxic agents in persons looking after these patients.

Ocular decontamination of poisons

Ocular decontamination requires copious irrigation with either water or sodium chloride 0.9%. For substances that
are irritant and minimally corrosive, irrigation for 15 to 20 minutes is usually sufficient. For corrosive agents,
irrigation should continue longer.

Enhanced elimination of poisons

Multiple-dose activated charcoal

Seek the advice of a clinical toxicologist.

There is limited evidence for multiple-dose activated charcoal, but it is recommended for overdose of some drugs
(eg dapsone, carbamazepine, colchicine, phenytoin, phenobarbitone, theophylline). Before each dose of activated
charcoal the presence of bowel sounds must be confirmed.

In adults, use:

1 activated charcoal 50 g orally or via orogastric or nasogastric tube, 4- to 6-hourly. Patients

must be able to protect their airway or be intubated
 OR

1 activated charcoal 10 g orally or via orogastric or nasogastric tube, hourly. Patients must
be able to protect their airway or be intubated.

In children, use:

activated charcoal 1 g/kg up to 50 g, as an initial dose, orally or via orogastric or

nasogastric tube, followed by 0.5 g/kg, 4-hourly. Patients must be able to protect their
airway or be intubated.

Extracorporeal elimination
Extracorporeal elimination techniques should only be undertaken in severe and life-threatening poisonings with
appropriate toxicological and critical care advice. They require specialised staff, equipment and monitoring, and
are invasive with risks of adverse events.

Haemodialysis: intermittent or continuous haemodialysis may be beneficial in select poisonings, depending

on the ratio of clearance by the machine to the endogenous clearance of the toxin. Machines with the highest
flux are most effective, while low-flow continuous veno-venous haemodialysis gives low overall clearance.
In some cases, haemodialysis is beneficial for reasons other than removal of the drug or toxin, such as
acidosis in metformin overdose where it is used to remove lactate.
Haemoperfusion: rarely used due to limited benefit in addition to haemodialysis and the limited availability
of activated charcoal cartridges.
Plasmapheresis: despite numerous reports in the early literature there is no evidence for the use of
plasmapheresis in the removal of drugs or toxins. There may be potential benefit for complications such as
rhabdomyolysis.

Extracorporeal techniques of elimination may be indicated for the following drugs and toxins:

methanol and ethylene glycol (see Toxicology: alcohols [toxic])

anticonvulsants—sodium valproate (see Toxicology: sodium valproate), carbamazepine (see Toxicology:
carbamazepine)
theophylline (see Toxicology: theophylline and caffeine)
lithium (see Toxicology: lithium)
metformin (see Toxicology: metformin)
aspirin (see Toxicology: aspirin).

Urinary alkalinisation
Urinary alkalinisation with sodium bicarbonate has a limited role except in poisoning by salicylates (see
Toxicology: aspirin) and chlorphenoxy herbicides (see Toxicology: herbicides).

Potassium and kidney function should be monitored every 4 hours. A dipstick urinalysis should be done regularly
to make sure the urine remains alkaline.

Chelation therapy

Chelating agents bind metals and allow them to be removed from the body. Chelation therapy is used uncommonly
in toxicology. There is little evidence for the use of these agents for acute ingestions, and dosing regimens are
empirical. In many situations, the major practical issue is obtaining the chelating agent [Note 7]. The dosing of
individual agents is specific to each type of poisoning because it depends on whether the exposure is acute or
chronic and on the type of metal. The use of chelation therapy for individual patients should be discussed with a
clinical toxicologist.

Note 7: Most chelating agents are not registered for use in Australia but are available via the Special Access
Scheme (SAS). Pharmacists or emergency staff should also check the Emergency and Life-saving Drugs
Register for their state. This register lists hospitals that hold specific SAS drugs, which may be borrowed in an
emergency.

Specific pharmacological therapies for poisoning

Antidotal therapy

Indications for and doses of specific antidotes are included under each drug or toxin. Many antidotes are toxic
themselves so their use must be carefully considered.
Sedation
Sedation is required in a number of situations in toxicology, most importantly in patients with agitation and
delirium. Benzodiazepines are the main drugs used, but in difficult cases, sedative antipsychotics such as
droperidol may be required.

In adults, use:

1 diazepam 2.5 to 5 mg IV, repeat every 3 to 4 minutes until the required level of sedation is
obtained, up to a maximum of 20 to 30 mg

OR

1 diazepam 20 mg orally, if the patient is willing to take it

OR

1 midazolam 2.5 to 5 mg IV or IM, repeat every 3 to 4 minutes until the required level of
sedation is obtained, up to a maximum of 20 mg

OR (in difficult cases)

1 droperidol 5 to 10 mg IV or IM, repeat once after 15 minutes if required.

In children, use:

1 diazepam 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, repeat once after 15 minutes if
required, up to a maximum of 5 mg

OR

1 midazolam 0.05 to 0.1 mg/kg IV or IM, repeat once after 15 minutes if required, up to a
maximum of 5 mg.

Anticonvulsant therapy
Benzodiazepines should be used as the primary anticonvulsant in overdose patients if seizures are not self-limiting
within minutes. Use:

1 diazepam 10 to 20 mg (child: 0.1 to 0.25 mg/kg up to 20 mg) IV over 2 to 5 minutes, not

exceeding 5 mg/minute. Repeat once after 15 minutes if seizure continues

OR

1 midazolam 5 to 10 mg (child: 0.15 to 0.2 mg/kg up to 10 mg) IV over 2 to 5 minutes.

Repeat once after 15 minutes if seizure continues.

If intravenous access is not possible, use:

1 diazepam 0.5 mg/kg rectally

OR

1 midazolam 5 to 10 mg (child: 0.15 to 0.2 mg/kg up to 10 mg) IM. Repeat once after 15
minutes if seizure continues.

For intractable seizures in the overdose setting (eg theophylline poisoning), barbiturates should be used. If this is
required after specialist advice, use:

phenobarbitone sodium 20 mg/kg up to 1 to 2 g (child: 20 mg/kg up to 1 g) IV over 30

minutes.

Specific drugs may be required with some poisons.

Phenytoin is ineffective for drug-induced seizures and drug withdrawal, and should not be used because it blocks
sodium channels and may increase the risk of arrhythmias.

Antiarrhythmic therapy
Antiarrhythmic drugs should generally be avoided in the overdose setting due to the potential for proarrhythmic
effects. However, standard advanced life support protocols should be followed for ventricular fibrillation and
asystolic cardiac arrests (see flowcharts developed by the Australian Resuscitation Council).

For the treatment of QRS widening and QT prolongation, see QRS widening and sodium channel blockade and QT
prolongation and torsades de pointes.

Aspiration pneumonitis in cases of poisoning

Clinical features
Aspiration pneumonitis in overdose patients results from aspiration of acidic stomach contents and subsequent
chemical injury to the lung parenchyma. It is most commonly associated with sedation in overdose patients.
Although aspiration pneumonitis may cause respiratory failure requiring oxygen and respiratory support, it is
rarely associated with bacterial colonisation and sepsis.

Aspiration pneumonitis must be distinguished from aspiration pneumonia, which is seen in patients with dysphagia
or gastric dysmotility, and is usually a result of bacterial infection with oral flora (see Aspiration pneumonia). In
overdose patients, those with aspiration pneumonitis have a significantly increased mortality (8.5% compared to
0.4% in the group without aspiration pneumonitis [Note 8]) and an almost 10-fold increase in hospital length of
stay.

Note 8: Isbister GK, Downes F, Sibbritt D, Dawson AH, Whyte IM. Aspiration pneumonitis in an overdose
population: frequency, predictors, and outcomes. Crit Care Med 2004;32(1):88-93. [URL]

Risk factors
Risk factors for aspiration pneumonitis are:

increasing age
decreased level of consciousness (Glasgow Coma Scale score less than 15)
vomiting
delayed presentation to hospital (more than 4 hours)
seizure
tricyclic antidepressant overdose (independent of other risk factors)
pesticide or hydrocarbon ingestions.

Key investigations
The key investigations in aspiration pneumonitis are a chest X-ray and arterial blood gases.

Treatment of aspiration pneumonitis

The mainstay for treatment of aspiration pneumonitis is supportive care with oxygen therapy and ventilatory
support. There is continuing controversy over the use of antibiotics in this patient group. Antibiotics may be
considered if there is ongoing high fever for more than 48 hours or other objective evidence of sepsis (see
Aspiration pneumonia).

Rhabdomyolysis in cases of poisoning

Introduction
Rhabdomyolysis is an often unappreciated complication in overdose patients. It occurs as a result of injury to
skeletal muscle—which can result from sustained direct pressure to muscles in patients with depressed conscious
state, hyperthermia or, less commonly, as a direct drug/toxin effect. The syndrome is characterised by muscle
breakdown and necrosis, with leakage of intracellular elements into the circulation. Myoglobinuria is associated
with more severe rhabdomyolysis and can lead to kidney injury.

Compartment syndrome can occur in the toxicological context as a result of injury to discrete muscle groups
(especially in weightbearing areas such as the deltoid and gluteal regions). Following the primary insult, pressure
increases within a muscular compartment—leading to further muscle fibre injury and necrosis. As well as general
supportive care, this syndrome may require urgent surgical intervention to limit ongoing injury. A high index of
suspicion is needed to diagnose this condition in patients with confirmed rhabdomyolysis.

Complications

The complications of rhabdomyolysis include:

potentially life-threatening hyperkalaemia

acute kidney failure
hypocalcaemia (often transient).

Key investigations
The key investigations in rhabdomyolysis include:

Creatine kinase—rises within 12 hours but peaks day 1 to 3.

Urea and electrolytes.

Treatment of rhabdomyolysis
The mainstays of treatment are detection and treatment of life-threatening hyperkalaemia, and ensuring early and
generous intravenous fluids to maintain urine output at 1 to 2 mL/kg/hour. Treatment also should be directed at
eliciting and eliminating the cause where possible, which includes surgical assessment of clinically concerning
muscular compartments.

Oliguria and worsening kidney function may require renal replacement therapy (dialysis) which may be required
for weeks in some cases. Other therapies such as mannitol, loop diuretics and urinary alkalinisation are
controversial and have little supporting evidence in the literature.

Observation and disposition of toxicology patients

Disposition of toxicology patients is based on the risk assessment. The aim is for the patient to be in the right
location, at the right time, and for the right length of time to appropriately manage predicted complications. The
criteria for admission and discharge are outlined under each drug or toxin, and take into account the physical
aspects of poisoning.

All patients with deliberate self-poisoning require an assessment of their psychiatric status before discharge.
Patients may require a longer period of observation than outlined in the monographs, to facilitate psychiatric
assessment and treatment when indicated. This may apply even to patients using recreational drugs because
deliberate self-harm is common in this group. An assessment of the social situation and reason for unintentional
poisoning is important in young children.

Key references
Toxicology: key investigations

Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug–induced QT prolongation and torsades de pointes: evaluation of
a QT nomogram. QJM 2007;100(10):609–15. [ ]

Toxicology: decontamination

Kumar VV, Oscarsson S, Friberg LE, Isbister GK, Hackett LP, Duffull SB. The effect of decontamination procedures on
the pharmacokinetics of venlafaxine in overdose. Clin Pharmacol Ther 2009;86(4):403–10. [ ]

Toxicology: rhabdomyolysis

Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med 2007;2(3):210–8. [ ]

Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians. Crit
Care 2005;9(2):158–69. [ ]

Published July 2012. Amended July 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: toxidromes
Introduction to toxidromes
Grouping signs and symptoms of a poisoning into a toxidrome can be useful, especially when the toxin is not
known, which is common in the initial stages of the presentation. This grouping can be useful for narrowing the
differential diagnoses. However, it is uncommon for patients to present with a pure toxidrome because multiple
substances are often ingested and most drugs have effects at multiple receptor sites, particularly in overdose.

Anticholinergic (antimuscarinic) toxidrome

Introduction
Pure anticholinergic agents include atropine, benztropine, benzhexol, and anticholinergic plants (eg Brugmansia
species or Angel's Trumpet).

Drugs with anticholinergic effects include tricyclic antidepressants, antihistamines, and antipsychotic drugs.
Carbamazepine inhibits acetylcholine release and therefore has anticholinergic-like effects.

Clinical presentation

Peripheral anticholinergic effects include dry skin, dry mouth, mydriasis, tachycardia, urinary retention,
gastrointestinal ileus (decreased bowel sounds) and hyperthermia (children).

Central anticholinergic effects include hallucinations, delirium, agitation, aggression and, occasionally, sedation
and seizures.

Treatment
The major management issue with centrally acting anticholinergic agents is acute delirium, with associated
hallucinations, agitation and aggression. Pharmacological sedation is almost always required and this should be
done with intravenous benzodiazepines (see Sedation). In the majority of cases intravenous sedation is required,
but if the patient agrees to take oral medication and they are not dangerously aggressive, oral medication can be
given. Oral sedation may be used following reversal with physostigmine.

Antidotal therapy

Centrally acting anticholinesterases reverse anticholinergic effects such as delirium. Physostigmine is the only
parenteral anticholinesterase available and has a short half-life. This makes it useful for the initial diagnosis,
particularly when the history is unclear. It also makes it possible to treat ongoing delirium with oral sedatives. Use:

physostigmine 2 mg (child: 0.02 mg/kg up to 0.5 mg) IV, which can be repeated if there is
only a partial response [Note 1].

Physostigmine should be administered in a resuscitation area. It should not be used without consulting a clinical
toxicologist for poisoning with agents that do not cause pure anticholinergic effects (eg tricyclic antidepressants,
antihistamines). Serious adverse effects have been reported in this setting, including seizures and cardiac
arrhythmias.

When anticholinergic effects cause life-threatening toxicity with hyperthermia, seizures and coma (as can occur
particularly in children), ongoing therapy with physostigmine may be required.

Long-acting oral anticholinesterase drugs (eg donepezil) should also be effective for the treatment of acute
anticholinergic delirium, but there is little published experience.

Note 1: Physostigmine is not registered for use in Australia but is available via the Special Access Scheme.

Cholinergic toxidrome
Drugs or toxins with cholinergic activity
Cholinergic agents include both acetylcholinesterase inhibitors and acetylcholine receptor agonists.

Acetylcholinesterase inhibitors cause both muscarinic and nicotinic systemic effects. This pharmacological group
includes:

organophosphorus pesticides
chemical warfare nerve agents
carbamate insecticides
drugs used for dementia (eg donepezil, rivastigmine)
drugs used for myasthenia gravis (eg neostigmine).

Examples of acetylcholine receptor agonists are nicotinic agonists (eg nicotine [tobacco products and plants,
nicotine patches] and varenicline) and agents acting on muscarinic receptors (eg mushrooms [Inocybe and
Clitocybe species]).

Clinical presentation

The clinical effects of cholinergic stimulation include:

central nervous system (CNS) excitation—delirium, coma, seizures

neuromuscular excitation—fasciculations, weakness and paralysis (nicotinic)
autonomic effects—salivation, lacrimation, diaphoresis, flushing, miosis (muscarinic)
respiratory effects—bronchorrhoea, bronchoconstriction (muscarinic)
cardiovascular effects—bradycardia or tachycardia, hypertension, hypotension (with severe toxicity),
arrhythmias
metabolic effects—hypokalaemia, hyperglycaemia, metabolic acidosis
gastrointestinal effects—abdominal pain, vomiting and diarrhoea.

Treatment

Airway, breathing and circulation should be attended to with particular attention to increased pulmonary
secretions.

Specific treatments include atropine for muscarinic effects, benzodiazepines to treat any agitation or seizures, and
specific antidotes (eg pralidoxime for organophosphorus compounds, see Toxicology: organophosphates).

Antidotal therapy

Anticholinergic therapy with atropine is used to treat muscarinic effects. Atropine requirements vary enormously
between patients and different cholinergic agents, so a dosing protocol that doubles each subsequent dose is
required to load the patient rapidly. Use:

atropine 1.2 to 3 mg (child: 0.05 mg/kg) IV as an initial bolus. If there is no improvement

in the first 3 of the 5 target end-points (see Target end points for atropinisation, below)
after 5 minutes, double the initial dose. Continue to double the dose every 5 minutes until
atropinised (doses of up to 100 mg may be required). Once the patient is atropinised an
infusion should be commenced with 10% to 20% of the total loading dose given every
hour.

The patient needs to be carefully observed for signs of under- or over-atropinisation [Note 2] and the infusion
altered accordingly (either stopping the infusion or giving another bolus dose).

Target end points for atropinisation are (aim to rapidly achieve the first 3):

chest clear and no wheeze on auscultation

heart rate greater than 80 beats per minute
systolic blood pressure greater than 80 mm Hg
pupils no longer constricted
dry axillae.

Note 2: Signs of over-atropinisation: confusion, pyrexia and absent bowel sounds are the most important signs
of atropine toxicity.

Methaemoglobinaemia toxidrome
Introduction
Methaemoglobinaemia occurs when ferrous iron in red blood cells is oxidised to the ferric form. Acquired
methaemoglobinaemia occurs with ingestion of certain oxidants. Such oxidants include nitrates and nitrites, which
are found in fertilisers, disinfectants, well-water and foods. In addition, methaemoglobinaemia can be caused by a
number of drugs and other chemicals. There are, however, common and important susceptibility factors (eg
glucose-6-phosphate dehydrogenase [G6PD] deficiency), and some patients develop methaemoglobinaemia
following minimal or therapeutic exposure to these oxidising agents.

Drugs or metabolites that can cause methaemoglobinaemia include:

local anaesthetics—articaine, benzocaine (also in teething gels), lidocaine, prilocaine, procaine

antibiotics—sulfamethoxazole, clofazimine, dapsone
antimalarials—chloroquine, primaquine
prodrugs or sources of nitric oxide—sodium nitrite (in liniments and laxatives), sodium nitrate, sodium
nitroprusside, glyceryl trinitrate, amyl nitrite.

Nondrug toxins which can cause methaemoglobinaemia include pesticides and herbicides (eg paraquat, propanil),
aniline dyes, naphthalene and nitrobenzene. Numerous other chemicals in fertilisers, dyes and industrial products
can produce methaemoglobinaemia and usually relate to occupational exposure.

Clinical presentation

The clinical effects relate to the concentration of methaemoglobin in the blood and the effectiveness of the
compensatory cardiovascular response to reduced oxygen carrying capacity. These are detailed in Table 17.3.

Haemolytic anaemia may accompany methaemoglobinaemia due to oxidant-induced Heinz body haemolysis.
However, this is usually delayed 12 to 24 hours after the development of methaemoglobinaemia.

Clinical effects of methaemoglobinaemia related to concentration of methaemoglobin (Table

17.3)

Methaemoglobin (%) Clinical effects

less than 10 nil
10 to 20 slate grey discolouration, cyanosis
20 to 30 headache, anxiety, tachycardia
30 to 50 drowsiness, fatigue, confusion, tachypnoea
increasing CNS depression, coma, seizures, arrhythmias,
50 to 70
acidosis
more than 70 lethal
CNS = central nervous system

Laboratory findings

Pulse oximetry and arterial blood gases may be only slightly abnormal in methaemoglobinaemia.

Pulse oximetry does not measure methaemoglobin. The apparent oxygen saturation decreases to about 85% with
moderate methaemoglobinaemia, but does not go any lower. Even newer pulse oximeters that claim to detect
methaemoglobinaemia and carboxyhaemoglobin with co-oximetry are very inaccurate and should not be relied on.

Many blood gas machines can accurately measure methaemoglobin. If this is not available there is a simple colour
chart method that is accurate to within 10% [Note 3]. However, the partial pressure of oxygen (PaO2) in arterial
blood gas measurements does not provide an accurate estimate of tissue oxygenation.

Note 3: See Shihana F, Dissanayake DM, Buckley NA, Dawson AH. A simple quantitative bedside test to
determine methaemoglobin. Ann Emerg Med 2010;55(2):184-9. [Available at: URL]

Treatment
Initial treatment of methaemoglobinaemia should be with oxygen although this only provides a minimal increase
in oxygen-carrying capacity. Many patients with increased concentrations of methaemoglobin (eg 10% to 30%)
only require supportive care.

Antidotal therapy

In patients with symptomatic methaemoglobinaemia and a methaemoglobin concentration of greater than 20%, or
in asymptomatic patients with methaemoglobin greater than 30%, methylene blue is indicated. Use:
 methylene blue 1% solution 0.1 to 0.2 mL/kg (1 to 2 mg/kg) IV over 3 to 5 minutes.

Methaemoglobin concentrations should be measured hourly to ensure that there is a rapid recovery. If there is
persistent methaemoglobinaemia, a second dose of methylene blue can be administered after 1 hour at a dose of
0.1 mL/kg (1 mg/kg). Further doses are rarely required, except in cases where there is ongoing formation of
methaemoglobin, such as in dapsone poisoning. A total dose of 0.7 mL/kg (7 mg/kg) of the 1% solution of
methylene blue should not be exceeded in a 24-hour period.

Neuroleptic malignant syndrome toxidrome

Introduction
Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening condition if not diagnosed and
treated early. Extrapyramidal features are invariably present, but other features (fever, and autonomic and cognitive
features) are also required to make the diagnosis. By definition, NMS can only be diagnosed if a patient has
recently received a dopamine receptor-blocking drug or been withdrawn from a dopaminergic drug (eg levodopa,
bromocriptine). Almost all antipsychotics, first- and second-generation, have been associated with NMS.

Clinical presentation
NMS develops over a period of hours to days—this is an important distinguishing feature from serotonin toxicity.
The classic tetrad of clinical features in NMS is:

hyperthermia
extrapyramidal effects—‘lead-pipe’ rigidity, bradykinesia or akinesia, dystonias, abnormal movements and
postures, dysphagia, tremor
autonomic effects—tachycardia, hypertension, labile blood pressure, diaphoresis, tachypnoea
central nervous system (CNS) effects—drowsiness, confusion, coma, mutism, incontinence.

Laboratory findings

Common abnormal laboratory findings in NMS syndrome are elevated creatine kinase, leucocytosis and low serum
iron. Other laboratory tests are done to detect complications such as dehydration, metabolic acidosis, pneumonia
and other infections, pulmonary emboli, and kidney failure.

Computerised tomography (CT) and magnetic resonance imaging (MRI) are normal in NMS but the
electroencephalogram (EEG) may show diffuse slowing, consistent with metabolic encephalopathies. Lumbar
puncture may be normal, or have a slightly elevated protein concentration.

Diagnosis

The DSM IV diagnostic criteria for NMS syndrome are:

severe muscle rigidity

elevated temperature
other related findings (eg diaphoresis, dysphagia, incontinence, changes in level of consciousness ranging
from confusion to coma, mutism, elevated or labile blood pressure, elevated creatine kinase [CK]).

It can only be diagnosed when these features develop in association with the use of neuroleptic medication or the
patient has been withdrawn from a dopaminergic drug.

Treatment

Respiratory and circulatory support

Treatment of NMS must focus on supportive care, prevention of complications and cessation of dopamine
antagonists (see Antidotal therapy). Aggressive fluid replacement is usually required and patients with hypotension
should be given fluid replacement (see Circulation). In severe cases with muscle rigidity involving the chest wall,
the patient may require respiratory support with intubation, sedation and paralysis.

Cooling for hyperthermia

If the patient's temperature is greater than 39 °C, the patient should be cooled with tepid sponging and ice packs.
Antipyretic drugs are ineffective (see Key management issues).
Sedation

Many patients require sedation for confusion and agitation or, in severe cases, for intubation and paralysis. For
drug and dosing recommendations, see Sedation.

Antidotal therapy

Although the effectiveness of antidotal therapy has not been demonstrated in controlled trials, clinical experience
and case reports support the use of bromocriptine (a dopamine agonist). Use:

bromocriptine 2.5 mg orally or via nasogastric tube, 8-hourly; the dose can be gradually
increased based on clinical response up to 5 mg, 4-hourly.

Bromocriptine should be titrated to clinical effect, looking for a lowering of the temperature and reduction of
muscle rigidity. Severe NMS should be discussed with a clinical toxicologist or a unit experienced in treatment of
this rare condition.

Serotonin toxidrome
Clinical presentation

Serotonin toxicity develops within hours of commencing the serotonergic agent or interacting drugs. A list of drugs
which have been associated with serotonin toxicity is provided in Table 17.4.

Serotonin toxicity is best characterised by a triad of clinical effects:

neuromuscular excitation—hyperreflexia, clonus (inducible or spontaneous), ocular clonus, myoclonus,

shivering, tremor, hypertonia or rigidity
autonomic effects—hyperthermia (mild: less than 38.5 °C; severe: greater than 38.5 °C or rapidly rising),
diaphoresis, flushing, mydriasis, tachycardia
central nervous system (CNS) effects—agitation, anxiety, confusion.

Drugs that have been associated with serotonin toxicity (Table 17.4)

Pharmacological
Clinical subgroups Specific drugs
action
selective serotonin reuptake citalopram, escitalopram, fluoxetine, fluvoxamine,
inhibitors paroxetine, sertraline
other antidepressants
serotonin reuptake (including serotonin and clomipramine, desvenlafaxine, duloxetine, imipramine,
inhibitors noradrenaline reuptake venlafaxine
inhibitors)
opioid analgesics dextromethorphan, pethidine, tramadol
herbal St John's wort
irreversible phenelzine, tranylcypromine
monoamine oxidase reversible monoamine
moclobemide
inhibitors oxidase A inhibitor
other linezolid, methylene blue
appetite suppressant fenfluramine
serotonin releasing
drugs amphetamines, methylenedioxymethamphetamine
stimulants
(MDMA, ecstasy)
mood stabiliser lithium
miscellaneous
sedative amino acid tryptophan

Severity

Serotonin toxicity is best described as a spectrum (ie not ‘serotonin syndrome’), and can be roughly divided into
three groups based on impact of the symptoms and medical severity:

Mild serotonin toxicity—unlikely to interfere with the patient and often seen with therapeutic doses.
Moderate serotonin toxicity—symptomatic effects that cause distress to the patient and where symptomatic
relief is indicated.
Severe serotonin toxicity/serotonin crisis—characterised by rapidly progressive hyperthermia and muscle
rigidity. It most commonly occurs with a combination of serotonergic drugs acting at different sites. This is a
 medical emergency and progresses to multi-organ failure if not treated within hours.

Differential diagnoses

There are several rare but clinically serious conditions with possible common features to serotonin toxicity (ie
fever, headache, altered mental status, neuromuscular symptoms). Some differentiating features are outlined in
Table 17.5. The key differentiating feature for serotonin toxicity is neurological excitation, namely clonus
(inducible or spontaneous), ocular clonus and myoclonus, which can be elicited during clinical examination.

Features to assist in the diagnosis of serotonin toxicity (Table 17.5)

Clinical entity Key distinguishing feature(s)

neuromuscular clonic excitation [NB1]
serotonin toxicity autonomic effects [NB2]

history of intrathecal baclofen pump

acute baclofen withdrawal response to baclofen

absence of clonic excitation [NB1]

bowel sounds absent
anticholinergic delirium
dry skin

absence of clonic excitation [NB1]

+/– vomiting (encephalitis)
CNS infection (encephalitis, meningitis)
+/– neck stiffness (meningitis)

absence of clonic excitation [NB1]

malignant hyperthermia anaesthetic exposure

absence of clonic excitation [NB1]

neuroleptic malignant syndrome bradykinesia, ‘lead-pipe’ rigidity and other
extrapyramidal signs (ie Parkinsonian features)

usually afebrile
possible history of epilepsy
nonconvulsive seizures electroencephalographic features
dramatic response to benzodiazepines

absence of clonic excitation [NB1]

sympathomimetic toxicity prominent cardiovascular features

CNS = central nervous system

NB1: clonus (inducible or spontaneous), ocular clonus, myoclonus
NB2: hyperthermia (mild: less than 38.5 °C; severe: greater than 38.5 °C or rapidly rising), diaphoresis, flushing, mydriasis, tachycardia

Treatment
In all cases of serotonin toxicity the inciting agent(s) needs to be ceased. Severe serotonin toxicity is life-
threatening and the patient should be sedated, intubated, paralysed and cooled (see Heat-related illness key
management issues). In mild to moderate serotonin toxicity, treatment is not usually required.

Antidotal therapy has been used successfully for serotonin toxicity in anecdotal cases, but there have been no
controlled trials to confirm this. The risks and benefits need to be carefully considered, particularly for
chlorpromazine, where postural hypotension is common and may be catastrophic in dehydrated patients.

In patients with significant agitation and neuromuscular excitation, oral cyproheptadine may be used. Use:

cyproheptadine 12 mg orally, as a single dose. This can be repeated once if there is a

partial response.

For cases of serotonin toxicity due to drugs with long half-lives (eg fluoxetine) or slow-release formulations (eg
tramadol), and where clinical effects are continuing, ongoing cyproheptadine can be used:

cyproheptadine 4 to 8 mg orally, 3 times daily.

In patients with severe serotonin toxicity who are unable to take oral medications, chlorpromazine may be used as
an alternative drug for sedation. Use:

chlorpromazine 12.5 to 50 mg in 100 mL sodium chloride 0.9% by slow IV infusion over

30 to 60 minutes, with careful monitoring of blood pressure; repeat doses can be given (if
there are no adverse effects) for ongoing sedation.

Sedation with benzodiazepines may be beneficial. For drug and dosing recommendations, see Sedation.

Sympathomimetic toxidrome
Introduction
The sympathomimetic syndrome can be caused by a number of different drugs:

catecholamines (eg adrenaline, dopamine)

indirect sympathomimetics (eg pseudoephedrine)
amphetamines, amphetamine derivatives, cocaine
xanthines (eg theophylline, caffeine)
monoamine oxidase inhibitors (eg moclobemide)
noradrenaline reuptake inhibitors (eg reboxetine, duloxetine, venlafaxine).

The spectrum and severity of the sympathomimetic syndrome differs with each drug because, with the exception
of catecholamines, they also have other toxic mechanisms.

Clinical presentation
Systemic effects of sympathomimetic drugs include:

cardiovascular effects—tachycardia, hypertension, hypotension (with severe toxicity), myocardial

depression, arrhythmias
central nervous system (CNS) excitation—euphoria, agitation, delirium, seizures
neuromuscular features—hyperreflexia, tremor
autonomic effects—hyperthermia, diaphoresis, flushing, pallor, mydriasis
metabolic effects—hypokalaemia, hyperglycaemia, metabolic acidosis
gastrointestinal effects—nausea, vomiting, diarrhoea.

Complications of poisoning with catecholaminergic drugs include:

rhabdomyolysis—occasionally causing secondary kidney failure

intracranial haemorrhage—mainly reported with cocaine and amphetamines
myocardial ischaemia or infarction
aortic or carotid dissection
pulmonary oedema
multiorgan failure secondary to hyperthermia.

Treatment

Initial resuscitation with attention to airway, breathing and circulation may be required in severe cases of
sympathomimetic syndrome.

The main treatment is sedation with intravenous benzodiazepines for both the CNS excitation and the tachycardia
and hypertension. Oral benzodiazepines may be used in patients with mild to moderate agitation if they are
cooperative.

For drug and dosing recommendations, see Sedation.

Hypertension should initially be treated with titrated intravenous benzodiazepines, but if it persists despite CNS
sedation, short-acting vasodilators may be used. Use:

1 glyceryl trinitrate 10 micrograms/minute (child: 0.5 micrograms/kg/minute) IV infusion,

increasing by 10 micrograms/minute every 3 minutes (child: increasing by 0.5
micrograms/kg/minute every 3 minutes up to a maximum of 5 micrograms/kg/minute)
until systolic blood pressure is at normal level

OR

2 phentolamine 1 mg (child: 0.1 mg/kg) IV, repeat every 5 minutes as required

 OR

2 sodium nitroprusside 0.3 microgram/kg/minute IV infusion for 10 minutes, then

increasing or decreasing by 0.3 microgram/kg/minute every 5 to 10 minutes (up to a
maximum of 10 micrograms/kg/minute) to maintain the individual target blood pressure
for that patient [Note 4].

Seizures need to be rapidly controlled and intravenous benzodiazepines should be used commencing with larger
doses than those used for agitation alone. For drug and dosing recommendations, see Anticonvulsant therapy.

If the patient is hyperthermic (has a temperature greater than 39 °C) or has a rapidly rising temperature, they
should be cooled with tepid sponging and ice packs (see also Heat stroke and Heat-related illness: key
management issues). Physical restraints should be avoided as these may increase the risk of hyperthermia. If there
is no response, the patient may need to be intubated and paralysed, and cooled with more invasive techniques.

Note 4: Administration of sodium nitroprusside is complex, and product information should be consulted.

Key references
Toxidromes: anticholinergic (antimuscarinic) agents

Noyan MA, Elbi H, Aksu H. Donepezil for anticholinergic drug intoxication: a case report. Prog Neuropsychopharmacol
Biol Psychiatry 2003;27(5):885–7. [ ]

Toxidromes: methaemoglobinaemia

Shihana F, Dissanayake DM, Buckley NA, Dawson AH. A simple quantitative bedside test to determine
methemoglobin. Ann Emerg Med 2010;55(2):184–9. [ ]

Touger M, Birnbaum A, Wang J, Chou K, Pearson D, Bijur P. Performance of the RAD-57 pulse CO-oximeter
compared with standard laboratory carboxyhemoglobin measurement. Ann Emerg Med 2010;56(4):382–8. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: paediatric poisoning
Epidemiology of paediatric poisoning
Unintentional poisoning in children most commonly occurs in the 1- to 6-year-old age group with a peak at 2
years of age. For example, of the calls to the NSW Poisons Information Centre in 2010 for children 0 to 15
years of age, 88% were regarding children 0 to 6 years, with the majority (77%) regarding children 0 to 3
years of age [Note 1].

Frequency of reports to poisons information centres differs to some extent from the frequency of
presentations to hospital emergency departments. Those drugs or toxins most commonly causing paediatric
presentation to emergency departments reflect availability in the household and perceived toxicity by the
carer. Sedative medications, pesticides, ethanol and caustic agents cause relatively more admissions than
other drugs and household products.

For a list of drugs and toxins that are highly toxic in small doses in children, see Box 17.3. For a list of drugs
and toxins that are minimally toxic in children, see Box 17.4.

Poisoning and overdose are uncommon in the 6- to 10-year-old age group although this has changed with the
increasing use of medications such as dexamphetamine, methylphenidate and clonidine to treat attention
deficit hyperactivity disorder in children (see Toxicology: stimulant drugs and Toxicology: clonidine).
Overdoses in adolescents (children over 10 years of age) are usually deliberate and the medical treatment is
similar to deliberate self-poisoning in adults.

Drugs and toxins that are highly toxic in small doses in children (Box 17.3)

The following drugs and toxins can cause significant toxicity in children with the ingestion of just one
tablet or a mouthful:

antiarrhythmic drugs, including flecainide, disopyramide, and sotalol (see Toxicology: beta blockers)
amphetamines and synthetic derivatives (eg methylenedioxymethamphetamine [MDMA]) (see
Toxicology: stimulant drugs)
antipsychotic drugs
beta blockers, particularly propranolol
calcium channel blockers
camphor
chloroquine, hydroxychloroquine and quinine
clonidine
diphenoxylate+atropine (see Toxidromes: anticholinergic (antimuscarinic) agents and Opioids)
gamma-hydroxybutyrate (GHB)
methyl salicylate (see Toxicology: aspirin [acetyl salicylate])
opioids, including dextropropoxyphene
organophosphates
paraquat (see Toxicology: herbicides)
sulfonylureas (see Toxicology: hypoglycaemic drugs)
theophylline
toxic alcohols
tricyclic antidepressants.
Drugs and toxins that are minimally toxic in children (Box 17.4)

Most household products are of low toxicity but still generate calls to poisons centres and visits to
emergency departments. The following list is not exhaustive but represents common exposures:

antacids
adhesives and cyanoacrylate (super glue)
antiperspirants
bubble blowing solutions
calcium carbonate
cosmetics
crayons
ink
silica gel and other desiccants
matches and fire starters
shampoo and conditioners
creams and ointments [NB1]
nail polish and nail polish removers
glow in the dark products
paint
plastic and polystyrene foam
sunscreens
toothpaste.

NB1: except any that contain methyl salicylate

Note 1: NSW Poisons Information Centre annual report 2010. Westmead, NSW: The Children's Hospital at
Westmead; 2010.

Estimating the ingested dose in paediatric poisoning

It is important that the amount of toxin or drug that a child has ingested is estimated as accurately as possible.
But, if there is doubt it is preferable to overestimate, to allow a margin of safety. The following points should
be taken into consideration:

The remaining contents of the bottle for liquid formulations should be measured and subtracted from
the total volume.
If known, the amount used before the ingestion should also be subtracted.
For liquid ingestions, the amount spilt should not be subtracted because it is difficult to make an
accurate estimate.
For tablet ingestions, it is important to examine the mouth of the child for evidence of ingestion or
remaining tablet fragments.
Small, sugar-coated and chewable tablets are more likely to be ingested in multiples than large or
unpalatable medicines.

Box 17.3 provides a list of agents that can cause significant toxicity in children with the ingestion of just one
tablet or a mouthful.

Decontamination for poisoned children

Activated charcoal is rarely indicated in children and should only be used in potentially severe poisoning
where the benefits outweigh the risks of aspiration (see Single-dose activated charcoal).

Activated charcoal is rarely indicated in children.

Commonly ingested drugs and toxins in unintentional paediatric

poisonings
Antihistamines
Most ingestions of antihistamines are minor and may just cause sedation or vomiting. Ingestions of larger
amounts may cause central nervous system (CNS) sedation, anticholinergic effects or hyperactivity. Children
who ingest more than 4 times the paediatric daily dose, or who have excessive drowsiness (not easily
rousable) or significant hyperstimulation should be referred to hospital for observation.

For the management of significant ingestions, see Toxicology: antihistamines, less sedating and Toxicology:
antihistamines, sedating.

Anticoagulant rodenticides
Anticoagulant rodenticides can be of the older warfarin type and short acting, or can be one of the long-acting
so-called superwarfarins. Young children rarely ingest enough to cause any problems because most have a
taste deterrent in them. In the vast majority of cases no investigations or treatment is required unless
substantial amounts have been consumed (not a few pellets). Consider nonaccidental poisoning in any child
who has evidence of bleeding or elevated international normalised ratio (INR) after exposure to these agents.

For management of significant ingestions, see Toxicology: long-acting anticoagulant rodenticides and
Toxicology: warfarin.

Benzodiazepines
Benzodiazepines are commonly ingested by children and rarely cause harm. There is potential for CNS and
respiratory depression with significant ingestions. Children with ingestions of 3 times the therapeutic sedative
dose should be observed in hospital.

For the management of significant ingestions, see Toxicology: benzodiazepines.

Colchicine
Colchicine is highly toxic, but children rarely ingest toxic amounts. Any child with a history of ingestion and
gastrointestinal symptoms should be assessed in hospital (see Toxicology: colchicine).

Cough and cold preparations

Ingestion of ‘cough and cold’ preparations is common, but severe effects are rare because, in most cases, the
amount ingested is minimal. These preparations contain a mixture of ingredients, most commonly
paracetamol, phenylephrine, and an antihistamine or dextromethorphan. Management is similar to
antihistamines. See also Toxicology: paracetamol, Sympathomimetic syndrome, Toxicology: antihistamines,
less sedating and Toxicology: antihistamines, sedating.

Essential oils and vaporiser solutions

Pure eucalyptus oil, tea tree oil and aromatherapy oils are common examples of essential oils. Large
ingestions of essential oils may cause rapid-onset seizures and CNS depression. They also represent an
aspiration hazard. For management, see Toxicology: essential oils.

Vaporiser solutions have properties similar to those of essential oils, but are much less concentrated (eg 20%
to 25% concentrations are common).

Household cleaning products

The term ‘cleaning agent’ encompasses a large group of substances, many of which cause only
gastrointestinal irritant effects. To determine whether an agent is potentially toxic, it is important to provide
the product name when contacting the Poisons Information Centre (see Poisons information centres).

This group includes:

simple detergents (eg hand dishwashing detergents, toilet discs and cages, hard surface cleaners)—
cause gastrointestinal irritation if ingested
disinfectants (which typically contain 1% to 1.5% benzalkonium chloride)—cause gastrointestinal
irritation if ingested
bath and tile cleaners—typically acidic, but have low concentrations of organic acids present and are
 unlikely to be corrosive
automatic dishwashing machine detergents, laundry detergents, household bleaches, ammonia-based
cleaners—alkaline products and potentially corrosive if large quantities are ingested (see Toxicology:
caustic ingestions), but this is uncommon
drain, oven and grill cleaners—concentrated alkaline products with the potential to cause significant
tissue damage. All but the most minor exposures should be assessed and observed in hospital (see
Toxicology: caustic ingestions).

Hydrocarbons

Simple hydrocarbons such as petrol, mineral turpentine, paint thinners and kerosene represent an aspiration
hazard. All children with a history of aspiration require 6 hours of observation. Systemic toxicity (ataxia and
rapid CNS depression) is rare due to the large toxic volumes required.

Ibuprofen and other nonsteroidal anti-inflammatory drugs

Unintentional ingestion of ibuprofen or other nonsteroidal anti-inflammatory drugs (NSAIDs) rarely causes
major problems. The most commonly ingested NSAID in overdose is ibuprofen, which requires no treatment
unless more than 200 mg/kg has been ingested. Children who have ingested more than 25 mg/kg of
mefenamic acid should be observed in hospital due to the risk of seizures. See also Toxicology: nonsteroidal
anti-inflammatory drugs.

Iron

Iron is uncommonly ingested in toxic doses by children. Systemic toxicity is likely for ingestions greater than
60 mg/kg of elemental iron. Children should be assessed and observed in hospital for ingestions greater than
40 mg/kg of elemental iron (see Toxicology: iron).

Opioids

Opioids are potent depressants of respiratory drive, and always represent a large percentage of the mortality
group when statistics are compiled. Long-acting drugs such as methadone, diphenoxylate+atropine, and
extended-release morphine and oxycodone are particularly dangerous, because the onset of action may be
delayed. Children are particularly at risk of apnoea and respiratory arrest during the overnight period, while
unobserved. For management of opioid poisoning, see Toxicology: opioids.

Oral contraceptives
A single ingestion of multiple oral contraceptive tablets causes mild to moderate nausea and vomiting only,
which is usually delayed for 8 to 12 hours. Overdose of oral contraceptives has no effect on endocrine
function (unless they are ingested regularly as in their intended use).

Paracetamol
Most cases of unintentional paracetamol ingestion require no treatment unless the child has ingested more
than 200 mg/kg. For management of paracetamol poisoning, see Toxicology: paracetamol.

Perfume, cologne, aftershave and alcohol-based hand rubs

These substances can contain very high ethanol concentrations (up to 70%). Ethanol toxicity in children
causes CNS depression and hypoglycaemia, which can lead to seizures and exacerbate the CNS effects.
Children who have ingested more than 0.4 mL/kg body weight of pure (100%) ethanol should be observed
for 6 hours after ingestion and have blood glucose concentrations measured. Children with moderate to
severe poisoning are likely to require observation and supportive care. Delayed hypoglycaemia may occur.
See also Alcohol overdose.

Plants
Most plant ingestions cause minor effects because only a small amount is ingested and most are relatively
nontoxic. Many plants either taste awful or cause local stinging, preventing further ingestion. In these cases,
symptomatic measures are all that is required.

The plant and fungi kingdoms are vast. Contacting the Poisons Information Centre can help with
identification and management of plant ingestions (see Poisons information centres).

Key references
Toxicology: paediatric poisoning

NSW Poisons Information Centre annual report 2010. Westmead, NSW: The Children's Hospital at Westmead;
2010. [543 KB]. [URL]

Victorian Poisons Information Centre Annual Report 2010. Heidelberg, Vic: Austin Hospital; 2010. [URL]

Bakerink JA, Gospe SM, Jr., Dimand RJ, Eldridge MW. Multiple organ failure after ingestion of pennyroyal oil
from herbal tea in two infants. Pediatrics 1996;98(5):944–7. [ ]

Bar-Oz B, Levichek Z, Koren G. Medications that can be fatal for a toddler with one tablet or teaspoonful: a 2004
update. Paediatr Drugs 2004;6(2):123–6. [ ]

Eisen JS, Koren G, Juurlink DN, Ng VL. N-acetylcysteine for the treatment of clove oil-induced fulminant hepatic
failure. J Toxicol Clin Toxicol 2004;42(1):89–92. [ ]

Hartnoll G, Moore D, Douek D. Near fatal ingestion of oil of cloves. Arch Dis Child 1993;69(3):392–3. [ ]

Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic review. Drug Saf
2005;28(11):1029–44. [ ]

Kearney TE, Van Bebber SL, Hiatt PH, Olson KR. Protocols for pediatric poisonings from nontoxic substances:
are they valid? Pediatr Emerg Care 2006;22(4):215–21. [ ]

Lin YR, Liu TH, Liu TA, Chang YJ, Chou CC, Wu HP. Pharmaceutical poisoning exposure and outcome analysis
in children admitted to the pediatric emergency department. Pediatr Neonatol 2011;52(1):11–7. [ ]

McCoubrie D, Murray L, Daly FF, Little M. Toxicology case of the month: ingestion of two unidentified tablets by a
toddler. Emerg Med J 2006;23(9):718–20. [ ]

McKenzie LB, Ahir N, Stolz U, Nelson NG. Household cleaning product-related injuries treated in US emergency
departments in 1990-2006. Pediatrics 2010;126(3):509–16. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: alcohol (toxic)
Introduction to managing toxic alcohol poisoning
Methanol and ethylene glycol are the most common toxic alcohol poisonings. There are numerous other toxic
alcohols including diethyl glycol, triethyl glycol, isopropyl alcohol and polyethylene glycols. However, these are
much rarer poisonings and there is very limited information on their metabolism, pathophysiology and risk
assessment so a clinical toxicologist should be consulted. For the management of ethanol poisoning, see Alcohol
overdose.

In Australia, methylated spirits does not contain methanol and methanol cannot be purchased except by laboratory
or industrial suppliers. Other sources of methanol include model aeroplane or rocket fuel, and car racing fuel.
Ethylene glycol and other glycols are found in coolants, anti-freeze, brake fluids and some solvents.

Risk assessment for toxic alcohol poisoning

Toxic dose
More than 10 mL of 100% methanol can cause significant toxicity, so almost any deliberate ingestion is likely to
result in toxicity.

More than 1 mL/kg ethylene glycol is associated with significant toxicity and death.

Toxic concentration
Methanol concentrations of more than 50 mg/dL (0.5 g/L) (mmol/L x 0.032 = g/L) are associated with severe
toxicity and antidotal treatment should be undertaken.

Ethylene glycol concentrations of more than 50 mg/dL are associated with severe toxicity.

Other predictors of toxicity

Osmolar gap, anion gap and pH

In methanol poisoning, osmolar gap, anion gap and pH (acidosis) are significantly associated with death; low pH is
the most predictive of severe toxicity.

In ethylene glycol poisoning, osmolar gap and anion gap are significantly associated with death, and anion gap is
the most predictive of severe toxicity; pH is a less reliable predictor of toxicity than in methanol poisoning.

Oxalate crystals

Oxalate crystals in the urine are indicative of ethylene glycol ingestion.

Creatinine concentration

An elevated creatinine is associated with a worse prognosis and decreases the elimination of toxic alcohols.
However, a falsely elevated creatinine concentration can occur in methanol poisoning from model rocket or
aeroplane fuel because of the presence of nitromethane, and is not indicative of kidney impairment.

Co-ingestion of ethanol

The co-ingestion of ethanol with methanol or ethylene glycol is protective, and may occur when patients ingest a
mixture of ethanol and methanol (eg traditional methylated spirits).

Clinical presentation
Systemic effects include:

CNS effects
 –
CNS depression—initially this resembles alcohol intoxication, but coma and seizures may occur later
due to metabolic acidosis
–
retinal toxicity (methanol only)—blurred vision, decreased visual acuity progressing to blindness
gastrointestinal effects—nausea, vomiting, abdominal pain
cardiovascular effects—hypotension secondary to acidosis
metabolic effects—metabolic acidosis (normal anion gap), hyperkalaemia
kidney effects—acute kidney failure, oxalate crystals in the urine (ethylene glycol only).

Key investigations in toxic alcohol poisoning

The key investigations in toxic alcohol poisoning include:

Electrolytes, creatinine—monitor kidney function; calcium concentration is important in ethylene glycol

poisoning.
Methanol and ethylene glycol concentrations (if available)—measure an initial concentration in all patients
and toxic serial concentrations until less than 20 mg/dL (0.2 g/L).
Ethanol concentrations—measure before ethanol is administered as an antidote.
Osmolar gap—although a difference between calculated osmolarity and measured osmolarity always occurs
with methanol poisoning, it is unlikely to influence the treatment of the patient. Due to the inherent errors in
the calculation, the presence of ethanol, and individual variability, a normal osmolar gap cannot definitively
exclude poisoning.

Treatment of toxic alcohol poisoning

Airway and breathing

CNS sedation is common and may require airway support and ventilation. When ethanol is administered as an
antidote, intubation may be required to facilitate safe definitive therapy.

Circulation

Patients require intravenous fluid replacement due to dehydration (see Resuscitation: circulation).

Decontamination
There is no role for activated charcoal due to the rapid absorption of toxic alcohols.

Enhanced elimination
Once hepatic metabolism of methanol or ethylene glycol by alcohol dehydrogenase has been inhibited by antidotal
therapy (ethanol or fomepizole), the elimination half-life of the parent alcohols increases. For methanol the half-
life increases to about 50 hours and for ethylene glycol up to 20 hours.

Indications for haemodialysis (or high-flux continuous veno-venous haemodialysis):

methanol or ethylene glycol concentration greater than 50 mg/dL (0.5 g/L) (if fomepizole is not available)
history of a large ingestion
metabolic acidosis
kidney impairment or failure.

Haemodialysis should be continued until the toxic alcohol concentration is less than 20 mg/dL (0.2 g/L), and the
acidosis has resolved. Haemodialysis also removes ethanol, so haemodialysis may need to be increased based on
ethanol concentrations. In some settings it is possible to treat ethylene glycol ingestions without dialysis—but
large ingestions require protracted antidote therapy, which can be problematic if ethanol is being used.

Specific pharmacological therapies

Antidotal therapy

Antidotal therapy aims to inhibit alcohol dehydrogenase and prevent the metabolism of methanol and ethylene
glycol to acid metabolites, which cause metabolic acidosis and are responsible for most other toxic effects.
Whether ethanol or fomepizole is used depends on availability, cost and the risks associated with administering
ethanol. Seek advice of a clinical toxicologist. There is no evidence that ethanol is less effective than fomepizole,
and ethanol is readily available in Australia compared to fomepizole. Use:
 1 ethanol 10% 6 mL/kg IV or via nasogastric tube as a loading dose, followed by 50 to 100
mL/hour IV or via nasogastric tube as a continuous infusion to maintain a plasma ethanol
concentration between 0.1 to 0.2 g/dL (measure regularly)

OR

2 fomepizole (4-methylpyrazole) 15 mg/kg IV as a loading dose, followed by 10 mg/kg

twice daily.

Measure the plasma ethanol concentration before administering the loading dose of ethanol or fomepizole. In
patients with ethanol intoxication, the loading dose can be omitted. Antidotal therapy should be continued until the
methanol or ethylene glycol concentration is less than 20 mg/dL (0.2 g/L).

If ethanol 10% is not available then white spirits (eg vodka), or sweet formulations (eg Kahlua, Baileys) in
children, can be administered via nasogastric tube using the plasma ethanol concentration to determine the rate of
administration. Use:

ethanol 0.6 g/kg via nasogastric tube as a loading dose, followed by 5 to 10 g/hour via
nasogastric tube as a continuous infusion to maintain a plasma ethanol concentration
between 0.1 to 0.2 g/dL.

The following formula can be used to calculate the volume of liquid required based on its ethanol concentration:

For example, if the patient weighs 50 kg, the loading dose of ethanol is 30 g (0.6 g/kg x 50 kg). If 37% vodka is
used then the loading dose is:

Nasogastric administration of ethanol is just as effective as intravenous administration, and may more effectively
deliver ethanol to the liver.

Other

In methanol poisoning, folate supplementation is recommended because it is a cofactor in the metabolism of

formic acid to nontoxic metabolites. Use:

1 calcium folinate 50 mg IV, 4 times daily for 2 days

OR

1 folic acid 50 mg IV, 4 times daily for 2 days.

In ethylene glycol poisoning, pyridoxine or thiamine are recommended because they are cofactors in the
metabolism of glyoxylic acid to nontoxic metabolites. Use:

1 pyridoxine 50 mg IV, 4 times daily for 2 days [Note 1]

OR

1 thiamine 100 mg IV, 4 times daily for 2 days.

Note 1: Intravenous pyridoxine is not registered for use in Australia but is available via the Special Access
Scheme.

Observation and patient disposition after toxic alcohol poisoning

Criteria for discharge: Patients with suspected toxic alcohol ingestions can only be discharged once the methanol
or ethylene glycol concentration is less than 20 mg/dL (0.2 g/L).

Criteria for admission: All suspected methanol or ethylene glycol poisonings should be admitted to a high-
dependency or intensive care unit with access to dialysis or high-flux continuous veno-venous haemodialysis.

Key references
Toxicology: alcohol (toxic)

Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice
guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002;40(4):415–46. [ ]

Coulter CV, Farquhar SE, McSherry CM, Isbister GK, Duffull SB. Methanol and ethylene glycol acute poisonings:
predictors of mortality. Clin Toxicol (Phila) 2011. [ ]

Coulter CV, Isbister GK, Duffull SB. The pharmacokinetics of methanol in the presence of ethanol: a case study. Clin
Pharmacokinet 2011;50(4):245–51. [ ]

Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings.
Intensive Care Med 2005;31(2):189–95. [ ]

Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: angiotensin converting enzyme
inhibitors and angiotensin II receptor blockers
Risk assessment for ACEI or ARB poisoning
The severity of toxicity is dependent not only on the dose ingested, but also whether the patient has been
taking this group of drugs previously. Angiotensin converting enzyme inhibitor (ACEI) and angiotensin II
receptor blocker (ARB) overdoses usually result in mild hypotension only.

In children, ingestion of more than twice the adult daily therapeutic dose may cause symptoms.

Clinical presentation of ACEI or ARB poisoning

Overdoses of ACEIs and ARBs rarely cause major noncardiovascular effects.

The presenting cardiovascular symptom is hypotension due to peripheral vasodilatation.

Treatment of ACEI or ARB poisoning

There is no specific treatment or antidote.

Hypotension will respond to intravenous fluids (see Resuscitation: circulation).

Decontamination is not recommended.

Observation and patient disposition after ACEI or ARB poisoning

Criteria for discharge: If there are no effects 2 hours after ingestion, no treatment is required. Beware of
other cardiac medications that may have been ingested at the same time (eg beta blockers).

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: antiepileptic drugs
Introduction to managing antiepileptic drug poisoning
Carbamazepine, sodium valproate and barbiturate overdoses are well described, and associated with serious
toxicity. These drugs are therefore addressed individually (see Toxicology: carbamazepine, Toxicology:
sodium valproate and Toxicology: barbiturates).

Overdoses of other antiepileptic drugs, including benzodiazepines, gabapentin, lamotrigine, levetiracetam,

oxcarbazepine, phenytoin, and pregabalin, rarely cause major effects.

Tiagabine (seizures, dystonia) and topiramate (acidosis) may have more serious adverse effects, but clinical
data to date are limited, so specific advice is not provided. There is little information on overdose with
ethosuximide, lacosamide, sulthiame, vigabatrin and zonisamide.

Risk assessment for poisoning caused by antiepileptic drugs

Toxic dose
The doses predictably causing morbidity or potentially fatal outcomes are not well defined for most of these
drugs. Medical observation is recommended for antiepileptic drug overdoses as listed in Table 17.6.

Antiepileptic drug overdoses for which medical observation is recommended (Table 17.6)
[NB1]

Drug Dose
gabapentin more than 500 mg/kg
lamotrigine more than 40 mg/kg
levetiracetam more than 60 mg/kg
oxcarbazepine more than 30 mg/kg
phenytoin [NB2] more than 20 mg/kg
pregabalin more than 50 mg/kg
tiagabine more than 1 mg/kg
topiramate more than 14 mg/kg
NB1: Doses predictably causing morbidity or potentially fatal outcomes are not well defined for most of these drugs.
NB2: Metabolism of phenytoin is saturable, and thus effects can be very prolonged after large overdoses.

Clinical presentation
Central nervous system (CNS) toxicity is the major effect of most antiepileptic drugs in overdose.

Systemic effects include:

CNS effects—horizontal and vertical nystagmus, ataxia, dysarthria, increasing CNS depression with
severity, and respiratory depression with severe poisoning; seizures are rare
gastrointestinal effects—nausea, vomiting
cardiovascular effects—mild hypotension, tachycardia, bradycardia.

Key investigations in poisoning caused by antiepileptic drugs

The key investigations in antiepileptic overdose include:

Antiepileptic drug concentrations—these confirm overdose and may help indicate when the drugs can
be restarted. In phenytoin overdose, plotting serial concentrations may give an indication of the time
until recovery is expected.
ECG—drugs with sodium channel blocking actions (eg phenytoin, lamotrigine) may cause QRS
 widening although arrhythmias are very rare.

Treatment of poisoning caused by antiepileptic drugs

Airway and breathing
In severe poisoning, patients may require airway support and ventilation due to CNS depression.

Circulation
Intravenous fluid replacement may be required for patients with persistent vomiting (see Resuscitation:
circulation). Cardiac monitoring is not generally required for patients with oral overdoses.

Decontamination
Activated charcoal should be administered to cooperative patients or those with a protected airway if the
patient presents within 1 hour of the estimated time of ingestion and a large overdose has been ingested (see
Single-dose activated charcoal).

Activated charcoal may be of benefit longer than 1 hour after ingestion and should be considered when
massive amounts of phenytoin have been ingested.

Enhanced elimination
Multiple-dose activated charcoal may be considered in phenytoin poisoning because it increases clearance
(see Multiple-dose activated charcoal). Although multiple-dose activated charcoal may reduce the duration of
CNS effects and length of hospital stay, there is no evidence that it prevents life-threatening toxicity.

Observation and patient disposition after antiepileptic drug

poisoning
Criteria for admission: All patients with a significant poisoning (see Table 17.6) with an antiepileptic drug
should be observed initially for 6 hours.

Key references
Toxicology: antiepileptic drugs

TOXINZ: poisons information [database]. Dunedin, NZ: National Poisons Centre. (Subscriber access). [URL]

Bodmer M, Monte AA, Kokko J, Yin S. Safety of non-therapeutic levetiracetam ingestions: a poison center based
study. Pharmacoepidemiol Drug Saf 2011;20(4):366–9. [ ]

Craig S. Phenytoin poisoning. Neurocrit Care 2005;3(2):161–70. [ ]

Klein-Schwartz W, Shepherd JG, Gorman S, Dahl B. Characterization of gabapentin overdose using a poison
center case series. J Toxicol Clin Toxicol 2003;41(1):11–5. [ ]

Lofton AL, Klein-Schwartz W. Evaluation of toxicity of topiramate exposures reported to poison centers. Hum Exp
Toxicol 2005;24(11):591–5. [ ]

Spiller HA, Winter ML, Ryan M, Krenzelok EP, Anderson DL, Thompson M, et al. Retrospective evaluation of
tiagabine overdose. Clin Toxicol (Phila) 2005;43(7):855–9. [ ]

Wisniewski M, Lukasik-Glebocka M, Anand JS. Acute topiramate overdose: clinical manifestations. Clin Toxicol
(Phila) 2009;47(4):317–20. [ ]

Wood DM, Berry DJ, Glover G, Eastwood J, Dargan PI. Significant pregabalin toxicity managed with supportive
care alone. J Med Toxicol 2010;6(4):435–7. [ ]
Published July 2012. Amended October 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: antihistamines, less sedating
Management of poisoning caused by less-sedating antihistamines
Cetirizine, desloratadine, fexofenadine, levocetirizine and loratadine are less-sedating antihistamines
available in Australia.

The key feature of toxicity in overdose of less-sedating antihistamines is prolongation of the QT interval with
associated risk of torsades de pointes. For assessing the risk of torsades de pointes in drug-induced QT
prolongation, see QT prolongation and for management, see QT prolongation and torsades de pointes.

Most patients only develop minor nausea and sedation when less-sedating antihistamines are taken in
overdose. In a minority of cases patients may develop an anticholinergic delirium requiring treatment with
titrated doses of benzodiazepines (see Sedation).

Some over-the-counter cough and cold preparations with antihistamines also contain sympathomimetics (eg
pseudoephedrine), opioids (eg codeine, dextromethorphan) and paracetamol. In these cases, the co-ingestant
is the more important determinant of toxicity.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: antihistamines, sedating
Availability
Brompheniramine, cyproheptadine, diphenhydramine, dexchlorpheniramine, doxylamine, pheniramine,
promethazine and trimeprazine are sedating antihistamines that are available in Australia. Dimenhydrinate is
available in combination with hyoscine and caffeine for travel sickness.

Risk assessment for poisoning caused by sedating antihistamines

Anticholinergic toxicity and sedation occur in a predictable dose-dependent manner following overdose.
Most patients require only supportive care, but large overdoses may lead to orthostatic hypotension, sedation
requiring airway support, anticholinergic delirium, and in the case of diphenhydramine and dimenhydrinate,
cardiac conduction abnormalities.

Toxic dose
The toxic dose is not clear for many antihistamines and tolerance seems to develop in some patients. Those
who have ingested more than three times the regular dose of sedating antihistamines warrant medical
observation.

Doses less than 300 mg diphenhydramine (7.5 mg/kg in children) are unlikely to cause major effects;
amounts more than 1 g are associated with severe effects.

Doses less than 500 mg dimenhydrinate (12.5 mg/kg in children) are unlikely to cause major effects. Note
that 50 mg dimenhydrinate is equivalent to 29 mg diphenhydramine. Dimenhydrinate must first dissociate
into diphenhydramine, so its onset of effect is slower than that of diphenhydramine.

The probability of delirium developing following promethazine overdose increases with the dose taken (31%
following 250 mg, 42% following 500 mg and 55% following 1000 mg) [Note 1].

Note 1: Page CB, Duffull SB, Whyte IM, Isbister GK. Promethazine overdose: clinical effects, predicting
delirium and the effect of charcoal. QJM 2009;102(2):123-31. [URL]

Other predictors of toxicity

The type of antihistamine also determines toxicity (see Table 17.7).

Some over-the-counter cough and cold preparations with antihistamines also contain sympathomimetics (eg
pseudoephedrine), opioids (eg codeine, dextromethorphan) and paracetamol. In these cases, the co-ingestant
may be the more important determinant of toxicity.

Clinical presentation
The clinical effects of sedating antihistamines are similar—mainly dose-dependent sedation, anticholinergic
effects and mild hypotension, but there are some important differences (see Table 17.7). Sedation occurs early
and usually masks any anticholinergic delirium. However, sedation wears off after about 12 to 24 hours and
anticholinergic delirium may be the major clinical effect and management issue after this.

Systemic effects include:

CNS effects—sedation, anticholinergic effects (including delirium), seizures (rare)

cardiovascular effects
–
common—tachycardia, orthostatic hypotension
–
rare—arrhythmias (sodium channel effects), myocardial depression
other effects—rhabdomyolysis, urinary retention.
Major clinical toxicity of sedating antihistamines (Table 17.7)

Pharmacological group Antihistamine Cardiac effects Other effects

phenothiazines promethazine tachycardia delirium
trimeprazine tachycardia
tachycardia
ethanolamines doxylamine rate-dependent bundle rhabdomyolysis
branch block
sodium channel effects
diphenhydramine
QT prolongation
seizures
dimenhydrinate
torsades de pointes
reported
alkylamines pheniramine tachycardia seizures (30%)
dexchlorpheniramine
tachycardia
brompheniramine
others cyproheptadine not reported less sedating

Key investigations for poisoning caused by sedating antihistamines

The key investigations in sedating antihistamine overdose include:

ECG— QRS widening occurs in massive overdoses of some drugs.

Paracetamol concentration—measure if a combination cough and cold preparation has been ingested.

Treatment of poisoning caused by sedating antihistamines

Airway and breathing

Airway support and mechanical ventilation are only required in large overdoses of sedating antihistamine or
with co-ingestion of other sedating drugs where there is significant CNS depression.

Circulation
Intravenous fluids should be administered to all patients with hypotension (see Resuscitation: circulation).
Patients who remain hypotensive despite fluid resuscitation require treatment with an alpha-receptor agonist,
such as noradrenaline, and admission to a critical care unit (see Inotropic support).

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening. Arrhythmias
associated with QRS widening should be treated (see QRS widening and sodium channel blockade).

Decontamination
There is little role for activated charcoal because of the rapid onset of sedation and most effects can be
managed easily with supportive care. For massive ingestions of sedating antihistamines that can cause cardiac
toxicity or rhabdomyolysis, activated charcoal may be considered (see Single-dose activated charcoal).

Specific pharmacological therapies

Antidotal therapy

After the sedative effects of the antihistamine have worn off, physostigmine may be beneficial to treat
anticholinergic delirium (see Anticholinergic (antimuscarinic) agents).

Sedation
Paradoxically, patients who have overdosed with sedating antihistamines may require sedation 12 to 24 hours
after ingestion to manage delirium once antihistaminergic sedation has worn off. However, caution should be
exercised before administering sedative drugs, particularly in patients recently extubated or who remain
partially sedated. It should only be done in a critical care area.

For drug and dosing recommendations, see Sedation.

Treatment of urinary retention

Urinary retention should be treated by insertion of a urethral catheter. Untreated urinary retention may
exacerbate anticholinergic-related agitation.

Observation and patient disposition after poisoning with sedating

antihistamines
Criteria for discharge: Patients who remain asymptomatic and have a normal ECG 6 hours after ingestion
are unlikely to become toxic and can be medically discharged.

Criteria for admission: Any patient with significant sedation, or cardiovascular dysfunction should be
admitted for supportive care and monitoring as appropriate.

Key references
Toxicology: antihistamines, sedating

Page CB, Duffull SB, Whyte IM, Isbister GK. Promethazine overdose: clinical effects, predicting delirium and the
effect of charcoal. QJM 2009;102(2):123–31. [ ]

Ten Eick AP, Blumer JL, Reed MD. Safety of antihistamines in children. Drug Saf 2001;24(2):119–47. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: antipsychotics
Introduction to poisoning caused by antipsychotic drugs
Antipsychotics include amisulpride, aripiprazole, chlorpromazine, clozapine, haloperidol, olanzapine,
paliperidone, pericyazine, quetiapine, risperidone, trifluoperazine [Note 1] and ziprasidone.

Common clinical effects of antipsychotics following overdose are sedation, respiratory depression,
tachycardia and mild anticholinergic effects. Extrapyramidal side-effects occur commonly with some drugs
(eg haloperidol, risperidone). In larger doses some antipsychotics (eg chlorpromazine) produce hypotension
via alpha-receptor blockade. Amisulpride and ziprasidone are associated with QT prolongation and torsades
de pointes.

Management of antipsychotic drug toxicity is primarily supportive.

Note 1: Trifluoperazine was discontinued in Australia in 2018.

Risk assessment for poisoning caused by antipsychotic drugs

Toxic dose
Exposures to antipsychotics in treatment-naive patients may produce significant effects, particularly sedation
and hypotension. In children, a single adult therapeutic dose of an antipsychotic drug is enough to cause
moderate toxicity, and warrants hospital assessment. For toxic doses of antipsychotics, see Table 17.8.

Toxic doses of antipsychotics (Table 17.8)

Antipsychotic Toxic dose

Ingestion of more than 4 g amisulpride has been associated with torsades de
amisulpride
pointes, and more than 8 g with significant sedation and hypotension.
The lowest reported ingestion causing significant (more than mild sedation)
aripiprazole toxicity requiring hospital assessment in a child under 12 years of age is 15 mg,
and over 12 years of age is 50 mg.
Sedation is possible following any ingestion in patients who are naive to
chlorpromazine.
chlorpromazine
Significant toxicity is likely after ingesting more than 15 mg/kg chlorpromazine
in children.
Deliberate overdose is uncommon because the use of clozapine is so restricted.
Most clinically significant exposures are due to therapeutic doses in treatment
naive patients.
clozapine Ingestion of more than 2.5 mg/kg clozapine is associated with significant toxicity
in children. The lowest reported ingestion causing significant (more than mild
sedation) toxicity requiring hospital assessment in a child under 12 years of age is
50 mg, and over 12 years of age is 62.5 mg.
Ingestion of more than 0.15 mg/kg haloperidol may produce toxicity in children.
haloperidol
Ventricular arrhythmias have been reported with ingestions of more than 200 mg
haloperidol in adults.
Ingestion of more than 0.5 mg/kg olanzapine may produce toxicity in children.
The lowest reported ingestion causing significant (more than mild sedation)
olanzapine
toxicity requiring hospital assessment in a child under 12 years of age is 10 mg,
and over 12 years of age is 25 mg.
Little is known about the toxic dose.
pericyazine Children should be assessed in hospital following ingestion of any
supratherapeutic amount.
 Toxicity is likely following ingestion of more than 10 mg/kg quetiapine in adults.
quetiapine
Ingestions of more than 3 g quetiapine have been associated with severe toxicity.
Ingestions of more than 30 mg paliperidone in adults and more than 24 mg
paliperidone
paliperidone in children have been associated with severe toxicity.
Relatively benign except in very large ingestions (poorly defined, but at least 1
mg/kg risperidone). Extrapyramidal adverse effects are more frequent.
risperidone The lowest reported ingestion causing significant (more than mild sedation)
toxicity requiring hospital assessment in a child under 12 years of age is 1 mg,
and over 12 years of age is 5 mg.
trifluoperazine [NB1] There is little published information regarding the toxic dose.
The lowest reported ingestion causing significant (more than mild sedation)
ziprasidone toxicity requiring hospital assessment in a child under 12 years of age is 80 mg,
and over 12 years of age is 100 mg.
NB1: Trifluoperazine was discontinued in Australia in 2018.

Other predictors of toxicity

Clinical effects appear to be worse in patients not taking antipsychotics before overdose—therefore,
therapeutic doses may cause toxicity in antipsychotic-naive persons.

Clinical presentation
Sedation and sinus tachycardia occur in a dose predictable manner following ingestion, and typically manifest
within 4 hours.

Systemic effects include:

CNS effects—progressively decreasing level of consciousness, respiratory depression, seizures with

clozapine and massive ingestions (eg olanzapine and quetiapine), delirium (more common with
olanzapine and may occur simultaneously with sedation), miosis
extrapyramidal effects—generally uncommon, but appear to be more common with haloperidol and
risperidone, and in children
cardiovascular effects—tachycardia, hypotension (peripheral vasodilatation from alpha-receptor
blockade) is more common with chlorpromazine and clozapine; cardiac arrhythmias are very rare
–
amisulpride may display significant cardiovascular effects following overdose. QT prolongation
may be delayed for up to 16 hours following overdose, or may occur in the absence of other signs
of toxicity. Bradycardia almost always occurs in severe toxicity. QT prolongation has been
reported with ziprasidone.

The major effects of the benzodiazepine-related antipsychotics (eg clozapine, olanzapine, quetiapine) are CNS
depression and tachycardia.

The therapeutic use of all antipsychotic medicines has been associated with the development of neuroleptic
malignant syndrome (see Neuroleptic malignant syndrome). Although rare, it is important to recognise this
syndrome, as early aggressive supportive care is the key to good outcomes.

Key investigations for poisoning caused by antipsychotic drugs

The key investigations in antipsychotic overdose include:

ECG— QT prolongation occurs more commonly with amisulpride overdose.

Electrolytes—check calcium, magnesium and potassium because deficiencies worsen QT prolongation
and increase the risk of torsades de pointes.

Treatment of poisoning caused by antipsychotic drugs

Airway and breathing
Airway support and mechanical ventilation may be required with large ingestions causing coma.

Circulation

Hypotension responds to intravenous fluid therapy (see Resuscitation: circulation).

In the case of quetiapine induced hypotension, treatment with adrenaline has been associated with profound
hypotension. Hypotension that is unresponsive to intravenous fluid therapy should be treated using
noradrenaline (see Inotropic support).

QT prolongation and torsades de pointes

Serial 12-lead ECGs and continuous ECG monitoring should be done for 16 hours after ingestion of more
than 4 g amisulpride, and for 12 hours following ingestion of ziprasidone. For details on the management of
QT prolongation and torsades de pointes, see QT prolongation and torsades de pointes.

Decontamination

If the patient presents within 1 hour of a large ingestion of an antipsychotic drug likely to produce significant
toxicity (see Toxic dose), decontamination with activated charcoal may be useful (see Single-dose activated
charcoal).

Specific pharmacological therapies

Treatment of delirium

The treatment of delirium in antipsychotic overdose is difficult. Patients are often drowsy, but when roused
become agitated and aggressive. Initial treatment should be:

limiting contact, nursing in quiet darkened room

gently and verbally attempting to waken the patient
applying physical restraint if needed for patient safety.

The use of sedation is likely to result in profound CNS depression and require airway support and mechanical
ventilation. However, this may be the only option in some patients. For drug and dosing recommendations,
see Sedation.

Extrapyramidal effects

Dystonic reactions should be treated with anticholinergics. Use:

benztropine 0.5 to 2 mg (child: 0.02 mg/kg) IV, titrated to response.

The intramuscular route can be used if intravenous access is not possible.

Patients can be discharged on 24 to 48 hours of oral therapy. Use:

benztropine 2 mg (child 0.02 mg/kg) orally, 3 times daily as necessary.

Observation and patient disposition after antipsychotic drug

poisoning
Criteria for discharge: Patients who remain asymptomatic and have a normal ECG may be discharged
following a period of observation:

6 hours after ingestion—amisulpride (ingestions of less than 4 g reported), aripiprazole,

chlorpromazine, clozapine, haloperidol, olanzapine, pericyazine, quetiapine, risperidone and
trifluoperazine [Note 2]
12 hours after ingestion (if QT interval is normal)—amisulpride (ingestions of more than 4 g reported)
and ziprasidone; patients with a QT interval abnormality should be observed until it has normalised as
plotted against the QT nomogram (see QT prolongation).
Criteria for admission: Patients who need ventilatory support or who have significant CNS sedation,
respiratory depression or hypotension require admission to a critical care unit.

Note 2: Trifluoperazine was discontinued in Australia in 2018.

Key references
Toxicology: antipsychotics

Isbister GK, Murray L, John S, Hackett LP, Haider T, O'Mullane P, et al. Amisulpride deliberate self-poisoning
causing severe cardiac toxicity including QT prolongation and torsades de pointes. Med J Aust 2006;184(7):354–
6. [ ]

Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. J Toxicol Clin Toxicol 2001;39(1):1–
14. [ ]

Cobaugh DJ, Erdman AR, Booze LL, Scharman EJ, Christianson G, Manoguerra AS, et al. Atypical antipsychotic
medication poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol
(Phila) 2007;45(8):918–42. [ ]

Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline infusions in massive
quetiapine overdose. Crit Care Resusc 2008;10(4):320–2. [ ]

Henderson RA, Lane S, Henry JA. Life-threatening ventricular arrhythmia (torsades de pointes) after haloperidol
overdose. Hum Exp Toxicol 1991;10(1):59–62. [ ]

Isbister GK, Balit CR, Macleod D, Duffull SB. Amisulpride overdose is frequently associated with QT prolongation
and torsades de pointes. J Clin Psychopharmacol 2010;30(4):391–5. [ ]

Isbister GK, Duffull SB. Quetiapine overdose: predicting intubation, duration of ventilation, cardiac monitoring and
the effect of activated charcoal. Int Clin Psychopharmacol 2009;24(4):174–80. [ ]

Klein-Schwartz W, Lofton AL, Benson BE, Spiller HA, Crouch BI. Prospective observational multi-poison center
study of ziprasidone exposures. Clin Toxicol (Phila) 2007;45(7):782–6. [ ]

Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects but not cardiac toxicity. J
Clin Psychopharmacol 2010;30(4):387–90. [ ]

Published July 2012. Amended December 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: arsenic
Risk assessment for arsenic poisoning
Acute arsenic poisoning results in severe toxicity—consult a clinical toxicologist early.

Acute arsenic poisoning may result from inhalation or ingestion, and leads to severe toxicity. Advice from a
clinical toxicologist should therefore be sought early.

Toxic dose
The minimum lethal dose is around 1 to 3 mg/kg inorganic arsenic. However, there are many arsenic-containing
poisons, and they vary widely in their toxic dose.

Toxic concentration
Blood and urine arsenic concentrations are rarely available in a timely manner, and most treatment is given
empirically. In acute arsenic poisoning, the 24-hour urine concentration is usually above 1000 micrograms/L.
Recent ingestion of fish containing relatively nontoxic organic arsenic may lead to a falsely elevated arsenic
concentration, because routine assays do not differentiate between forms of arsenic.

Other predictors of toxicity

Toxicity depends on the form of arsenic exposure (see Table 17.9).

Toxicity of arsenic exposure (Table 17.9)

Route of exposure Form of arsenic Toxicity

inhaled arsine gas highly toxic, causes severe haemolysis
highly toxic; trivalent (+3) more prevalent and more toxic
inorganic arsenic oxides and than pentavalent (+5)
ingested
salts
found in pesticides (termites or ants)
relatively low toxicity
organic arsenic
concentrated in seafood

Clinical presentation

Acute arsenic poisoning

Immediate effects of acute overdose include severe nausea, vomiting, diarrhoea, abdominal pain, QT prolongation,
arrhythmias, cardiac failure or collapse, and multiorgan failure.

Delayed effects in survivors occur days to weeks after exposure, and include bone marrow suppression, hepatitis,
sensori-motor peripheral neuropathy, and pigmented skin lesions.

Chronic arsenic poisoning

Chronic arsenic poisoning can cause a range of peripheral and central nervous system effects as well as cardiac
and skin problems.

Key investigations in arsenic poisoning

The key investigations in arsenic poisoning include:

ECG— QT prolongation can occur; serial ECGs should be done until the QT normalises or 24 hours have
passed.
 Full blood count, creatinine, electrolytes, liver biochemistry.
Urine arsenic concentration—24-hour urine collection.
Chest and abdominal X-rays—perform when arsenic has been ingested.

Treatment of arsenic poisoning

Airway and breathing
Intubation and mechanical ventilation may be required in patients with multiorgan failure.

Circulation
Most patients need aggressive fluid replacement due to large gastrointestinal losses, which may be compounded by
myocardial depression in severe poisoning (see Resuscitation: circulation).

QT prolongation and torsades de pointes

Continuous ECG monitoring and regular 12-lead ECGs are required to assess the QT interval (see QT prolongation
and torsades de pointes).

Decontamination

There is no role for activated charcoal.

Specific pharmacological therapies

A clinical toxicologist should be consulted early.

Chelation therapy

Chelation is the mainstay of treatment in acute arsenic poisoning. Use:

succimer (dimercaptosuccinic acid) 30 mg/kg/day orally, in 3 divided doses for 5 days,

followed by 20 mg/kg/day in 2 divided doses for a further 14 days or until urine arsenic
concentration is less than 50 micrograms/L in a 24-hour urine collection [Note 1].

If succimer is not immediately available, commence treatment with:

sodium calcium edetate (calcium EDTA) 50 to 75 mg/kg in 500 mL by slow IV infusion

over 24 hours
EITHER ALONE, OR IN ADDITION TO EITHER:
1 penicillamine 25 to 35 mg/kg/day orally on an empty stomach, in 2 or 3 divided doses
[Note 2]

OR

1 dimercaprol 3 mg/kg IM, 4-hourly for 48 hours, then reduce to twice daily for up to 5 to 7
days [Note 3].

Treatment should be switched to succimer as soon as it becomes available.

Note 1: Succimer (dimercaptosuccinic acid) is not registered for use in Australia but is available via the Special
Access Scheme.

Note 2: The Australian approved name (AAN) for D-penicillamine is penicillamine.

Note 3: Dimercaprol is not registered for use in Australia but is available via the Special Access Scheme.

Observation and patient disposition after arsenic poisoning

Criteria for admission: All poisonings with arsenic should be admitted for assessment.
Key references
Toxicology: arsenic

Flora SJ, Pachauri V. Chelation in metal intoxication. Int J Environ Res Public Health 2010;7(7):2745–88. [ ]

Franzblau A, Lilis R. Acute arsenic intoxication from environmental arsenic exposure. Arch Environ Health
1989;44(6):385–90. [ ]

Gibb H, Haver C, Gaylor D, Ramasamy S, Lee JS, Lobdell D, et al. Utility of recent studies to assess the National
Research Council 2001 estimates of cancer risk from ingested arsenic. Environ Health Perspect 2011;119(3):284–90. [
]

Guha Mazumder DN. Chronic arsenic toxicity: clinical features, epidemiology, and treatment: experience in West
Bengal. J Environ Sci Health A Tox Hazard Subst Environ Eng 2003;38(1):141–63. [ ]

Isbister GK, Dawson AH, Whyte IM. Arsenic trioxide poisoning: a description of two acute overdoses. Hum Exp Toxicol
2004;23(7):359–64. [ ]

Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, et al. Arsenic: toxicity, oxidative stress and
human disease. J Appl Toxicol 2011;31(2):95–107. [ ]

Kosnett MJ. Chelation for heavy metals (arsenic, lead, and mercury): protective or perilous? Clin Pharmacol Ther
2010;88(3):412–5. [ ]

Munday SW, Ford M. Arsenic. In: Nelson LS, Goldfrank LR, editors. Goldfrank's toxicologic emergencies. 9th ed. New
York: McGraw-Hill Medical Pub. Division; 2011.

Vahidnia A, van der Voet GB, de Wolff FA. Arsenic neurotoxicity: a review. Hum Exp Toxicol 2007;26(10):823–32. [
]

WHO Task Group on Environmental Health Criteria for Arsenic and Arsenic Compounds. Environmental health criteria
224. Arsenic and arsenic compounds. 2nd ed. Geneva: World Health Organization; 2001. [URL]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: aspirin (acetyl salicylate)
Risk assessment for aspirin poisoning
Toxic dose
Chronic ingestion of more than 100 mg/kg aspirin has been associated with toxicity.

Oil of wintergreen used in topical preparations contains methyl salicylate and a single teaspoon contains up to 7 g
of salicylate. Some teething gels (eg Bongela, SM-33) contain salicylates and excessive doses or prolonged use
can be harmful in children.

The relationship between the dose ingested acutely and toxicity is outlined in Table 17.10.

Relationship between acute dose of aspirin ingested and toxicity (Table 17.10)

Dose of aspirin (acute ingestion) Clinical effects and severity

less than 150 mg/kg minor toxicity
mild to moderate toxicity: salicylism (ie nausea, vomiting,
150 to 300 mg/kg
tinnitus, hyperventilation)
300 to 500 mg/kg severe toxicity: metabolic acidosis, coma, seizures
more than 500 mg/kg potentially fatal

Toxic concentration

Salicylate concentrations greater than 2.2 mmol/L (300 mg/L) are indicative of toxicity. However, there is poor
correlation between drug concentration and clinical outcome. Nomograms are of no value.

Clinical presentation

Onset of the following clinical effects occurs over 6 to 12 hours:

gastrointestinal effects—nausea, vomiting

CNS effects—tinnitus, hearing impairment, vertigo, agitation; coma and seizures (with severe toxicity)
metabolic effects—primary respiratory alkalosis (early), metabolic acidosis (severe), hypokalaemia,
hypoglycaemia (sometimes hyperglycaemia)
other effects—hypothermia.

Chronic salicylate toxicity is uncommon, but the onset of toxicity is insidious and may be misdiagnosed. The
patient may have dizziness, delirium, dehydration, fever and metabolic acidosis, which are complicated by
pulmonary and cerebral oedema.

Key investigations in aspirin poisoning

The key investigations in aspirin overdose include:

Salicylate concentrations—measure every 4 to 6 hours to monitor progress, to exclude ongoing absorption

(with slow-release preparations) and to monitor elimination.
Electrolytes—measure potassium concentration.
Dipstick urine—regularly check urinary pH if administering intravenous sodium bicarbonate.

Treatment of aspirin poisoning

Airway and breathing
Airway and breathing support is required in severe poisoning with coma. Maintain the ventilation to avoid
systemic acidosis and advancing toxicity.

Circulation
Treat hypotension as per normal recommendations (see Resuscitation: circulation).

Intravenous fluid rehydration is essential and increases urinary excretion of salicylates. Urine output should be
maintained at 2 mL/kg/hour. Add potassium to the intravenous fluids if intravenous sodium bicarbonate is being
administered (see Urinary alkalinisation).

Decontamination

Activated charcoal should be administered to patients who have ingested greater than 150 mg/kg and who present
within 6 hours of the estimated time of ingestion, because of delayed gastric emptying (see Single-dose activated
charcoal).

Consider giving a further dose of activated charcoal 4 hours after the initial dose if serum salicylate concentrations
continue to rise.

Enhanced elimination

Urinary alkalinisation

Intravenous sodium bicarbonate is indicated in moderate to severe poisoning to increase the urinary elimination of
salicylates. In adults, use:

sodium bicarbonate 8.4% (= 1 mmol/mL) 1 mmol/kg IV as an initial bolus, followed by an

infusion of 25 to 50 mmol/hour (to give 25 mmol/hour, dilute sodium bicarbonate 100
mmol in 1000 mL of sodium chloride 0.9% and infuse at 250 mL/hour). The rate should
be adjusted to maintain a urinary pH greater than 7.5.

In children, use:

sodium bicarbonate 8.4% (= 1 mmol/mL) 0.25 mmol/kg orally, 6- to 12-hourly. The

dosage should be adjusted to maintain a urinary pH greater than 7.5.

If hypokalaemia develops, either oral or intravenous potassium should be administered. Use:

1 potassium chloride 14 to 16 mmol orally, 3 times daily (child: 1 mmol/kg/day in 2 to 4

divided doses) [Note 1]

OR

1 potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV over 1 to 2 hours (child: 0.6

mmol/kg IV over 3 hours), preferably as a premixed solution of the appropriate
intravenous fluid [Note 2].

Monitor potassium and kidney function every 4 hours, and do a regular dipstick urinalysis to make sure the urine
remains alkaline. Continue treatment until the salicylate concentration is back into the normal range and the
acidosis has resolved.

Note 1: Effervescent immediate-release tablets of potassium contain 14 mmol potassium per tablet, and slow-
release tablets contain 8 mmol potassium per tablet. The slow-release formulations of potassium are almost
completely absorbed within one hour.

Note 2: Extemporaneous addition of ampoules of potassium chloride to intravenous fluids is no longer regarded
as safe, because inadequate mixing may result in delivery of potassium at a lethal concentration. If premixed
intravenous solution is unavailable, potassium chloride concentrate injection must be added to a large volume of
parenteral fluid and mixed thoroughly before infusion. The usual maximum concentration is 40 mmol/L.

Extracorporeal elimination

Haemodialysis removes salicylate, but is rarely required because the majority recover with either no treatment or
urinary alkalinisation. Indications for dialysis are not well defined but it should be considered if there is:

clinical deterioration of the patient despite maximal supportive care

rising salicylate concentrations
worsening metabolic acidosis or electrolyte imbalance despite appropriate treatment
oliguric or anuric kidney failure.
Specific pharmacological therapies

Glucose supplementation

All patients with coma or seizures require intravenous glucose. In adults, use:

glucose 50% 50 mL IV, preferably via a central line as a bolus, or via a large peripheral
vein as a slow injection.

In children, use:

glucose 10% 2.5 mL/kg IV via a large peripheral vein as a bolus.

All patients should receive glucose in their intravenous fluids, not just sodium chloride 0.9%, as tissue glucose
concentrations may be lower than plasma glucose concentrations.

Anticonvulsant therapy

If seizures are self-limiting, then intravenous glucose should be administered but no anticonvulsants.

If seizures are persistent or repeated, they should be treated with benzodiazepines (see Anticonvulsant therapy).

Observation and patient disposition after aspirin poisoning

Criteria for discharge: Patients who have ingested less than 150 mg/kg aspirin and are asymptomatic may be
discharged after observation for 6 hours after ingestion.

Criteria for ICU admission: Patients who have ingested more than 300 mg/kg aspirin or who have any evidence
of acidosis must be admitted to a critical care area.

Key references
Toxicology: aspirin (acetyl salicylate)

O'Malley GF. Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am
2007;25(2):333–46. [ ]

Salicylates. In: Wiki Tox: open source clinical toxicology curriculum [website]; 2008. [URL]

Chan TY. The risk of severe salicylate poisoning following the ingestion of topical medicaments or aspirin. Postgrad
Med J 1996;72(844):109–12. [ ]

Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney
Int 2009;75(12):1349–53. [ ]

Proudfoot AT, Krenzelok EP, Brent J, Vale JA. Does urine alkalinization increase salicylate elimination? If so, why?
Toxicol Rev 2003;22(3):129–36. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: baclofen
Risk assessment for baclofen poisoning
Baclofen taken in large amounts can cause coma, seizures, prolonged delirium and respiratory depression.
Meticulous supportive care ensures recovery in the majority of cases.

Toxic dose
Patients who have ingested more than 200 mg baclofen require admission for close observation. If ingestion
is associated with coma, delirium or seizures, ICU admission and a prolonged length of stay is required.

Clinical presentation
Baclofen is an uncommon overdose, but can cause severe effects with large ingestions and may mimic brain
death in massive overdoses.

Systemic effects include:

CNS effects—decreased level of consciousness, respiratory depression, seizures and delirium

(develops after coma is resolving and may last 1 to 3 days), hypotonia, hyporeflexia, pupillary
abnormalities (miosis or mydriasis), hypothermia; severe toxicity may mimic brain death that lasts 24
to 48 hours
cardiovascular toxicity—bradycardia, tachycardia, hypertension, less commonly hypotension.

Treatment of baclofen poisoning

Airway and breathing
Airway support and mechanical ventilation with early intubation may be required with large ingestions of
baclofen causing coma.

Circulation
Hypotension is treated initially with intravenous fluid (see Resuscitation: circulation). Resistant hypotension
is treated with inotropes (see Inotropic support).

Decontamination
If the patient ingests more than 200 mg baclofen and presents within 1 hour of the estimated time of
ingestion, decontamination with activated charcoal may be beneficial (see Single-dose activated charcoal).

Specific pharmacological therapies

Anticonvulsant therapy

Seizures are generally self-limiting, but if persistent and recurrent they can be treated with benzodiazepines
(see Anticonvulsant therapy).

Delirium

Delirium may be difficult to treat, but initial management should be with benzodiazepines (see Sedation), or a
sedating antipsychotic such as droperidol.

Observation and patient disposition after baclofen poisoning

Criteria for discharge: Asymptomatic patients or those who have ingested less than 200 mg baclofen can be
discharged 4 hours after ingestion.

Criteria for admission: Patients who have ingested more than 200 mg baclofen should initially be observed
for 4 hours after ingestion. If severe toxicity develops they should be admitted.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: barbiturates
Risk assessment for barbiturate poisoning
Significant poisoning by long-acting barbiturates (eg phenobarbitone, primidone) can result in prolonged
CNS depression that may require ventilatory support for days. Pentobarbitone is a medium-acting barbiturate
that is used in animals and can also cause prolonged CNS depression.

Toxic dose
Ingestion of more than 3 g phenobarbitone or primidone associated with coma is potentially life-threatening.
However, tolerance develops with chronic dosing.

Clinical presentation
Systemic effects of barbiturate overdose include:

CNS effects—coma, areflexia, respiratory depression, apnoea

cardiovascular effects—hypotension (decreased vascular resistance and myocardial depression)
other effects—hypothermia, multi-organ failure (secondary to hypoxia).

Key investigations in barbiturate poisoning

The key investigations in barbiturate overdose include:

Blood glucose concentration.

Chest X-ray—perform if aspiration is suspected.

Treatment of barbiturate poisoning

Airway and breathing
Many barbiturate overdoses require intubation and ventilation.

Circulation
Patients with hypotension should initially be treated with intravenous fluids (see Resuscitation: circulation).

Persistent hypotension requires inotropes as for cardiogenic shock (see Inotropic support).

Decontamination
There is no indication for activated charcoal in barbiturate overdose due to the rapid onset of sedation, and
good outcome with supportive care.

Enhanced elimination

Multiple-dose activated charcoal

Multiple-dose activated charcoal may be beneficial in overdose in reducing the length of phenobarbitone and
primidone coma (see Multiple-dose activated charcoal).

Observation and patient disposition after barbiturate poisoning

Criteria for admission: All patients should be observed initially for 6 hours after ingestion to assess for CNS
and respiratory depression.
Risk of withdrawal: Patients who take barbiturates regularly are susceptible to withdrawal if the blood
barbiturate concentration drops rapidly. This is often noted 48 to 72 hours after ingestion and may be severe,
manifesting as seizures and delirium. Clinicians must be aware of this and consider restarting maintenance
phenobarbitone once toxicity has resolved.

Key references
Toxicology: barbiturates

Barbiturates. In: Wiki Tox: open source clinical toxicology curriculum [website]; Accessed: Feb, 2012. [URL]

Pond SM, Olson KR, Osterloh JD, Tong TG. Randomized study of the treatment of phenobarbital overdose with
repeated doses of activated charcoal. JAMA 1984;251(23):3104–8. [ ]

Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning: a systematic review. Clin Toxicol
(Phila) 2011;49(1):2–12. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: benzodiazepines
Introduction to benzodiazepine poisoning
Benzodiazepines available in Australia include alprazolam, bromazepam, clobazam, clonazepam, diazepam,
flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam and triazolam [Note 1].

Zolpidem and zopiclone are other hypnotics that have similar toxic effects to benzodiazepines, and overdoses
can be managed in the same way.

Note 1: Triazolam was discontinued in Australia in May 2015.

Risk assessment for benzodiazepine poisoning

Benzodiazepines cause CNS depression. When taken alone in overdose full recovery is expected with good
supportive care. Elderly patients and those with significant respiratory disease are more at risk of
complications.

Toxic dose
It is difficult to predict the severity of clinical effects from the dose of benzodiazepine ingested because of the
enormous range in patient tolerance. Some patients have significant CNS depression with only 1 to 4 times
the daily dose, whereas benzodiazepine-dependent patients may ingest 10 to 50 times the daily dose with
little effect. Alprazolam in overdose is relatively more toxic than other benzodiazepines, and is more likely to
produce CNS depression requiring intubation.

Clinical presentation
The effects of benzodiazepines are very similar across the class of drugs. The major difference is in the onset
of action (eg rapid for temazepam) and the duration of action (longer in the elderly and for drugs with longer
elimination half-lives).

Systemic effects include:

CNS effects—drowsiness, sedation, coma, respiratory depression

cardiac effects—bradycardia and hypotension (with very large overdoses)
other effects—hypothermia (with very large overdoses).

Treatment of benzodiazepine poisoning

Airway and breathing
Respiratory support is the primary treatment, but the majority of benzodiazepine overdoses do not require
intubation and ventilation. It is essential to recognise that the major toxic effect is respiratory depression
(evidenced by decreased respiratory rate and raised partial pressure of carbon dioxide [PaCO2] on blood gas
results). Patients who have poor respiratory effort should not be administered oxygen in the absence of
respiratory support (see Resuscitation: airway and breathing). Patients who are protecting their airway can be
placed in the left lateral position while their oxygen saturation and respiratory rate are monitored.

Circulation
Hypotension is initially treated with intravenous fluids (see Resuscitation: circulation).

Decontamination
There is no indication for activated charcoal in benzodiazepine overdose due to the rapid onset of sedation
and good outcome with supportive care.

Specific pharmacological therapies

Antidotal therapy

Flumazenil has little role in managing benzodiazepine overdose.

Flumazenil is a competitive antagonist at benzodiazepine receptors in the CNS. It has a duration of action of
approximately 45 to 60 minutes, after which time re-sedation may occur because most benzodiazepines have
a much longer duration of action. Therefore, patients must be observed for several hours after a dose of
flumazenil.

There is very little role for flumazenil in the management of benzodiazepine overdose. Flumazenil should not
be used as a diagnostic aid because it may precipitate seizures in patients with epilepsy, in patients who have
simultaneously ingested proconvulsants (eg tricyclic antidepressants) or in patients who are benzodiazepine-
dependent. Flumazenil infusions should only be used in a critical care setting because theoretically they may
increase the duration of effect of the benzodiazepine.

There are a few exceptions where use of flumazenil in management of benzodiazepine overdose is warranted,
namely:

in elderly or other patients with respiratory disease (eg chronic obstructive pulmonary disease) where
intubation should be avoided, as CNS depression with poor respiratory effort and poor cough may
result in atelectasis and respiratory infection
in the treatment of CNS depression due to iatrogenic over-treatment with benzodiazepines (eg in
procedural sedation), where short-term use of flumazenil may be beneficial
unintentional lone paediatric benzodiazepine ingestion with compromised airway and breathing
benzodiazepine overdose resulting in compromised airway or breathing in settings where resources for
intubation are not available.

In these circumstances, use:

flumazenil 0.1 to 0.2 mg (child: 5 micrograms/kg) IV bolus, repeat every 60 seconds

(up to a total dose of 40 micrograms/kg in children), titrated to clinical effect.

If an infusion is to be used in the critical care setting it should be titrated to effect, but the starting rate is
approximately half to two-thirds of the initial bolus dose each hour. Use:

flumazenil 0.1 to 0.5 mg/hour (child: 2 to 10 micrograms/kg/hour) IV infusion, titrated

to clinical effect.

If no response is seen after administration of a cumulative dose of 2 mg, other causes of CNS depression
should be sought.

Observation and patient disposition after benzodiazepine poisoning

Criteria for discharge: Patients who have minimal sedation 4 hours after ingestion may be discharged.
Those administered flumazenil should be observed at least 4 hours following the last dose.

Criteria for admission: Admission should be based on the clinical effects in the patient.

Key references
Toxicology: benzodiazepines

Buckley NA, Dawson AH, Whyte IM, O'Connell DL. Relative toxicity of benzodiazepines in overdose. BMJ
1995;310(6974):219–21. [ ]

Published July 2012. Amended June 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: beta blockers
Introduction to beta blocker poisoning
Beta blockers are heterogeneous in overdose. Drugs with sodium channel blocking effects (propranolol) or
potassium channel effects (sotalol) are potentially lethal when taken alone. Other beta blockers are relatively less
toxic unless taken with other cardiovascular-acting agents, where severe toxicity can be observed. These include
atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nebivolol and oxprenolol.

Risk assessment for beta blocker poisoning

Toxic dose
No clear toxic dose of beta blockers has been identified except for propranolol, where ingestions of more than 2 g
are associated with depressed conscious state, seizures and sodium channel blockade.

Other predictors of toxicity

There are a number of important risk factors in beta-blocker poisoning:

type of beta blocker

–
propranolol—coma, seizures, QRS widening and sodium channel blockade
–
sotalol—more severe cardiac effects and QT prolongation
patient's age or underlying heart disease
co-ingestion of calcium antagonist or digoxin.

Clinical presentation
The presenting features of beta-blocker overdose include:

CNS effects—seizures, delirium and coma occur with lipophilic beta blockers such as propranolol
cardiovascular effects—hypotension is due to a combination of myocardial depression and bradycardia. The
most common arrhythmia is sinus bradycardia. In severe cases, there can be first- to third-degree heart block,
junctional bradycardia, ventricular bradycardia and asystole
respiratory effects—bronchospasm and pulmonary oedema particularly in patients with underlying airways
disease
metabolic effects—hypoglycaemia, hyperglycaemia, hyperkalaemia.

Key investigations in beta blocker poisoning

The key investigations in beta-blocker overdose include:

ECG— QRS widening can occur with propranolol poisoning and QT prolongation with sotalol poisoning.
Blood glucose concentration.

Treatment of beta blocker poisoning

Airway and breathing
Ensure that there is an adequate airway and breathing. Intubation and ventilation should be considered early with
severe poisoning where refractory cardiovascular instability and depression in conscious state are observed.

Coma and seizures are common with severe propranolol poisoning and require early intervention.

Circulation
Treat hypotension with intravenous fluids (see Resuscitation: circulation). Persistent hypotension will require
inotropes (see Inotropic support).
Serial 12-lead ECGs and continuous ECG monitoring should be done in all but minor poisonings with beta
blockers. Bradycardia can be treated with atropine if there is hypotension. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02 mg/kg up
to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of 1 mg).

Severe bradycardia with persistent hypotension may require temporary transvenous pacing.

QRS widening and sodium channel blockade

QRS widening may occur with propranolol poisoning and the QRS complex should be assessed with continuous
ECG monitoring and regular 12-lead ECGs. Cardiovascular instability associated with QRS widening should be
treated (see QRS widening).

QT prolongation and torsades de pointes

Torsades de pointes may occur with sotalol poisoning and the QT interval should be measured regularly with
continuous ECG monitoring and regular 12-lead ECGs. For details on the management of QT prolongation and
torsades de pointes, see QT prolongation and torsades de pointes. The rate of isoprenaline intravenous infusion
may need to be rapidly increased to give double, quadruple or higher doses as required to overcome the beta
blockade.

Inotropic support

Careful selection of inotropes is required in beta-blocker poisoning and advice from a clinical toxicologist should
be obtained early. Although glucagon is often recommended there is no evidence to support its effectiveness. The
dose of glucagon used in the toxicology setting is much larger than the dose used in the management of
hypoglycaemia, and there is rarely enough glucagon kept in hospitals to maintain treatment for longer than an
hour.

The following inotropes are recommended based on animal studies and anecdotal experience.

If the patient is hypotensive and bradycardic, give adrenaline (with high-dose insulin euglycaemia therapy [HIET]
if needed). Use:

adrenaline 10 to 20 micrograms (child: 0.1 micrograms/kg) IV bolus, repeat every 2 to 3

minutes depending on clinical response. Then start an adrenaline infusion (see Box 17.7)

PLUS, if necessary, and on advice from a clinical toxicologist, high-dose insulin euglycaemia therapy (HIET):

short-acting insulin 1 unit/kg IV as an initial bolus, followed by an infusion of 1

unit/kg/hour (see Table 18.4 for insulin formulations). The dose can be increased to 2
units/kg/hour or more, but this should be discussed with a clinical toxicologist

PLUS

glucose 10% IV infusion, increased to glucose 50% if blood glucose concentration is

low. Give according to instructions in Box 17.5.

If the patient is predominantly bradycardic without significant hypotension, isoprenaline can be used as an
alternative chronotrope to adrenaline. Use:

isoprenaline 20 micrograms IV, repeat according to clinical response up to a maximum of

100 micrograms, followed by an infusion of 2 to 4 micrograms/minute (see Box 17.8).
The rate may need to be rapidly increased to give double, quadruple or higher doses as
required to overcome beta blockade.

May also consider:

1 milrinone 50 micrograms/kg IV slowly over 10 minutes, followed by an infusion of 0.375

to 0.75 micrograms/kg/minute, adjusting according to clinical and haemodynamic
response, up to a maximum of 1.13 mg/kg daily [Note 1]

OR

2 glucagon 5 to 10 mg (= 5 to 10 units) IV as an initial bolus, followed by an infusion of 5

to 10 mg/hour.
If the patient has a cardiac arrest, prolonged cardiopulmonary resuscitation should be undertaken (4 to 8 hours), as
the majority of these patients are healthy before the overdose (see flowcharts developed by the Australian
Resuscitation Council). Patients should be aggressively alkalinised with sodium bicarbonate and hyperventilation.
Cardiac assist devices and extracorporeal circulatory support should be considered if available.

Note 1: Compatible dilution fluids for milrinone are sodium chloride 0.9% or glucose 5%.

Decontamination
Consider an initial dose of activated charcoal up to 2 hours after the estimated time of ingestion in severe
poisoning if the patient has a protected airway (see Single-dose activated charcoal).

Specific pharmacological therapies

Treatment of hypoglycaemia

Hypoglycaemia should be treated. In adults, use:

1 glucose 10% 250 mL IV via a large peripheral vein as a bolus

OR

1 glucose 50% 50 mL IV, preferably via a central line as a bolus, or via a large peripheral
vein as a slow injection.

In children, use:

glucose 10% 2.5 mL/kg IV via a large peripheral vein as a bolus.

For ongoing management of hypoglycaemia, see Box 17.5.

Anticonvulsant therapy

Once euglycaemia is confirmed, persistent seizures seen in propranolol poisoning should be treated with
benzodiazepines (see Anticonvulsant therapy).

Observation and patient disposition after beta blocker poisoning

Criteria for admission: All patients with deliberate self-poisoning or patients who have unintentionally ingested
more than the daily dose of a beta blocker should be observed for at least 6 hours after ingestion.

Key references
Toxicology: beta blockers

DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-
blocker toxicity. Toxicol Rev 2004;23(4):223–38. [ ]

Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium
channel-blocker poisoning. Clin Toxicol (Phila) 2011;49(4):277–83. [ ]

Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: bupropion
Risk assessment for bupropion poisoning
Seizures are common following any overdose of bupropion and severe cardiovascular toxicity has been
associated with massive ingestions (greater than 9 g bupropion).

Toxic dose
The risk of seizures significantly increases with doses greater than 4.5 g bupropion (occurs in 50% of
patients). Seizures are more likely in patients with a lower seizure threshold and in those who have also taken
other proconvulsant drugs.

Ingestions greater than 9 g bupropion have been associated with severe cardiovascular toxicity including
hypotension, QRS widening and arrhythmias. Although QT prolongation is reported it is likely to be related
to the coexisting tachycardia seen with toxicity. The QT interval should be interpreted using a QT nomogram
(see QT prolongation).

Clinical presentation
Overdose with bupropion is characterised by severe agitation and a significant risk of seizures (a third of
patients in one series [Note 1]). Seizures may be delayed in onset up to 24 hours after ingestion of the slow-
release preparation, which is the most commonly available.

Systemic effects include:

gastrointestinal effects—nausea, vomiting

CNS effects—agitation, aggression, seizures, hallucinations, tremor
cardiovascular effects—hypertension, tachycardia, rare reports of hypotension and arrhythmias with
massive ingestions.

Note 1: Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust 2003;178(2):61-
3. [URL]

Key investigations in bupropion poisoning

The key investigations in bupropion overdose include:

ECG— QRS widening and QT prolongation can occur.

Treatment of bupropion poisoning

Airway and breathing
CNS arousal with agitation and aggression often requires parenteral sedation (see sedation), but occasionally
intubation is required for uncontrollable agitation.

Circulation
Supportive care with intravenous fluids may be required with massive ingestions of more than 9 g bupropion
(see Resuscitation: circulation).

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening. Arrhythmias
associated with QRS widening should be treated (see QRS widening and sodium channel blockade).
Decontamination
Consider activated charcoal within 4 hours of the estimated time of ingestion in patients who are cooperative
and not agitated (see Single-dose activated charcoal).

Specific pharmacological therapies

Anticonvulsant therapy

Seizures are usually short and self-limiting and do not require treatment. In some cases multiple seizures
occur. If seizures are not self-limiting within minutes, treat with benzodiazepines (see Anticonvulsant
therapy), which are also beneficial for the treatment of agitation.

Sedation

The most common management issue is control of severe agitation and aggression. Pharmacological sedation
is almost always required (see sedation).

Observation and patient disposition after bupropion poisoning

Criteria for discharge: All patients who have ingested less than 4.5 g bupropion and who are asymptomatic
(with no tachycardia or agitation) can be discharged 16 hours after ingestion.

Criteria for admission: Any patient with agitation or hypertension, or who has ingested more than 4.5 g
bupropion, should be observed for 24 hours or until they are clinically well.

Key references
Toxicology: bupropion

Isbister GK, Balit CR. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother
2003;37(7–8):999–1002. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: calcium channel blockers
Introduction to calcium channel blocker poisoning
Verapamil and diltiazem can produce refractory shock and are potentially lethal in overdose. Other calcium
channel blockers are relatively less toxic except with massive ingestions. These include amlodipine, felodipine,
lercanidipine, nifedipine and nimodipine.

Risk assessment for calcium channel blocker poisoning

Toxic dose
The toxic dose varies in adult deliberate self-poisoning and unintentional poisoning. Severe toxicity may be
observed with ingestions of more than 10 higher-dose formulation verapamil or diltiazem tablets. However, in
elderly patients, toxicity may develop with just 2 to 3 times the normal daily dose of verapamil or diltiazem. In
children, ingestion of less than 12 mg/kg verapamil, or less than 2.7 mg/kg nifedipine, is unlikely to cause toxicity.
However, ingestion of two or more higher-dose formulation verapamil or diltiazem tablets can lead to severe
toxicity.

Other predictors of toxicity

Patients with underlying cardiac disease or who have co-ingested beta blockers or digoxin are likely to have more
severe effects.

Clinical presentation
The main presenting features of calcium channel blocker overdose include:

cardiovascular effects—hypotension (combination of peripheral vasodilatation and myocardial depression)

progressing to cardiogenic shock; bradycardia, first degree heart block progressing to junctional bradycardia
(no P wave), idioventricular rhythms and asystole; pulmonary oedema
CNS effects—drowsiness, confusion, agitation, rarely seizures. Coma is usually secondary to hypotension or
hypoxia from cardiovascular collapse
gastrointestinal effects—nausea, vomiting
metabolic effects—hyperglycaemia, lactic acidosis, hypocalcaemia, hyperkalaemia.

Key investigations in calcium channel blocker poisoning

The key investigations in calcium channel blocker overdose include:

ECG—should be done in all patients.

Blood glucose concentration.
Electrolytes.

Treatment of calcium channel blocker poisoning

Airway and breathing
Ensure that there is an adequate airway and breathing. Prompt intubation and ventilation should be considered
where severe cardiovascular effects have begun to manifest.

Circulation
Treat hypotension with intravenous fluids (see Resuscitation: circulation).

Calcium therapy (see Antidotal therapy) should be considered early before the use of inotropes. The effect if
observed may be short-lived, but may provide some stability while other therapies are instituted.

Persistent hypotension will require inotropes (see Inotropic support).

Serial 12-lead ECGs and continuous ECG monitoring should be done in all but minor poisonings with calcium
channel blockers. Bradycardia can be treated initially with atropine if there is hypotension, use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02 mg/kg up
to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of 1 mg).

Severe bradycardia with persistent hypotension may require temporary transvenous pacing, but ventricular rather
than atrial pacing will be required due to atrioventricular (AV) nodal blockade.

Inotropic support

The choice of inotrope will depend partly on the particular calcium channel blocker ingested. In cases with
refractory hypotension, an echocardiogram may assist in targeting therapy. Hypotension will usually result from a
combination of myocardial depression, heart block and peripheral vasodilatation. Use:

1 adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7)

OR

1 noradrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7)

PLUS (if necessary in addition to either adrenaline or noradrenaline AND on advice from a clinical toxicologist)

high-dose insulin euglycaemia therapy (HIET):

short-acting insulin 1 unit/kg IV as an initial bolus, followed by an infusion of 1

unit/kg/hour (see Table 18.4 for insulin formulations). The dose can be increased to 2
units/kg/hour or more, but this should be discussed with a clinical toxicologist
PLUS
glucose 10% IV infusion, increased to glucose 50% if blood glucose concentration is
low. Give according to instructions in Box 17.5.

The use of a combination of inotropes such as dobutamine and noradrenaline (see Box 17.2) may be an appropriate
option, but should be done in consultation with a critical care specialist. Vasopressors such as metaraminol or low-
dose adrenaline may be useful in the short term for hypotension. Use:

1 adrenaline 0.01 to 0.02 mg (child: 0.1 micrograms/kg) IV bolus, repeat every 2 to 3

minutes depending on clinical response. An adrenaline infusion should then be
commenced (see Box 17.7)

OR

1 metaraminol 0.5 to 1 mg (child: 0.01 mg/kg) IV bolus, repeat if there is a clinical

response.

In patients in cardiac arrest the following should be used in addition to standard advanced life support protocols
(see flowcharts developed by the Australian Resuscitation Council):

adrenaline 1 mg (child: 0.01 mg/kg) IV bolus, repeat every 2 to 5 minutes depending on

clinical response. An adrenaline infusion should then be commenced (see Box 17.7)

PLUS EITHER [Note 1]

1 calcium gluconate 10% 60 mL (child: 1 mL/kg) IV, repeat every 2 to 5 minutes if there is
no response

OR

2 calcium chloride 10% 20 mL (child: 0.2 mL/kg) IV, repeat every 2 to 5 minutes if there is
no response

PLUS (on advice from a clinical toxicologist)

high-dose insulin euglycaemia therapy (HIET):

 short-acting insulin 1 unit/kg IV as an initial bolus, followed by an infusion of 1
unit/kg/hour (see Table 18.4 for insulin formulations). The dose can be increased to 2
units/kg/hour or more, but this should be discussed with a clinical toxicologist
PLUS
glucose 10% IV infusion, increased to glucose 50% if blood glucose concentration is
low. Give according to instructions in Box 17.5.

Prolonged cardiopulmonary resuscitation should be undertaken (4 to 8 hours), as the majority of these patients are
healthy before the overdose. Cardiac assist devices and/or extracorporeal circulatory support should be considered
if available.

Note 1: Calcium gluconate is preferred to calcium chloride as it causes less local irritation.

Decontamination

Single-dose activated charcoal

Consider an initial dose of activated charcoal up to 4 hours after severe poisoning with calcium channel blockers,
if the patient has a protected airway (see Single-dose activated charcoal). Calcium channel blockers can cause
ileus, which is a contraindication to activated charcoal.

Whole bowel irrigation

Whole bowel irrigation should be considered for potentially lethal ingestions of slow-release preparations where
patients present early without manifest cardiovascular toxicity (see Whole bowel irrigation). However, evidence of
benefit is based on single case reports and this must be weighed against the risk of aspiration in sedated patients
and the availability of resources to administer whole bowel lavage.

Specific pharmacological therapies

Antidotal therapy

A specific antidote does not exist for calcium channel blocker overdose. However, the administration of calcium to
increase extracellular calcium appears to partially reverse the heart block and arrhythmias induced by calcium
channel blocker overdose—usually found with verapamil or diltiazem. In patients with heart block or cardiac
dysrhythmias, use [Note 2]:

1 calcium gluconate 10% 30 mL (child: 0.6 mL/kg) IV over 10 minutes, repeat every 5
minutes if there is no response

OR

2 calcium chloride 10% 10 mL (child: 0.2 mL/kg) IV over 10 minutes, repeat every 5
minutes if there is no response.

Large doses of calcium may be required and up to 10 g has been used as an initial dose in severe toxicity. If there
is a response to calcium then an infusion is recommended. Use:

1 calcium gluconate 10% 3 to 30 mL/hour (child: 0.06 to 0.6 mL/kg/hour) IV infusion

OR

1 calcium chloride 10% 1 to 10 mL/hour (child: 0.02 to 0.2 mL/kg/hour) IV infusion by a

central line.

Serum calcium needs to be measured in all patients. The aim is to produce hypercalcaemia and generally patients
have minimal adverse effects. It is reasonable to aim to maintain the ionised serum calcium above 2 mmol/L.

Note 2: Calcium gluconate is preferred to calcium chloride as it causes less local irritation.

Correction of acidosis

Sodium bicarbonate should be administered to patients with severe acidosis provided they have adequate
ventilation (either spontaneous or mechanical ventilation). To rapidly change blood pH, use:
 sodium bicarbonate 8.4% (= 1 mmol/mL) 1 to 2 mmol/kg IV bolus, every 3 to 5 minutes,
titrated to a narrowing of the QRS complex, resolution of arrhythmias and pH greater than
7.3. If no response, urgently seek advice from a poisons information centre. Maximum
total dose 10 mmol/kg.

Bicarbonate infusions are not appropriate because the body will buffer the change. If alkalaemia is required, this is
best maintained using hyperventilation.

Observation and patient disposition after calcium channel blocker

poisoning
Criteria for discharge: All patients who have ingested slow-release formulations must be observed for 24 hours
after ingestion. If no clinical or ECG effects develop they can be discharged.

Criteria for admission: All patients who have ingested more than twice the daily dose or who have evidence of
toxicity must be admitted to a critical care unit for close observation.

Key references
Toxicology: calcium channel blockers

DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium channel blocker and beta-
blocker toxicity. Toxicol Rev 2004;23(4):223–38. [ ]

Belson MG, Gorman SE, Sullivan K, Geller RJ. Calcium channel blocker ingestions in children. Am J Emerg Med
2000;18(5):581–6. [ ]

Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium
channel-blocker poisoning. Clin Toxicol (Phila) 2011;49(4):277–83. [ ]

Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: carbamazepine
Risk assessment for carbamazepine poisoning
Carbamazepine overdose is potentially life-threatening and may have delayed toxicity. Early management
decisions may be critical and expert advice should be sought for large ingestions.

Toxic dose
Ingestion of 50 mg/kg carbamazepine (or more than 3 g) is associated with significant toxicity.

Toxic concentration
There is reasonable correlation between the drug concentration and clinical effects of carbamazepine (although this
varies between patients):

20 to 50 micromol/L (5 to 12 mg/L)—therapeutic range

40 to 85 micromol/L (10 to 20 mg/L)—nystagmus, sedation, ataxia
85 to 170 micromol/L (20 to 40 mg/L)—horizontal and vertical nystagmus, coma
more than 170 micromol/L (40 mg/L)—respiratory depression, seizures, cardiac arrhythmias.

Clinical presentation
Carbamazepine has prolonged and erratic absorption due to anticholinergic-like effects and the physicochemical
properties of the drug. Patients may have very delayed onset of effect and delayed peak effects (more than 48
hours), or recurrent effects with peaks and plateaus in concentration due to intermittent ileus and delayed
absorption.

Systemic effects include:

CNS effects—horizontal and then vertical nystagmus, ataxia increasing with severity, dysarthria, drowsiness
progressing to coma, respiratory depression, paradoxical seizures, delirium
gastrointestinal effects—ileus
cardiovascular effects—tachycardia, hypotension (due to peripheral effects and dehydration), progression to
life-threatening cardiac arrhythmias (heart block, QRS widening, ventricular fibrillation)
other effects—urinary retention.

Key investigations in carbamazepine poisoning

The key investigations in carbamazepine overdose include:

Carbamazepine concentration—measure every 3 to 6 hours in severe cases.

ECG—abnormalities are uncommon except in massive ingestions and carbamazepine concentrations greater
than 170 micromol/L (40 mg/L), where heart block, QRS widening and ventricular arrhythmias may occur.

Treatment of carbamazepine poisoning

Airway and breathing

Intubation is required for airway protection in unconscious patients unable to protect their airway, and mechanical
ventilation is needed for respiratory depression.

Circulation
Intravenous fluid replacement is essential in all carbamazepine poisonings (see Resuscitation: circulation).

Patients with carbamazepine concentrations more than 170 micromol/L (40 mg/L) should be monitored in a critical
care area with facilities to treat life-threatening arrhythmias.

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening. Arrhythmias
associated with QRS widening should be treated (see QRS widening and sodium channel blockade).

Decontamination
Consider an initial dose of activated charcoal up to 24 hours [Note 1] after severe poisoning if the patient has a
protected airway (see Single-dose activated charcoal). Carbamazepine can cause ileus due to its anticholinergic-
like effects, which may limit the use of activated charcoal.

Note 1: Pharmacobezoar and prolonged absorption are common in carbamazepine overdose.

Enhanced elimination

Multiple-dose activated charcoal

Multiple-dose activated charcoal should be considered in severe carbamazepine poisoning. However, once a
patient has established poisoning, it is important to carefully weigh the moderate benefits against the risks due to
sedation and gastrointestinal ileus. For dosing recommendations, see Multiple-dose activated charcoal.

Extracorporeal circulation

The indications for high-flux haemodialysis or haemoperfusion have not been established in carbamazepine
poisoning. This should be discussed with a clinical toxicologist.

Specific pharmacological therapies

Anticonvulsant therapy

Benzodiazepines are the primary anticonvulsant in carbamazepine overdose patients and should be used if seizures
are not self-limiting within minutes. Sodium channel blocking anticonvulsants such as phenytoin are relatively
contraindicated. For drug and dosing recommendations, see Anticonvulsant therapy.

Antiarrhythmic therapy

Ventricular arrhythmias should be treated according to standard advanced life support protocols (see flowcharts
developed by the Australian Resuscitation Council for adults and children), but class I anti-arrhythmic drugs,
magnesium and beta blockers may exacerbate the effects of carbamazepine. Sodium bicarbonate is the first-line
antiarrhythmic drug for all arrhythmias. Atropine should be tried in patients with heart block, but it is frequently
ineffective (not surprising given the pseudo-anticholinergic effects of carbamazepine). Isoprenaline is more likely
to be effective, but if heart block persists then electrical pacing may be required. Use:

1 sodium bicarbonate 8.4% (= 1 mmol/mL) 1 to 2 mmol/kg IV bolus over 1 to 2 minutes,

repeat as required to reach pH 7.45 to 7.55 (this pH can be maintained with
hyperventilation). If no response, urgently seek advice from a poisons information centre.
Maximum total dose 10 mmol/kg

OR

2 atropine 0.5 to 1.5 mg IV bolus (child: 0.02 mg/kg up to 0.5 mg IV bolus, repeat after 5
minutes if necessary up to a maximum of 1 mg)

OR

2 isoprenaline 0.5 to 10 micrograms/minute (child: 0.05 to 2 micrograms/kg/minute) IV

infusion, titrate to clinical response.

Treatment of other complications

Urinary retention

Urinary retention should be treated by insertion of a urethral catheter.

Observation and patient disposition after carbamazepine poisoning

Criteria for discharge: Asymptomatic patients who have ingested less than 50 mg/kg carbamazepine can be
discharged 6 hours after ingestion.

Criteria for admission: All patients who have ingested more than 50 mg/kg carbamazepine should be initially
admitted and observed for 12 hours after ingestion, with at least two carbamazepine serum concentrations
measured during that time. Admission to a critical care unit depends on the clinical status and drug concentrations.

Key references
Toxicology: carbamazepine

Brahmi N, Kouraichi N, Thabet H, Amamou M. Influence of activated charcoal on the pharmacokinetics and the clinical
features of carbamazepine poisoning. Am J Emerg Med 2006;24(4):440–3. [ ]

Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: carbon monoxide
Risk assessment for carbon monoxide poisoning
A number of factors have been associated with long-term complications of carbon monoxide poisoning:

underlying cardiovascular or cerebrovascular disease

sustained loss of consciousness
neurological abnormalities after waking from coma
length of exposure more than 15 hours (for unintentional poisoning with indoor heaters).

Blood carboxyhaemoglobin concentrations are only a weak predictor of prognosis.

Clinical presentation
A broad spectrum of clinical effects has been reported with carbon monoxide poisoning, and any organ can
be affected due to tissue hypoxia. However, in deliberate self-harm cases with modern cars, the majority of
patients have only mild nonspecific effects that resolve over hours.

Systemic effects include:

CNS effects—headache, confusion, ataxia, dizziness, nausea, weakness, loss of consciousness or coma,
respiratory depression, seizures. A wide range of neurological sequelae, including cerebellar
abnormalities, and mild to severe cognitive impairment, including effects on memory, have been
reported
cardiovascular effects—tachycardia, hypotension, hypertension. With severe poisoning, effects include
myocardial ischemia and infarction, ECG changes and arrhythmias
metabolic effects—lactic acidosis, rhabdomyolysis, hyperglycaemia.

Delayed and persistent neurological effects can occur in severely poisoned patients and occasionally may
take weeks or even months to manifest. Common effects are depressed mood (even in unintentional
poisoning cases) and impaired higher function such as short-term memory. More severe effects include
parkinsonism and speech abnormalities.

Key investigations in carbon monoxide poisoning

The key investigations in carbon monoxide poisoning include:

ECG—exclude acute coronary syndromes in patients with loss of consciousness, chest pain or a history
of cardiac disease.
Troponin—exclude acute coronary syndromes in patients with loss of consciousness, chest pain or a
history of cardiac disease.
Electrolytes.
Blood glucose concentration.
Blood (venous sample) carboxyhaemoglobin concentrations—confirms diagnosis if high, but low
concentrations do not exclude severe poisoning. Serial measurements may indicate how long high-flow
oxygen is required, but usually this can be estimated from the initial concentration and the expected
half-life.

Treatment of carbon monoxide poisoning

Airway and breathing
All patients should initially receive high-flow oxygen (15 L/minute) on arrival at hospital, or in the
prehospital setting, for 6 hours. The evidence for continued oxygen therapy is lacking, but in patients with
ongoing clinical effects it is reasonable to continue administering oxygen. Airway support and mechanical
ventilation are required in severely poisoned patients.
In severely poisoned patients, administer continuous oxygen by a nonocclusive face mask at 15 L/minute;
100% oxygen is given to ventilated patients. Nonventilated patients can also be given 100% oxygen using a
tight-fitting, nonrebreathing, reservoir mask (such as a continuous positive airway pressure [CPAP] mask),
but this is uncomfortable and can only be used for short periods.

Hyperbaric oxygen therapy

There is significant controversy over the use of hyperbaric oxygen in carbon monoxide poisoning. A
Cochrane review states there is not sufficient evidence for hyperbaric oxygen to be recommended for the
treatment of carbon monoxide poisoning in the majority of patients [Note 1]. Although there is no evidence,
theoretical considerations would support the use of hyperbaric oxygen in pregnant women to improve foetal
oxygenation. However, this must be balanced with the risks and costs of transporting the patient for such
therapy. Seek the advice of a clinical toxicologist.

Note 1: Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for carbon
monoxide poisoning. [URL]

Circulation

Circulatory support may be required because of myocardial depression in severe poisoning. This should be
managed with intravenous fluids (see Resuscitation: circulation) and inotropes (see Inotropic support). In
severe poisoning, patients should have continuous ECG monitoring with serial 12-lead ECGs and an
echocardiogram to assess myocardial injury.

Observation and patient disposition after carbon monoxide

poisoning
Criteria for admission: All patients should be observed and given oxygen therapy for 6 hours after
exposure. Further treatment or discharge is determined by whether the patient has full recovery or ongoing
toxicity. Neuropsychological testing should be considered.

Key references
Toxicology: carbon monoxide

Buckley NA, Juurlink DN, Isbister G, Bennett MH, Lavonas EJ. Hyperbaric oxygen for carbon monoxide
poisoning. Cochrane Database Syst Rev 2011;(4):CD002041. [ ]

Published July 2012. Amended February 2013. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: caustic ingestions
Risk assessment for poisoning caused by caustic ingestions
Overview
Alkali ingestions are more common than acid ingestions because alkalis are contained in numerous domestic and
industrial cleaning agents.

Ingestions of highly caustic agents can a cause rapid onset of life-threatening airway compromise and severe injury
to the upper gastrointestinal tract. Early airway intervention can be lifesaving.

The degree of injury due to caustic ingestion is associated with the:

type of agent
–
dilute household bleaches, detergents and ammonia are unlikely to cause major effects compared to
acids and strong alkalis
–
hydrofluoric acid ingestions result in local caustic burns, but also hypocalcaemia which should be
treated as for other hydrofluoric acid exposures (see Toxicology: hydrofluoric acid)
concentration, and volume or amount ingested
pH—extreme pH is associated with more severe injury, even with exposures to small quantities—agents
with a pH of more than 12 or less than 3 (eg oven cleaners, dishwasher detergents, acids and drain cleaners)
are associated with significant injuries, and should be investigated and/or observed
formulation—solid formulations are more likely to cause severe injury than liquids (eg button batteries can
cause corrosive injury and perforation in the oesophagus).

Clinical presentation
Caustic ingestions present primarily with gastrointestinal effects, including mouth and throat pain, abdominal pain,
nausea, vomiting, peritonitis and oesophageal, gastric or duodenal injury and perforation. Oral burns and
ulceration can occur, but their absence does not exclude significant oesophageal injury, particularly for deliberate
ingestions. Patients may also have stridor, drooling and persistent coughing. As a general rule, strong alkalis tend
to cause oesophageal injuries while acids cause stomach and duodenal injuries.

Key investigations in poisoning caused by caustic ingestions

The key investigations in caustic ingestions include:

Thoraco-abdominal CT scan—may help predict cases where oesophageal strictures develop.

Endoscopy—the role of endoscopy is controversial. There is little evidence to support its early use in the
majority of cases, but it can help guide therapy in cases where clinical features and risk assessment suggest
significant injury is likely.
Neck, chest and abdomen X-ray—used to locate button batteries; also important for suspected perforation.

Treatment of poisoning caused by caustic ingestions

The major management issue with caustic ingestions is deciding which patients require observation and treatment.
Major injuries and perforations manifest within hours and require surgical investigation and treatment. The
majority of cases require observation for 12 hours and can be discharged if there are no ongoing symptoms (see
Observation and disposition).

See also this Royal Children's Hospital Melbourne Clinical practice guideline for alkalis poisoning for a further
summary of paediatric management.

Airway and breathing

The upper airway should be assessed for compromise; early intubation is indicated in all patients with upper
airway oedema suggested by stridor or dyspnoea.
Circulation
Treat hypotension aggressively with intravenous fluids (see Resuscitation: circulation).

Decontamination
There is no role for activated charcoal. The mouth can be rinsed with water, but the patient should initially remain
nil by mouth until assessed. In minor ingestions, fluids can be re-introduced if the patient remains asymptomatic.

Button batteries should be removed urgently by endoscopy if they are lodged in the oesophagus or airway—
serious burns can occur within 2 hours. Once a battery has passed into the stomach, endoscopy is not required
unless a magnet was also ingested, the patient develops symptoms likely related to the battery ingestion, or a large
battery (15 mm or greater) was ingested by a child younger than 6 years and it remains in the stomach for 4 days.

Specific pharmacological therapies

Analgesia

Pain should be treated with titrated intravenous opioids. Use:

1 fentanyl 50 to 100 micrograms (child: 0.5 to 2 micrograms/kg) IV as an initial dose, then

titrated to effect every 5 to 10 minutes with further incremental doses of 50 to 100
micrograms (child: 0.5 to 2 micrograms/kg)

OR

1 morphine 2.5 to 5 mg (child: 0.1 to 0.2 mg/kg up to 2.5 mg) IV as an initial dose, then
titrated to effect every 5 to 10 minutes with further incremental doses of 2.5 to 5 mg
(child: 0.1 to 0.2 mg/kg).

Monitor conscious state with a sedation score (see Table 1.25).

Corticosteroids

Corticosteroids are often recommended based on animal studies showing that they reduce the risk of late
oesophageal stricture formation. However, there is insufficient evidence to support their routine use.

Observation and patient disposition after poisoning caused by caustic

ingestions
Criteria for discharge: Children with minor unintentional caustic ingestions can be discharged if they remain
asymptomatic for 4 hours after ingestion. Adults with caustic ingestions (eg household bleaches, detergents and
ammonia) who only have minor symptoms can be discharged after an initial observation period of 12 hours.

Criteria for admission: Patients should be admitted for observation if they have ingested strong alkalis or acids,
have pain requiring parenteral analgesia, or if there is any evidence of perforation or peritonitis.

Key references
Toxicology: caustic ingestions

Isbister GK, Page CB. Early endoscopy or CT in caustic injuries: a re-evaluation of clinical practice. Clin Toxicol (Phila)
2011;49(7):641–2. [ ]

Ryu HH, Jeung KW, Lee BK, Uhm JH, Park YH, Shin MH, et al. Caustic injury: can CT grading system enable
prediction of esophageal stricture? Clin Toxicol (Phila) 2010;48(2):137–42. [ ]

Tohda G, Sugawa C, Gayer C, Chino A, McGuire TW, Lucas CE. Clinical evaluation and management of caustic injury
in the upper gastrointestinal tract in 95 adult patients in an urban medical center. Surg Endosc 2008;22(4):1119–25. [
]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: chloroquine, hydroxychloroquine and
quinine
Introduction to chloroquine, hydroxychloroquine or quinine
poisoning
Chloroquine and hydroxychloroquine overdose can produce rapid onset of cardiovascular collapse, with
associated conduction abnormalities and hypokalaemia. In addition to these effects, quinine may produce
direct retinotoxicity and ototoxicity, which can be irreversible.

Risk assessment for chloroquine, hydroxychloroquine or quinine

poisoning
Toxic dose
Ingestion of more than 5 g chloroquine, hydroxychloroquine or quinine is associated with severe poisoning.
Quinine retinotoxicity is dose related with an incidence of up to 80% with ingestions greater than 5 g.

Other predictors of toxicity

Other predictors of severe toxicity include:

hypotension—systolic blood pressure less than 90 mm Hg

QRS widening—greater than 120 msec
coma
hypokalaemia—serum potassium less than 3.0 mmol/L.

Clinical presentation
Chloroquine and hydroxychloroquine overdose is characterised by a rapid onset of depressed conscious state,
cardiovascular collapse, cardiac conduction abnormalities and hypokalaemia.

Other systemic effects with these drugs include:

CNS effects—seizures
cardiovascular effects—hypotension, QRS widening, QT prolongation, ventricular arrhythmias,
pulmonary oedema.

Quinine overdose is characterised by cinchonism (vertigo, nausea, vomiting and tinnitus) and visual toxicity.
With larger ingestions of quinine, effects as for chloroquine and hydroxychloroquine may also be seen.
Transient changes in hearing have been reported.

Quinine-induced visual toxicity causes blurred vision, loss of peripheral vision and blindness (quinine
amblyopia). It is seen in severe quinine poisoning and may have a delayed onset over hours. In about half of
patients there is full resolution over 12 to 24 hours. In the remaining half, recovery may take up to 10 weeks
and permanent peripheral field constriction may occur. Permanent blindness is rare.

Key investigations in chloroquine, hydroxychloroquine or quinine

poisoning
The key investigations in chloroquine, hydroxychloroquine and quinine overdose include:

ECG— QRS widening, QT prolongation, and ventricular arrhythmias can occur.

Electrolytes—hypokalaemia is associated with severe toxicity.
Treatment of chloroquine, hydroxychloroquine or quinine poisoning
Airway and breathing
Intubation should be considered early for patients with progressively reducing level of consciousness and
emerging cardiovascular collapse.

Circulation
Intravenous fluid therapy is required for hypotension (see Resuscitation: circulation).

Inotropic support

In severe poisoning, hypotension may not respond to fluid therapy and inotropes will be required. Use:

adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7), titrated to blood

pressure; large amounts may be required.

The use of other inotropes is less well defined and should be discussed with a clinical toxicologist (see
Inotropic support).

In patients in cardiac arrest, standard advanced life support protocols should be followed (see flowcharts
developed by the Australian Resuscitation Council).

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening. Arrhythmias
associated with QRS widening should be treated (see QRS widening and sodium channel blockade).

Decontamination
Activated charcoal should be administered early to all but the most minor overdoses so long as the patient is
relatively asymptomatic. With emerging signs of severe toxicity this therapy should be delayed until the
airway is protected, in which case it would be reasonable to administer activated charcoal up to 4 hours after
the estimated time of ingestion (see Single-dose activated charcoal).

Enhanced elimination
Multiple-dose activated charcoal has been shown to increase elimination of quinine (see Multiple-dose
activated charcoal).

Specific pharmacological therapies

Antidotal therapy

Historically high-dose diazepam has been used to treat severe chloroquine toxicity; however, the exact role of
diazepam remains poorly defined. Discussion with a clinical toxicologist is recommended in cases of life-
threatening chloroquine toxicity.

Electrolyte replacement

Potassium replacement should be given for hypokalaemia. Overcorrection of hypokalaemia should be

avoided, as redistribution of potassium when toxicity resolves can lead to significant hyperkalaemia. Use:

potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV over 1 to 2 hours (child: 0.6

mmol/kg IV over 3 hours), preferably as a premixed solution of the appropriate
intravenous fluid [Note 1].
Note 1: Extemporaneous addition of ampoules of potassium chloride to intravenous fluids is no longer
regarded as safe, because inadequate mixing may result in delivery of potassium at a lethal concentration. If
premixed IV solution is unavailable, potassium chloride concentrate injection must be added to a large
volume of parenteral fluid and mixed thoroughly before infusion. The usual maximum concentration is 40
 mmol/L.

Anticonvulsant therapy

Seizures are generally self-limiting, but if persistent and recurrent they can be treated with benzodiazepines
(see Anticonvulsant therapy).

Observation and patient disposition after chloroquine,

hydroxychloroquine or quinine poisoning
Criteria for discharge: Patients with a normal level of consciousness, a normal blood pressure and a normal
ECG can be discharged 6 hours after ingestion.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: clonidine
Risk assessment for clonidine poisoning
Clonidine is a centrally acting alpha2 agonist that produces a reduced level of consciousness including coma
with mild bradycardia and hypotension in overdose. In children, the effects can be more significant.

Toxic dose
Ingestions of more than 10 micrograms/kg clonidine are associated with potentially significant poisoning in
children, and such patients should be admitted.

Clinical presentation
Clonidine is commonly ingested in young children and adolescents but rarely causes major problems if less
than 10 micrograms/kg is ingested. The classic presentation is CNS depression, bradycardia and miosis.
Bradycardia may persist for 24 to 48 hours.

Systemic effects of clonidine overdose include:

CNS effects—drowsiness progressing to coma, respiratory depression, miosis

cardiovascular effects—early transient hypertension, bradycardia, hypotension
other less common effects—hypotonia, hypothermia, seizures.

Treatment of clonidine poisoning

Airway and breathing
The majority of cases will not require airway or ventilatory support, but intubation and mechanical
ventilation are indicated for coma and respiratory depression in severe poisoning. Consider the potential for
profound bradycardia with the use of suxamethonium. Atropine is useful to minimise this effect. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02
mg/kg up to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of
1 mg).

Circulation
Hypotension due to the effects of clonidine on the peripheral circulation should be treated with fluids (see
Resuscitation: circulation).

Although bradycardia will respond transiently to the administration of atropine, it is only indicated if there is
associated hypotension. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02
mg/kg up to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of
1 mg).

Patients should be observed for the duration of their bradycardia, although heart rate monitoring is sufficient
in patients without hypotension.

Early hypertension is rarely observed because it has usually resolved before presentation. No treatment is
required because it resolves spontaneously and the antihypertensive drugs will exacerbate the hypotensive
phase.

Decontamination
Activated charcoal should be considered with caution because of the potential for rapid-onset CNS
depression. Only consider activated charcoal in a cooperative patient within 1 hour of the estimated time of
ingestion if there are no features of CNS depression (see Single-dose activated charcoal).

Specific pharmacological therapies

Antidotal therapy

Although there are reports of naloxone being effective for reversing respiratory and CNS depression,
particularly in children, clonidine overdose can be safely managed with supportive care.

Naloxone may be trialled, in the severely symptomatic patient, while specialist intervention is arranged.

Observation and patient disposition after clonidine poisoning

Criteria for discharge: Patients should be monitored for 4 hours after ingestion and can be discharged if no
effects are observed.

Criteria for admission: All patients with symptoms should be observed for at least 12 hours after ingestion
or until the bradycardia has resolved. Any child who has ingested a dose of more than 10 micrograms/kg
requires admission.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: colchicine
Risk assessment for colchicine poisoning
Urgently contact a poisons information centre (p: 13 11 26) or clinical toxicologist if colchicine poisoning is suspected.

Colchicine is a highly toxic drug for which there is no antidote, and even the best supportive care may not be life-
saving in severe poisoning. Urgently contact a poisons information centre (p: 13 11 26) or clinical toxicologist if
colchicine poisoning is suspected.

Toxic dose
There is some relationship between the acute dose ingested and toxicity:

less than 6 mg colchicine is not associated with significant toxicity

more than 0.5 mg/kg colchicine is associated with severe toxicity.

Clinical presentation
Colchicine causes widespread toxicity leading to multiorgan failure in overdose. The clinical features can be
divided into four stages:

gastrointestinal effects (2 to 8 hours after ingestion)—vomiting and profuse diarrhoea leading to

hypovolaemia and leucocytosis
multiorgan failure and cardiovascular collapse (24 hours to 7 days)—myocardial depression, arrhythmias,
respiratory depression, metabolic acidosis, kidney failure, rhabdomyolysis, hypocalcaemia, neurotoxicity,
consumptive coagulopathy, liver failure
bone marrow suppression (5 to 10 days)—mainly severe neutropenia; thrombocytopenia
recovery (10 or more days)—alopecia, rebound leucocytosis.

Key investigations in colchicine poisoning

There are no specific investigations for colchicine poisoning and investigations should be guided by the clinical
condition:

Electrolytes and creatinine.

Liver biochemistry.
Full blood count (important with delayed bone marrow suppression).

Treatment of colchicine poisoning

Airway and breathing
Patients rarely have CNS depression or respiratory depression initially, until they develop multiorgan failure when
airway support and mechanical ventilation are required.

Circulation

Aggressive fluid therapy is required due to the large initial fluid loss with profuse diarrhoea (see Resuscitation:
circulation).

Inotropic support

In severe poisoning, myocardial depression requires inotropic support. Initially use adrenaline:

adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7), titrated to blood

pressure; large amounts may be required.
The use of other inotropes should be guided by standard critical care principles. Potential drugs include:

1 dobutamine 2.5 to 10 micrograms/kg/minute (child: 5 to 20 micrograms/kg/minute) IV

infusion

OR

1 milrinone (adult) 50 micrograms/kg IV slowly over 10 minutes, followed by an infusion

of 0.375 to 0.75 micrograms/kg/minute, adjusting according to clinical and
haemodynamic response, up to a maximum of 1.13 mg/kg daily
milrinone (child 30 kg or less) 1.5 mg/kg in 50 mL, 2.5 mL (= 75 micrograms/kg) IV over
1 hour, then 1 to 1.5 mL/hour (= 0.5 to 0.75 micrograms/kg/minute)

or milrinone (child more than 30 kg) 1.5 mg/kg in 100 mL, 5 mL (= 75 micrograms/kg) IV over 1 hour, then 2 to 3
mL/hour (= 0.5 to 0.75 micrograms/kg/minute) [Note 1].

Patients with cardiogenic shock should be managed in a tertiary intensive care unit. Cardiac assist devices have
been used with limited success in these cases.

Note 1: Compatible dilution fluids for milrinone are sodium chloride 0.9% or glucose 5%.

Decontamination
Early decontamination after colchicine poisoning is recommended.

If the patient has ingested more than 0.1 mg/kg or 6 mg (whichever is less) colchicine, offer activated charcoal.

Severe colchicine poisoning lacks effective treatment. Therefore, if the patient has ingested more than 0.3 mg/kg
or 20 mg (whichever is less) colchicine, give activated charcoal. Uncooperative patients may need sedation and
intubation.

Activated charcoal should be used even if it is more than 1 hour after colchicine was ingested.

Enhanced elimination
Due to biliary secretion of colchicine, multiple-dose activated charcoal should theoretically be effective and should
be considered in severe poisoning (see Multiple-dose activated charcoal).

Specific pharmacological therapies

Treatment of neutropenia

In patients with severe bone marrow failure, a clinical haematologist should be consulted and the patient managed
in an appropriate facility for neutropenic patients. There is increasing evidence that treatment with granulocyte
colony-stimulating factor (G-CSF) shortens the period of neutropenia that occurs. Use:

1 filgrastim 300 micrograms (child: 5 micrograms/kg) SC, daily

OR

1 lenograstim 263 micrograms (child: 150 micrograms/m2) SC, daily.

Observation and patient disposition after colchicine poisoning

Criteria for admission: Any patient who has ingested more than 6 mg colchicine should be observed and
transferred to an intensive care unit or appropriate hospital if signs of severe poisoning develop.

Key references
Toxicology: colchicine

Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. Colchicine poisoning: the dark side of
an ancient drug. Clin Toxicol (Phila) 2010;48(5):407–14. [ ]
Published July 2012. Amended July 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: cyanide
Risk assessment for cyanide poisoning
Exposure
The majority of cases of cyanide poisoning are due to exposure by inhalation in domestic or industrial fires, and
concurrent carbon monoxide poisoning is common. Ingestion of cyanide-containing products can result in rapidly
life-threatening poisoning.

Clinical presentation
Cyanide poisoning can be rapidly fatal. Patients with cyanide poisoning that arrive in hospital usually have mild to
moderate symptoms.

Systemic effects of acute cyanide exposure include:

CNS effects—headache, weakness, confusion; progressing to coma and seizures

cardiovascular effects—tachycardia, hypotension, ECG changes, arrhythmias, cardiac arrest
gastrointestinal effects—nausea, vomiting
respiratory effects—dyspnoea, cyanosis, respiratory failure.

Key investigations in cyanide poisoning

The key investigations in cyanide exposure include:

Lactate concentrations—blood lactate greater than 10 mmol/L is a marker of severe poisoning.

Electrolytes and creatinine.
ECG.
Venous blood gases—venous partial pressure of oxygen (PaO2) may be high, indicating impaired tissue
oxygen extraction. A reduction in the arterial/venous oxygen saturation difference is a marker of reduced
tissue oxygen extraction (which is seen in cyanide poisoning).

Treatment of cyanide poisoning

Airway and breathing

Patients with a decreased level of consciousness or respiratory failure require early intubation and ventilation.

Circulation
Patients with hypotension should be treated with intravenous fluids (see Resuscitation: circulation).

Arrhythmias should be treated according to standard protocols (see Acute management of arrhythmias).

Decontamination
Activated charcoal should only be given if the patient presents within 1 hour of the estimated time of ingestion,
and after the airway has been secured. This is because of the rapid absorption of cyanide and the potential for CNS
depression (see Single-dose activated charcoal). This should not delay resuscitation or antidotal therapy if
required.

Specific pharmacological therapies

Antidotal therapy

Cyanide concentrations are not available in time to influence management, and therefore antidotal therapy should
be initiated in suspected cyanide poisoning.

Although there are a number of antidotes available for cyanide poisoning, they all have drawbacks—either a risk
of significant adverse effects, or a high cost and limited availability. Two antidotes, hydroxocobalamin and sodium
thiosulfate, can be given empirically, although hydroxocobalamin is not universally available [Note 1].
Hydroxocobalamin may be given in the prehospital setting. Dicobalt edetate is another antidote that can be used. It
is associated with severe adverse effects, which may be life-threatening. These reactions are more common in
patients without cyanide poisoning, so it should not be used unless the patient is critically unwell and there is a
reasonable suspicion of cyanide poisoning. Early discussion with a clinical toxicologist is essential.

In mild poisoning (normal conscious state, nausea, dizziness, and no hypotension), use:

sodium thiosulfate 12.5 g (= 50 mL of 25% solution) (child: 400 mg/kg) IV over 10

minutes; the dose can be repeated after 30 to 60 minutes if there is no clinical
improvement

PLUS (if there is any deterioration in clinical state)

hydroxocobalamin 5 g (child: 50 mg/kg [Note 2]) IV over 30 minutes (diluted in 200 mL

of glucose 5%); the dose can be repeated after 30 to 60 minutes if there is no clinical
improvement [Note 1].

In moderate to severe poisoning (altered conscious state, seizures, hypotension, systemic acidosis, raised lactate,
cardiac arrest), use:

sodium thiosulfate 12.5 g (= 50 mL of 25% solution) (child: 400 mg/kg) IV over 10

minutes; the dose can be repeated after 30 to 60 minutes if there is no clinical
improvement

PLUS

hydroxocobalamin 5 g (child: 50 mg/kg [Note 2]) IV over 30 minutes (diluted in 200 mL

of glucose 5%); the dose can be repeated after 30 to 60 minutes if there is no clinical
improvement [Note 1].

If hydroxocobalamin is not available, use:

1 sodium nitrite 300 mg (= 10 mL of 3% solution) (children: 4 to 10 mg/kg up to 300 mg [=

0.13 to 0.33 mL/kg of 3% solution up to 10 mL]) IV over 5 to 20 minutes

PLUS
sodium thiosulfate 12.5 g (= 50 mL of 25% solution) (child: 400 mg/kg) IV over 10
minutes. The dose can be repeated after 30 to 60 minutes if there is no clinical
improvement

OR

2 dicobalt edetate 300 mg (= 20 mL of 1.5% solution) (child: 7.5 mg/kg) IV over 1 minute

FOLLOWED IMMEDIATELY BY
glucose (adults) 50% 50 mL IV, preferably via a central line as a bolus, or via a large
peripheral vein by slow injection
glucose (children) 10% 2.5 mL/kg IV via a large peripheral vein as a bolus.

Note 1: Hydroxocobalamin 5 g vials are not registered for use in Australia but are available via the Special
Access Scheme.

Note 2: The paediatric dose of hydroxocobalamin as an antidote in cyanide poisoning has not been determined,
but an initial dose of 50 mg/kg has been suggested in Murray L, Daly F, Little M, Cadogan M. Toxicology
handbook. Sydney: Elsevier Australia, Churchill Livingstone; 2011.

Observation and patient disposition after cyanide poisoning

Criteria for discharge: If patients remain asymptomatic for 6 hours after ingestion and have normal arterial blood
gases they can be discharged.

Criteria for admission: All patients with moderate to severe poisoning should be admitted to a critical care unit.
Seek early advice from a clinical toxicologist.

Key references
Toxicology: cyanide

Baud FJ, Borron SW, Megarbane B, Trout H, Lapostolle F, Vicaut E, et al. Value of lactic acidosis in the assessment of
the severity of acute cyanide poisoning. Crit Care Med 2002;30(9):2044–50. [ ]

Cummings TF. The treatment of cyanide poisoning. Occup Med (Lond) 2004;54(2):82–5. [ ]

Fortin JL, Giocanti JP, Ruttimann M, Kowalski JJ. Prehospital administration of hydroxocobalamin for smoke
inhalation-associated cyanide poisoning: 8 years of experience in the Paris Fire Brigade. Clin Toxicol (Phila) 2006;44
Suppl 137–44. [ ]

Murray L. Toxicology handbook. 2nd ed. Chatswood, NSW: Elsevier Australia; 2011.

Sauer SW, Keim ME. Hydroxocobalamin: improved public health readiness for cyanide disasters. Ann Emerg Med
2001;37(6):635–41. [ ]

Vogel SN, Sultan TR, Ten Eyck RP. Cyanide poisoning. Clin Toxicol 1981;18(3):367–83. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: digoxin
Risk assessment for digoxin poisoning
Acute digoxin poisoning results in a delayed onset (hours) of hyperkalaemia and cardiovascular toxicity that can
be lethal without digoxin antibodies.

Chronic digoxin poisoning is often missed and is associated with an appreciable 7-day mortality.

Toxic dose
Severe acute digoxin toxicity has been associated with ingestions of greater than 10 mg in adults and greater than 4
mg in children.

Toxic concentration
Acute overdose: digoxin concentration is not a good indicator of acute toxicity, particularly in the first 6 hours
after ingestion. Peak concentrations greater than 15 nmol/mL are associated with lethality.

Chronic toxicity: digoxin concentration is a useful tool in the diagnosis of chronic toxicity. Concentrations of 1.9
nmol/L (1.5 micrograms/L or ng/mL) or less are unlikely to be associated with toxicity. Conversely, steady-state
digoxin concentrations greater than 2.0 nmol/L with associated systemic effects (see Clinical presentation) are
more closely correlated with toxicity.

Clinical presentation
The clinical effects of digoxin poisoning are similar following chronic toxicity and acute overdose. In acute
overdose, the peak effects occur approximately 6 hours after ingestion and the delay is due to distribution to
myocardial tissue.

Systemic effects of digoxin poisoning include:

gastrointestinal effects—nausea, vomiting, abdominal pain, diarrhoea

CNS effects—uncommon, but visual disturbance and confusion may develop with chronic toxicity
cardiovascular effects
–
minor or early ECG changes—ST depression with the characteristic 'reverse tick' appearance; extra-
systolic beats; minor degrees of atrioventricular (AV) nodal block
–
bradyarrhythmias—slow atrial fibrillation; second- and third-degree AV block
–
junctional and atrial tachycardia
–
ventricular tachycardia and ventricular fibrillation (high mortality)
–
cardiac arrest (asystole)
–
hypotension.

Key investigations in digoxin poisoning

The key investigations in digoxin poisoning include:

ECG.
Digoxin concentration
–
In acute overdose, a serum concentration measured earlier than 6 hours does not correlate well with
clinical effects due to ongoing distribution of digoxin. An initial concentration should be taken at 6
hours, then every 2 to 4 hours until the concentration has decreased to less than 6.4 nmol/L (5
micrograms/L or ng/mL). Serum digoxin concentrations are unable to be interpreted following
administration of digoxin immune Fab.
–
 In chronic digoxin poisoning, an initial concentration is obtained at least 6 hours from the last
digoxin dose, then every 6 to 12 hours until the concentration has decreased to within the therapeutic
range. Serum digoxin concentrations are unable to be interpreted following administration of digoxin
immune Fab.
–
Most Australian laboratories now use the International System of Units (SI) for digoxin
concentrations (nmol/L). To convert micrograms/L (or ng/mL) to nmol/L, multiply by 1.28.
–
Most assays measure the total digoxin in serum, which increases after the administration of digoxin
antibodies because the antibodies will bind the digoxin in the circulation. Free digoxin concentration
can be measured, but this is not as readily available and is unlikely to change clinical management.
Electrolytes—creatinine, urea, potassium, sodium, bicarbonate, magnesium and calcium should be done.
–
Hypokalaemia and hypomagnesaemia may exacerbate digoxin toxicity.
–
Hyperkalaemia (potassium concentration greater than 5.5 mmol/L) is a manifestation of severe
digoxin toxicity.

Treatment of digoxin poisoning

Circulation
Hypotension should be treated with intravenous fluids (see Resuscitation: circulation), except in patients with
chronic digoxin toxicity who have cardiac or kidney failure, where large fluid boluses may be detrimental.

Acute digoxin overdose

All patients with acute digoxin poisoning require continuous ECG monitoring and regular 12-lead ECGs. The
majority of patients will develop some evidence of digoxin toxicity on a 12-lead ECG.

Digoxin immune Fab administration is indicated when the ingested dose and clinical features are suggestive of a
potentially lethal ingestion:

ingested dose (more than 10 mg in adults, more than 4 mg in children)

cardiac arrest
potassium concentration above 5.0 mmol/L
life-threatening ventricular arrhythmias
decompensation (hypotension) from bradyarrhythmias.

For dose recommendations, see Acute digoxin overdose below.

Chronic digoxin toxicity

Digoxin immune Fab has been associated with lowering of mortality, length of stay and cost of care in chronic
digoxin poisonings. Indications are significant clinical features of digoxin toxicity associated with an elevated
concentration (above 2.0 nmol/L). Use may obviate the need for cardiac monitoring and critical care. For dose
recommendations, see Chronic digoxin toxicity below.

Decompensated atrioventricular nodal block should be treated with digoxin antibodies but if these are not available
or delayed, initially use:

atropine 0.6 to 1.2 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02 mg/kg up
to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of 1 mg).

Decontamination
In acute overdose, activated charcoal can be administered to cooperative patients within 2 hours of the estimated
time of ingestion (see Single-dose activated charcoal). Administration may be problematic if the patient is
vomiting.

Specific pharmacological therapies

Antidotal therapy

Digoxin antibodies (digoxin-specific immune antigen binding fragments [digoxin immune Fab]) bind digoxin in
the circulation and remove it from its site of action, the sodium/potassium adenosine triphosphatase (Na+/K+
ATPase) pump. One vial of digoxin antibodies contains 38 mg of digoxin specific fragments, which will bind
approximately 0.5 mg of digoxin.

The dose of digoxin antibodies can be calculated from the body burden, see Table 17.11, which is calculated based
on either:

the amount of digoxin ingested in acute overdose (if known), or

the digoxin concentration in chronic toxicity.

However, limited evidence suggests it is best to titrate to clinical effect by giving half of this dose (calculated from
the body burden) and repeating as required.

Acute digoxin overdose

For acute digoxin overdose when the amount ingested is known, use:

digoxin immune Fab half of calculated dose (see Table 17.11) by slow IV infusion over 30
minutes, or as an IV bolus in cardiac arrest. This can be repeated after 30 to 60 minutes if
there has been no clinical response. Consider discussion with a clinical toxicologist.

For acute digoxin overdose when the amount ingested is not known, use:

digoxin immune Fab 380 mg (= 10 vials) by slow IV infusion over 30 minutes, or as an IV

bolus in cardiac arrest. This dose can be repeated after 30 to 60 minutes if there has been
no clinical response. Consider discussion with a clinical toxicologist.

Acute overdose patients should be monitored for 12 hours to make sure there is no recurrence of clinical effects. If
there is deterioration, the same dose should be repeated.

Chronic digoxin toxicity

For chronic digoxin poisoning when the serum digoxin concentration is known, use:

digoxin immune Fab half of calculated dose (see Table 17.11) by slow IV infusion over 30
minutes. This can be repeated after 30 to 60 minutes if there has been no clinical response.
Consider discussion with a clinical toxicologist.

For chronic digoxin poisoning when the serum digoxin concentration is not known, use:

digoxin immune Fab 76 mg (= 2 vials) by slow IV infusion over 30 minutes. This dose
can be repeated after 30 to 60 minutes if there has been no clinical response. Consider
discussion with a clinical toxicologist.

Patients should be monitored until resolution of cardiac effects. This is particularly important in chronic poisoning,
where there is slow mobilisation of digoxin from the tissues, but the digoxin antibodies are eliminated over 12 to
24 hours.

Note that the binding of digoxin by digoxin immune Fab in the circulation will cause a rapid rise in total plasma
digoxin concentration. However, free digoxin concentrations, which correlate with toxicity, are reduced.

Calculation of digoxin immune Fab dose (Table 17.11)

Step 1. Calculate body burden of digoxin

In acute digoxin overdose (based on amount of digoxin ingested):

body burden (mg) = amount ingested (mg) x 0.8 [NB1]

In chronic digoxin toxicity (based on serum digoxin concentration) [NB2]:

body burden (mg) = serum digoxin (nmol/L) x 0.4

OR

body burden (mg) = serum digoxin (micrograms/L or nanograms/mL) x 0.5

Step 2. Calculate digoxin immune Fab dose
number of vials = body burden (mg) / 0.5 [NB3]
Digoxin immune Fab = digoxin-specific immune antigen binding fragments
NB1: The oral bioavailability of digoxin is 0.8.
 NB2: These equations give an approximate indication of body burden based on a 70 kg adult, with a volume of distribution of 7 L/kg. The conversion
factor from mass units (micrograms/L or nanograms/mL) to molar units (nmol/L) is 1.28.
NB3: One 38 mg vial of digoxin immune Fab binds approximately 0.5 mg digoxin.

Electrolyte management

Patients with hypomagnesaemia should have their magnesium replaced.

In adults, use:

magnesium sulfate 50% 5 to 10 mL (= 2.5 to 5 g or 10 to 20 mmol) IV over 30 to 60

minutes.

In children, use:

magnesium sulfate 50% 0.1 mL/kg (= 50 mg/kg or 0.2 mmol/kg) IV over 20 minutes
[Note 1], followed by an infusion of 0.06 mL/kg/hour (= 30 mg/kg/hour or 0.12
mmol/kg/hour).

Patients with hypokalaemia should have their potassium replaced. If the patient is able to take and absorb oral
potassium, use:

potassium chloride 14 to 16 mmol orally, 3 times daily (child: 1 mmol/kg/day in 2 to 4

divided doses) [Note 2].

If the serum potassium is less than 3 mmol/L or the patient is unable to take or absorb oral potassium, use:

potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV over 1 to 2 hours (child: 0.3 to 0.6
mmol/kg IV over 3 hours), preferably as a premixed solution of the appropriate
intravenous fluid [Note 3].

In patients with hyperkalaemia where digoxin antibodies are not immediately available, the following treatment
should be used:

short-acting insulin 10 units (child: 0.1 units/kg) IV bolus (see Table 18.4 for insulin
formulations)

PLUS
glucose (adults) 50% 50 mL IV, preferably via a central line over 5 minutes, or via a
large peripheral vein by slow injection
glucose (children) 10% 2.5 mL/kg IV via a large peripheral vein over 5 minutes

PLUS

sodium bicarbonate sodium bicarbonate 8.4% (= 1 mmol/mL) 50 mL (child: 1 mL/kg) IV

over 5 to 10 minutes, under ECG control. This may be repeated in 60 to 120 minutes.
Calcium should not be used for the treatment of hyperkalaemia in the setting of digoxin toxicity.

Note 1: Magnesium can be given intramuscularly in infants or children if urgent IV access is not possible.

Note 2: Effervescent immediate-release tablets of potassium contain 14 mmol potassium per tablet, and slow-
release tablets contain 8 mmol potassium per tablet. The slow-release formulations of potassium are almost
completely absorbed within one hour.

Note 3: Extemporaneous addition of ampoules of potassium chloride to intravenous fluids is no longer regarded
as safe, because inadequate mixing may result in delivery of potassium at a lethal concentration. If premixed IV
solution is unavailable, potassium chloride concentrate injection must be added to a large volume of parenteral
fluid and mixed thoroughly before infusion. The usual maximum concentration is 40 mmol/L.

Observation and patient disposition after digoxin poisoning

Criteria for discharge: Patients should only be discharged once they are well and symptom free. In the case of
chronic digoxin poisoning the precipitating cause also must have resolved.
Criteria for admission: All patients who have ingested a toxic dose of digoxin should be admitted for monitoring,
and for measurement of a digoxin concentration at 6 hours after ingestion.

Key references
Toxicology: digoxin

Abad-Santos F, Carcas AJ, Ibanez C, Frias J. Digoxin level and clinical manifestations as determinants in the
diagnosis of digoxin toxicity. Ther Drug Monit 2000;22(2):163–8. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: essential oils
Introduction to poisoning caused by essential oils
An essential oil is any plant-derived, volatile oil that contains the 'essence' or distinctive aroma of the plant.
Eucalyptus oil, tea tree oil and aromatherapy oils are common examples.

Vaporiser solutions have properties similar to those of essential oils, but are much less concentrated (eg 20%
to 25% concentrations are common).

Risk assessment for poisoning caused by essential oils

Overview

Essential oils are rapidly absorbed and symptoms, if they develop, usually occur within 30 minutes of
ingestion. Most poisonings occur in children, who have minor effects or remain asymptomatic. Significant
toxicity is more likely in adults with deliberate self-poisoning involving large volumes.

Toxic dose

The severity of toxicity is dependent on the dose ingested.

In adults, the toxic dose is unclear but there is potential for toxicity with any deliberate self-poisoning.

In children, the toxicity is dose-dependent. For eucalyptus oil:

2 to 3 mL of 100% oil—minor CNS depression

more than 7.5 mL of 100% oil—severe CNS depression.

These doses may be different for other essential oils. For example, clove oil, pennyroyal oil and camphor
products may be more toxic.

Clinical presentation
Eucalyptus oil is the most common essential oil poisoning. Less information is available on other essential
oils although the effects are similar, namely:

CNS effects—CNS depression, drowsiness, coma, seizures

respiratory effects—aspiration and aspiration pneumonitis with cough, choking and respiratory distress
gastrointestinal effects—nausea, vomiting
cardiovascular effects—severe poisoning can cause hypotension, tachycardia.

Key investigations in poisoning caused by essential oils

The key investigations in essential oil poisoning include:

Chest X-ray—perform if there is a history of, or symptoms or signs consistent with, potential
aspiration.

Treatment of poisoning caused by essential oils

The mainstay of care is supportive and there are no specific treatments. Provide supportive care for airway
and breathing if there is CNS depression or aspiration pneumonitis.

Decontamination is of no value due to rapid absorption of the volatile oils.

Observation and patient disposition after poisoning with essential

oils
Criteria for discharge: If the patient is asymptomatic on admission, observe for 1 hour after ingestion and
discharge if still asymptomatic.

Criteria for admission: If CNS or respiratory effects are present, or develop within an hour of ingestion,
admit and observe.

Key references
Toxicology: essential oils

Webb NJ, Pitt WR. Eucalyptus oil poisoning in childhood: 41 cases in south-east Queensland. J Paediatr Child
Health 1993;29(5):368–71. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: flecainide
Risk assessment for flecainide poisoning
Flecainide is a class IC antiarrhythmic with potent sodium channel–blocking effects. Overdose is rare, but
may be rapidly lethal with profound cardiovascular collapse.

Toxic dose
In adults, ingestion of more than 800 mg flecainide should be considered life-threatening. In children,
ingestion of 50 mg flecainide (a single tablet) may be life-threatening.

Clinical presentation
The onset of clinical effects of flecainide poisoning is rapid and occurs within 30 to 60 minutes of ingestion.

Systemic effects of flecainide overdose include:

cardiovascular effects— QRS widening, QT prolongation, bradycardia with variable atrioventricular

(AV) nodal block, ventricular tachycardia, ventricular fibrillation, asystole and pulseless electrical
activity; hypotension, pulmonary oedema
CNS effects—sedation and dizziness; coma and seizures in more severe cases
gastrointestinal effects—nausea, vomiting
metabolic effects—hypokalaemia, hyperglycaemia, metabolic acidosis.

Key investigations in flecainide poisoning

The key investigations in flecainide overdose include:

ECG—increased PR interval, QRS widening (sodium channel blockade) and QT prolongation all occur
with flecainide toxicity, but may occur to a lesser extent in poisonings in patients already taking
therapeutic doses.

Treatment of flecainide poisoning

Airway and breathing
Patients with a decreased level of consciousness, seizures or coma should be intubated and have mechanical
ventilation.

Circulation

Hypotension is common and should be treated initially with intravenous fluids (see Resuscitation:
circulation).

Inotropic support

Hypotension unresponsive to intravenous fluids requires inotropic support. Use:

adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7), titrated to blood

pressure; large amounts may be required.

The use of other inotropes is less well defined and should be discussed with a clinical toxicologist (see
Inotropic support).

All patients should have continuous ECG monitoring and regular 12-lead ECGs. ECG changes and
arrhythmias should be treated initially by following standard advanced life support protocols (see flowcharts
developed by the Australian Resuscitation Council).

QRS widening and sodium channel blockade

The most common important ECG change in flecainide overdose is QRS widening (more than 120 msec).
Arrhythmias associated with QRS widening should be treated (see QRS widening and sodium channel
blockade).

QT prolongation and torsades de pointes

Although QT prolongation occurs in flecainide overdose, torsades de pointes is rare. QT prolongation should
be monitored and any other precipitating factors should be determined and treated if possible (see QT
prolongation and torsades de pointes).

If there is deterioration to ventricular fibrillation or asystole, standard advanced life support protocols should
be followed (see flowcharts developed by the Australian Resuscitation Council).

Decontamination
Activated charcoal should be administered to any patient who has ingested a toxic dose of flecainide (see
Single-dose activated charcoal).

Specific pharmacological therapies

Antiarrhythmic drugs

The use of antiarrhythmic drugs is problematic and sufficient amounts of sodium bicarbonate should be used
first (see QRS widening and sodium channel blockade). Ventricular fibrillation and asystole should be
managed according to standard advanced life support protocols (see flowcharts developed by the Australian
Resuscitation Council), but antiarrhythmic drugs are generally contraindicated.

Observation and patient disposition after flecainide poisoning

Criteria for discharge: Asymptomatic patients with a normal ECG 4 hours after ingestion of flecainide are
unlikely to develop toxicity.

Criteria for admission: All patients who have ingested a toxic dose of flecainide should be admitted and
monitored initially for 4 hours after ingestion. If any ECG or clinical effects develop the patient should be
admitted to a critical care area.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: gamma-hydroxybutyrate
Introduction to gamma-hydroxybutyrate poisoning
Gamma-hydroxybutyrate (GHB) is a drug of abuse (see also Problem use of gamma-hydroxybutyrate). Most
ingestions are of the precursors gamma-butyrolactone or 1,4-butanediol, which the body rapidly converts to
GHB.

Risk assessment for gamma-hydroxybutyrate poisoning

GHB produces a rapid onset of euphoria. It has a steep dose-response curve and recreational doses often lead
to coma, which can be life-threatening, especially when taken with other sedatives, particularly alcohol. A
full recovery is expected with good airway management and supportive care.

Toxic dose
The ingested dose of GHB is rarely known because of its illicit use, so is not often useful in predicting
toxicity. More than 50 mg/kg GHB potentially causes decreased level of consciousness and coma.

Clinical presentation
The onset of the clinical effects is very rapid and the duration is short. Recovery usually occurs over about 2
to 4 hours.

Systemic effects include:

CNS effects—rapidly developing CNS depression, loss of airway protection, coma and collapse;
myoclonic jerks, dystonia, generalised seizures; delirium and agitation may occur after waking
cardiovascular effects—bradycardia, hypotension
other effects—hypothermia, vomiting.

Treatment of gamma-hydroxybutyrate poisoning

Airway and breathing
Close observation is essential to ensure an adequate airway in all patients. In many cases the patient can be
nursed in the left lateral position if this maintains an adequate airway. However, if this is inadequate, then the
patient needs to be intubated and ventilated. Airway support is rarely required for more than 2 to 4 hours.

Circulation
All patients should receive intravenous fluids for dehydration and hypotension (see Resuscitation:
circulation).

ECG monitoring is required to assess cardiovascular toxicity. Bradycardia is not uncommon, but seldom
requires intervention. Atropine is indicated if there is associated hypotension. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02
mg/kg up to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of
1 mg).

Decontamination

Decontamination is not indicated due to the rapid absorption of the liquid formulation, the rapid onset of a
decreased level of consciousness, and the good outcomes with supportive care.

Specific pharmacological therapies

Anticonvulsant therapy

Myoclonic jerks do not require treatment. Generalised seizures are rare and are generally self-limiting, but if
persistent and recurrent they can be treated with benzodiazepines (see Anticonvulsant therapy).

Observation and patient disposition after gamma-hydroxybutyrate

poisoning
Criteria for discharge: Patients can be discharged after they have been asymptomatic for 1 hour after
ingestion.

Criteria for admission: All patients with CNS depression require observation in the emergency department.
The duration of action of GHB is short (2 to 4 hours) so admission to intensive care is not warranted.

Key references
Toxicology: gamma-hydroxybutyrate

Chin RL, Sporer KA, Cullison B, Dyer JE, Wu TD. Clinical course of gamma-hydroxybutyrate overdose. Ann
Emerg Med 1998;31(6):716–22. [ ]

Galicia M, Nogue S, Miro O. Liquid ecstasy intoxication: clinical features of 505 consecutive emergency
department patients. Emerg Med J 2011;28(6):462–6. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: herbicides
Risk assessment for herbicide poisoning
Overview
Herbicides include chlorphenoxy herbicides, diquat, dicamba, glyphosate, paraquat and propanil.

All herbicide concentrates may cause severe toxicity with deliberate ingestion. Even when the active ingredients
are relatively nontoxic, the surfactants have significant toxicity. Further, propanil may cause severe
methaemoglobinaemia, chlorphenoxy herbicides may cause mitochondrial toxicity, and paraquat may cause severe
oxidative stress. Death can occur suddenly more than 24 hours after ingestion of chlorphenoxy herbicides in
patients who do not appear severely affected. Seek expert toxicological advice as soon as possible.

Delayed and unexpected sudden death can occur. Seek urgent toxicological advice.

Toxic dose

Toxic doses of herbicides vary widely by agent and formulation. All deliberate ingestions of concentrated solutions
and any ingestion of paraquat should be regarded as potentially fatal. In contrast, most unintentional and dermal
exposures to herbicides (other than paraquat) do not cause significant toxicity.

Clinical presentation
The main features common to most herbicide poisonings are listed in Table 17.12.

Additional systemic effects commonly associated with individual herbicides include:

chlorphenoxy herbicides—fasciculations, rhabdomyolysis, uncoupling of oxidative phosphorylation

paraquat—pancreatitis, mediastinitis, progressive pulmonary fibrosis
propanil— methaemoglobinaemia, haemolysis.

Classification of severity of herbicide poisoning based on clinical features (Table 17.12)

Severity Clinical features

gastrointestinal effects: mouth or throat pain, nausea, vomiting, diarrhoea
mild
severe gastrointestinal effects lasting more than 24 hours, gastrointestinal
haemorrhage and corrosive injury to the oropharynx and oesophagus
hypotension responding to IV fluids
moderate
respiratory distress
transient kidney impairment or metabolic acidosis

pulmonary oedema or respiratory failure requiring intubation

kidney failure
hepatic dysfunction
severe metabolic acidosis, hyperkalaemia
hypotension requiring inotropes, cardiac arrest
coma, seizures

Key investigations in herbicide poisoning

The key investigations in herbicide poisoning include:

Electrolytes—detect severe toxicity, particularly metabolic acidosis, hyperkalaemia and kidney failure.
Chest X-ray—detects aspiration pneumonitis and pulmonary oedema.
Full blood count.
Blood gases.
 Creatine kinase.
Liver biochemistry.

Treatment of herbicide poisoning

No proven specific treatments are available for most herbicides. Supportive care in moderate to severe cases is the
mainstay of therapy.

In propanil poisoning, specific treatment is as for methaemoglobinaemia.

In chlorphenoxy herbicide poisoning, urinary alkalinisation is indicated.

In paraquat poisoning, numerous treatments are available—seek expert toxicological advice.

Airway and breathing

Intubation and ventilation is required in severe cases due to respiratory dysfunction or pulmonary oedema. Early
intubation is indicated in severe cases due to local corrosive injury and the risk of swelling of the upper airways.

Circulation
Treat hypotension due to fluid loss initially with intravenous fluids (see Resuscitation: circulation).

Inotropic support

Hypotension unresponsive to intravenous fluids requires inotropic support. Initially use:

adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7), titrated to blood

pressure.

Additional inotropic therapy should be guided by the patient's haemodynamics. Seek the advice of a clinical
toxicologist.

Decontamination
Except for paraquat ingestion, decontamination with activated charcoal is not recommended due to the risk of
vomiting and aspiration of surfactants.

Enhanced elimination
Urinary alkalinisation and extracorporeal elimination may be useful in some poisonings by these agents (see
below). This should be discussed with a clinical toxicologist.

Urinary alkalinisation

In chlorphenoxy herbicide poisoning, intravenous sodium bicarbonate is indicated in adults and oral sodium
bicarbonate is indicated in children. Use:

sodium bicarbonate (adults) 8.4% (= 1 mmol/mL) 1 mmol/kg IV as an initial bolus,

followed by an infusion of 25 to 50 mmol/hour (to give 25 mmol/hour, dilute sodium
bicarbonate 100 mmol in 1000 mL of sodium chloride 0.9% and infuse at 250 mL/hour).
The rate should be adjusted to maintain a urinary pH greater than 7.5

OR

sodium bicarbonate (children) 8.4% (= 1 mmol/mL) 0.25 mmol/kg orally, 6- to 12-hourly.

The dosage should be adjusted to maintain a urinary pH greater than 7.5.

If hypokalaemia develops, either oral or intravenous potassium should be administered. Use:

1 potassium chloride 14 to 16 mmol orally, 3 times daily (child: 1 mmol/kg/day in 2 to 4

divided doses) [Note 1]

OR

potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV over 1 to 2 hours (child: 0.6

 1 mmol/kg IV over 3 hours), preferably as a premixed solution of the appropriate
intravenous fluid [Note 2].

Monitor potassium and kidney function every 4 hours and do a regular dipstick urinalysis to make sure the urine
remains alkaline. Continue treatment until the metabolic acidosis has resolved.

Note 1: Effervescent immediate-release tablets of potassium contain 14 mmol potassium per tablet, and slow-
release tablets contain 8 mmol potassium per tablet. The slow-release formulations of potassium are almost
completely absorbed within one hour.

Note 2: Extemporaneous addition of ampoules of potassium chloride to intravenous fluids is no longer regarded
as safe, because inadequate mixing may result in delivery of potassium at a lethal concentration. If premixed IV
solution is unavailable, potassium chloride concentrate injection must be added to a large volume of parenteral
fluid and mixed thoroughly before infusion. The usual maximum concentration is 40 mmol/L.

Extracorporeal elimination

Haemodialysis may be required in severe cases for acute kidney failure, metabolic acidosis and hyperkalaemia.
However, there is no expected benefit in enhancing elimination.

Observation and patient disposition after herbicide poisoning

Criteria for discharge: Except for paraquat, patients with unintentional oral, dermal and inhalational herbicide
exposures should be observed for 6 hours after exposure and discharged if asymptomatic.

Criteria for admission: All patients with paraquat poisoning should be admitted for observation. All patients with
other herbicide poisonings who are symptomatic 6 hours after exposure should be admitted for observation.
Patients with any evidence of moderate to severe poisoning should be admitted to a critical care area and may
require early resuscitation.

Key references
Toxicology: herbicides

Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. Br J Clin Pharmacol 2011;72(5):745–57. [
]

Roberts DM, Buckley NA. Urinary alkalinisation for acute chlorophenoxy herbicide poisoning. Cochrane Database Syst
Rev 2007;(1):CD005488. [ ]

Roberts DM, Buckley NA, Mohamed F, Eddleston M, Goldstein DA, Mehrsheikh A, et al. A prospective observational
study of the clinical toxicology of glyphosate-containing herbicides in adults with acute self-poisoning. Clin Toxicol
(Phila) 2010;48(2):129–36. [ ]

Roberts DM, Heilmair R, Buckley NA, Dawson AH, Fahim M, Eddleston M, et al. Clinical outcomes and kinetics of
propanil following acute self-poisoning: a prospective case series. BMC Clin Pharmacol 2009;93. [ ]

Roberts DM, Seneviratne R, Mohammed F, Patel R, Senarathna L, Hittarage A, et al. Intentional self-poisoning with
the chlorophenoxy herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA). Ann Emerg Med 2005;46(3):275–84. [
]

Senarathna L, Eddleston M, Wilks MF, Woollen BH, Tomenson JA, Roberts DM, et al. Prediction of outcome after
paraquat poisoning by measurement of the plasma paraquat concentration. QJM 2009;102(4):251–9. [ ]

Zawahir S, Roberts DM, Palangasinghe C, Mohamed F, Eddleston M, Dawson AH, et al. Acute intentional self-
poisoning with a herbicide product containing fenoxaprop-P-ethyl, ethoxysulfuron, and isoxadifen ethyl: a prospective
observational study. Clin Toxicol (Phila) 2009;47(8):792–7. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: hydrofluoric acid (hydrogen fluoride)
Risk assessment for hydrofluoric acid poisoning
Overview
Most poisonings with hydrofluoric acid involve dermal exposures of relatively low concentrations that can cause
severe pain. Systemic fluorosis can be life-threatening and can occur following dermal exposure involving a large
surface area or high-concentration solutions, or can occur following deliberate ingestion.

For ingestion of hydrofluoric acid, see also Toxicology: caustic ingestions.

Exposure

Determinants of toxicity are:

route of exposure—inhalation, ingestion, ocular or dermal exposure

duration of exposure
body surface area exposed
concentration of solution.

Clinical presentation
The clinical effects depend on the route of exposure.

Dermal exposure

Local effects

Dermal exposure to high-concentration hydrofluoric acid solutions (60% to 100%) can cause severe and life-
threatening toxicity. Death has been reported with 100% hydrofluoric acid solution contacting 2.5% of the body
surface area.

The most common presentation is due to dermal exposure to low-concentration solutions (4% to 10%) over
extended periods of time, causing delayed and severe local pain lasting 12 to 48 hours.

Other local effects are pallor and blanching (first few hours), and blistering and tissue loss (days).

Systemic fluorosis

Systemic fluorosis occurs with dermal exposure to high concentrations and large or concentrated oral ingestions.
Effects include:

metabolic effects—hypocalcaemia, hypomagnesaemia, hyperkalaemia, metabolic acidosis

cardiovascular effects—secondary to electrolyte disturbance— QT prolongation, ventricular arrhythmias,
cardiac arrest
CNS effects—CNS depression, tetany, seizures.

Inhalational exposure

Inhalational exposure can irritate the eyes, nose and throat. Respiratory effects include cough, wheeze, dyspnoea
and, in severe cases, pulmonary oedema.

Ingestion

Large or concentrated oral ingestions can result in systemic fluorosis. See also Toxicology: caustic ingestions.

Ocular exposure

Ocular exposure is similar to dermal exposure in terms of severe pain, but with the additional risk to vision. Urgent
ophthalmological review should be sought.
Key investigations in hydrofluoric acid poisoning
The key investigations in hydrofluoric acid poisoning include:

ECG— QT prolongation can occur.

Electrolytes—check potassium, calcium, magnesium.

Treatment of hydrofluoric acid poisoning

Airway and breathing

The upper airway should be assessed for compromise and early intubation is indicated in all patients with upper
airway oedema.

Circulation

Patients should be treated with intravenous fluids (see Resuscitation: circulation).

QT prolongation and torsades de pointes

Continuous ECG monitoring and regular 12-lead ECGs are required to assess the QT interval. The QT interval acts
as a surrogate indicator of hypocalcaemia.

For details on the management of QT prolongation and torsades de pointes, see QT prolongation and torsades de
pointes.

Decontamination

For dermal exposure, the patient's clothes should be removed and their skin washed (see also Skin
decontamination).

For ocular exposure, the eye should be irrigated with water or sodium chloride 0.9%.

Specific pharmacological therapies

Antidotal therapy

Calcium gluconate or calcium chloride should be used for the treatment of systemic effects and pain in
hydrofluoric acid poisoning. The route of administration depends on the type of exposure.

For systemic toxicity and hypocalcaemia, calcium should be administered intravenously. Use:

calcium gluconate 10% 10 to 20 mL IV over 10 to 30 minutes; this may need to be

repeated regularly based on monitoring of serum calcium.

For dermal exposure, a gel of calcium gluconate should be applied. Use:

1 calcium gluconate 2.5% gel applied liberally to the exposure site

OR

1 calcium gluconate 10% solution 10 mL mixed with 30 g (or 30 mL) of water-soluble gel
applied liberally to the exposure site.

For persistent severe local pain with larger exposures to the arm and forearm, calcium can be administered by
regional intravenous infusion (Bier's block) or intra-arterial infusion. This should be discussed with a clinical
toxicologist. Use:

calcium gluconate 10% 10 mL, diluted in 40 mL of sodium chloride 0.9% IV, using a
Bier's block technique (pneumatic tourniquet); the cuff should be released after 20
minutes.

Intra-arterial calcium gluconate should only be administered after consultation with a clinical toxicologist and in a
critical care area. An arterial cannula is inserted into the radial, brachial or femoral artery depending on the
exposure site. Use:

calcium gluconate 10% 10 mL diluted in 40 mL of sodium chloride 0.9% intra-arterially

over 4 hours; this can be repeated 2 or more times depending on response and ongoing
pain.

Intradermal injection of calcium gluconate has been attempted, but it is not suitable for fingers, and has had limited
success.

For inhalational exposure, nebulised calcium gluconate can be used. Use:

calcium gluconate 2.5% (1 mL of calcium gluconate 10% in 3 mL of sodium chloride

0.9%) by nebuliser.

Electrolyte replacement

Patients with hypomagnesaemia should have their magnesium replaced [Note 1].

In adults, use:

magnesium sulfate 50% 5 to 10 mL (= 2.5 to 5 g or 10 to 20 mmol) IV over 30 to 60

minutes.

In children, use:

magnesium sulfate 50% 0.1 mL/kg (= 50 mg/kg or 0.2 mmol/kg) IV over 20 minutes
[Note 2], followed by an infusion of 0.06 mL/kg/hour (= 30 mg/kg/hour or 0.12
mmol/kg/hour).
Note 1: In toxicology patients, the correction of magnesium deficiency, if required, needs to be done rapidly
while the patient has a prolonged QT interval and is at risk of torsades de pointes.

Note 2: Magnesium can be given intramuscularly in infants or children if urgent IV access is not possible.

Anticonvulsant therapy

Seizures are generally self-limiting, but if persistent and recurrent they can be treated with benzodiazepines (see
Anticonvulsant therapy).

Analgesia

Pain should be treated with oral or parenteral analgesia.

Observation and patient disposition after hydrofluoric acid poisoning

Criteria for discharge: All patients should be initially observed for 6 hours after exposure. Asymptomatic
patients with a normal serum calcium concentration can be discharged.

Key references
Toxicology: hydrofluoric acid (hydrogen fluoride)

Ryan JM, McCarthy GM, Plunkett PK. Regional intravenous calcium: an effective method of treating hydrofluoric acid
burns to limb peripheries. J Accid Emerg Med 1997;14(6):401–2. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: hypoglycaemic drugs
Risk assessment for poisoning caused by hypoglycaemic drugs
Introduction
This section relates only to insulin and sulfonylureas, as there is currently minimal experience with other
hypoglycaemic drugs.

As metformin is not a hypoglycaemic drug, it is addressed separately (see Toxicology: metformin).

Toxic dose

Insulin: no toxic dose has been established for diabetic or non-diabetic patients. The duration of hypoglycaemia
depends on the dose given and the type of insulin (eg short- or long-acting preparations).

Sulfonylureas: no toxic dose has been established, but in children one tablet of any sulfonylurea, or in healthy
adults a few tablets, may cause hypoglycaemia. Patients with non–insulin-dependent diabetes already taking
sulfonylureas appear to be affected to a lesser extent by sulfonylurea overdose, possibly due to their insulin
resistance.

Clinical presentation
Hypoglycaemic drugs in overdose cause confusion, anxiety, sweating, shaking and palpitations. If hypoglycaemia
is left untreated, it results in coma, seizures and death.

Key investigations in poisoning caused by hypoglycaemic drugs

The key investigations in hypoglycaemic drug overdose include:

Blood glucose concentration—a finger prick test is the most important investigation and should be done
hourly in asymptomatic patients. In patients with hypoglycaemia, blood glucose concentrations should be
measured every 30 to 60 minutes until the blood glucose concentration has remained normal for 4 hours;
then measure every 4 hours. The blood glucose concentration should be maintained between 5.5 and 11
mmol/L (see Antidotal therapy).
Electrolytes—measure concentrations to detect hypokalaemia, hypomagnesaemia, hypophosphataemia.
Insulin concentrations (if available)—high concentrations help confirm sulfonylurea poisoning and a
reduction to low concentrations is a useful indicator of effective octreotide treatment (see Octreotide). The
normal range is poorly defined for nonfasting patients, but insulin concentrations greater than 100
microunits/mL (or milliunits/L) are associated with poisoning.
C-peptide concentrations (if available)—may assist in the management of patients without diabetes because
the C-peptide concentration increases as exogenous insulin is excreted.

Treatment of poisoning caused by hypoglycaemic drugs

Overview
In patients with diabetes, management of insulin overdose is relatively straightforward because it is easy to titrate
glucose replacement to the blood glucose concentration. Once the blood glucose concentration begins to rise,
glucose replacement can be gradually weaned and ceased.

In patients without diabetes, there is no obvious rise in blood glucose as the exogenous insulin is eliminated
because the normal pancreas simply begins to secrete endogenous insulin in response to the glucose therapy.
Weaning and cessation of glucose therapy in this setting is complex and a clinical toxicologist should be consulted.

Treatment of sulfonylurea overdose needs to focus on hypoglycaemia initially with glucose replacement and then
octreotide.

Airway and breathing

Supportive care may be required in severe or prolonged hypoglycaemia that has resulted in seizures and coma,
with secondary hypoxia.

Circulation
Although fluid replacement is required, this is usually satisfied by the large amounts of glucose 5% or 10%
solutions required to treat the hypoglycaemia.

Decontamination

In sulfonylurea overdose, as there is a safe and effective antidote available, activated charcoal should only be
administered to cooperative patients within 1 hour of the estimated time of ingestion (see Single-dose activated
charcoal). Treatment of hypoglycaemia must take precedence.

Specific pharmacological therapies

Antidotal therapy

Glucose

Hypoglycaemia needs treatment with glucose. If the patient is awake, oral glucose can be given.

If the patient is drowsy or unconscious, intravenous glucose should be given. In adults, use:

1 glucose 10% 250 mL IV via a large peripheral vein as an initial bolus

OR

1 glucose 50% 50 mL IV, preferably via a central line as an initial bolus, or via a large
peripheral vein by slow injection.

In children, use:

glucose 10% 2.5 mL/kg IV via a large peripheral vein as an initial bolus.

In insulin overdose, the blood glucose concentration should then be maintained between 5.5 and 11 mmol/L with a
glucose infusion (see Box 17.5).

In sulfonylurea overdose, an ongoing infusion of glucose causes further insulin secretion by the pancreas, leading
to a vicious cycle of increasing insulin secretion, further hypoglycaemia and increasing glucose requirements.
Following an initial intravenous bolus of glucose, patients should be treated with octreotide.
 Intravenous infusion of glucose (Box 17.5)

The concentration of glucose (5%, 10% or 50%) for IV infusion depends on the glucose requirements
(determined by the blood glucose concentration) and the limitations to administering large volumes of fluid,
particularly in children. In severe cases, 50% glucose needs to be administered via a central venous catheter.

Note that 10% glucose solutions can cause pain at the infusion site, which may limit the rate of administration.
The use of two peripheral cannulae with 10% glucose may allow larger amounts to be given without using a
central line.

In adults, use:

1 glucose 10% IV by infusion through a large peripheral vein, commencing at a rate of

100 mL/hour (= 10 g/hour) and increasing until the blood glucose concentration is
maintained between 5.5 and 11 mmol/L

OR

1 glucose 50% IV by infusion through a central venous catheter, commencing at a rate of

20 mL/hour (= 10 g/hour) and increasing until the blood glucose concentration is
maintained between 5.5 and 11 mmol/L.

In children, use:

1 glucose 10% IV by infusion through a large peripheral vein at a rate of 3 to 5

mL/kg/hour (= 5 to 8 mg/kg/minute) increasing until the blood glucose concentration is
maintained between 5.5 and 11 mmol/L

OR

1 glucose 50% IV by infusion through a central venous catheter at a maximum rate of 1

mL/kg/hour (= 8 mg/kg/minute) to maintain the blood glucose concentration between
5.5 and 11 mmol/L.

Octreotide

Octreotide is a somatostatin analogue that specifically blocks the secretion of insulin by the pancreas and therefore
blocks the effect of sulfonylureas. In sulfonylurea overdose, octreotide should be commenced following a single
bolus of glucose instead of a glucose infusion. Use:

1 octreotide 50 micrograms IV as an initial bolus, followed by an infusion of 25

micrograms/hour for at least 24 hours (child: 1 micrograms/kg/hour IV infusion)

OR

1 octreotide 50 micrograms (child: 2 micrograms/kg) SC, 8-hourly for at least 24 hours.

Octreotide should be continued initially for 24 to 48 hours. It can then be stopped. However, patients then require
regular blood glucose concentrations and observation for another 24 hours to confirm that the sulfonylurea toxicity
has resolved. Alternatively an insulin concentration can be measured 1 to 4 hours after ceasing octreotide. A high
insulin concentration indicates that octreotide should be continued. This can be discussed with a clinical
toxicologist.

Observation and patient disposition after poisoning caused by

hypoglycaemic drugs
Criteria for discharge: All patients with overdose should be observed until they have been euglycaemic for at
least 8 hours after poisoning. In the event of uncertainty, discussion with a clinical toxicologist is recommended.

Criteria for admission: Any patient with ongoing hypoglycaemia should be admitted.

Key references
Toxicology: hypoglycaemic drugs

Little GL, Boniface KS. Are one or two dangerous? Sulfonylurea exposure in toddlers. J Emerg Med 2005;28(3):305–
10. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: iron
Risk assessment for iron poisoning
Risk depends on the dose of elemental iron ingested, serum iron concentrations and clinical features related to
the time of ingestion. Most paediatric iron overdoses are unintentional and low risk.

Toxic dose
To determine the amount of elemental iron ingested, it is essential to establish which specific product was
ingested, as they contain different amounts of elemental iron (see Table 17.13). Toxicity relates to the amount
of elemental iron ingested and peak serum iron concentration as outlined in Table 17.14 and Table 17.15.

Elemental iron content of different iron salts (Table 17.13)

Iron salt Elemental (ferrous) iron (%)

ferrous fumarate 33
ferrous gluconate 11.6
ferrous sulfate (dried) 30
ferrous sulfate (nondried, heptahydrate) 20

Risk assessment based on dose of elemental iron ingested (Table 17.14)

Elemental iron dose ingested (mg/kg) [NB1] Risk assessment

less than 60 asymptomatic or minor gastrointestinal toxicity
60 to 120 systemic toxicity
greater than 120 potentially lethal
NB1: Calculations must be based on amount of elemental iron ingested, not the weight of the iron salt (see Table 17.13).

Risk assessment based on peak serum iron concentration (Table 17.15)

Serum iron concentration (micromol/L) 4 to

Risk assessment
6 hours after iron ingestion
10 to 30 (normal range) asymptomatic
30 to 90 generally not associated with significant systemic toxicity
90 to 180 systemic toxicity often seen and desferrioxamine indicated
greater than 180 severe life-threatening poisoning

Clinical presentation
The clinical presentation of iron poisoning is outlined in Table 17.16 (below).

Presentation of iron overdose (Table 17.16)

Time since ingestion Possible clinical features

haemorrhagic gastroenteritis: nausea, vomiting, haematemesis, bloody
30 minutes to 6 hours
diarrhoea; can result in dehydration, hypotension and metabolic acidosis
6 hours to 24 hours asymptomatic window
multiorgan failure: haemorrhagic gastroenteritis, metabolic acidosis,
24 hours to 48 hours intractable hypotension, kidney failure, CNS toxicity (coma, seizures),
pulmonary oedema, hepatotoxicity, coagulopathy
long-term sequelae gastrointestinal scarring and obstruction

Key investigations in iron poisoning

The key investigations in iron overdose include:

Peak serum iron concentration—helps to define toxicity. Peak serum concentrations occur 4 to 6 hours
after ingestion of immediate-release preparations, and 8 hours after ingestion of slow-release
preparations.
Abdominal X-rays—may be useful early in suspected iron overdoses to confirm the history and to guide
decontamination. However, with liquid and multivitamin preparations, or in delayed presentations, the
iron product may not be seen.

Other investigations in severe iron poisoning include:

Full blood count.

Electrolytes and creatinine.
Liver biochemistry and coagulation studies.
Blood glucose concentration.

Treatment of iron poisoning

Airway and breathing
Intubation and ventilation is rarely required unless severe multiorgan failure occurs.

Circulation
Intravenous fluid therapy is required for dehydration and hypotension (see Resuscitation: circulation).

Decontamination
If the patient is seen within 2 hours of ingestion and has ingested more than 60 mg/kg of elemental iron,
decontamination with whole bowel irrigation may be considered (see Whole bowel irrigation). This is only
likely to be beneficial in patients with a substantial number of radio-opaque tablets on abdominal X-ray.

Aspiration of gastric contents (not lavage) may be considered if the patient is seen within 1 hour of a life-
threatening ingestion of elemental iron (more than 120 mg/kg).

Specific pharmacological therapies

Antidotal therapy

Desferrioxamine is indicated in patients with severe systemic toxicity (gastrointestinal bleeding, coma, shock
or early metabolic acidosis), or in patients with an iron concentration greater than 90 micromol/L. For adults
and children, use:

desferrioxamine 15 mg/kg/hour IV infusion, increased to a maximum of 35

mg/kg/hour if necessary, depending on severity of clinical symptoms. The total IV
dose in general should not exceed 80 mg/kg/24 hours.

Desferrioxamine has been used safely in pregnancy. The dose should be reduced by 50% in severe kidney
impairment. Histamine release may lead to hypotension, flushing and urticaria. Infusion-related hypotension is
common, so ensure adequate hydration before commencing.

Desferrioxamine interferes with most assays for serum iron concentration and chelated iron often turns the
urine orange-red. Ideal titration and end-points for desferrioxamine therapy remain unclear and expert advice
from a clinical toxicologist should be sought. Due to the risk of acute respiratory distress syndrome and
respiratory toxicity, desferrioxamine should not be used for longer than 24 hours unless there are exceptional
circumstances.

Expert advice from a clinical toxicologist should be sought if using desferrioxamine therapy.

Observation and patient disposition after iron poisoning

Criteria for discharge: Patients who have ingested less than 40 mg/kg elemental iron can be medically
discharged.

Criteria for admission: Patients who have ingested more than 60 mg/kg of elemental iron, or who have
systemic effects, should be admitted.

Key references
Toxicology: iron

Iron. In: Wiki Tox: open source clinical toxicology curriculum [website]. [URL]

Klein-Schwartz W, Oderda GM, Gorman RL, Favin F, Rose SR. Assessment of management guidelines. Acute
iron ingestion. Clin Pediatr (Phila) 1990;29(6):316–21. [ ]

Manoguerra AS, Erdman AR, Booze LL, Christianson G, Wax PM, Scharman EJ, et al. Iron ingestion: an
evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2005;43(6):553–70. [
]

Mills KC, Curry SC. Acute iron poisoning. Emerg Med Clin North Am 1994;12(2):397–413. [ ]

Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. J Toxicol Clin Toxicol 1996;34(5):485–
9. [ ]

Nelson LS, Goldfrank LR, editors. Goldfrank's toxicologic emergencies. 9th ed. New York: McGraw-Hill Medical
Pub. Division; 2011.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: lead
Introduction to lead poisoning
Most lead poisonings in adults are from inhaled occupational exposure. Sources include:

lead mining
manufacturing of batteries, pigments, solder, ammunitions, car radiators, some cosmetics, and ceramic
ware with lead glazes
illegally distilled alcohol and ayurvedic medications
lead paint
lead piping.

The skeleton acts as a reservoir for lead. Significant quantities of lead can accumulate in bone in chronic
exposure, and continue to be released into the blood long after the contaminant is removed.

Risk assessment for lead poisoning

Toxic concentration

There is a reasonable correlation between whole blood lead concentration and clinical effects. However, these
vary in adults and children (see Table 17.17) and depend on whether the exposure is acute or chronic (see
also Clinical presentation).

Clinical features of lead toxicity related to blood lead concentration (Table 17.17)

Adults
Blood lead concentration
Clinical features
(micrograms/dL)
anaemia, arthralgia, myalgia, hypertension, peripheral
neuropathy, decreased hearing acuity, nephropathy,
30 to 100
hyperuricaemia, gout, kidney impairment, Fanconi syndrome,
decreased fertility (men), decreased T3/T4, gastrointestinal colic
more than 100 encephalopathy, seizures, coma, death
Children
Blood lead concentration
Clinical features
(micrograms/dL)
subtle neuropsychological changes, decreased hearing,
10 to 45
decreased growth velocity
more prominent developmental and neuropsychological effects,
45 to 80 headache, lethargy, decreased nerve conduction velocity,
abdominal pain, nausea
more than 80 anaemia, nephropathy, encephalopathy, seizures, coma, death

Clinical presentation

Acute poisoning

Systemic effects of acute poisoning include:

gastrointestinal effects—abdominal pain, nausea, vomiting

CNS effects—fatigue, weakness, headache; in severe and life-threatening toxicity, encephalopathy,
cerebral oedema, coma, seizures
other effects—haemolytic anaemia, hepatitis.

Chronic poisoning
Chronic lead poisoning is insidious in onset, and adverse health effects have been reported with any
detectable blood lead concentrations. These include:

CNS effects—poor concentration, headaches, impaired coordination, aggressive behaviour, irritability,

intellectual impairment in children
gastrointestinal effects—abdominal pain, anorexia, weight loss
kidney and cardiovascular effects—hypertension, hyperuricaemia, gout, kidney impairment, Fanconi
syndrome
other effects—anaemia, arthralgia, myalgia, decreased fertility, increased incidence of dental caries.

Key investigations in lead poisoning

The key investigations in lead poisoning include:

Whole blood lead concentration.

Urine lead concentration—24-hour urine collection.
Full blood count—investigate for anaemia (normochromic, normocytic); basophilic stippling is
characteristic, but may not be present in mild toxicity.
Abdominal X-ray—perform for confirmation and location of ingested lead objects (eg sinkers, lead
pellets).
Electrolytes, creatinine, urate and calcium.
Liver biochemistry.
Iron studies—iron deficiency is associated with increased lead absorption.

Treatment of lead poisoning

Any patient with an altered conscious state, seizures, or a blood lead concentration greater than 100
micrograms/dL must be referred to hospital for urgent assessment, identification and removal of lead source,
and consideration of chelation therapy. Investigate for iron deficiency and treat appropriately (see Iron
deficiency).

Decontamination
If lead has been ingested, removal should be attempted. A chest and abdominal X-ray should be performed
and the foreign body removed by either gastroscopy if above the gastro-oesophageal junction, or by whole
bowel irrigation if beyond this point. For whole bowel irrigation, see Whole bowel irrigation.

Abdominal X-rays should be repeated every 24 hours to monitor the progress of the foreign body until it is
passed in the faeces.

Decreasing exposure
It is important to determine the source of the lead exposure and to make efforts to reduce ongoing exposure to
the individual and to the general public. This includes a detailed occupational and social history. Should the
exposure be of public or occupational health concern, this should be discussed with your local public health
unit.

Specific pharmacological therapies

Chelation therapy

A clinical toxicologist should be contacted regarding any patient who presents to hospital with lead
encephalopathy (altered consciousness or seizures in the context of lead exposure), and the patient should be
treated urgently with intravenous chelation therapy. Use:

sodium calcium edetate (calcium EDTA) 50 to 75 mg/kg in 500 mL by slow IV

infusion over 24 hours.

The major potential toxicity of sodium calcium edetate is kidney dysfunction. Prolonged treatment is more
likely to lead to significant micronutrient deficiencies. If the patient is not pregnant, switch to oral chelation
therapy with succimer as soon as symptoms improve in response to sodium calcium edetate and the patient
can tolerate oral therapy (see dosage below). Various other experimental and combinational therapies exist
and may be advised by a clinical toxicologist.
Symptomatic adults without encephalopathy but with blood lead concentrations above 70 micrograms/dL,
and any child without encephalopathy but with a blood lead concentration above 45 micrograms/dL, should
receive oral chelation therapy. Use:

succimer (dimercaptosuccinic acid) 30 mg/kg/day orally, in 3 divided doses for 5 days

[Note 1].

Advice should be sought from a clinical toxicologist after initiating chelation therapy, as there are cases in
which succimer therapy may need to be continued for up to 19 days. Blood lead concentrations should be
monitored during therapy, and again 1 week after completion of therapy to allow for lead redistribution.
Succimer should not be used in pregnant women. Common adverse effects of succimer include abdominal
pain, transient rash, elevated liver transaminase enzymes, and neutropenia.

All chelation therapies carry the risk of micronutrient deficiency, including iron, zinc and copper, so these
blood concentrations should be checked before and during chelation therapy, and any deficiencies corrected.

For patients with lower blood lead concentrations and minimal symptoms, identifying the lead source and
decreasing further exposure is of utmost importance. Serial blood lead concentrations may help confirm
decreased exposure. Family members and colleagues should also be investigated and treated as appropriate.
Chelation therapy in this context is controversial and should be used in consultation with a clinical
toxicologist.

Note 1: Succimer (dimercaptosuccinic acid) is not registered for use in Australia but is available via the
Special Access Scheme.

Pregnancy and lactation

Maternal blood lead concentrations above 5 micrograms/dL may be of concern to the developing fetus. There
is increased mobilisation of maternal skeletal lead during pregnancy, which increases foetal lead exposure.
Efforts should be made to eliminate any ongoing exposure in pregnant and lactating women. Consultation
with a toxicologist may be useful to discuss risks, benefits and timing of chelation during pregnancy.

Observation and patient disposition after lead poisoning

Criteria for discharge: Asymptomatic patients who do not require foreign body evacuation or chelation
therapy can be discharged.

Criteria for admission: All patients with clinical effects or elevated lead concentrations that require
chelation therapy should be admitted until a satisfactory response to therapy is observed.

Admitted patients who are receiving oral chelation therapy may be discharged to complete the course at home
following discussion with a clinical toxicologist.

Key references
Toxicology: lead

Position paper: whole bowel irrigation. J Toxicol Clin Toxicol 2004;42(6):843–54. [ ]

Bradberry S, Vale A. Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead poisoning. Clin Toxicol (Phila)
2009;47(7):617–31. [ ]

Canfield RL, Henderson CR, Jr., Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. Intellectual impairment in
children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 2003;348(16):1517–26. [
]

Frith D, Yeung K, Thrush S, Hunt BJ, Hubbard JG. Lead poisoning: a differential diagnosis for abdominal pain.
Lancet 2005;366(9503):2146. [ ]

Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, et al. Recommendations for
medical management of adult lead exposure. Environ Health Perspect 2007;115(3):463–71. [ ]

Lustberg M, Silbergeld E. Blood lead levels and mortality. Arch Intern Med 2002;162(21):2443–9. [ ]
Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ. Lead exposure and cardiovascular disease: a
systematic review. Environ Health Perspect 2007;115(3):472–82. [ ]

Rogan WJ, Dietrich KN, Ware JH, Dockery DW, Salganik M, Radcliffe J, et al. The effect of chelation therapy with
succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344(19):1421–6. [
]

Saper RB, Kales SN, Paquin J, Burns MJ, Eisenberg DM, Davis RB, et al. Heavy metal content of ayurvedic
herbal medicine products. JAMA 2004;292(23):2868–73. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: lithium
Introduction to lithium poisoning
Acute lithium toxicity usually presents with gastrointestinal symptoms, and rarely causes major problems.
Major morbidity is usually secondary to CNS effects such as coma and seizures associated with chronic
poisoning. Cardiovascular effects, such as QT prolongation can occur, but are rarely clinically important.
Toxicity is more serious and more common in the setting of chronic usage.

Risk assessment for lithium poisoning

Toxic dose

Acute lithium poisoning rarely leads to significant toxicity due to the rapid elimination by the kidneys and
slow uptake into the CNS. Acute ingestions of less than 25 g lithium are unlikely to cause major effects
unless patients have kidney failure. Acute-on-chronic ingestions are similar to acute overdose.

Chronic lithium poisoning usually occurs in patients taking therapeutic doses where there has been a change
in dose, addition of other medications (eg nonsteroidal anti-inflammatory drugs [NSAIDs], diuretics) or
decreased elimination (kidney impairment). Chronic lithium poisoning is associated with significant
morbidity and mortality.

Toxic concentration
Lithium concentrations can be difficult to interpret, and the lithium concentration in blood only reflects the
concentration in the CNS in chronic poisoning.

In chronic lithium poisoning, a concentration greater than 2 mmol/L is associated with severe poisoning.

In acute lithium poisoning, patients may have a concentration greater than 5 mmol/L and yet this may not
indicate severe poisoning.

Risk factors for chronic lithium poisoning

There are a number of risk factors for developing chronic lithium poisoning:

impaired kidney function

dehydration
age greater than 50 years
drug interactions (eg recent medication changes)
nephrogenic diabetes insipidus
thyroid dysfunction.

Clinical presentation
The main clinical features of lithium toxicity are:

gastrointestinal effects—nausea, vomiting and diarrhoea

CNS effects—tremor, hyperreflexia, ataxia and dysarthria in mild to moderate toxicity; confusion,
coma and seizures in severe toxicity
cardiovascular effects— QT prolongation and hypotension in severe cases.

Key investigations in lithium poisoning

The key investigations in lithium overdose include:

ECG— QT prolongation occurs with severe poisoning, but rarely results in arrhythmias.
Lithium concentration
 –
Chronic poisoning—serum lithium concentrations reflect CNS lithium concentrations, and are
more likely to correlate with clinical effects. They can be used to guide treatment such as
dialysis. However, neurological recovery may not be as rapid as the decrease in serum lithium
concentrations due to the slow movement of lithium out of the CNS.
–
Acute poisoning—serum lithium concentrations do not reflect CNS or body load of lithium.
Serial serum lithium concentrations establish that lithium is being eliminated.
Creatinine and urea—check kidney function.

Treatment of lithium poisoning

Overview
Most patients with acute poisoning require no specific treatment except serial measurement of lithium
concentrations to confirm elimination. Chronic poisoning has an insidious onset and more often requires
treatment with intravenous fluids and occasionally dialysis. Clinical recovery can take days to weeks and is
significantly delayed compared with the decrease in serum lithium concentrations. Some neurological effects
may be permanent.

Circulation
Sufficient fluid replacement is essential in all patients with lithium poisoning (see Resuscitation: circulation).
Intravenous fluid therapy with sodium chloride 0.9% is the first-line treatment and increases lithium
elimination in patients with normal kidney function.

Many patients on long-term lithium therapy have diabetes insipidus, so it is essential that this is taken into
consideration when giving intravenous fluids (ie larger fluid requirements to replace increased urine output).

Decontamination
Decontamination is not indicated for acute ingestions less than 50 g lithium. Activated charcoal does not bind
lithium.

For massive ingestions of lithium (more than 50 g), whole bowel irrigation can be considered if given within
the first 6 hours and the patient is awake and cooperative (see Whole bowel irrigation).

Enhanced elimination
This should be discussed with a clinical toxicologist.

Haemodialysis increases the clearance of lithium, but is rarely required in patients with normal kidney
function. Suggested indications for haemodialysis include:

lithium concentration greater than 2.5 mmol/L (in chronic intake)

severe clinical effects—delirium, seizures, coma or hypotension
lithium concentration greater than 1.5 mmol/L associated with
–
persistent clinical effects
–
little response to intravenous fluids
–
persistent kidney impairment despite fluids.

Dialysis should be continued until lithium concentrations are below 1 mmol/L and further concentrations
should be measured to detect rebound. Lithium clearance is proportional to flow rate, so either haemodialysis
or high-flux continuous veno-venous haemodialysis should be used to rapidly remove lithium.

Observation and patient disposition after lithium poisoning

Criteria for discharge: In acute overdose, asymptomatic patients can be discharged once the lithium blood
concentration is within the therapeutic range.
Criteria for admission: All patients with chronic lithium toxicity require admission.

Key references
Toxicology: lithium

Smith SW, Ling LJ, Halstenson CE. Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg
Med 1991;20(5):536–9. [ ]

Waring WS. Management of lithium toxicity. Toxicol Rev 2006;25(4):221–30. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: long-acting anticoagulant rodenticides
(superwarfarins)
Risk assessment for poisoning caused by long-acting anticoagulant
rodenticides
Overview
Superwarfarins are a class of higher potency and vastly longer acting (months) anticoagulant rodenticides.
Unintentional paediatric exposures to less than a box of poison have not been associated with adverse effects, but
large adult ingestions can result in a delayed onset anticoagulated state that can last for months. Vitamin K remains
an effective antidote, but must not be administered until anticoagulation is confirmed and may need to be
continued for months.

Toxic dose

The most common long-acting anticoagulant rodenticide agent is brodifacoum. It is available at a concentration of
0.005% and large amounts need to be ingested to have any effect. More concentrated formulations are also
available so the dose ingested should always be estimated by the weight of brodifacoum (milligrams) ingested
rather than the amount of bait.

Paediatrics: ingestions of less than 0.5 mg brodifacoum are not associated with clinically important bleeding.

Adults: ingestions of less than 1 mg brodifacoum are not associated with clinically important bleeding.

Ingestions exceeding the amounts specified above may cause anticoagulation, although severe anticoagulation
usually requires much larger amounts. There is enormous individual variability in response to these agents, similar
to warfarin.

Clinical presentation

Overview

Patients will most commonly be asymptomatic until they develop bleeding complications. Clinical effects will be
delayed because the anticoagulant effect takes time to develop and is dependent on the half-life of clotting factors
II, VII, IX and X. An increase in the international normalised ratio (INR) will begin to occur after 12 to 24 hours
with the clearance of factor VII (half-life = 6 hours). Bleeding complications may then take days to develop
depending on the patient and their pre-existing medical illnesses.

Bleeding complications

The effects of haemorrhage in different systems are outlined below:

intracranial haemorrhage—impaired mental state, focal neurological signs and symptoms

gastrointestinal haemorrhage—haematemesis, rectal bleeding, retroperitoneal bleeding (may present as
abdominal pain)
genitourinary haemorrhage—haematuria
pulmonary haemorrhage—haemoptysis, dyspnoea
haemorrhagic shock secondary to massive bleeding
external signs of bleeding—bruising, epistaxis, bleeding gums.

Key investigations in poisoning caused by long-acting anticoagulant

rodenticides
The key investigations in long-acting anticoagulant rodenticide poisoning include:

Coagulation studies—INR (may be normal on presentation).

Other bloods tests—full blood count, blood group and cross-match.
Treatment of poisoning caused by long-acting anticoagulant
rodenticides
Airway and breathing
In the rare occurrence of an intracranial bleed, the patient may require intubation and ventilation measures to
reduce intracranial pressure.

Circulation
Patients with massive bleeding (usually gastrointestinal) will need fluid resuscitation (see Resuscitation:
circulation), blood cross-matching and blood transfusion in addition to antidotal therapy and clotting factor
replacement.

Decontamination
In patients who have ingested a toxic dose of a superwarfarin, consider activated charcoal within 1 hour of the
estimated time of ingestion (see Single-dose activated charcoal).

Specific pharmacological therapies

Antidotal therapy

Vitamin K1 (phytomenadione) is effective in superwarfarin poisoning, as used in warfarin overdose or over-

anticoagulation, except much larger doses are required and for a protracted period. It should not be administered
prophylactically as a single dose because it will just delay the onset of anticoagulation.

The aim is to maintain a normal INR and treatment may need to continue for weeks to months due to the slow
elimination of brodifacoum. It is difficult to determine the appropriate initial dose, but safest to start with a
relatively large dose and titrate to maintain a normal INR. In patients with an INR greater than 2.0, use:

phytomenadione 20 to 100 mg orally or IV, twice daily [Note 1].

For patients with an INR greater than 10, the higher end of the dosage range should be used.

The dose may need to be increased for large ingestions based on daily INR. Therapy should continue for a
minimum of 1 month with weekly INRs, and then be weaned if the INR remains normal (using daily INRs).

The vitamin K analogue menadione (vitamin K3) or any other vitamin K analogue except K1 (phytomenadione),
cannot be used for treatment of long-acting warfarin rodenticide overdose.

Note 1: The Australian approved name (AAN) for vitamin K is phytomenadione.

Clotting factor replacement

If there is active bleeding the patient should be treated with:

Prothrombinex -VF 25 to 50 units/kg IV [Note 2]

PLUS

fresh frozen plasma 150 to 300 mL IV.

Note 2: Prothrombinex-VF is the commercial name for prothrombin complex factors. It contains human
antithrombin III, factor II, factor IX, factor V, factor VII and factor X, and porcine heparin.

Observation and patient disposition after poisoning caused by long-

acting anticoagulant rodenticides
Criteria for discharge: Children who have ingested less than 0.5 mg brodifacoum can be discharged. Adults who
have ingested less than 1 mg brodifacoum can be discharged.

Criteria for admission: All ingestions of more than 0.5 mg brodifacoum in children, and more than 1 mg
brodifacoum in adults, should be admitted for at least 48 hours after ingestion for serial INR.

Key references
Toxicology: long-acting anticoagulant rodenticides (superwarfarins)

Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant overdose: brodifacoum kinetics and
optimal vitamin K dosing. Ann Emerg Med 2000;36(3):262–7. [ ]

Ingels M, Lai C, Tai W, Manning BH, Rangan C, Williams SR, et al. A prospective study of acute, unintentional,
pediatric superwarfarin ingestions managed without decontamination. Ann Emerg Med 2002;40(1):73–8. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: metformin
Risk assessment for metformin poisoning
Overview
Metformin is associated with the development of lactic acidosis, which may be profound and fatal (especially
in chronic toxicity with coexisting kidney impairment). Elevated metformin concentrations can occur acutely
in overdose or as an acute-on-chronic problem. The elderly and those with kidney impairment are most at
risk. Metformin-induced lactic acidosis may be precipitated by a change in medication or intercurrent illness,
especially in at-risk patients.

Toxic dose
No clear toxic dose of metformin has been established because of the importance of pre-existing medical
conditions. In children, ingestions of less than 1700 mg metformin are not associated with significant
poisoning.

Other predictors of toxicity

A number of indicators are associated with the severity of poisoning, but none are good predictors of
outcome:

lactic acidosis—no absolute lactate concentration or pH has been established as a cut-off for toxicity,
but one systematic review found no deaths occurred if the serum lactate was less than 25 mmol/L and
the pH was greater than 6.9 [Note 1]
multiorgan dysfunction—one retrospective review found that multiorgan dysfunction, best predicted by
acute liver dysfunction, is the best predictor of death [Note 2]
pre-existing medical conditions—elderly (more than 65 years), diabetes, other medical conditions that
may contribute to acidosis
kidney impairment—metformin is eliminated by the kidneys
hypotension—particularly if there are co-ingestants involved.

Note 1: Dell'Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW. Acute metformin
overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus
nonsurvivors: a systematic review of the literature. Ann Emerg Med 2009;54(6):818-23. [URL]

Note 2: Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic

and therapeutic study. Crit Care Med 2009;37(7):2191-6. [URL]

Clinical presentation
The main effect of metformin poisoning is lactic acidosis and the majority of the clinical effects are a result
of acidosis.

Metformin poisoning does not cause hypoglycaemia.

Systemic effects include:

metabolic effects—elevated lactate, metabolic acidosis, hyperkalaemia

cardiovascular effects—hypotension and tachycardia secondary to acidosis or dehydration; may
progress to cardiogenic shock
CNS effects—sedation, coma and seizures secondary to acidosis
gastrointestinal effects—nausea, vomiting.
Key investigations in metformin poisoning
The key investigations in metformin poisoning include:

Lactate concentration.
Electrolytes and creatinine.

Treatment of metformin poisoning

Airway and breathing
Airway support and mechanical ventilation may be required with severe metabolic acidosis and multiorgan
failure.

Circulation

Fluid replacement is essential in all but the most minor cases (see Resuscitation: circulation).

Decontamination

Single-dose activated charcoal

Consider activated charcoal within 1 hour of the estimated time of ingestion in patients who are cooperative
(see Single-dose activated charcoal).

Whole bowel irrigation

Consider whole bowel irrigation for up to 4 hours after the ingestion of slow-release preparations in patients
who are cooperative (see Whole bowel irrigation).

Enhanced elimination
Although some metformin is removed with haemodialysis, the main aim is removal of lactate in severe lactic
acidosis. Any form of haemodialysis removes lactate proportional to the flow rate.

The indications for haemodialysis are rapidly rising lactate concentrations associated with hypotension or
other end-organ sequelae of lactic acidosis.

A lactate-free dialysate promotes lactate removal.

Observation and patient disposition after metformin poisoning

Criteria for discharge: All patients without lactic acidosis should be observed for at least 8 hours after
ingestion, and for at least 12 hours if a slow-release formulation has been ingested.

Criteria for admission: Patients with risk factors for severe toxicity (pre-existing medical illness, elderly,
kidney failure, hypotension) should be observed in hospital. Patients with lactic acidosis and systemic effects
should be considered for retrieval to a centre where dialysis is available.

Key references
Toxicology: metformin

Perrone J, Phillips C, Gaieski D. Occult metformin toxicity in three patients with profound lactic acidosis. J Emerg
Med 2011;40(3):271–5. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: methotrexate
Introduction to methotrexate poisoning
There are no reports of toxicity following acute oral ingestions and most cases with severe effects are from
dosing interval errors (dose administered daily instead of weekly). High-dose intravenous methotrexate
chemotherapy with acute kidney failure can result in severe toxicity. Inadvertent intrathecal overdose can
result in severe and life-threatening CNS toxicity.

Risk assessment for methotrexate poisoning

Toxic dose

Single acute oral ingestion

Ingestion of less than 500 mg methotrexate in adults, or less than 5 mg/kg methotrexate in children, is
unlikely to cause toxicity.

Repeat oral ingestion

Oral methotrexate is most toxic when the dosing interval is decreased, most commonly as an error from
weekly to daily, especially if weekly doses are taken for more than 3 consecutive days.

Intravenous administration (chemotherapeutic use)

Intravenous methotrexate doses more than 400 mg/m2 generally require rescue calcium folinate therapy, but
this varies and should be guided by the treating oncologist. In rare cases, patients administered high-dose
intravenous methotrexate develop acute kidney failure resulting in life-threatening toxicity. These patients
require immediate treatment with antidotal therapy.

Intrathecal overdose

Although uncommon there are numerous reports of inadvertent administration of the incorrect dose of
methotrexate intrathecally, usually due to the intravenous preparation being given intrathecally. This rapidly
results in life-threatening neurotoxicity.

Clinical presentation
Systemic effects of methotrexate poisoning include:

gastrointestinal effects—dose-related nausea and vomiting; gastrointestinal epithelial damage with

severe stomatitis, diarrhoea and gastrointestinal bleeding. Hepatotoxicity occurs in severe cases
bone marrow toxicity—myelosuppression is worst 7 to 14 days after onset of toxicity
CNS toxicity (particularly with intrathecal overdose)—seizures, coma, chemical meningitis.

Key investigations in methotrexate poisoning

The key investigations in methotrexate overdose include:

Full blood count—important with delayed bone marrow suppression.

Treatment of methotrexate poisoning

Circulation
Intravenous fluid therapy is important due to fluid loss and prevention of kidney failure (see Resuscitation:
circulation).

Decontamination
If the patient presents within 1 hour of ingestion of more than 500 mg methotrexate (more than 5 mg/kg in
children), decontamination with activated charcoal may be useful (see Single-dose activated charcoal).

Specific pharmacological therapies

Antidotal therapy

Calcium folinate

Calcium folinate (also known as folinic acid) rescue therapy is recommended for patients who have ingested
greater than 500 mg methotrexate as an acute overdose (greater than 5 mg/kg in children), or when weekly
doses have been taken daily for more than 3 days. Calcium folinate should also be considered in any
symptomatic patient. Use:

calcium folinate 15 mg IV, 6-hourly for 3 days.

Calcium folinate is usually given 24 hours after intravenous methotrexate therapy to 'rescue' normal cells, and
should be given under the advice of a clinical toxicologist. Calcium folinate is a substrate for glucarpidase,
and so doses of these drugs should be separated by at least 2 hours.

Glucarpidase

Glucarpidase is a specific antidote for methotrexate poisoning that metabolises methotrexate to inactive
metabolites. It is available from major tertiary oncology centres if required. Glucarpidase is indicated in
methotrexate poisoning from high-dose intravenous methotrexate therapy in patients that have developed
acute kidney failure. Advice should be obtained from an oncologist or a clinical toxicologist. Calcium
folinate is a substrate for glucarpidase, and so doses of these drugs should be separated by at least 2 hours.
Use:

glucarpidase 50 units/kg IV, repeated after 48 hours if methotrexate concentration is

persistently raised [Note 1].

Intrathecal methotrexate overdose (dose more than 100 mg) should be treated with immediate lumbar
puncture for cerebrospinal fluid drainage, followed by intrathecal administration of glucarpidase. Advice
should be obtained from an oncologist or clinical toxicologist. Use:

glucarpidase 2000 units intrathecally [Note 1].

If glucarpidase is not available, the patient may have to undergo ventriculolumbar perfusion if the procedure
is available.

Note 1: Glucarpidase is not registered for use in Australia but is available via the Special Access Scheme.

Observation and patient disposition after methotrexate poisoning

Criteria for discharge: Patients who have ingested less than 500 mg methotrexate (children less than 5
mg/kg) can be discharged.

Criteria for admission: Patients with myelosuppression should be managed in a specialist

haematology/oncology unit with barrier nursing and appropriate pharmacotherapy.

Key references
Toxicology: methotrexate

Balit CR, Daly FFS, Little M, Murray L. Oral methotrexate overdose [conference abstract, European Association
of Poisons Centres and Clinical Toxicologists]. Clinical Toxicology 2006;44(4):411. [URL]
LoVecchio F, Katz K, Watts D, Wood I. Four-year experience with methotrexate exposures. J Med Toxicol
2008;4(3):149–50. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: mirtazapine
Risk assessment for mirtazapine poisoning
Mirtazapine is a central alpha2-adrenoreceptor blocker, which increases noradrenaline and serotonin release.
It is relatively safe in overdose, and the most commonly reported effects are mild CNS and cardiovascular
symptoms, which are dose dependent.

Toxic dose
Mirtazapine doses greater than 300 mg in adults and 4 mg/kg in children are associated with toxicity.

Clinical presentation
Mirtazapine causes only mild effects in overdose. Systemic effects include:

CNS effects—drowsiness, tremor, seizures, CNS depression with large overdoses

cardiovascular effects—tachycardia.

Treatment of mirtazapine poisoning

Airway and breathing
Although sedation and CNS depression occur, this does not require intervention unless there are significant
sedative co-ingestants (see Airway and breathing).

Decontamination
No decontamination is required.

Observation and patient disposition after mirtazapine poisoning

Criteria for discharge: Patients should be observed for 6 hours after ingestion, and can be discharged if
asymptomatic.

Key references
Toxicology: mirtazapine

Bremner JD, Wingard P, Walshe TA. Safety of mirtazapine in overdose. J Clin Psychiatry 1998;59(5):233–5. [
]

LoVecchio F, Riley B, Pizon A, Brown M. Outcomes after isolated mirtazapine (Remeron) supratherapeutic
ingestions. J Emerg Med 2008;34(1):77–8. [ ]

Waring WS, Good AM, Bateman DN. Lack of significant toxicity after mirtazapine overdose: a five-year review of
cases admitted to a regional toxicology unit. Clin Toxicol (Phila) 2007;45(1):45–50. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: nicotine
Risk assessment for nicotine poisoning
Overview
Nicotine poisoning is uncommon, but is most likely to occur in young children who unintentionally chew on
nicotine-containing substances (eg cigarettes, gum or patches) or in adults on nicotine replacement therapy
who continue to smoke. Nicotine toxicity can also be from exposure to nicotine-containing insecticides and
rarely plants.

Toxic dose
For nonsmokers, 60 mg nicotine is potentially fatal (about 30 to 40 cigarettes if all the nicotine is absorbed).
The nicotine in one cigarette is enough to make a toddler ill.

For smokers, 120 mg nicotine is potentially fatal.

Clinical presentation

The symptoms of nicotine poisoning are due to excessive stimulation of nicotinic cholinergic receptors.
Nicotine is rapidly absorbed. A short-lived early phase of stimulation is followed by a more prolonged phase
of inhibition.

Systemic effects of nicotine poisoning include:

CNS effects
–
early transitory agitation, fasciculations, and seizures that are usually self-limiting
–
progression to muscular weakness, lethargy, CNS depression and coma
cardiovascular effects
–
early tachycardia and hypertension
–
progression to hypotension, bradycardia; cardiac arrhythmias occur uncommonly
respiratory effects—respiratory muscle paralysis, bronchorrhoea, bronchoconstriction
gastrointestinal effects—vomiting, diarrhoea, abdominal cramps
other effects—excessive salivation.

Key investigations in nicotine poisoning

The key investigations in nicotine poisoning include:

ECG.

Treatment of nicotine poisoning

There is no antidote for nicotine poisoning and good supportive care is the mainstay of treatment.

Airway and breathing

Airway support and mechanical ventilation may be required in patients with decreasing levels of
consciousness in severe toxicity.

Excessive secretions and bronchoconstriction can be managed with atropine. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02
 mg/kg up to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of
1 mg).

Circulation
Early hypertension and tachycardia is usually transitory and does not require treatment.

If hypotension occurs, it usually responds to intravenous fluids (see Resuscitation: circulation).

Bradycardia can be treated with atropine. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02
mg/kg up to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of
1 mg).

Decontamination
For dermal exposure, clothing should be removed and skin washed in a soapy shower until all contaminant is
removed.

For ingestion, the risks of activated charcoal outweigh any potential benefit and it should not be used.

Specific pharmacological therapies

Anticonvulsant therapy

Seizures are usually self-limiting, but if persistent and recurrent they can be treated with benzodiazepines (see
Anticonvulsant therapy).

Observation and patient disposition after nicotine poisoning

Criteria for discharge: Asymptomatic patients can be discharged 4 hours after exposure.

Criteria for admission: Symptomatic patients should be observed for 24 hours after exposure and
discharged once asymptomatic. Patients with cardiovascular, CNS or respiratory effects require admission to
a high dependency or intensive care area.

Key references
Toxicology: nicotine

Lavoie FW, Harris TM. Fatal nicotine ingestion. J Emerg Med 1991;9(3):133–6. [ ]

Rogers AJ, Denk LD, Wax PM. Catastrophic brain injury after nicotine insecticide ingestion. J Emerg Med
2004;26(2):169–72. [ ]

Smolinske SC, Spoerke DG, Spiller SK, Wruk KM, Kulig K, Rumack BH. Cigarette and nicotine chewing gum
toxicity in children. Hum Toxicol 1988;7(1):27–31. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: nonsteroidal anti-inflammatory drugs
Introduction to NSAID poisoning
Poisoning with nonsteroidal anti-inflammatory drugs (NSAIDs) is reasonably frequent because of their
availability, but in the majority of cases the effects are minimal.

Ibuprofen is the most commonly ingested NSAID in overdose. Other NSAIDs include celecoxib, diclofenac,
etoricoxib, indomethacin, ketoprofen, ketorolac, mefenamic acid, meloxicam, naproxen, parecoxib,
piroxicam, sulindac and tiaprofenic acid.

For aspirin overdose, see Aspirin.

Risk assessment for NSAID poisoning

NSAIDs are relatively nontoxic and large numbers of tablets need to be ingested for serious toxicity to occur.

Toxic dose
Ingestion of less than 400 mg/kg ibuprofen is unlikely to cause major effects.

There is a risk of seizures with ingestion of more than 25 mg/kg mefenamic acid.

Clinical presentation
Systemic effects include:

gastrointestinal effects—gastro-oesophageal irritation and inflammation, but rarely more than transient
symptoms
metabolic effects—metabolic acidosis can occur with massive ingestions
kidney effects—similar to the therapeutic use of NSAIDs, kidney impairment can occur, particularly in
dehydrated patients
CNS effects—rare except for mefenamic acid, which can cause seizures.

Key investigations in NSAID poisoning

The key investigations in NSAID overdose include:

Electrolytes and creatinine—check to exclude kidney impairment.

Treatment of NSAID poisoning

Circulation
Rehydration fluid is important to prevent kidney injury (see Resuscitation: circulation).

Decontamination
Activated charcoal is rarely required but may be potentially beneficial within 1 hour of a massive ingestion
(see Single-dose activated charcoal).

Specific pharmacological therapies

Anticonvulsant therapy

Seizures are generally self-limiting but if persistent and recurrent they can be treated with benzodiazepines
(see Anticonvulsant therapy).

Other pharmacological treatment

There are no data on the treatment of gastritis after overdose of NSAIDs, but symptomatic treatment with
antacids is likely to be safe and effective.

Observation and patient disposition after NSAID poisoning

Criteria for discharge: Patients who are asymptomatic after observation for 4 hours after ingestion and have
normal kidney function can be discharged.

Criteria for admission: Patients with kidney function or acid-base abnormalities, or significant symptoms
should be admitted.

Key references
Toxicology: nonsteroidal anti-inflammatory drugs

Smolinske SC, Hall AH, Vandenberg SA, Spoerke DG, McBride PV. Toxic effects of nonsteroidal anti-
inflammatory drugs in overdose. An overview of recent evidence on clinical effects and dose-response
relationships. Drug Saf 1990;5(4):252–74. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: opioids
Risk assessment for opioid poisoning
Overview
Opioid drugs are the most common cause of drug-related death in Australia. They cause respiratory
depression which is disproportionately severe compared to their sedative effect. Death from this can occur
many hours after ingestion of long-acting drugs if patients are not carefully monitored.

Opioid drugs available include alfentanil, buprenorphine, codeine, dextropropoxyphene, fentanyl,

hydromorphone, methadone, morphine, oxycodone, pethidine, remifentanil, sufentanil and tramadol. For
tramadol poisonings, see Toxicology: serotonin and noradrenaline reuptake inhibitors.

Toxic dose and concentration

Clinical toxicity cannot be predicted from the dose ingested or the drug concentration due to the tolerance
that develops in opioid-dependent patients. The extent of tolerance also determines whether buprenorphine (a
partial agonist) causes sedation or withdrawal.

Other predictors of toxicity

The duration of action is important because overdose with long-acting opioids (eg methadone and slow-
release formulations of morphine and oxycodone) requires inpatient admission and critical care observation.

Clinical presentation
The main presenting features are:

CNS effects—CNS depression is the major manifestation and ranges from drowsiness to coma with
respiratory depression; miosis; serotonin toxicity (pethidine)
cardiovascular effects
–
dextropropoxyphene—QRS widening, atrioventricular (AV) nodal block and tachyarrhythmias
similar to those with tricyclic antidepressants
–
methadone—QT prolongation and torsades de pointes
gastrointestinal effects—nausea, vomiting
respiratory effects—aspiration pneumonitis, noncardiogenic pulmonary oedema.

Key investigations in opioid poisoning

The key investigations in opioid overdose include:

Blood gases—consider because partial pressure of carbon dioxide (PaCO2) is the best measure of
hypoventilation.
Chest X-ray—required in patients with hypoxia in the absence of respiratory depression, or patients
who have persistent hypoxia despite ventilatory support or reversal with naloxone.
ECG—required for methadone and dextropropoxyphene.

Treatment of opioid poisoning

Airway and breathing
The patient's airway and breathing should be supported as required. It is essential that the respiratory rate (in
the undisturbed state) is closely observed, particularly in patients with known opioid dependence. Opioid-
dependent patients may appear to be rousable (Glasgow Coma Scale score of 14), but still have respiratory
depression. In patients with a respiratory rate less than 12 breaths/minute, hypoventilation can be confirmed
by a PaCO2, but this must not delay treatment in patients with severe respiratory depression. Oxygen should
not be administered in the absence of ventilatory support (see Airway and breathing).

Aspiration, aspiration pneumonitis and noncardiogenic pulmonary oedema should be managed with oxygen
therapy and ventilatory support as required.

Circulation

Cardiac arrest following opioid overdose is usually due to prolonged hypoxia and should be managed
according to standard advanced life support protocols (see flowcharts developed by the Australian
Resuscitation Council).

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening in
dextropropoxyphene overdose. Monitoring should continue for at least 6 hours and until the 12-lead ECG is
normal. Arrhythmias associated with QRS widening should be treated (see QRS widening and sodium
channel blockade).

QT prolongation and torsades de pointes

QT prolongation with methadone overdose requires continuous ECG monitoring and regular 12-lead ECGs to
assess QT prolongation. For details on the management of QT prolongation and torsades de pointes, see QT
prolongation and torsades de pointes.

Decontamination
Activated charcoal is rarely indicated in oral opioid overdoses (with the possible exceptions mentioned
below) because of the risk of sedation and aspiration, and the availability of an effective and easily
administered antidote (naloxone). Activated charcoal is never indicated for short-acting opioids.

There is no absolute indication for any form of decontamination in opioid overdose because opioid toxicity
can be managed with naloxone or with respiratory supportive care. However, decontamination may
significantly reduce the duration of toxicity for slow-release preparations and opioids with a longer half-life.

For methadone (a long-acting opioid) overdose, activated charcoal may be considered if it can be
administered within 1 hour of the estimated time of ingestion to a cooperative patient (see Single-dose
activated charcoal).

For slow-release preparations, activated charcoal and whole bowel irrigation can be considered in
cooperative, nonsedated patients who have ingested large amounts and if treatment can be given within 6
hours of the estimated time of ingestion. For drug and dosing recommendations, see Single-dose activated
charcoal and Whole bowel irrigation.

Specific pharmacological therapies

Antidotal therapy

Naloxone is a parenteral opioid antagonist and is an important adjunct treatment in opioid overdose. Use:

naloxone 50 to 200 micrograms IV bolus, titrated to clinical effect every 2 to 3

minutes up to a maximum of 2 mg [Note 1].

Reversal of opioid overdose is best indicated by an increased level of consciousness, and normal respiratory
drive (respiratory rate or PaCO2 as measured by blood gas). The aim is to reverse hypoventilation and
increase the level of consciousness sufficient to protect the airway. Titration of naloxone is important to avoid
acute withdrawal. Sudden or complete reversal can result in medical complications—myocardial infarction in
the elderly or patients with coronary artery disease, or an agitated delirium in patients who are opioid-
dependent.

In the majority of overdoses of short-acting opioids (injectable or immediate-release oral morphine, heroin,
pethidine, fentanyl), only one dose of naloxone is required.
For long-acting opioids (methadone) or slow-release formulations, a naloxone infusion is usually required
after the initial or subsequent bolus. The infusion should be titrated to effect, but the usual hourly infusion
rate is half to two-thirds of the total initial effective bolus dose.

Cessation of naloxone infusion should be based on clinical effects, with a gradual reduction in dose.

Note 1: Much larger doses of naloxone (up to 12 mg) may be required to reverse buprenorphine overdose.

Observation and patient disposition after opioid poisoning

Criteria for discharge: Discharge must be based on the clinical condition of the patient and cannot be
predicted from the ingested dose of opioid.

Criteria for admission: Any patient requiring more than a single dose of naloxone or a continuous infusion
of naloxone must be admitted to a critical care area with the facility to manage airway and breathing.

Key references
Toxicology: opioids

Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous naloxone.
Ann Emerg Med 1986;15(5):566–70. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: organophosphates
Staff safety for organophosphate poisoning
Universal precautions (gloves, gowns, eye protection) are sufficient to ensure full staff safety when managing
patients with organophosphate poisoning [Note 1].

Universal precautions ensure full staff safety.

Note 1: Little M, Murray L. Consensus statement: risk of nosocomial organophosphate poisoning in

emergency departments. Emerg Med Australas 2004;16(5-6):456-8. [URL]

Risk assessment for organophosphate poisoning

Toxic dose
Significant toxicity may occur with deliberate ingestion of any amount of a concentrated organophosphate
formulation larger than a mouthful. Dermal and inhalational exposures are much more common, but rarely
severe. World Health Organisation (WHO) classification of organophosphate pesticides (based on animal
LD50) is not a good guide to toxicity in humans after ingestion.

Red cell cholinesterase

Depression of red blood cell (RBC) cholinesterase is associated with increasing toxicity (see Key
investigations). Values of RBC cholinesterase less than 25% of normal (normal is approximately 600
milliunits/micromol haemoglobin) are associated with severe poisoning.

Clinical presentation

The organophosphorus pesticides all inhibit cholinesterase activity, but have a wide and variable range of
toxicity. This may reflect differences in potency in inhibiting acetylcholinesterase and plasma cholinesterase
(butyrylcholinesterase), but also that there are other less well understood mechanisms. The severity and
spectrum of clinical effects and response to treatment varies enormously based on chemical structure
(especially dimethyl versus diethyl versus other), elimination half-lives, fat solubility and the need for
metabolic activation. Table 17.18 provides information on the common organophosphate pesticides available
in Australia.

Clinical features of organophosphate poisoning most commonly include:

CNS effects—seizures, confusion, coma

acute autonomic features ('cholinergic crisis')
–
muscarinic toxicity—diaphoresis, miosis, bradycardia, hypotension, salivation, lacrimation,
diarrhoea, urinary frequency, bronchorrhoea, bronchoconstriction
–
nicotinic toxicity—fasciculations, paralysis, hypertension, tachycardia
gastrointestinal effects—nausea, vomiting, diarrhoea (may be due to nonspecific effects of the solvent
or pesticide, or occur as part of the acute cholinergic crisis)
cardiovascular effects—arrhythmias, refractory shock (occurs more commonly with dimethoate)
later complications—progressive neuromuscular junction dysfunction and respiratory failure over 1 to 4
days; pneumonia.

Properties of organophosphate pesticides (Table 17.18)

Reactivation of
Physicochemical Clinical syndrome (see also Toxidromes:
Pesticide acetylcholinesterase
properties cholinergic agents)
with oxime therapy
 diethyl-OP
chlorpyrifos high fat solubility cholinergic effects and neuromuscular good
long half-life paralysis

diethyl-OP
early cholinergic effects but delayed
diazinon short half-life good
neuromuscular paralysis is uncommon
dimethyl-OP
low fat solubility high mortality, early cholinergic and
dimethoate poor
short half-life neuromuscular effects; refractory shock

dimethyl-OP often mild initial cholinergic features and

fenthion high fat solubility delayed (24 to 96 hours) neuromuscular poor
long half-life
effects
dimethyl-OP
moderate fat typical features but lower toxicity except
malathion solubility very poor
in large ingestions
short half-life

OP = organophosphorus

Key investigations in organophosphate poisoning

Introduction
The key investigations in organophosphate poisoning include:

ECG— QT prolongation is reported.

Chest X-ray—aspiration and other respiratory complications are very common.

Cholinesterase testing
This may be difficult to interpret and expert advice should be obtained.

Plasma butyrylcholinesterase

Plasma butyrylcholinesterase is highly sensitive to organophosphate exposure and may be useful when the
diagnosis is in doubt (as the diagnosis of organophosphate poisoning is unlikely if the plasma
butyrylcholinesterase is normal). The plasma butyrylcholinesterase concentration does not correlate with
severity of poisoning.

Red cell acetylcholinesterase

Red cell acetylcholinesterase more closely reflects acetylcholinesterase activity at neural synapses and has a
better correlation with severity of poisoning. Ex vivo reactions continue and the most accurate results are
found when whole blood is put into an EDTA tube, diluted 1:20 with water, put onto ice and then transported
rapidly to the laboratory. Samples taken before and after treatment with an oxime may show the extent of
reactivation of acetylcholinesterase. Samples taken before and 6 hours after ceasing oximes may indicate if
inhibitory activity is still present.

Treatment of organophosphate poisoning

Airway and breathing
Early intervention to secure the airway and provide ventilatory support is essential in severe poisoning. All
patients with a decreasing level of consciousness should be intubated early for airway protection. Ventilation
is usually necessary for patients with neuromuscular paralysis and may be required for as long as 2 to 3
weeks.

Circulation
All patients except those with mild poisoning should receive intravenous fluids (see Resuscitation:
circulation).

Decontamination

Gastrointestinal decontamination is unlikely to be effective due to rapid absorption and distribution of

pesticides. If needed, dermal decontamination is done immediately (by staff using universal precautions) by
removing clothes that have been contaminated and washing the patient with soap and water. This should not
take priority over resuscitation and atropinisation.

Specific pharmacological therapies

Antidotal therapy

Anticholinergic (antimuscarinic) therapy

Anticholinergic therapy with atropine is used to treat muscarinic effects. Atropine requirements vary
enormously between patients and different cholinergic agents, so a dosing protocol that doubles each
subsequent dose is required to load the patient rapidly. Use:

atropine 1.2 to 3 mg (child: 0.05 mg/kg) IV as an initial bolus. If the first 3 of the 5
target end-points are not achieved (see Target end points for atropinisation below) after
5 minutes, double the initial dose. Continue to double the dose every 5 minutes until
atropinised (doses of up to 100 mg may be required). Once the patient is atropinised an
infusion should be commenced with 10% to 20% of the total loading dose given every
hour.

Observe the patient carefully for signs of under- or over-atropinisation [Note 2] and alter the infusion
accordingly (either stopping the infusion or giving another bolus dose).

Target end points for atropinisation are (aim to rapidly achieve the first 3):

chest clear and no wheeze on auscultation

heart rate greater than 80 beats per minute
systolic blood pressure greater than 80 mm Hg
pupils no longer constricted (however, beware of topical ocular contamination maintaining pupil
constriction)
dry axillae.

Note 2: Signs of over-atropinisation: confusion, pyrexia and absent bowel sounds are the most important
signs of atropine toxicity.

Oxime therapy

Pralidoxime is used to reactivate acetylcholinesterases inhibited by organophosphate pesticides. It can only be

effective if ageing (irreversible inhibition [Note 3]) of the acetylcholinesterase-organophosphate complex has
not occurred. Routine use is not effective. It is reasonable to use pralidoxime in organophosphate poisoning
when there is ongoing severe poisoning with inadequate response to other treatments. Use:

pralidoxime iodide 1 to 2 g (child: 15 to 30 mg/kg up to 2 g) IV as an initial bolus,

followed by an infusion of 250 to 500 mg/hour (child: 10 to 20 mg/kg/hour up to 500
mg/hour) [Note 4].

The response varies considerably according to agent, severity, and time to treatment (see Table 17.18). The
optimal duration of therapy is unknown. In most cases pralidoxime should be continued for 12 to 24 hours and
then reviewed. Ongoing treatment should be discussed with a clinical toxicologist. Pralidoxime is largely
eliminated by the kidneys and maintenance infusion doses should be reduced in proportion to the extent of
kidney impairment.

Note 3: Irreversible inhibition would be apparent from a lack of effect on the red cell acetylcholinesterase if
this was being measured.

Note 4: Pralidoxime iodide is the only pralidoxime salt available in Australia; it is not dose-equivalent to
 pralidoxime chloride (1 g pralidoxime iodide = 0.65 g pralidoxime chloride).

Anticonvulsant therapy

Seizures are uncommon, but may indicate severe poisoning, inadequate atropinisation or hypoxia on initial
presentation. Intubation, ventilation, atropine and oximes need to take precedence over specific anticonvulsant
therapy. For drug and dosing recommendations, see Anticonvulsant therapy.

Treatment of other complications

Aspiration pneumonitis

Aspiration pneumonitis should be treated with oxygen therapy and ventilator support (see Aspiration
pneumonitis).

Observation and patient disposition after organophosphate

poisoning
Criteria for discharge: Patients with unintentional and dermal exposures who remain asymptomatic for 6
hours after exposure can be discharged.

Criteria for admission and ICU admission: All patients with deliberate self-poisoning should be observed
closely as they may deteriorate rapidly. If they remain asymptomatic for 24 hours after exposure and
cholinesterase is normal, then consideration can be given to discharge. Any patient requiring atropine or other
antidotal therapy should be admitted to a critical care area.

Key references
Toxicology: organophosphates

Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute organophosphate pesticide poisoning.
Cochrane Database Syst Rev 2011;(2):CD005085. [ ]

Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning.
Lancet 2008;371(9612):597–607. [ ]

Eddleston M, Eyer P, Worek F, Juszczak E, Alder N, Mohamed F, et al. Pralidoxime in acute organophosphorus
insecticide poisoning: a randomised controlled trial. PLoS Med 2009;6(6):e1000104. [ ]

Little M, Murray L. Consensus statement: risk of nosocomial organophosphate poisoning in emergency

departments. Emerg Med Australas 2004;16(5–6):456–8. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: paracetamol
Risk assessment for paracetamol poisoning
Paracetamol poisoning is common and the treatment of the majority of acute overdoses is well-defined. However, risk
assessment and treatment of staggered or supratherapeutic ingestions, or ingestions involving slow-release preparations, may
be complicated and advice can be obtained from a clinical toxicologist.

Toxic dose
Poisoning with paracetamol can occur in the setting of either acute overdose or repeated supratherapeutic dose.

Acute overdose: There is potential for toxicity with a single paracetamol ingestion of more than 10 g or 200 mg/kg
(whichever is less).

Repeated ingestion of supratherapeutic doses: Risk of paracetamol hepatotoxicity is associated with ingesting:

more than 10 g or 200 mg/kg (whichever is less) in a single 24-hour period

more than 6 g or 150 mg/kg (whichever is less) per 24 hours during a 48-hour period
more than 4 g/day or 100 mg/kg/day (whichever is less) in patients with predisposing risk factors (chronic alcohol
abuse; patients with potential glutathione depletion such as in malnutrition, acute illness, or anorexia; or patients taking
CYP450-inducing drugs).

Intravenous paracetamol: Dosing errors are often 10-fold. Little evidence exists but a very conservative estimate of the
minimum dose leading to toxicity would be 60 mg/kg paracetamol.

Toxic concentration
Acute overdose: Liver injury can occur in patients with paracetamol concentrations above the curved nomogram line (see
Figure 17.2) and acetylcysteine [Note 1] should be given (see Antidotal therapy). Paracetamol concentration can be reported as
micromol/L or mg/L—check the paracetamol concentration units before using the nomogram (left axis: micromol/L; right
axis: mg/L).

Repeated ingestion of supratherapeutic doses: The paracetamol treatment nomogram should not be used. The dose ingested
or abnormal liver biochemistry indicates toxicity (see Repeated ingestion of supratherapeutic doses).

Paracetamol treatment nomogram (Figure 17.2)

Note 1: Acetylcysteine is also commonly known as N-acetylcysteine and therefore the abbreviation to NAC will be found in
many texts and local protocols.

Delay to treatment
Delay to treatment with acetylcysteine is associated with worse outcomes. If acetylcysteine is administered within 8 hours of
acute overdose, it usually prevents toxicity completely.

Slow-release formulations of paracetamol

There is little evidence as to whether the risk of toxicity differs with slow-release formulations. If more than 200 mg/kg or 10
g (whichever is less) has been ingested, acetylcysteine treatment should be started immediately (see Antidotal therapy). If less
than this amount has been ingested, serum paracetamol concentrations may be used to determine the need for acetylcysteine.
In all cases, serum paracetamol concentrations should be taken 4 or more hours after ingestion (as with standard preparations)
and repeated 4 hours later. If either concentration is above the nomogram line, acetylcysteine should be commenced or
continued. Acetylcysteine may be discontinued if both concentrations are below the nomogram line and decreasing.

Repeated ingestion of supratherapeutic doses

Most patients present with an acute overdose where the clinical sequelae are fairly predictable based on the dose ingested.
However, repeated supratherapeutic ingestion can occur, for example in the following common clinical situations:

ingestions of more than 150 to 200 mg/kg daily for a period of a few days, usually for severe pain such as dental pain
repeated ingestion of combination products of paracetamol and codeine for weeks to months, usually to obtain the
codeine
use of supratherapeutic doses in unwell and dehydrated children for greater than 48 hours.

The risk assessment in patients with repeated ingestion of supratherapeutic doses is difficult and the paracetamol treatment
nomogram should not be used. All patients with abnormal liver transaminases or paracetamol concentrations greater than 133
micromol/L (20 mg/L) should be treated with acetylcysteine. Reassessment should occur, with repeated liver biochemistry,
following 8 hours of therapy with acetylcysteine, and acetylcysteine may be discontinued if these remain static or are
normalising.

Clinical presentation
Although paracetamol overdose is common it rarely results in severe liver injury or death.

Systemic effects of acute overdose include:

gastrointestinal effects—nausea, anorexia, persistent vomiting, right upper quadrant abdominal pain
liver failure—hypoglycaemia, metabolic acidosis, severe coagulopathy, hepatic encephalopathy
kidney impairment—may occur with severe liver failure or occasionally as isolated kidney impairment
mild coagulopathy—a mild elevation in international normalised ratio (INR) (no greater than 2.0) may occur early in the
absence of liver failure due to direct inhibition of clotting factor production by paracetamol.

In addition, massive ingestions (more than 50 g) may present with a reduced level of consciousness, acidosis and cardiac
effects.

Key investigations in paracetamol poisoning

The key investigations in paracetamol overdose include:

Paracetamol concentration
–
Measure 4 hours after an acute overdose of a solid dose form of paracetamol (repeat 4 hours after initial
concentration for slow-release preparations).
–
Measure 2 hours after ingestion of liquid preparations (usually paediatric).
Liver biochemistry (including aspartate aminotransferase [AST], alanine aminotransferase [ALT], INR).
Blood glucose concentration.
Electrolytes and creatinine.

Treatment of paracetamol poisoning

Circulation

Ensure rehydration and maintenance intravenous fluids (see Resuscitation: circulation).

Decontamination

Activated charcoal should be used in cooperative patients within:

 2 hours of ingesting more than 200 mg/kg or 10 g (whichever is less) of a solid dose form of immediate-release
paracetamol
4 hours of ingesting more than 30 g of a solid dose form of immediate-release paracetamol
4 hours of ingesting more than 200 mg/kg or 10 g (whichever is less) of slow-release paracetamol.

See Single-dose activated charcoal for management.

Liver failure
Any patient who develops signs of liver failure, including hepatic encephalopathy, hypoglycaemia, severe coagulopathy (INR
more than 6.5), metabolic acidosis (pH less than 7.3) or acute kidney failure (serum creatinine more than 300 mmol/L), should
be referred to a specialist liver unit.

Specific pharmacological therapies

Antidotal therapy

Dose calculation

Timely use of acetylcysteine [Note 2] can prevent hepatotoxicity after paracetamol overdose. Numerous cases of incorrect
dose calculations have occurred with the administration of acetylcysteine, often resulting in underdosing. The dose and volume
of acetylcysteine to be added to each infusion should be carefully checked.

Note 2: Acetylcysteine is also commonly known as N-acetylcysteine and therefore the abbreviation to NAC will be found in
many texts and local protocols.

Indications

If the patient presents within 8 hours of ingestion—acetylcysteine should be administered if the drug concentration is above
the curved nomogram line (see Figure 17.2). In patients presenting within 4 hours of ingesting a paracetamol overdose,
acetylcysteine can be withheld until a 4-hour concentration is measured, if this result will be available within 8 hours.

If the patient presents 8 or more hours after ingestion and has ingested a toxic dose (or where the paracetamol concentration
will not be known for 8 or more hours post ingestion)—acetylcysteine should be commenced, then ceased if the paracetamol
concentration indicates that treatment is not required and if liver biochemistry is normal.

If the patient presents an unknown time after ingestion of a toxic dose or presents with abnormal liver biochemistry
following a recent paracetamol overdose—acetylcysteine should be administered.

If the patient has ingested repeated supratherapeutic doses of paracetamol (see Toxic dose) and has abnormal liver
biochemistry—acetylcysteine should be administered.

If the patient has ingested more than 200 mg/kg or 10 g of a slow-release paracetamol preparation (whichever is less)—
acetylcysteine should be commenced. If both paracetamol concentrations (taken four hours apart) are below the nomogram
line and decreasing, acetylcysteine can be stopped (see Slow-release formulations of paracetamol).

If the patient has ingested a liquid paracetamol preparation and the 2-hour concentration is above 1000 micromol/L (150
mg/L)—contact a poisons information centre for advice [Note 3].

For intravenous paracetamol dosing errors—take a paracetamol concentration within 30 minutes and contact a poisons
information centre for advice.

Note 3: Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with
acetaminophen overdose. J Pediatr 1999;135(3):290-5. [URL]

Dosage

Acetylcysteine is administered as a series of three infusions over approximately 20 hours. The dose of the third infusion
depends on the initial paracetamol concentration.

For the first infusion, use:

acetylcysteine 150 mg/kg IV infusion, over 15 to 60 minutes.

For the second infusion, use:

acetylcysteine 50 mg/kg IV infusion, over 4 hours.

If the paracetamol concentration was less than double the nomogram line, for the third infusion, use:

acetylcysteine 100 mg/kg IV infusion, over 16 hours.

If the paracetamol concentration was more than double the nomogram line, for the third infusion, use:

acetylcysteine 200 mg/kg IV infusion, over 16 hours.

Prolonged treatment with acetylcysteine may be necessary for overdoses of slow-release paracetamol and large overdoses of
other paracetamol preparations. Seek the advice of a clinical toxicologist.

Liver biochemistry and INR should be tested before stopping acetylcysteine in patients at high risk of toxicity. This includes
those who:

have treatment delayed for more than 8 hours after ingestion

have ingested more than 200 mg/kg or 10 g (whichever is less) of a slow-release paracetamol preparation—also retest
the paracetamol concentration before stopping acetylcysteine
present with a paracetamol concentration more than double the nomogram line—also retest the paracetamol
concentration before stopping acetylcysteine.

Patients who develop abnormal liver biochemistry or liver failure or still have detectable paracetamol concentrations require
an extended duration of therapy. Most experts would continue acetylcysteine until after the peak in the AST, ALT and INR,
and the paracetamol concentration is undetectable, but advice should be obtained from a clinical toxicologist.

Acetylcysteine is generally well tolerated. Non–IgE-mediated anaphylactoid reactions may occur with acetylcysteine in 10%
to 25% of cases with rash, urticaria, flushing, and rarely bronchospasm and hypotension. If such reactions occur, cease the
infusion and recommence at a slower rate.

Anaphylaxis should be treated according to a standard protocol (see the Australian Prescriber anaphylaxis wallchart here).
Such reactions may be more common in asthmatics. Reactions are highly unlikely to occur more than an hour after completion
of the initial loading dose.

Observation and patient disposition after paracetamol poisoning

Criteria for discharge: Asymptomatic patients with a paracetamol concentration under the nomogram line require no further
medical treatment. Asymptomatic patients treated with acetylcysteine within 8 hours of paracetamol ingestion may be
discharged once the 20-hour regimen is complete.

Criteria for admission: Patients who develop severe liver failure should be offered consultation with a specialist liver unit.

Key references
Toxicology: paracetamol

Buckley NA, Whyte IM, O'Connell DL, Dawson AH. Oral or intravenous N-acetylcysteine: which is the treatment of choice for
acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 1999;37(6):759–67. [ ]

Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose.
J Pediatr 1999;135(3):290–5. [ ]

Chiew AL, Fountain JS, Graudins A, Isbister GK, Reith D, Buckley NA. Summary statement: new guidelines for the management of
paracetamol poisoning in Australia and New Zealand. Med J Aust 2015;203(5):215–218 .

Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA. Massive paracetamol overdose: an observational study of the
effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (Phila) 2017;55(10):1055–1065 .

Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA. Guidelines for the management of paracetamol poisoning in Australia
and New Zealand: explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian
poisons information centres. Med J Aust 2008;188(5):296–301. [ ]

Graudins A, Chiew A, Chan B. Overdose with modified-release paracetamol results in delayed and prolonged absorption of
paracetamol. Intern Med J 2010;40(1):72–6. [ ]

Gray T, Hoffman RS, Bateman DN. Intravenous paracetamol: an international perspective of toxicity. Clin Toxicol (Phila)
2011;49(3):150–2. [ ]

Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of
choice for paracetamol poisoning. Br Med J 1979;2(6198):1097–100. [ ]

Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002;40(1):3–20. [ ]

Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet 1995;346(8974):547–52. [ ]

Wong IC, Ghaleb MA, Franklin BD, Barber N. Incidence and nature of dosing errors in paediatric medications: a systematic review.
Drug Saf 2004;27(9):661–70. [ ]
Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and
distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: potassium (oral overdose)
Risk assessment for potassium poisoning
Overview
Acute oral potassium overdose is uncommon. Hyperkalaemia is most commonly seen in the setting of kidney
failure (see Hyperkalaemia), but sometimes occurs as the result of an overdose. The most serious effect of
potassium ingestion is cardiac arrest due to hyperkalaemia. ECG monitoring and reduction of potassium
concentrations are the mainstays of care.

Slow-release potassium chloride tablets contain 8 mmol potassium per tablet. Effervescent potassium supplement
tablets contain 14 mmol potassium per tablet.

Toxic dose

Doses greater than 2.5 mmol/kg potassium potentially cause hyperkalaemia.

Toxic concentration
In an acute setting, serum potassium greater than 6 mmol/L is potentially associated with clinically important
toxicity.

Clinical presentation

Hyperkalaemia from causes other than acute ingestion is discussed in Hyperkalaemia. The onset of hyperkalaemia
after acute ingestion may occur within 1 hour but can also be delayed due to the slow-release formulation.

Systemic effects include:

cardiovascular effects
–
arrhythmias secondary to hyperkalaemia
–
myocardial depression
–
ECG features—peaked T waves, flattened P waves, increased PR interval, QRS widening and deep S
wave. Severe hyperkalaemia results in a 'sine' wave appearance deteriorating to asystole
CNS effects—respiratory depression, paraesthesia, weakness, flaccid paralysis
gastrointestinal effects—nausea, vomiting, abdominal pain.

Key investigations in potassium poisoning

The key investigations in oral potassium overdose include:

ECG—see clinical presentation for ECG features of hyperkalaemia.

Electrolytes—serial serum potassium.
Abdominal X-ray—slow-release potassium preparations may be radio-opaque.

Treatment of potassium poisoning

Initial assessment should include a serum potassium concentration, ECG, and an abdominal X-ray to determine if
there are undissolved tablets. Management is based on whether there is already hyperkalaemia with or without
cardiac effects, and the presence of tablets on X-ray.

Airway and breathing

In severe poisoning, patients may require airway support and ventilation.

Circulation
Patients should be monitored in a critical care area with regular 12-lead ECGs and serum potassium measurements.
ECG changes such as peaked T waves and cardiac arrhythmias secondary to hyperkalaemia should be treated with
intravenous calcium [Note 1]. Use:

calcium gluconate 10% 10 mL IV over 2 to 3 minutes into a large vein, with ECG
monitoring of the response if possible.

Repeated boluses of calcium may need to be given every 5 to 30 minutes depending on response and the severity
of the hyperkalaemia.

Note 1: Calcium should not be used for the treatment of hyperkalaemia if there is coexistent digoxin toxicity.

Decontamination
Whole bowel irrigation should be considered within the first 2 hours of ingestion for patients ingesting greater than
2.5 mmol/kg potassium, if the persistence of tablets is confirmed on abdominal X-ray (see Whole bowel
irrigation). In many cases the decision whether to decontaminate is based on knowledge of the number of tablets
ingested, the feasibility of administration if the patient already has severe hyperkalaemia, and the time since
ingestion.

Specific pharmacological therapy

Treatment of hyperkalaemia related to potassium overdose

Principles of management

The principles of management of hyperkalaemia are to:

stabilise the cardiac membrane if required (see Circulation)

reduce the serum potassium
remove potassium from the body.

Serum potassium

Options to reduce serum potassium include:

1 glucose 50% 50 mL (child: glucose 10% 2.5 mL/kg) IV, over 5 minutes preferably via a
central line, or by slow IV injection via a large peripheral vein

PLUS
short-acting insulin 10 units (child: 0.1 units/kg) IV bolus (may not be necessary in
patients without diabetes who have mild hyperkalaemia) (see Table 18.4 for insulin
formulations). This decreases the serum potassium concentration by 0.5 to 1.5
mmol/L over 30 minutes

OR

1 sodium bicarbonate 8.4% (= 1 mmol/mL) 50 mL IV over 5 to 10 minutes, under ECG

control. This may be repeated in 60 to 120 minutes

OR

2 salbutamol 10 mg by nebuliser. This can be expected to decrease the serum potassium

concentration by 0.5 to 1.5 mmol/L in 30 to 90 minutes.

Removal of potassium from the body

Hyperkalaemia resulting from ingestion of potassium differs from hyperkalaemia occurring with kidney failure in
that kidney function may be preserved and excretion of potassium by the kidneys can occur normally. Options to
remove potassium from the body in the setting of overdose include removal of potassium from the bowel lumen,
and dialysis.

Dialysis is probably only required in association with kidney impairment. A number of modalities are available
and all are effective. Depending on the clinical context, consultation with a nephrologist or critical care specialist
and/or a toxicologist is advised.
Observation and patient disposition after potassium poisoning
Criteria for discharge: Patients can be discharged if they have a normal serum potassium concentration and ECG
after observation for 6 hours after poisoning.

Criteria for admission: Any patient with an abnormal ECG or elevated serum potassium concentration after 6
hours since poisoning should be admitted for ongoing treatment and cardiac monitoring.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: selective serotonin reuptake inhibitors
Risk assessment for SSRI poisoning
Overview
Selective serotonin reuptake inhibitors (SSRIs) include citalopram, escitalopram, fluoxetine, fluvoxamine,
paroxetine and sertraline. Overdose of selective serotonin reuptake inhibitors usually produces relatively mild
toxicity, and recovery is expected with supportive care. Mild serotonin toxicity can occur, but is only severe
with co-ingestion of serotonergic drugs that act via a different mechanism (eg monoamine oxidase inhibitors).
Cardiovascular toxicity is uncommon, although citalopram and escitalopram produce dose-dependent QT
prolongation.

Toxic dose

Citalopram (and escitalopram): more than 600 mg citalopram (more than 300 mg escitalopram) has been
associated with QT prolongation.

Other SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine): toxic dose is not well established, but there are
reports of ingestion of large amounts, more than 50 times the defined daily dose, without severe effects
occurring.

Other predictors of toxicity

The combination of an SSRI with a monoamine oxidase inhibitor can lead to severe and life-threatening
serotonin toxicity.

Clinical presentation
SSRI overdoses rarely cause major effects. Systemic effects include:

CNS effects
–
CNS depression is uncommon and never severe; seizures rarely occur
–
serotonin toxicity occurs in 15% of SSRI ingestions, but is only severe if combined with other
serotonergic drugs
cardiovascular effects—SSRIs rarely cause severe effects except for citalopram and escitalopram,
which have been reported to cause QT prolongation and torsades de pointes. Mild bradycardia has been
reported with citalopram, escitalopram and fluoxetine.

Key investigations in SSRI poisoning

The key investigations in SSRI overdose include:

ECG—an ECG should be done in all cases, particularly for citalopram and escitalopram (see QT
prolongation).

Treatment of SSRI poisoning

Airway and breathing
Difficulties with airway and breathing occur only with severe serotonin toxicity causing respiratory paralysis
and hyperthermia.

Circulation
QT prolongation and torsades de pointes: citalopram and escitalopram

Continuous ECG monitoring and regular 12-lead ECGs should be done for all citalopram overdoses greater
than 1000 mg (or greater than 600 mg if no activated charcoal is given within 4 hours of the estimated time of
ingestion). For escitalopram, the threshold doses for cardiac monitoring and regular 12-lead ECGs are 400
mg (or greater than 300 mg if no activated charcoal is given within 4 hours of the estimated time of
ingestion). The serial ECGs should continue for 13 hours or until the QT interval has normalised after an
abnormal QT.

For details on the management of QT prolongation and torsades de pointes, see QT prolongation and torsades
de pointes.

Decontamination
Decontamination is rarely required in SSRI overdose unless the patient has taken a massive overdose and
presents within 1 hour of ingestion. However, based on pharmacokinetic-pharmacodynamic studies of
citalopram and escitalopram, activated charcoal is recommended for overdoses of more than 600 mg
citalopram or 300 mg escitalopram when the patient presents within 4 hours of the estimated time of
ingestion. For dosing information, see Single-dose activated charcoal.

Specific pharmacological therapies

For management of serotonin toxicity, see Serotonin toxicity.

Observation and patient disposition after SSRI poisoning

Criteria for discharge: For most SSRIs, asymptomatic patients who have been observed for 6 hours after
ingestion can be discharged.

For citalopram and escitalopram, a longer period of observation is required. Patients who have ingested more
than 600 mg citalopram, or 300 mg escitalopram, can be discharged 13 hours after ingestion if they are
asymptomatic and have a normal QT interval.

Criteria for admission: For citalopram and escitalopram, patients who have ingested more than 1000 mg
citalopram or 400 mg escitalopram (or more than 600 mg citalopram or 300 mg escitalopram and have not
received activated charcoal) should be monitored for 13 hours after ingestion and/or until the QT interval is
normal.

Patients with severe serotonin toxicity require admission to a critical care unit.

Key references
Toxicology: selective serotonin reuptake inhibitors

Isbister GK, Friberg LE, Duffull SB. Application of pharmacokinetic-pharmacodynamic modelling in management
of QT abnormalities after citalopram overdose. Intensive Care Med 2006;32(7):1060–5. [ ]

van Gorp F, Duffull S, Hackett LP, Isbister GK. Population pharmacokinetics and pharmacodynamics of
escitalopram in overdose and the effect of activated charcoal. Br J Clin Pharmacol 2011. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: serotonin and noradrenaline reuptake
inhibitors
Introduction to SNRI poisoning
Serotonin and noradrenaline reuptake inhibitors (SNRIs) include desvenlafaxine, duloxetine, reboxetine,
tramadol and venlafaxine. Tramadol is used as an analgesic, not an antidepressant, but is pharmacologically
an SNRI. Desvenlafaxine and venlafaxine are only available as slow-release formulations; tramadol is
available in immediate- and slow-release formulations.

Risk assessment for SNRI poisoning

Toxic dose

Desvenlafaxine: toxic dose is not known, but the therapeutic dose of desvenlafaxine is two-thirds of the
therapeutic dose of venlafaxine (50 mg desvenlafaxine versus 75 mg venlafaxine).

Duloxetine: estimated toxic dose is 600 mg or 8.5 mg/kg.

Reboxetine: toxic dose is not well defined. Toxicity is likely with ingestions of more than 3 mg/kg.

Tramadol: toxic dose is not clearly defined, but ingestions of more than 5 g tramadol are associated with
severe toxicity. Seizures are likely with ingestion of more than 1.5 g.

Venlafaxine: risk of seizures increases with dose ingested (seizures likely in all ingestions more than 5 g).
Cardiotoxicity is rare except in massive ingestions (eg more than 8 g) where hypotension and
tachyarrhythmias may occur.

Other predictors of toxicity

The co-ingestion of another serotonergic drug with SNRIs may increase the risk and severity of serotonin
toxicity. This is particularly important with the co-ingestion of a monoamine oxidase inhibitor (eg
moclobemide, phenelzine).

Clinical presentation
Noradrenergic features of SNRIs tend to predominate in overdose producing a sympathomimetic toxidrome.
Severe clinical features include delayed-onset seizures (up to 16 hours following ingestion of slow-release
preparations), hypotension, arrhythmias, hyperthermia and severe serotonin toxicity.

Opioid effects of sedation and miosis are not prominent in tramadol overdose.

Serotonin toxicity is only severe if SNRIs are co-ingested with other serotonergic drugs that act via a
different mechanism (eg monoamine oxidase inhibitors).

Treatment of SNRI poisoning

Airway and breathing
Airway and breathing should be supported as required and the respiratory rate (undisturbed) should be
closely observed.

Circulation
Hypotension is usually mild and responds to intravenous fluid (see Resuscitation: circulation). Hypotension
may be severe following massive ingestions (eg more than 8 g venlafaxine or more than 5 g tramadol) and
require specific inotropes (see Inotropic support). Seek advice of a clinical toxicologist.

Patients ingesting more than 8 g venlafaxine should have ECG monitoring to detect tachyarrhythmias.

Decontamination
Activated charcoal is recommended for large ingestions if it can be administered within 1 hour of the
estimated time of ingestion (see Single-dose activated charcoal). Large ingestions (more than 5 g tramadol or
5 g venlafaxine) may benefit from early intubation and administration of activated charcoal and whole bowel
irrigation. Seek advice from a clinical toxicologist.

For slow-release preparations (tramadol, venlafaxine, desvenlafaxine), activated charcoal may be considered
up to 4 hours after ingestion.

Specific pharmacological therapies

Serotonin toxicity

In patients with significant agitation and neuromuscular excitation not controlled with benzodiazepines, oral
cyproheptadine may be used (see Serotonin toxicity).

Anticonvulsant therapy

Seizures are generally self-limiting but if persistent and recurrent they can be treated with benzodiazepines
(see Anticonvulsant therapy).

Observation and patient disposition after SNRI poisoning

Criteria for discharge: Asymptomatic patients can be discharged 6 hours after ingestion of immediate-
release preparations and 16 hours after ingestion of slow-release preparations.

Criteria for admission: All patients require observation for 6 hours after ingestion of immediate-release
preparations and 16 hours after ingestion of slow-release preparations.

Cardiac monitoring is required for large ingestions (eg more than 5 g tramadol or 5 g venlafaxine).

Patients who have ingested more than 5 g venlafaxine are at risk of delayed seizures and should be observed
for 24 hours after ingestion.

Key references
Toxicology: serotonin and noradrenaline reuptake inhibitors

Griffith J, Spiller H, Weber J, Lintner C, Casavant M, Baker S. Toxicity from duloxetine ingestion [abstract]. Clin
Toxicol 2008;46(7):591–645.

Agelink MW, Ullrich H, Passenberg P, Sayar K, Brockmeyer NH. Superior safety of reboxetine over amitryptiline
in the elderly. Eur J Med Res 2002;7(9):415–6. [ ]

Bandinelli PL, Polselli GM. Asymptomatic reboxetine overdose. Int J Neuropsychopharmacol 2006;9(2):257. [
]

Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235
consecutive cases. Br J Clin Pharmacol 2007;64(2):192–7. [ ]

Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. Br J Clin Pharmacol
2009;67(5):572–6. [ ]

Kumar VV, Isbister GK, Duffull SB. The effect of decontamination procedures on the pharmacodynamics of
venlafaxine in overdose. Br J Clin Pharmacol 2011;72(1):125–32. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: sodium valproate
Risk assessment for sodium valproate poisoning
Most sodium valproate poisonings are not serious, but some large overdoses lead to life-threatening
metabolic effects. Severe toxicity does not occur with doses that do not also cause sedation.

Toxic dose
The severity of toxicity is dependent on the dose of sodium valproate ingested:

less than 200 mg/kg—unlikely to develop more than minor effects

200 to 400 mg/kg—moderate toxicity with CNS depression
more than 400 mg/kg—severe toxicity
more than 1 g/kg—potentially life-threatening.

Toxic concentration
Valproate concentrations are available in many hospitals and the normal therapeutic range is 350 to 700
micromol/L (50 to 100 mg/L or micrograms/mL). Concentrations more than 6000 micromol/L (850 mg/L or
micrograms/mL) are associated with severe poisoning.

Other predictors of toxicity

Other predictors of toxicity include hypernatraemia, hypocalcaemia and an elevated ammonia or lactate with
associated metabolic acidosis. In rural or peripheral hospitals, a high serum sodium concentration may be
very useful to indicate a significant ingestion.

Clinical presentation
Ingestions less than 400 mg/kg sodium valproate may cause no effects or only minor effects.

Systemic effects include:

gastrointestinal effects—nausea, vomiting, abdominal pain

CNS effects—drowsiness and ataxia progressing to coma in severe poisoning, cerebral oedema,
seizures, respiratory depression
cardiovascular effects—QT prolongation (torsades de pointes not reported), hypotension, tachycardia
metabolic effects—hypernatraemia (secondary to sodium load in sodium valproate), metabolic
acidosis, increased lactate, hypocalcaemia, hypoglycaemia, hyperammonaemia
myelosuppression—mild to moderate thrombocytopenia and neutropenia.

Key investigations in sodium valproate poisoning

The key investigations in sodium valproate overdose include:

ECG—QT prolongation occurs with large overdoses.

Valproate concentrations—in patients with altered consciousness, measure every 4 to 6 hours until the
patient has recovered full consciousness.
Blood glucose concentration.

Treatment of sodium valproate poisoning

There is no proven specific antidote or pharmacological treatment for valproate poisoning, so early
decontamination and supportive care is essential for severe poisoning.

Airway and breathing

Patients with severe poisoning require intubation and ventilation for airway protection.

Circulation
Treat hypotension with fluid resuscitation (see Resuscitation: circulation).

If there is inadequate response, then inotropes need to be commenced (see Inotropic support). Use:

adrenaline 1 to 20 micrograms/minute IV infusion (see Box 17.7), titrated to blood

pressure.

Decontamination

Activated charcoal should be given if more than 400 mg/kg sodium valproate has been ingested and the
patient presents within 2 hours of the estimated time of ingestion (see Single-dose activated charcoal).

Enhanced elimination
Consider haemodialysis early in patients with life-threatening poisoning, including ingestions of more than 1
g/kg with valproate concentrations greater than 6000 micromol/L (850 mg/L or micrograms/mL). Any patient
with such severe poisoning should be discussed with a clinical toxicologist and transferred to a hospital with
haemodialysis or high-flux continuous veno-venous haemodialysis.

Observation and patient disposition after sodium valproate

poisoning
Criteria for admission: All patients should be observed for at least 12 hours after ingestion. Patients with
altered mental state should have serial sodium valproate concentrations monitored.

Patients who have ingested more than 400 mg/kg sodium valproate or require mechanical ventilation should
be admitted.

Patients who have ingested more than 1 g/kg sodium valproate or with valproate serum concentrations more
than 6000 micromol/L (850 mg/L or micrograms/mL) should be transferred to an intensive care unit with
dialysis facilities.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: stimulant drugs
Introduction to poisoning caused by stimulant drugs
Stimulant drugs include amphetamines, cathinones, cocaine, dexamphetamine, methylphenidate and piperazines.

There is enormous variability in the chemical constituents of street drugs, and street drugs often contain
combinations of substances. Although numerous amphetamine derivatives have been synthesised and used, the
commonest are methamphetamine ('speed') and methylenedioxymethamphetamine (MDMA or 'ecstasy').

Dexamphetamine and methylphenidate are used to treat attention deficit hyperactivity disorder and both have
similar effects in overdose to other amphetamines. Methylphenidate poisoning commonly occurs in the 6- to 12-
year-old age group, with a significant number resulting from therapeutic errors.

Other agents structurally related to amphetamines that cause similar clinical effects include:

mephedrone and other cathinone derivatives

phenylpiperazine analogues—benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are
the commonest.

Risk assessment for poisoning caused by stimulant drugs

Toxic dose

There is a dose-toxicity relationship for amphetamines and cocaine, but individual variability in tolerance and
unreliable dosing makes estimated dose a poor predictor of toxicity.

For cocaine, exposures greater than 1 g are potentially lethal.

For methylphenidate, doses greater than 2 mg/kg are likely to be associated with toxicity.

Exposure

Ingestion of multiple stimulant drugs can produce more pronounced toxicity. Co-ingestion of ethanol with cocaine
increases the degree and duration of cocaine toxicity.

Clinical presentation
The main clinical effects of stimulant drugs in overdose are consistent with sympathomimetic excess (see
Sympathomimetic syndrome). Significant life-threatening complications of stimulant drug overdose include:

CNS effects—agitation, seizures, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and
associated cerebral oedema
cardiovascular effects—acute coronary syndrome (particularly with cocaine), subarachnoid haemorrhage,
aortic dissection, arrhythmias (QRS widening with cocaine)
respiratory effects—pneumothorax, pulmonary oedema
other effects—hyperthermia, mesenteric ischemia.

Amphetamine toxicity is characterised by cardiovascular and autonomic stimulation, delirium, hallucinations and
agitation. The most common management problem is delirium and agitation.

Acute exposure to cocaine rapidly (within 1 hour) leads to a multitude of clinical effects secondary to
sympathomimetic stimulation and sodium channel blockade, including life-threatening cardiovascular toxicity.

The majority of methylphenidate poisonings cause minor effects. However, minor inhibition of monoamine
oxidase can occur, and co-ingestion of other serotonergic drugs may cause serotonin toxicity.

Key investigations in poisoning caused by stimulant drugs

The key investigations in stimulant drug overdose include:

ECG—perform in all patients (some may require sedation). Cocaine can cause cardiac conduction delays,
 broad complex (QRS widening) arrhythmias and QT prolongation.
Electrolytes, kidney function and creatine kinase.
Troponin concentration—measure in patients with chest pain or evidence of myocardial ischaemia.
Chest X-ray—perform in all patients with chest pain to look for evidence of dissection, pneumothorax or
pneumomediastinum. A normal chest X-ray does not exclude a diagnosis of dissection.
Blood glucose concentration—measure in all patients with altered conscious state.
Brain CT scan—perform in all patients with altered conscious state without a readily identifiable cause, or
those complaining of headache (as an initial investigation to exclude subarachnoid haemorrhage,
intracerebral haemorrhage or cerebral oedema). A negative CT scan cannot exclude subarachnoid
haemorrhage without follow-up lumbar puncture.
Angiography—perform in
–
all patients with acute coronary syndrome with infarction or not responding to medical management
(identify vasospasm or thrombosis)
–
suspected cases of mesenteric ischemia, aortic or carotid dissection, or peripheral limb ischaemia.

Treatment of poisoning caused by stimulant drugs

Airway and breathing
Airway support and mechanical ventilation are rarely required unless there is multiorgan failure.

Circulation
All patients require intravenous fluids (see Resuscitation: circulation).

Hypertension

Hypertension should initially be treated with titrated intravenous benzodiazepines (see Sedation). If hypertension
persists despite CNS sedation, short-acting vasodilators may be used. Use:

1 glyceryl trinitrate 10 micrograms/minute (child: 0.5 micrograms/kg/minute) IV infusion,

increasing by 10 micrograms/minute every 3 minutes (child: increasing by 0.5
micrograms/kg/minute every 3 minutes up to a maximum of 5 micrograms/kg/minute)
until systolic blood pressure is at normal level

OR

2 phentolamine 1 mg (child: 0.1 mg/kg) IV, repeat every 5 minutes as required

OR

2 sodium nitroprusside 0.3 micrograms/kg/minute IV infusion for 10 minutes, then

increasing or decreasing by 0.3 micrograms/kg/minute every 5 to 10 minutes (up to a
maximum of 10 micrograms/kg/minute) to maintain the individual target blood pressure
for that patient [Note 1].

Beta-blockers are contraindicated in treatment of stimulant drug induced hypertension.

Note 1: Administration of sodium nitroprusside is complex, and product information should be consulted.

Myocardial ischaemia

Myocardial ischaemia and myocardial infarction should be managed as detailed in Acute coronary syndromes,
except beta blockers are contraindicated and benzodiazepines are required.

Persistent chest pain associated with ECG changes (particularly ST elevation) mandates consideration of coronary
angiography and intraluminal administration of vasodilators or thrombolytics. Peripheral administration of
thrombolysis is contraindicated if there is uncontrolled hypertension, seizures or aortic dissection.

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess the QRS widening. Arrhythmias
associated with QRS widening should be treated (see QRS widening and sodium channel blockade).
Cocaine-related broad complex arrhythmias refractory to sodium bicarbonate should be treated with lidocaine.
Use:

lidocaine 1.5 mg/kg IV as an initial bolus, followed by an infusion of 2 mg/minute.

QT prolongation and torsades de pointes

Continuous ECG monitoring and regular 12-lead ECGs are required to assess the QT interval. For details on the
management of QT prolongation and torsades de pointes, see QT prolongation and torsades de pointes.

Supraventricular tachycardia

Supraventricular tachycardia should be treated with benzodiazepines as for sedation. If there is no response,
verapamil or adenosine can be administered. Use:

1 adenosine 6 to 12 mg (child: 0.1 mg/kg up to 6 mg, followed by 0.2 mg/kg up to 12 mg)

IV

OR

2 verapamil 5 mg (child: 0.1 mg/kg up to 5 mg) IV.

If there is deterioration to ventricular fibrillation or asystole, standard advanced life support protocols should be
followed (see flowcharts developed by the Australian Resuscitation Council).

Decontamination
There is almost no role for decontamination in stimulant drug toxicity and there is significant risk and difficulty in
administering it. In rare cases, when patients present early (within 1 hour after ingestion) and their clinical status
allows them to protect their airway, activated charcoal may be considered (see Single-dose activated charcoal).

Body packers [Note 2] require observation in a monitored environment. Conservative management using laxatives
is associated with minimal complications. Active treatment with whole bowel irrigation is widely practised, but
more controversial.

Note 2: Body packing refers to the swallowing of plastic- or latex-wrapped packages of illicit drugs for
concealment from inspection. Presentation to the emergency department is often long after swallowing the
packages, which have therefore usually entered the small or large intestine.

Specific pharmacological therapies

Sedation

The main treatment for overdose with stimulant drugs is sedation with intravenous benzodiazepines for CNS
excitation, tachycardia, hypertension, hyperpyrexia and sympathomimetic stimulation (producing complications
such as hyperthermia). Oral benzodiazepines may be used in patients with mild to moderate agitation if they are
cooperative. For drug and dosing recommendations, see Sedation.

Anticonvulsant therapy

Seizures should be rapidly controlled with intravenous benzodiazepines commencing with larger doses than those
used for agitation alone (see Anticonvulsant therapy).

Treatment of other complications

Hyperthermia

If the patient's temperature is greater than 39 °C, they should be cooled using active measures (see also Heat stroke
and Key management issues). If there is no response, the patient may need to be intubated and paralysed, and
cooled with more invasive techniques.

Rhabdomyolysis
Manage rhabdomyolysis with aggressive intravenous fluids to maintain urine output at 1 to 2 mL/kg/hour (see
Rhabdomyolysis).

Hyponatraemia

Severe hyponatraemia (sodium concentration less than 125 mmol/L) should only be treated if the patient has
seizures or an acutely altered mental state. Use:

sodium chloride 3% 4 mL/kg IV over 10 to 30 minutes.

Psychosis

Amphetamine-induced psychosis may occur in acute toxicity, but usually results from repeated use. Once acute
toxicity has resolved, patients may require psychiatric assessment if they have ongoing delusions and
hallucinations.

Observation and patient disposition after poisoning caused by stimulant

drugs
Criteria for discharge: Children exposed to a stimulant drug should be observed in hospital for at least 4 hours
after ingestion.

Criteria for admission: All patients with evidence of stimulant drug toxicity must be admitted until toxicity has
resolved. Patients with chest pain or ECG changes require continuous monitoring. Those with significant
complications (eg arrhythmias, hyperthermia, acute coronary syndrome, intracerebral haemorrhage, aortic
dissection, ongoing seizures) require admission to a critical care unit.

Key references
Toxicology: stimulant drugs

Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med 2001;345(5):351–8. [ ]

Westover AN, Nakonezny PA. Aortic dissection in young adults who abuse amphetamines. Am Heart J
2010;160(2):315–21. [ ]

Wood DM, Dargan PI, Hoffman RS. Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel
dysfunction. Clin Toxicol (Phila) 2009;47(1):14–23. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: theophylline and caffeine
Risk assessment for theophylline or caffeine poisoning
Theophylline and caffeine are methylxanthines and in significant overdose have the potential to cause life-
threatening seizures and arrhythmias. Methylxanthines have a narrow therapeutic index and wide individual
susceptibility.

Toxic dose
Theophylline: ingestion of supratherapeutic doses (greater than 10 mg/kg daily) may cause toxicity. Severe and
life-threatening toxicity is associated with doses greater than 50 mg/kg.

Caffeine: rarely causes major effects except after massive ingestions. The toxic dose is unclear but doses greater
than 15 to 30 mg/kg cause mild to moderate toxicity, and doses greater than 150 mg/kg cause severe and
potentially life-threatening toxicity.

Some over-the-counter combination preparations contain up to 100 mg caffeine per tablet. See Caffeine for
approximate amounts of caffeine in commonly consumed beverages.

Toxic concentration
Clinical effects correlate with theophylline concentrations in acute poisonings:

less than 110 micromol/L (20 mg/L)—unlikely to have significant toxicity

220 to 550 micromol/L (40 to 100 mg/L)—mild to moderate toxicity
greater than 550 micromol/L (greater than 100 mg/L)—severe, life-threatening toxicity; increased risk of
seizures.

In chronic theophylline poisoning, severe effects may be associated with lower theophylline concentrations (eg
greater than 330 micromol/L [60 mg/L]).

Other predictors of toxicity

Other predictors of toxicity in theophylline and caffeine overdose include:

hypokalaemia—potassium concentration less than 3.0 mmol/L

blood glucose concentration greater than 10 mmol/L
age greater than 60—significant predictor of severity and poor outcome in chronic toxicity (not acute).

Clinical presentation
Many of the clinical effects of theophylline and caffeine toxicity are due to catecholamine excess and so the
clinical picture is similar to the sympathomimetic syndrome.

Patients with chronic theophylline toxicity are more likely to present with seizures or arrhythmias.

Systemic effects of theophylline and caffeine overdoses include:

gastrointestinal effects—nausea, vomiting

cardiovascular effects—tachycardia, atrial and ventricular ectopy; hypotension (beta2-mediated
vasodilatation). Arrhythmias (supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation)
are rare and occur with drug concentrations greater than 100 mg/L. Myocardial infarction has been reported
CNS effects—agitation, tremor, seizures
metabolic effects—hyperglycaemia, hypokalaemia, metabolic acidosis, hypercalcaemia
other effects—hyperventilation.

Key investigations in theophylline or caffeine poisoning

The key investigations in theophylline and caffeine overdose include:

ECG—arrhythmias can occur.

 Theophylline concentrations—should be done every 2 to 4 hours (mg/L x 5.55 = micromol/L).
Electrolytes and creatinine—check kidney function.
Blood glucose concentration.

Treatment of theophylline or caffeine poisoning

Airway and breathing
Airway support and mechanical ventilation are rarely required unless the patient has intractable seizures and
requires large amounts of benzodiazepines and/or barbiturates.

Circulation
Fluid replacement should be commenced in all patients as for dehydration due to large losses from vomiting (see
Resuscitation: circulation).

Electrolyte replacement is rarely required. In particular, potassium replacement should be undertaken cautiously
because hypokalaemia is due to a shift of potassium into cells and not net loss of potassium.

In the rare circumstance that a patient develops hypotension unresponsive to fluid replacement, vasopressors can
be used. The use of other inotropes and/or beta blockers should be discussed with a clinical toxicologist.

Vasopressors with selective alpha-agonist activity are recommended. Use:

1 metaraminol 0.5 to 1 mg (child: 0.01 mg/kg) IV bolus, repeat if there is a clinical response

OR

1 noradrenaline 1 to 20 micrograms/minute (child: 0.02 to 0.1 microgram/kg/minute) IV

infusion (see Box 17.7).

Ventricular tachyarrhythmias and ventricular fibrillation are rare and should be treated according to standard
advanced life support protocols (see flowcharts developed by the Australian Resuscitation Council).

Decontamination

Activated charcoal is indicated in all but the most minor poisonings even more than 1 hour after the estimated time
of ingestion (see Single-dose activated charcoal).

For slow-release theophylline preparations, activated charcoal may be considered up to 4 hours after ingestion.

Antiemetics are often required to allow the administration of activated charcoal. For antiemetic dosing, see
Specific pharmacological therapies: other).

Enhanced elimination

Multiple-dose activated charcoal

Multiple-dose activated charcoal has been shown to increase the elimination of theophylline. All patients with
moderate to severe poisoning should be commenced on multiple-dose activated charcoal if they have a protected
airway and there is no ileus (see Multiple-dose activated charcoal).

Extracorporeal elimination

Haemodialysis increases clearance of theophylline by about 1.5- to 2-fold and although not as effective as
haemoperfusion (2- to 5-fold increase), it is more readily available and associated with less risk of adverse effects
(coagulopathy and electrolyte disturbances). The use of haemodialysis should be considered in severe poisoning,
although there is no evidence that it is more effective than multiple-dose activated charcoal. Balancing the
advantages and risks of haemodialysis versus multiple-dose activated charcoal can be discussed with a clinical
toxicologist. Suggested indications for haemodialysis are:

theophylline concentration greater than 550 micromol/L (100 mg/L) in acute toxicity
theophylline concentration greater than 330 micromol/L (60 mg/L) in chronic toxicity
severe clinical features.
Specific pharmacological therapies

Anticonvulsant therapy

Seizures in theophylline toxicity are associated with significant morbidity and mortality, and may be persistent
(status epilepticus). For this reason rapid control of seizures is essential. Initially benzodiazepines should be used
but barbiturates may be required. For dosing recommendations of benzodiazepines, see Anticonvulsant therapy.

Sedation

Patients with agitation can be treated with benzodiazepines. For drug and dosing recommendations, see Sedation.

Other

Treatment of severe and persistent vomiting is indicated in theophylline poisoning.

In adults, use:

metoclopramide 10 to 20 mg IV as a single dose

If there is ongoing vomiting, use:

1 granisetron 3 mg IV as a single dose

OR

1 ondansetron 8 mg IV as a single dose

OR

1 tropisetron 5 mg IV as a single dose

OR

2 dolasetron 100 mg IV as a single dose [Note 1].

In children, use:

1 ondansetron 0.15 mg/kg IV or orally, 8-hourly

OR

2 metoclopramide 0.2 mg/kg IV, IM or orally, 8-hourly [Note 2].

Note 1: Dolasetron has been discontinued in Australia.

Note 2: There is evidence of an increased risk of neurological adverse effects with metoclopramide in children.
For more information and drug dosing advice, see the February 2015 Medicines Safety Update.

Observation and patient disposition after theophylline or caffeine

poisoning
Criteria for discharge:

Theophylline: Patients should only be discharged if they have not developed any signs of toxicity 6 hours after
overdose of an immediate-release formulation (including syrup) or 12 hours after overdose of a slow-release
formulation of theophylline.

Caffeine: Patients ingesting less than 2 g caffeine can be discharged 6 hours after ingestion if they are
asymptomatic and have a normal ECG.
Criteria for admission:

Theophylline: Any patient with moderate to severe toxicity should be admitted to a critical care unit with dialysis
facilities.

Caffeine: Patients ingesting more than 2 g (30 mg/kg) caffeine should be admitted for observation and monitoring.

Published July 2012. Amended June 2015. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: tricyclic antidepressants
Risk assessment for poisoning caused by tricyclic antidepressants
Overview
Tricyclic antidepressants (TCAs) include amitriptyline, clomipramine, dothiepin, doxepin, imipramine,
nortriptyline and trimipramine.

TCAs are associated with significant morbidity and mortality when ingested in overdose. Coma, seizures and
cardiovascular toxicity manifest rapidly and are frequently fatal without aggressive intervention. Airway support,
administration of sodium bicarbonate and meticulous supportive care in an intensive care unit are crucial to good
outcome.

Toxic dose

Ingestions of more than 10 mg/kg in adults and more than 5 mg/kg in children are potentially toxic.

Severe toxicity results from ingestion of more than 20 mg/kg.

ECG changes

TCA toxicity produces a variety of ECG changes, including sinus tachycardia. QRS interval prolongation to more
than 100 msec is associated with seizures, and to more than 160 msec with ventricular arrhythmias. TCA toxicity
produces a more rightward frontal plane QRS vector, manifesting as an S wave in lead I and an R wave in lead
aVR. An R wave height of 3 mm in lead aVR is a sensitive marker for seizures and arrhythmias. QT prolongation
occurs in both therapeutic and supra-therapeutic administration of TCAs, and is not a specific predictor of TCA-
associated adverse outcome.

Clinical presentation
Clinical effects develop rapidly and patients often deteriorate before admission or during transport to hospital.

Systemic effects include:

anticholinergic-like syndrome—usually less severe than with pure anticholinergic agents. May include
mydriasis or mid-range pupil size, warm-dry skin, tachycardia, dry mouth and occasionally urinary retention
and decreased bowel sounds. Anticholinergic delirium can occur in the 24- to 48-hour period following
recovery from severe toxicity
CNS effects—rapidly decreasing level of consciousness in moderate to severe poisoning; seizures in severe
poisoning and the resulting metabolic acidosis may lead to progressive life-threatening cardiovascular
toxicity
cardiovascular effects
–
hypotension—due to volume depletion, alpha blockade and myocardial depression
–
broad complex tachycardias—may be sinus or supraventricular tachycardias with QRS widening, or
ventricular tachycardia
–
bradycardia—severe toxicity bradycardia occurs with a progressive QRS widening and conduction
block due to sodium channel blockade
–
QT prolongation (associated with the QRS widening).

Key investigations in poisoning caused by tricyclic antidepressants

The key investigations in TCA overdose include:

ECG—see ECG changes (above) for details.

Treatment of poisoning caused by tricyclic antidepressants

Airway and breathing
Patients should be intubated at the first sign of CNS depression.

Circulation
Hypotension should be treated with intravenous fluids (see Resuscitation: circulation).

QRS widening and sodium channel blockade

Continuous ECG monitoring and regular 12-lead ECGs are required to assess QRS widening. When QRS
widening is progressive and associated with a decompensation in airways, breathing or circulation (see QRS
widening), intravenous boluses of sodium bicarbonate and concurrent hyperventilation therapy (by intubation and
mechanical ventilation) should be used to increase the pH to a target of 7.45 to 7.55. Use:

sodium bicarbonate 8.4% (= 1 mmol/mL) 1 to 2 mmol/kg IV bolus, every 3 to 5 minutes,

titrated to a narrowing of the QRS complex. If no response, urgently seek advice from a
poisons information centre. Maximum total dose 10 mmol/kg

PLUS

hyperventilation following intubation and mechanical ventilation (where indicated).

Decontamination
Administer activated charcoal if the patient presents within 1 hour of the estimated time of ingestion (see Single-
dose activated charcoal).

Consider activated charcoal after 1 hour from the estimated time of ingestion in severe poisoning via a nasogastric
or orogastric tube (if the patient can protect their airway or has been intubated).

Specific pharmacological therapies

Anticonvulsant therapy

Seizures are usually short and self-limiting and do not require treatment. However, seizures worsen acidosis and
should be treated with benzodiazepines if they are not self-limiting within minutes (see Anticonvulsant therapy).

Anti-arrhythmic drugs

Sodium bicarbonate is the antiarrhythmic drug of choice (see QRS widening and sodium channel blockade above,
and in Toxicology: general approach).

Resistant arrhythmias should be discussed with a clinical toxicologist.

Class 1A antiarrhythmic drugs, such as quinidine or procainamide, are contraindicated.

Observation and patient disposition after poisoning caused by tricyclic

antidepressants
Criteria for discharge: In less severe cases, patients with a normal ECG and no CNS depression can be
discharged 6 hours after ingestion.

Criteria for admission: Patients with CNS depression or more severe poisoning require admission to a critical
care unit.

Key references
Toxicology: tricyclic antidepressants

Bateman DN. Tricyclic antidepressant poisoning: central nervous system effects and management. Toxicol Rev
2005;24(3):181–6. [ ]

Bradberry SM, Thanacoody HK, Watt BE, Thomas SH, Vale JA. Management of the cardiovascular complications of
tricyclic antidepressant poisoning: role of sodium bicarbonate. Toxicol Rev 2005;24(3):195–204. [ ]

Caravati EM. The electrocardiogram as a diagnostic discriminator for acute tricyclic antidepressant poisoning. J
Toxicol Clin Toxicol 1999;37(1):113–5. [ ]

Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute
tricyclic antidepressant toxicity. Ann Emerg Med 1995;26(2):195–201. [ ]

Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: cardiovascular toxicity. Toxicol Rev 2005;24(3):205–
14. [ ]

Published July 2012. Amended March 2018. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Toxicology: warfarin
Risk assessment for warfarin poisoning
Overview
Warfarin overdose or poisoning (deliberate or unintentional self-poisoning) usually presents without symptoms
and results in a delayed increase in the international normalised ratio (INR). Risk of bleeding depends on the INR.
If clinical bleeding is present rapid reversal therapy is required.

For management of poisonings in patients taking warfarin therapeutically, see Management of bleeding and/or
over-anticoagulation.

For the management of patients who have ingested a long-acting anticoagulant or superwarfarin rodenticide, see
Toxicology: long-acting anticoagulant rodenticides (superwarfarins).

Toxic dose

There is no clear toxic dose for warfarin.

INR

The INR is used to measure the effect of warfarin. It is a good predictor of toxicity and correlates with risk of
bleeding. Table 17.19 is a simple classification of risk based on INR.

Risk of severity of warfarin overdose classified according to INR (Table 17.19)

INR Risk of serious bleeding

Above therapeutic range but INR less than 5 low
INR from 5 to 9 moderate
INR 9 or greater high
INR = international normalised ratio

Clinical presentation

The clinical effects of warfarin poisoning or over-anticoagulation relate to bleeding complications. Clinical effects
will be delayed because the anticoagulant effect takes time to develop and is dependent on the half-life of clotting
factors II, VII, IX and X. An increase in the INR will begin to occur after 12 to 24 hours with the clearance of
factor VII (half-life = 6 hours). Bleeding complications may then take days to develop depending on the patient
and pre-existing medical illnesses.

Bleeding complications

The effects of haemorrhage in different systems are outlined below:

intracranial haemorrhage—impaired mental state, focal neurological signs and symptoms

gastrointestinal haemorrhage—haematemesis, rectal bleeding, retroperitoneal bleeding (may present as
abdominal pain)
genitourinary haemorrhage—haematuria
pulmonary haemorrhage—haemoptysis, dyspnoea
haemorrhagic shock secondary to massive bleeding
external signs of bleeding—bruising, epistaxis, bleeding gums.

Key investigations in warfarin poisoning

The key investigations in warfarin overdose include:

Coagulation studies—INR (may be normal at presentation).

Full blood count, blood group and cross-match.
Treatment of warfarin poisoning
Airway and breathing
In the rare occurrence of an intracranial bleed, the patient may require intubation and ventilation measures to
reduce intracranial pressure.

Circulation
Patients with massive bleeding (usually gastrointestinal) will need fluid resuscitation (see Resuscitation:
circulation), blood cross-matching and blood transfusion in addition to antidotal therapy and clotting factor
replacement (below).

Decontamination
In patients with a warfarin overdose, consider activated charcoal if the patient is cooperative and presents within 1
hour of the estimated time of ingestion (see Single-dose activated charcoal).

Specific pharmacological therapies

Antidotal therapy and clotting factor replacement

Warfarin overdose or poisoning (deliberate or unintentional self-poisoning) differs slightly from over-
anticoagulation during appropriate therapeutic use, because no other precipitating factor for the excessive
anticoagulation needs to be identified.

For patients taking warfarin therapeutically, see Management of bleeding and/or over-anticoagulation.

For patients not taking warfarin therapeutically, with deliberate or unintentional self-poisoning, use:

phytomenadione 10 to 20 mg orally or IV. This dose may need to be repeated 6- to 12-

hourly, for up to 7 days, depending on the amount of warfarin ingested and individual INR
response. Seek advice for further dosing [Note 1].

If the patient is actively bleeding, add:

Prothrombinex -VF 25 to 50 units/kg IV [Note 2]

PLUS

fresh frozen plasma 150 to 300 mL IV.

Monitor INR every 6 to 12 hours until normal.

Note 1: The Australian approved name (AAN) for vitamin K is phytomenadione.

Note 2: Prothrombinex-VF is the commercial name for prothrombin complex factors. It contains human
antithrombin III, factor II, factor IX, factor V, factor VII and factor X, and porcine heparin.

Observation and patient disposition after warfarin poisoning

Criteria for discharge: Asymptomatic patients with a normal INR can be discharged 48 hours after warfarin
poisoning.

Criteria for admission: Hospital admission for warfarin poisoning will be based on the INR and any bleeding
complications.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Snake bite
General information on snake bite
Although suspected snake bite is relatively common in regional and rural areas, snake envenoming is rare.
Envenoming is a potentially life-threatening condition. Current estimates suggest that there are approximately
3000 snake bites annually in Australia; antivenom is required in about 100 to 200 cases. One to four deaths
occur annually, mostly from brown snakes. Antivenoms exist for all major venomous terrestrial snakes and
there is a polyvalent sea snake antivenom.

Clinical presentation of snake bite

General considerations
In many cases of snake bite insufficient venom is injected to cause any effects. Significant envenoming is
characterised by local effects, systemic symptoms (nausea, vomiting, headache, abdominal pain, diarrhoea,
diaphoresis and collapse) and major organ effects.

Local effects are not a major feature of bites by Australian snakes. The local effects that do occur range from
minimal effects with brown snakes to local pain, swelling and occasionally tissue injury with black snake and
tiger snake bites. Local effects may be the only clinical manifestation of bites from some snakes of minor
importance such as whip snakes.

Major organ effects of snake bite include:

Coagulopathy: Venom-induced consumption coagulopathy (VICC) occurs in most severe cases of

envenoming. It is due to prothrombin activators contained in the snake venoms. It is the single most
important and common major effect of snake envenoming in Australia. Complete VICC is where all the
fibrinogen is consumed. Partial VICC is where the fibrinogen is low but still detectable. Recovery takes
12 to 36 hours after the bite. Some black snakes cause a reversible anticoagulant coagulopathy (see
Table 17.20).
Neurotoxicity: Neuromuscular paralysis is less common than coagulopathy (less than 10% of cases)
and is characterised by a progressive descending flaccid paralysis. Ptosis is usually the first sign, then
facial and bulbar involvement progressing to paralysis of the respiratory muscles and peripheral
weakness in severe cases. Antivenom can prevent the development or progression of neurotoxicity, but
rarely reverses it. Spontaneous recovery occurs over a period of days to weeks.
Myotoxicity: Myotoxicity occurs with some Australian snakes and is characterised by muscle pain,
tenderness and weakness associated with a rapidly rising creatine kinase and myoglobinuria. Secondary
kidney impairment can occur. Antivenom may prevent myotoxicity, but cannot reverse it once it has
developed.
Thrombotic microangiopathy: Thrombotic microangiopathy is characterised by thrombocytopenia,
microangiopathic haemolytic anaemia and acute kidney impairment or failure. It occurs in association
with VICC in brown snake, tiger snake and taipan envenoming.
Kidney damage: Nephrotoxicity occurs most commonly as part of thrombotic microangiopathy and
very rarely secondary to rhabdomyolysis.

Snake venom coagulopathy (Table 17.20)

VICC: a procoagulant coagulopathy Anticoagulant coagulopathy

prothrombin activators in the venom
leading to consumption of major
mechanism presence of anticoagulant in venom
coagulation factors, including
fibrinogen, factor V and factor VIII

brown snake
tiger snake
rough-scaled snake mulga snake
Hoplocephalus species (broad- Collett's snake
type of snake headed, pale-headed, and Stephen's red-bellied black snake
 banded snake)
taipan

high D-dimer concentration (remains

high for days so only useful for
diagnosis, not for monitoring
recovery)
coagulation screen high or unrecordable INR [NB1]
results high or unrecordable APTT [NB1]
low or undetectable fibrinogen
concentration (this assay is not
required for treatment or diagnosis)
only slight to moderate elevation of
clotting times (INR or APTT never
unrecordable)
normal fibrinogen and D-dimer
concentrations

complete VICC:

undetectable fibrinogen
concentration
high D-dimer concentration (at least
10 times the assay cut-off or more
than 2.5 mg/L)
severity INR more than 3.0 not clinically significant

partial VICC:

low but detectable fibrinogen

concentration
high D-dimer concentration
INR less than 3.0

12 to 36 hours after the

administration of antivenom. The
recovery rapidly reversed with antivenom
role of clotting factor replacement
remains unclear.

APTT = activated partial thromboplastin time; INR = international normalised ratio; VICC = venom-induced consumption coagulopathy
NB1: 'Unrecordable' means value greater than limits of measurement; the laboratory should be notified because usually a manual test needs to be
done.

Australian snakes
Seven major groups of medically important snakes occur in Australia. The clinical effects from the major
snake groups are outlined in Table 17.21.

The whip snake is not one of the seven major groups and does not cause major systemic effects, but it is a
common snake causing mild envenoming. Snake bite from a whip snake is characterised by painful local
swelling at the bite site that may be mistaken for local inflammation or infection.

Clinical effects of envenoming by Australian snakes (Table 17.21)

Diagnosis: serum
Snake type Major clinical effect Other clinical effects detection kit and
geography
often asymptomatic VDK +ve brown
brown snake VICC
thrombocytopenia mainland Australia

systemic symptoms VDK +ve tiger

VICC myotoxicity and south-eastern
tiger snake group [NB1]
neurotoxicity Australia

Hoplocephalus species VDK +ve tiger

(broad-headed, pale- VICC often asymptomatic south-eastern
headed and Stephen's Australia
banded snake)
anticoagulant VDK +ve black
red-bellied black snake systemic symptoms coagulopathy [NB2]
 myotoxicity eastern Australia

VDK +ve death

death adder neurotoxicity systemic symptoms adder
mainland Australia

VICC VDK +ve taipan

taipan systemic symptoms
neurotoxicity northern Australia

myotoxicity
VDK +ve black
mulga snake [NB3] anticoagulant systemic symptoms
not eastern seaboard
coagulopathy

VDK = venom detection kit; VICC = venom-induced consumption coagulopathy; +ve = positive
NB1: This group includes tiger snakes (Notechis species) and rough-scaled or Clarence River tiger snake (Tropidechis carinatus).
NB2: Often the VDK is positive for both tiger and black snake.
NB3: Bites by Collett's snake cause similar effects and are treated in the same way, but almost exclusively occur in snake handlers.

Initial management of snake bite

First aid

A pressure bandage over the whole affected limb, and complete immobilisation of the limb and patient, is required in all
cases of suspected snake bite.

A pressure bandage with immobilisation (PBI) of the limb and the patient should be applied in all cases of
suspected snake bite. A broad (15 cm) bandage is applied over the bite site and then distally and proximally to
cover the whole limb, using the same pressure as for a sprained ankle. An elastic bandage, if available, is
preferred to the more widely available crepe bandage. The patient must be completely immobilised in order
for bandaging to be effective. Bandaging and immobilisation is required until the patient is transferred to an
appropriate hospital (see Hospital management). The bite site should not be washed before bandaging because
a swab can be used for venom detection.

Hospital management
All patients with a history of snake bite need to be managed in a hospital with adequate antivenom, a 24-hour
on-site pathology service that can perform coagulation studies (activated partial thromboplastin time [APTT]
and international normalised ratio [INR] are sufficient), and a high-dependency unit or critical care setting
where antivenom can be safely administered (ie where anaphylaxis can be treated).

The pressure immobilisation bandage should only be removed from the envenomed patient once antivenom
therapy has commenced, or after clinical and laboratory assessment confirms there is no evidence of
envenoming. Even if the patient has no clinical or laboratory signs of envenoming, the bandage should only
be removed if antivenom and resuscitation equipment are available.

See Figure 17.3 for a summary of the acute management of snake bite.

Summary management of snake bite (Figure 17.3)

Print-friendly PDF
APTT = activated partial thromboplastin time; CK = creatine kinase; EUC = electrolytes, urea and creatinine; INR = international normalised
ratio; LDH = lactate dehydrogenase; PBI = pressure bandage with immobilisation; PT = prothrombin time; VDK = venom detection kit

NB1: Features of life-threatening envenoming: cardiac arrest, respiratory failure secondary to paralysis, and major haemorrhage (intracranial,
major gastrointestinal or other life-threatening bleeding). Another sign of severe envenoming is muscle paralysis (ptosis and facial muscles
first).

NB2: Blood tests: coagulation screen (INR or PT, APTT, D-dimer, fibrinogen); full blood count and blood film; EUC, CK, LDH, liver
biochemistry

NB3: Serial blood tests in non-envenomed patients: INR (or PT), APTT, CK.

NB4: Serial blood tests in envenomed patients: INR (or PT), APTT, CK, full blood count, EUC.

NB5: Any patient who has received antivenom should receive advice at the time of discharge about the possibility of symptoms of serum
 sickness occurring 4 to 14 days later.

Diagnosis of snake bite

Steps in diagnosis
There are two essential steps in the diagnosis of a snake bite:

determine if the patient has systemic envenoming

if so, determine which group of snakes is responsible—this determines whether antivenom is indicated
and which to use. In the majority of cases, envenoming requires antivenom treatment.

Systemic envenoming
Systemic envenoming is defined as any of the following:

significant coagulopathy (confirmed by laboratory assessment—see Appropriate investigations and

timing)
neurotoxicity
myotoxicity
thrombotic microangiopathy
kidney impairment
severe systemic symptoms (may not be an indication for antivenom by themselves).

Determination of the appropriate antivenom

Introduction

Determination of the snake group responsible for the bite, and therefore the appropriate monovalent
antivenom, is based on:

local geography—knowledge of the local snake fauna (see summary in Table 17.21)
clinical syndrome (see Table 17.21)
snake venom detection kit.

Snake venom detection kit

The snake venom detection kit (VDK) is designed only to confirm which of the major snake groups is
responsible and so determine which antivenom should be used. It should not be used in nonenvenomed
patients because of a high false positive rate, especially for brown snake. The VDK does not confirm or
exclude envenoming.

In all cases of suspected snake envenoming, a bite site swab should be collected and stored and then tested if
the patient becomes envenomed. The VDK is best done by laboratory staff, ideally using the bite site swab.
The use of the VDK on urine is more problematic than the bite site and the false positive rate is higher (again
especially for brown snake). Importantly, the common notion that a positive VDK on urine indicates systemic
toxicity is incorrect; in asymptomatic patients with normal laboratory studies this is far more likely to be a
false positive. The test should not be done on blood.

Immediate expert advice can be obtained from the Poisons Information Centre network if required (telephone
13 11 26; 24-hour access throughout Australia).

Appropriate investigations and timing

The following blood tests at appropriate times are key in the management of snake-bite:

Coagulation studies—measure international normalised ratio (INR) or prothrombin time (PT), activated
partial thromboplastin time (APTT), D-dimer and fibrinogen.
Full blood count—include blood film in cases with venom-induced consumption coagulopathy (VICC)
to look for red cell fragmentation.
Biochemistry—measure electrolytes, urea and creatinine; creatine kinase (CK); lactate dehydrogenase.

In envenomed patients, blood samples should be taken:

 at admission and before antivenom
6 and 12 hours after antivenom
every 12 to 24 hours until discharge.

In patients with snake bite but no evidence of envenomation, blood samples should be taken:

at admission
1 hour after removal of the pressure immobilisation bandage
6 hours after the bite (unless 6 hours have already passed)
12 hours after the bite.

The D-dimer remains raised for days, and so serial measurements are not useful. Also, the fibrinogen assay
used in many hospitals is no more sensitive than measuring recovery in APTT and INR.

In nonenvenomed patients, the only serial tests required are APTT, INR (or PT), CK, and neurological
examination. More extensive serial tests are required in envenomed patients.

Treatment of snake bite

Antivenom

General considerations

Antivenom is administered by slow intravenous infusion over at least 15 minutes following a 1:10 dilution
with sodium chloride 0.9% or Hartmann's (compound sodium lactate) solution. The degree of dilution may
require modification (eg 1:5) in young children and for large volumes of antivenom (eg polyvalent
antivenom). Antivenom must always be administered in a critical care area with readily available adrenaline
and resuscitation equipment. Premedication with adrenaline, antihistamines or corticosteroids is not
recommended in Australia (see Allergic or anaphylactic reactions).

A monovalent antivenom should be used when a specific type of snake is suspected. The recommended dose
of antivenom for Australian snakes is 1 vial of the appropriate antivenom (see Table 17.22). The dose is the
same for both adults and children. Further doses are not required and recovery is determined by the
reversibility of the effects, and the time it takes the body to recover once venom is neutralised. Response to
antivenom is listed in Table 17.23. Because there continues to be debate about doses for some snake
antivenom, discussion with an expert may be beneficial [Note 1].

One vial of snake antivenom is the recommended dose for both adults and children.

A polyvalent antivenom is available which can be used if there is significant doubt about the snake type.
However, this is a large-volume antivenom (50 mL in vial) and should be avoided as much as possible in areas
where the most likely snake envenomation is covered by the brown snake and tiger snake antivenoms. Both of
these antivenoms are a much smaller volume (approximately 5 to 10 mL). In the majority of cases, the doubt
is about whether the patient has been bitten by a brown snake or a tiger snake. In such cases it would be more
appropriate to administer 1 vial of each of the brown and tiger snake antivenoms.

All antivenoms contain equine protein except funnel-web spider (rabbit protein) and box jellyfish (sheep
protein). See Antivenom adverse reactions regarding risk and treatment of anaphylactic and serum sickness
reactions.

Antivenom dosing (Table 17.22) [NB1]

Antivenom dose (adults Administration (dilute 1:10 in H or NS) [NB2] [NB3]

Venomous creature
and children) [NB2] [NB4]
snakes
1 vial of the relevant
all terrestrial snakes slow IV infusion
antivenom
spiders
2 vials of red-back spider
red-back spider slow IV infusion
antivenom
2 vials of funnel-web spider
funnel-web spider slow IV injection
antivenom
marine
box jellyfish 1 vial of box jellyfish
IV over 5 to 10 minutes
(Chironex fleckeri) antivenom
1 vial of stonefish
stonefish slow IV infusion [NB5]
antivenom
1 vial of sea snake
sea snake slow IV infusion
antivenom
H = Hartmann's (compound sodium lactate) solution; NS = sodium chloride 0.9% solution
NB1: Contact with a toxicologist can be made through the Poisons Information Centre (telephone 13 11 26; 24-hour access throughout Australia).
NB2: Dose is same for adults and children but degree of dilution may need to be modified (eg 1:5) for younger children or for large volumes of
antivenom.
NB3: All antivenoms contain equine protein except funnel-web spider (rabbit protein) and box jellyfish (sheep protein). See Antivenom adverse
reactions regarding risk and treatment of anaphylactic and serum sickness reactions.
NB4: Slow IV infusion should be over at least 15 minutes.
NB5: Although stonefish antivenom can be used by either the intravenous or intramuscular route, intravenous antivenom is likely to be more
effective.

Benefits of antivenom (Table 17.23)

Clinical effect of venom Benefit of antivenom

venom-induced consumption coagulopathy neutralises toxin effect allowing clotting factors to be
(VICC) resynthesised and clotting to recover over 12 to 36 hours
neutralises a toxin inhibitor of coagulation with immediate
anticoagulant coagulopathy
improvement in coagulation studies
neutralises toxin in the intravascular compartment and may
neurotoxicity prevent further development of neurotoxicity—does not
reverse neurotoxic effects already present
neutralises myotoxins and may prevent further muscle
rhabdomyolysis
injury—does not reverse effects
local effects unlikely to reverse any already developed local effects
kidney damage unlikely to have an effect
generalised systemic symptoms: nausea,
rapidly reverses systemic symptoms and this can be a useful
vomiting, headache, abdominal pain, diarrhoea
indication of effectiveness
and diaphoresis

Note 1: Contact with a toxicologist can be made through the Poisons Information Centre (telephone 13 11
26; 24-hour access throughout Australia).

Antivenom adverse reactions

Allergic or anaphylactic reactions

Allergic or anaphylactic reactions to antivenoms are an important adverse effect and occur in about 25% of
cases in Australia, but are only severe in 5% (hypotension being the commonest severe manifestation). Early
allergic or anaphylactic reactions are thought to be due to complement activation. True IgE-mediated
hypersensitivity reactions are rare—they may occur in snake handlers who have had previous exposure to
venom and a reaction is therefore anaphylaxis to the venom and not the antivenom. Treatment consists of
ceasing the antivenom and, if the reaction is severe, administering intramuscular adrenaline [Note 2].

Premedication is not recommended in Australia, although there is some evidence for the effectiveness of
adrenaline if using an antivenom with a high reaction rate.

Note 2: For information on anaphylaxis treatment, see the Australian Prescriber wallchart here.

Serum sickness

Serum sickness is a delayed reaction occurring 4 to 14 days after administration of antivenom. It is

characterised by fever, rash, arthralgia, myalgia and nonspecific systemic features. All patients who have
received antivenom should be warned about serum sickness.

For moderate to severe cases of serum sickness, use:

 prednis(ol)one 25 to 50 mg (approximately 0.5 mg/kg) orally, daily for a maximum of
7 days, then cease [Note 3].
Note 3: prednis(ol)one = prednisolone or prednisone

Treatment of major complications of snake bite

Major complications of snake envenoming are uncommon and should be managed in a tertiary intensive care
unit in consultation with a clinical toxicologist. These include:

major bleeding
thrombotic microangiopathy seen in association with venom-induced consumption coagulopathy
(VICC)
rhabdomyolysis seen with black and tiger snake envenomings
persistent neuromuscular paralysis.

The treatment of major bleeding is not different from that in other settings. Once antivenom has been
administered, clotting factor replacement, surgical intervention and supportive care should proceed as for
major bleeding from other causes of coagulopathy.

Thrombotic microangiopathy seen in association with VICC (brown snake, tiger snake and taipan) has only
recently been clearly characterised and treatment options are still controversial. The condition is rare and
experience in its treatment is limited, so specific clinical toxicological and haematological advice can be
obtained via the Poisons Information Centre (telephone 13 11 26; 24-hour access throughout Australia).
Patients who develop severe thrombocytopenia and kidney failure should be managed in consultation with
both a clinical haematologist and nephrologist. Haemodialysis is the main treatment modality; the role of
plasmapheresis remains controversial.

Rhabdomyolysis should be managed similarly to any other medical cause of rhabdomyolysis. Experience
suggests that although the creatine kinase concentration may rise into the hundreds of thousands (while the
normal adult range is up to around 200 units/L), the frequency of acute kidney failure is low. Patients must
initially be managed with aggressive fluid replacement, then maintenance in an intensive care unit with
monitoring of electrolytes. The role of bicarbonate and plasmapheresis remains poorly defined.

Key references
Snake bite

Churchman A, O'Leary MA, Buckley NA, Page CB, Tankel A, Gavaghan C, et al. Clinical effects of red-bellied
black snake (Pseudechis porphyriacus) envenoming and correlation with venom concentrations: Australian
Snakebite Project (ASP-11). Med J Aust 2010;193(11–12):696–700. [ ]

Gan M, O'Leary MA, Brown SG, Jacoby T, Spain D, Tankel A, et al. Envenoming by the rough-scaled snake
(Tropidechis carinatus): a series of confirmed cases. Med J Aust 2009;191(3):183–6. [ ]

Isbister GK, Hooper MR, Dowsett R, Maw G, Murray L, White J. Collett's snake (Pseudechis colletti) envenoming
in snake handlers. QJM 2006;99(2):109–15. [ ]

Isbister GK, O'Leary MA, Schneider JJ, Brown SG, Currie BJ. Efficacy of antivenom against the procoagulant
effect of Australian brown snake (Pseudonaja sp.) venom: in vivo and in vitro studies. Toxicon 2007;49(1):57–67. [
]

Isbister GK, Scorgie FE, O'Leary MA, Seldon M, Brown SG, Lincz LF. Factor deficiencies in venom-induced
consumption coagulopathy resulting from Australian elapid envenomation: Australian Snakebite Project (ASP-10).
J Thromb Haemost 2010;8(11):2504–13. [ ]

Kulawickrama S, O'Leary MA, Hodgson WC, Brown SG, Jacoby T, Davern K, et al. Development of a sensitive
enzyme immunoassay for measuring taipan venom in serum. Toxicon 2010;55(8):1510–8. [ ]

Currie BJ. Snakebite in tropical Australia: a prospective study in the “Top End” of the Northern Territory. Med J
Aust 2004;181(11–12):693–7. [ ]

Ireland G, Brown SG, Buckley NA, Stormer J, Currie BJ, White J, et al. Changes in serial laboratory test results in
snakebite patients: when can we safely exclude envenoming? Med J Aust 2010;193(5):285–90. [ ]
Isbister GK, Brown SG, Miller M, Tankel A, Macdonald E, Stokes B, et al. A randomised controlled trial of
intramuscular vs. intravenous antivenom for latrodectism: the RAVE study. QJM 2008;101(7):557–65. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Spider bite
General information about spider bite
Spider bites can be divided into three medically relevant groups:

Big black spiders: bites from any large black-looking spider (especially in eastern Australia) must be
managed initially as suspected funnel-web spider bites (see Funnel-web spider bites).
Red-back spiders: red-back spider bites do not cause rapidly developing or life-threatening effects, but
many cause significant pain and systemic effects (see Red-back spider bites).
All other Australian spiders: bites from other Australian spiders cause minor effects and the patient can be
reassured. No specific treatment is required, but symptomatic relief can be offered.

In Australia, spider bites are very unlikely to cause necrotic lesions. Such cases presenting as suspected spider
bites should be thoroughly investigated for other causes.

Funnel-web spider bites

Introduction

Funnel-web spiders (Atrax and Hadronyche species) are the most dangerous spiders in Australia. They can cause
severe, life-threatening envenoming; however, this is rare (only 5 to 10 cases requiring antivenom annually).
Severe envenoming has been reported from southern New South Wales up to southern Queensland.

Clinical presentation

Most funnel-web spider bites cause only local pain associated with puncture marks and local bleeding. In some
cases mild envenoming occurs with local neurotoxicity (paraesthesia, numbness or fasciculations) and/or systemic
symptoms. Severe envenoming has been reported with six species including the Sydney funnel-web spider (Atrax
robustus), the southern tree funnel-web spider (Hadronyche cerberea) and the northern tree funnel-web spider
(Hadronyche formidabilis).

Severe envenoming is characterised by:

autonomic excitation—generalised diaphoresis, hypersalivation, lacrimation, piloerection, hypertension,

bradycardia or tachycardia, and miosis or mydriasis
neuromuscular excitation—paraesthesia (local, distal and oral), fasciculations (local or generalised,
commonly tongue fasciculations) and muscle spasms
systemic symptoms—abdominal pain, nausea, vomiting and headache
cardiorespiratory effects—pulmonary oedema and, less commonly, myocardial injury
CNS effects—agitation, anxiety and, less commonly, drowsiness or coma.

Bites from other big black spiders (eg the mouse spider [Missulena species]) may cause local neurotoxic effects
(paraesthesia, numbness) and systemic symptoms. However, because they are large black spiders and identification
cannot be confirmed, their bites should initially be treated (in endemic areas) as suspected funnel-web spider bites.

Treatment

First aid

First aid is the same as for snake bite, with pressure bandage and immobilisation, rapid transport to a hospital with
funnel-web spider antivenom available, and observation to determine whether systemic envenoming develops. The
pressure bandage can be removed once funnel-web spider antivenom is available.

Patients bitten by unidentified big black spiders in eastern Australia and who are asymptomatic should be observed
for 2 to 4 hours. Envenoming is very unlikely to develop after 2 hours. Patients with mild envenoming can be
similarly observed.

Antivenom

Severe funnel-web spider envenoming should be treated with antivenom. The patient should be admitted to a
critical care area and monitored for 12 to 24 hours until the effects of envenoming have resolved.

The dose of funnel-web spider antivenom is 2 vials, and is the same for both children and adults (see Table 17.22).
Further doses are usually not required. If the patient does not respond to the initial dose then discussion with a
clinical toxicologist is appropriate before further doses are given.

Antivenom is administered by a slow intravenous injection following a 1:10 dilution with sodium chloride 0.9% or
Hartmann's (compound sodium lactate) solution. The degree of dilution may require modification (eg 1:5) in
young children. Antivenom must always be administered in a critical care area with readily available adrenaline
and resuscitation equipment.

The funnel-web spider antivenom has been used in pregnant women.

Red-back spider bites

Introduction
Red-back spider bite is the most common significant envenoming in Australia. It is most common in temperate
regions of Australia, with very few bites reported in northern tropical Australia or south in cooler climates such as
Tasmania. These spiders prefer dark and dry places, and are also found in shoes, helmets, toys or equipment left
outdoors.

Clinical effects
A summary of the clinical effects is included in Box 17.6. The bite itself is often not felt, but pain increases over an
hour and may radiate proximally up the limb or to the trunk. This is followed by the development of regional and
systemic effects. The duration of effects ranges from hours up to 5 days in some cases. The diagnosis is clinical
and should be based on the circumstances of the bite and typical clinical features. Young children and infants may
present with undifferentiated pain, irritation or distress.

Red-back spider bite: clinical effects (Box 17.6)

pain
local—increasing pain at the bite site over minutes to hours, which can last for days
radiating—from the bite site to the draining lymph nodes, proximal limb, abdomen, chest or back
sweating
local
regional—unusual distributions of diaphoresis (eg bilateral below-knee)
nausea, vomiting and headache
malaise and lethargy
less common effects
local—piloerection, local erythema, fang marks (5%)
systemic—hypertension, irritability and agitation [NB1]; fever, paraesthesia or patchy paralysis,
muscle spasms, priapism

NB1: Hypertension, irritability and agitation are more common with paediatric cases.

Treatment

First aid

First aid for red-back spider bites is local application of an ice pack for symptomatic relief. A pressure bandage
should not be used.

Analgesia

All patients with significant pain should be offered appropriate analgesia. Use:

ibuprofen 200 to 400 mg (child: 8 to 10 mg/kg up to 400 mg) orally, 8-hourly up to a

maximum of 2400 mg daily

PLUS
 paracetamol 1000 mg (child: 15 mg/kg up to 1000 mg) orally, 4- to 6-hourly up to a
maximum of 4 g daily.

If this is ineffective, add:

oxycodone immediate-release 5 to 10 mg (child: 0.1 to 0.2 mg/kg up to 5 mg) orally, 4-

hourly.

For severe pain, if oral analgesia is inadequate, use:

1 fentanyl 25 to 50 micrograms (child: 0.5 micrograms/kg) IV as an initial dose, then

titrated to effect every 5 to 10 minutes with further incremental doses of 25 to 50
micrograms (child: 0.5 micrograms/kg up to an hourly dose limit of 3 micrograms/kg)

OR

1 morphine 2.5 to 5 mg (child: 0.1 to 0.2 mg/kg up to 2.5 mg) IV as an initial dose, then
titrated to effect every 5 to 10 minutes with further incremental doses of 2.5 to 5 mg
(child: 0.1 to 0.2 mg/kg).

Monitor conscious state with a sedation score (see Table 1.25).

Antivenom

Red-back spider antivenom is recommended for severe local or radiating pain, and systemic envenoming. The
antivenom is safe in breastfeeding and pregnant women.

The dose of red-back spider antivenom is 2 vials, and is the same for both children and adults (see Table 17.22).
Further doses are unlikely to be beneficial.

Antivenom is administered by slow intravenous infusion over 20 minutes in 200 mL of sodium chloride 0.9% or
Hartmann's (compound sodium lactate) solution. The degree of dilution may require modification (eg 1:5) in
young children. Antivenom must always be administered in a critical care area with readily available adrenaline
and resuscitation equipment.

There is ongoing controversy about the delayed use of antivenom (more than 48 hours after the bite) and most
cases should be discussed with a clinical toxicologist. In patients with a definite red-back spider bite (signs and
symptoms characteristic of red-back spider envenoming and a temporal relationship to the bite), antivenom may be
considered. However, in the majority of cases there is a questionable history of spider bite and unusual clinical
effects. These patients should be treated symptomatically rather than with antivenom.

Early allergic or anaphylactic reactions to red-back spider antivenom are uncommon and occur in about 4% of
cases following intravenous administration, although severe reactions are rare. Serum sickness develops after 4 to
14 days in about 10% of administrations and all patients should be warned about it. For moderate to severe cases
of serum sickness, use:

prednis(ol)one 25 to 50 mg (approximately 0.5 mg/kg) orally, daily for a maximum of 7

days, then cease [Note 1].
Note 1: prednis(ol)one = prednisolone or prednisone

Further reading
Isbister GK. Spider bite: a current approach to management. Australian Prescriber 2006;29(6):156–8. [URL]

Isbister GK, Fan HW. Spider bite. Lancet 2011;378(9808):2039–47. [URL]

Key references
Spider bite

Isbister GK. Mouse spider bites (Missulena spp.) and their medical importance. A systematic review. Med J Aust
2004;180(5):225–7. [ ]

Isbister GK, Gray MR, Balit CR, Raven RJ, Stokes BJ, Porges K, et al. Funnel-web spider bite: a systematic review of
recorded clinical cases. Med J Aust 2005;182(8):407–11. [ ]
Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Marine envenoming, including stings and bites
General information on marine envenoming
Jellyfish stings and injuries from other venomous sea creatures can cause symptoms ranging from transient local
discomfort to life-threatening cardiovascular collapse. There is much confusing information about the first aid for
jellyfish stings, and numerous remedies are suggested with little evidence.

In all cases the sting site can be washed with sea water (not fresh water) and the tentacles removed. For major box
jellyfish stings (mainly Chironex fleckeri) vinegar should be applied liberally as soon as available. The benefit of
vinegar for other types of jellyfish stings is unclear and may increase local pain. Hot water immersion has been
shown to reduce the pain for bluebottle (Physalia species) stings. Hot water may reduce the pain in other jellyfish
stings, but this has not been tested.

Medically important Australian jellyfish include:

bluebottles (Physalia species)

major box jellyfish (Chironex fleckeri)
Carukia barnesi, and other box jellyfish, that cause Irukandji syndrome
other minor jellyfish—mauve stinger (Pelagica species), hair jellyfish (Cyanea species), jimble and other
box jellyfish (Chiropsalmus species).

Bluebottle (Physalia species) jellyfish stings

Introduction
Bluebottles or Portuguese Man-of-War (Physalia species) are extremely common and thousands of stings occur
each summer all around Australia, mostly in New South Wales and Queensland. The vast majority are successfully
treated with first aid on beaches and only rarely present to hospital.

Clinical features

The characteristic clinical features of a bluebottle sting are:

immediate, intense local pain (lasts 1 or more hours)

linear red eruption at sting site (lasts 1 or more days)
systemic effects (nausea, vomiting, abdominal pain, myalgia and very rarely respiratory distress) occurring
in less than 2% of cases.

Treatment
In a randomised controlled trial, hot water immersion was significantly more effective than topical application of
ice packs in relieving the pain of bluebottle stings [Note 1].

First aid recommendations are:

wash the sting site with sea water (not fresh water)
remove any tentacles (use your hands or wash them off with sea water)
immerse in hot water (45 °C) for 20 minutes, after checking tolerance of the temperature on an unaffected
limb.

Use of vinegar is not helpful and may increase the pain.

If hot water immersion is not possible, alternatives include a hot shower or a constant flow of hot water on the
sting site.

Further medical treatment and transport to hospital is rarely required. Bullous wounds from severe local stings
may require dressings.

Note 1: Loten C, Stokes B, Worsley D, Seymour JE, Jiang S, Isbister GK. A randomised controlled trial of hot
water (45 degrees C) immersion versus ice packs for pain relief in bluebottle stings. Med J Aust
2006;184(7):329-33. [URL]
Major box jellyfish (Chironex fleckeri) sting
Introduction
Major box jellyfish (Chironex fleckeri) is the most dangerous jellyfish in Australia and occurs in the far north. The
majority of stings are minor, but severe envenoming occurs with several metres of skin contact in an adult, and has
occurred with just over 1 metre of skin contact in a child. Severe envenoming results in life-threatening systemic
effects characterised by cardiovascular collapse and death within 20 to 30 minutes.

Clinical presentation
The clinical features of box jellyfish sting are primarily severe local pain and an erythematous wheal. Superficial
necrosis can occur with more severe stings but rarely results in permanent scarring.

Severe envenoming (rare in children, very rare in adults) can result in cardiovascular collapse and death within 30 minutes.

Treatment

Initial treatment

Initial treatment comprises:

immediate cardiopulmonary resuscitation (CPR) for cardiovascular collapse

first aid
pain relief.

Survival, for both adults and children, depends on early CPR.

The treatment of all but very minor stings from Chironex fleckeri requires transport to hospital for parenteral
analgesia. In the case of severe life-threatening envenoming, ongoing resuscitation, administration of intravenous
antivenom and possibly magnesium therapy are required.

First aid recommendations are:

remove any tentacles immediately (use your hands, or wash them off with sea water)
apply vinegar liberally to the sting site and surrounding areas (once tentacles are removed)
apply ice packs
use oral and/or parenteral analgesia as necessary (see Hospital management: analgesia).

Vinegar deactivates the remaining nematocysts thus preventing further envenoming.

Intramuscular antivenom should not be used in the prehospital setting. Recent evidence has demonstrated that
intramuscular antivenom does not reach the systemic circulation for hours in patients with haemodynamic
compromise.

Hospital management

Analgesia

An intravenous opioid may be necessary. Use:

1 fentanyl 25 to 50 micrograms (child: 0.5 micrograms/kg) IV as an initial dose, then

titrated to effect every 5 to 10 minutes with further incremental doses of 25 to 50
micrograms (child: 0.5 micrograms/kg up to an hourly dose limit of 3 micrograms/kg)

OR

1 morphine 2.5 to 5 mg (child: 0.1 to 0.2 mg/kg up to 2.5 mg) IV as an initial dose, then
titrated to effect every 5 to 10 minutes with further incremental doses of 2.5 to 5 mg
(child: 0.1 to 0.2 mg/kg).

Monitor conscious state with a sedation score (see Table 1.25).

Treatment of cardiovascular collapse

Management is similar to that in cardiovascular collapse due to other causes (see advanced life support flowcharts
developed by the Australian Resuscitation Council for adults and children), except that the addition of intravenous
box jellyfish antivenom and magnesium should be tried in unresponsive cases. Use:

box jellyfish antivenom box jellyfish antivenom 1 vial IV as an initial bolus over 5 to 10
minutes. Repeat dose up to a maximum of 6 vials if patient remains in cardiac arrest

PLUS

magnesium sulfate 50% 0.1 mL/kg (= 50 mg/kg or 0.2 mmol/kg) up to 5 mL (child: 0.05
to 0.1 mL/kg) IV bolus over 5 to 15 minutes.

Antivenom is administered by slow intravenous injection or slow intravenous infusion over at least 15 minutes
following a 1:10 dilution with sodium chloride 0.9% or Hartmann's (compound sodium lactate) solution. The
degree of dilution may require modification (eg 1:5) in young children and when large volumes of antivenom are
given. Antivenom must always be administered in a critical care area with readily available adrenaline and
resuscitation equipment.

For ongoing cardiac arrest, CPR should continue until at least 6 vials of antivenom are given, repeating
magnesium and considering other cardioactive drugs.

The patient can be discharged once their symptoms are controlled. If they have received antivenom, they should be
advised of the possibility of serum sickness from the antivenom occurring about 4 to 14 days after its
administration (see Serum sickness).

Irukandji syndrome
Introduction
Irukandji syndrome mainly occurs in northern Australia and is classically associated with stings by the jellyfish
Carukia barnesi. The effects include delayed severe generalised pain, which usually takes 6 to 12 hours to resolve,
and uncommonly cardiac involvement that may require supportive care for 2 to 3 days.

Clinical presentation
The features of Irukandji syndrome are initial minor local effects, followed after 20 to 30 minutes by:

severe generalised back, abdominal, chest and muscle pain

tachycardia, hypertension
nausea and vomiting
anxiety and agitation.

In severe cases, cardiac effects may occur with electrocardiogram (ECG) changes (T wave inversion and ST
segment depression), progressing to myocardial depression with elevated troponin concentrations, and then
cardiogenic pulmonary oedema and cardiogenic shock.

Treatment
The patient should be transported to hospital for supportive treatment. This mainly involves titrated intravenous
opioid analgesia. Use:

1 fentanyl 25 to 50 micrograms (child: 0.5 micrograms/kg) IV as an initial dose, then

titrated to effect every 5 to 10 minutes with further incremental doses of 25 to 50
micrograms (child: 0.5 micrograms/kg up to an hourly dose limit of 3 micrograms/kg)

OR

1 morphine 2.5 to 5 mg (child: 0.1 to 0.2 mg/kg up to 2.5 mg) IV as an initial dose, then
titrated to effect every 5 to 10 minutes with further incremental doses of 2.5 to 5 mg
(child: 0.1 to 0.2 mg/kg).

Monitor conscious state with a sedation score (see Table 1.25).

In addition, for nausea, use:

 promethazine 10 to 25 mg (child: 0.2 to 0.5 mg/kg) slow IV, then 10 to 25 mg (child: 0.2
to 0.5 mg/kg) orally, IM or slow IV, 8- to 12-hourly if required.

Patients with systemic effects should be observed once pain-free for 6 hours without analgesia. Patients with
cardiac involvement should be admitted to a critical care unit.

Pulmonary oedema is cardiogenic in origin and should be treated with supportive care, including oxygen, positive
pressure ventilation and inotropes (see Acute cardiogenic pulmonary oedema).

Other jellyfish stings

Other common jellyfish occurring in all coastal waters in Australia are:

mauve stinger (Pelagica species)

hair jellyfish (Cyanea species)
jimble and other box jellyfish (Chiropsalmus species).

These jellyfish cause minor effects similar to bluebottles. Clinical features reported from stings of these species
include immediate intense local pain lasting up to an hour or more, and a linear red eruption at the sting site lasting
for 1 day or more. Systemic effects are uncommon.

Current first aid recommendations are similar to those for bluebottle stings, namely:

wash the sting site with sea water

remove any tentacles
consider hot water immersion.

Use of vinegar is not helpful.

People stung by these jellyfish rarely require transport to hospital or medical intervention, although bullous
wounds from severe local stings may require local dressings.

Penetrating venomous marine injuries

Venomous fish

Important venomous fish in Australia are catfish, stonefish and scorpion fish. Species of venomous fish are found
in all Australian coastal waters and some fresh water sites. All cause localised pain of varying severity associated
with a puncture wound. Pain may be severe and persistent, particularly with stonefish, bullrout or marine catfish.

Antivenom for stonefish stings should be used if there is evidence of systemic envenoming. Although it can be
used by either the intravenous or intramuscular route, intravenous antivenom is likely to be more effective.

The dose of stonefish antivenom is 1 vial, and is the same for both children and adults (see Table 17.22).

Antivenom by slow intravenous infusion should be administered over at least 15 minutes following a 1:10 dilution
with sodium chloride 0.9% or Hartmann's (compound sodium lactate) solution. The degree of dilution may require
modification (eg 1:5) in young children. Antivenom must always be administered in a critical care area with
readily available adrenaline and resuscitation equipment.

Stingray

Species of stingrays are found in all Australian coastal waters, and in fresh water in some regions. Stingray injuries
cause significant trauma and pain; this is compounded by venom that can cause local necrosis and pain. Most
injuries occur to the ankles, but divers may suffer severe thoracoabdominal trauma.

The major treatment issues are those of major trauma and secondary infection. Local pressure may be required for
bleeding. Thoracic or abdominal injuries require resuscitation and surgical intervention. Secondary infection with
marine or aquatic organisms is an important complication.

Sea urchins
Sea urchins occur throughout Australian coastal waters. The major problem in the treatment of injury from a sea
urchin is the removal of broken-off spines. After removal of spines close to the surface and radiography or
ultrasonography to identify any retained spines, the patient must be reviewed regularly until symptoms have
resolved. Further spine removal after additional radiographic or ultrasound imaging may be required.
Sponges
Species of venomous sponges can be found in all Australian coastal waters. Initially there may only be mild
localised itchiness and stinging. In some cases, this sensation increases and can cause intense symptoms for days.
Analgesia and antihistamines can provide symptomatic relief.

The most common clinical sign is erythema, but occasionally vesicles, local swelling and joint stiffness occur. Fire
sponges are reported to cause delayed reactions with desquamation after 2 to 3 weeks.

Treatment for any penetrating venomous marine injury

First aid

First aid for all penetrating marine injuries is hot water (45 °C) immersion of the affected limb for up to 90 minutes
until the pain subsides. An unaffected limb must be used to check tolerance of the temperature first.

Analgesia

Severe pain or pain not responsive to hot water immersion should be treated with oral or parenteral analgesia. Use:

ibuprofen 200 to 400 mg (child: 8 to 10 mg/kg up to 400 mg) orally, 8-hourly up to a

maximum of 2400 mg daily

PLUS

paracetamol 1000 mg (child: 15 mg/kg up to 1000 mg) orally, 4- to 6-hourly up to a

maximum of 4 g daily.

If this is ineffective, add:

oxycodone immediate-release 5 to 10 mg (child: 0.1 to 0.2 mg/kg up to 5 mg) orally, 4-

hourly.

For severe pain, if oral analgesia is inadequate, use:

1 fentanyl 25 to 50 micrograms (child: 0.5 micrograms/kg) IV as an initial dose, then

titrated to effect every 5 to 10 minutes with further incremental doses of 25 to 50
micrograms (child: 0.5 micrograms/kg up to an hourly dose limit of 3 micrograms/kg)

OR

1 morphine 2.5 to 5 mg (child: 0.1 to 0.2 mg/kg up to 2.5 mg) IV as an initial dose, then
titrated to effect every 5 to 10 minutes with further incremental doses of 2.5 to 5 mg
(child: 0.1 to 0.2 mg/kg).

Monitor conscious state with a sedation score (see Table 1.25).

Local anaesthetic infiltration of the wound is often an effective treatment.

Wound management

The general principles of management for all penetrating injuries apply. All wounds must be thoroughly cleaned
and irrigated. Any pieces of spine should be removed and radiographic imaging may assist in identifying foreign
bodies. Lacerations are best left open for delayed primary closure. Wounds that contain foreign material, involve
joints or sterile body cavities, or present late, usually require surgical exploration and debridement. For advice on
preventing infection of penetrating venomous marine injuries (including the role of antibiotic prophylaxis), see
here. For treatment of infected wounds, see also Empirical therapy for localised water-immersed wound infections
or Empirical therapy for water-immersed wound infections associated with systemic features or deeper tissues.

Tetanus prophylaxis applies as for any penetrating injury (see Table 2.63).

Blue-ringed octopus bites

Several species of blue-ringed octopi occur in tidal areas around Australia, but bites are very rare. They only occur
when the octopus is disturbed or handled. The bite is often painless, but leads to numbness and paraesthesia,
followed by an ascending flaccid paralysis. This is due to tetrodotoxin (see Tetrodotoxin poisoning) in the saliva of
the octopus.

Treatment consists of application of a pressure bandage and immobilisation of the limb and the patient, and basic
life support (see Australian Resuscitation Council basic life support flowchart), both before hospital and in
hospital. No antidote is available, and supportive care with mechanical ventilation is required until the respiratory
paralysis resolves (usually 2 to 5 days).

Sea snake bites

Sea snake bites are very rare in Australia. The bite may be painless. The main clinical effect is myotoxicity,
causing muscle pain and nonspecific weakness, which develops within hours of the bite. Systemic symptoms
include nausea, vomiting and malaise. Muscle pain may become severe with muscle spasms developing.
Neurotoxicity has been reported in bites from some sea snakes, with ascending flaccid or spastic paralysis
accompanied by ophthalmoplegia, ptosis, facial paralysis, and pupillary changes.

First aid for bites from sea snakes is the same as for bites from terrestrial snakes (see First aid).

If there is evidence of systemic envenoming (see Systemic envenoming), the antivenom for sea snakes should be
used (see Table 17.22). The dose of sea snake antivenom is 1 vial, and is the same for both children and adults.

Antivenom is administered by slow intravenous infusion over at least 15 minutes following a 1:10 dilution with
sodium chloride 0.9% or Hartmann's (compound sodium lactate) solution. The degree of dilution may require
modification (eg 1:5) in young children. Antivenom must always be administered in a critical care area with
readily available adrenaline and resuscitation equipment. Premedication with adrenaline, antihistamines or
corticosteroids is not recommended in Australia (see Allergic or anaphylactic reactions).

Supportive treatment for rhabdomyolysis and paralysis is outlined in Snake bite: treatment of major complications.

Key references
Marine envenoming

Huynh TT, Seymour J, Pereira P, Mulcahy R, Cullen P, Carrette T, et al. Severity of Irukandji syndrome and nematocyst
identification from skin scrapings. Med J Aust 2003;178(1):38–41. [ ]

Isbister GK. Venomous fish stings in tropical northern Australia. Am J Emerg Med 2001;19(7):561–5. [ ]

Isbister GK, Hooper JN. Clinical effects of stings by sponges of the genus Tedania and a review of sponge stings
worldwide. Toxicon 2005;46(7):782–5. [ ]

Loten C, Stokes B, Worsley D, Seymour JE, Jiang S, Isbister GK. A randomised controlled trial of hot water (45
degrees C) immersion versus ice packs for pain relief in bluebottle stings. Med J Aust 2006;184(7):329–33. [ ]

Published July 2012. Amended March 2020. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Marine poisoning
General information on marine poisoning
Some marine animals accumulate toxic compounds from their environment. When these animals are ingested,
toxic effects or poisoning can occur [Note 1]. This is distinct from envenoming (see Marine envenoming), where
the venomous animal produces toxins in a specialised gland and applies or injects the toxins parenterally.

Note 1: In some Australian jurisdictions the occurrence of marine poisoning is a notifiable event.

Ciguatera
Introduction

Ciguatera is caused by the ingestion of ciguatoxins that accumulate in some tropical and subtropical finfish. The
commonly implicated fish are included in Table 17.24. Although common, ciguatera is rarely fatal. No laboratory
test exists for ciguatera and the diagnosis is clinical.

Fish species implicated in cases of ciguatera from the Pacific and Caribbean oceans (Table
17.24)

Fish family Common names

Carangids jacks and scads (specific problem in the Caribbean)
Epinephelids cod, including flowery cod and spotted cod
Lethrinids emperors and scavengers
Lutjanids red bass, snappers
Muraenids moray eels (regarded as the most toxic ciguateric fish)
Scombrids mackerel, including tunas, Spanish mackerel
Serranids sea bass and groupers, including coral trout from the Great Barrier Reef
Sphyraenids barracuda (specific problem in the Caribbean)

Clinical presentation
Ciguatera is characterised by moderate to severe gastrointestinal effects (vomiting, diarrhoea and abdominal
cramps), neurological effects, pruritus and rarely other nonspecific effects. The onset of clinical effects varies and
may range from 1 to 48 hours. Usually the gastrointestinal effects occur early and resolve within 12 hours, and the
neurological effects develop over 24 hours. Distal and perioral paraesthesia, cold allodynia [Note 2] and numbness
are the major neurological symptoms. They are usually associated with objective signs of a predominantly sensory
polyneuropathy. Myalgia and ataxia can also occur.

Subacute and chronic forms of ciguatera are described, but are poorly defined. Reported symptoms include fatigue,
loss of energy, arthralgia (especially knees, ankles, shoulders and elbows), myalgia, headache, depression and
pruritus. Diagnosis and clearly ascribing the ciguatera to the ingestion of fish is difficult.

Note 2: Cold allodynia is an abnormal, unpleasant sensation (or dysaesthesia) when contacting cold water or
objects.

Treatment
No antidote exists for ciguatoxin and treatment consists of appropriate rehydration, observation and symptomatic
relief. Intravenous fluids should be given as for dehydration. Intravenous mannitol has been shown to be no more
effective than sodium chloride 0.9% in a randomised controlled trial [Note 3]. Treatment with anti-inflammatory
drugs may be useful.

Pharmacological treatment of chronic ciguatera should be undertaken in consultation with an expert.

Note 3: Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol
therapy. Neurology 2002;58(6):873-80. [URL]
Tetrodotoxin poisoning
Introduction
Tetrodotoxin (TTX) poisoning is the most common lethal marine poisoning. In Australia, puffer fish poisoning is
rare but continues to occur where toad fish or related puffer fish are ingested. Puffer fish poisoning is more
common in Japan with 'fugu' preparation and also in South-East Asia. Bites by blue-ringed octopi cause similar
effects because their saliva contains tetrodotoxin (see also Blue-ringed octopus bites).

Clinical presentation
The onset of clinical effects occurs within 1 to 2 hours and is more rapid with more severe poisoning. Neurological
manifestations include perioral numbness and paraesthesia, distal limb numbness and paraesthesia, ataxia,
dizziness and muscle weakness. There is usually nausea but vomiting is less common. In more severe cases, there
is respiratory muscle paralysis, coma and cardiovascular toxicity (hypotension and arrhythmias).

Treatment
No antidote is available and patients with more severe tetrodotoxin poisoning usually require ventilation for 2 to 5
days. Atropine is indicated for bradycardia. Use:

atropine 0.5 to 1.5 mg IV bolus, repeat after 15 minutes if necessary (child: 0.02 mg/kg up
to 0.5 mg IV bolus, repeat after 5 minutes if necessary up to a maximum of 1 mg).

Scombroid
Introduction
Scombroid poisoning is due to the ingestion of fish that contain high concentrations of histamine, which
accumulates during spoilage of the fish. A number of fish in the Scombridae family are implicated, including tuna,
mackerel, kingfish, albacore, wahoo and needlefish.

Clinical presentation
The clinical effects of scombroid poisoning are similar to an acute allergic reaction. They include skin
manifestations (diffuse erythema, urticaria, pruritus, flushing), gastrointestinal effects (nausea, vomiting,
abdominal cramps, diarrhoea) and headache. Severe scombroid is characterised by wheeze, dyspnoea and
hypotension. The onset of effects occurs within 30 minutes to a few hours and effects resolve within 6 to 12 hours.
The diagnosis is clinical, but can be confirmed by detecting high concentrations of histamine in the fish.

Treatment

Treatment of scombroid poisoning is similar to that of allergic reactions except that antihistamines (both H1- and
H2-receptor antagonists) should also be used. For mild to moderate poisoning without bronchospasm or
hypotension, patients can be treated with intravenous fluids and antihistamines. Use:

promethazine 10 to 25 mg (child: 0.2 to 0.5 mg/kg) slow IV

PLUS

ranitidine 50 mg (child: 1 mg/kg) IV.

In severe poisoning bronchospasm should be treated with bronchodilators. In adults and children, use:

salbutamol 5 mg by nebuliser.

Hypotension should be treated with a bolus of sodium chloride 0.9%, which can be repeated. Use:

sodium chloride 0.9% 20 mL/kg IV over 10 to 30 minutes.

Other marine poisoning

Other types of marine poisoning are uncommon in Australia, including shellfish poisoning [Note 4].

Note 4: Information on other marine poisoning can be obtained if required from Isbister GK, Kiernan MC.
Neurotoxic marine poisoning. Lancet Neurol 2005;4(4):219-28. [URL]

Key references
Marine poisoning

Isbister GK, Son J, Wang F, Maclean CJ, Lin CS, Ujma J, et al. Puffer fish poisoning: a potentially life-threatening
condition. Med J Aust 2002;177(11–12):650–3. [ ]

Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy.
Neurology 2002;58(6):873–80. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Tick bite
CIinical presentation of tick bite
Ticks are widespread in Australia. Only the scrub tick found on the eastern seaboard secretes a paralysing
toxin.

Tick bites are painless and may only be noticed once the tick becomes engorged (which may take 2 or more
days). They tend to be in moist or vascular areas such as the scalp or flexures. Anaphylaxis can occur early,
but is rare. Local reactions and infections are common, but usually take some days to manifest. Rarely,
systemic tick-borne infections such as those due to rickettsiae may be transmitted by the bite (see Rickettsial
infections for antibiotic recommendations).

Tick paralysis takes a few days to manifest and presents as an ascending paralysis, which shows first as leg
weakness and an unsteady gait. In more severe envenoming, the weakness increases to involve the upper
limbs, trunk and neck muscles. Facial and bulbar muscles can also be affected, causing ptosis, extraocular
muscular paralysis, dysarthria and stridor, and ultimately respiratory muscle paralysis. Tick paralysis is an
important differential diagnosis of ataxia in children. It can present in less severe cases as a regional or
cranial nerve palsy in adults, and may mimic facial nerve (Bell) palsy.

Patients should be warned that a prolonged local reaction (lasting weeks, with or without infection) is
common unless all of the tick, including the head, is removed.

Treatment of tick bite

Particular care must be taken to remove all of the tick and not to leave the head embedded. Attachment is
stronger the longer the tick has been present and feeding. The recommended methods for removing a tick
focus on removing all of its parts, in particular the embedded head.

Fine-pointed forceps or proprietary tick removal devices are effective or dental floss can be used. The key is
to place the points of the device as close to the skin as possible so that when the tick is pulled out it remains
intact.

Mild to moderate tick paralysis usually requires no intervention except observation and serial neurological
examinations for 48 hours, because the paralysis may progress after the tick is removed.

In severe poisoning, treatment consists of advanced life support with intubation and mechanical ventilation
for respiratory failure. Antivenom for tick paralysis is no longer available.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Altitude illness
General information on altitude illness
There are no locations in Australia of sufficient altitude to cause altitude-related illnesses. However, many
Australians travel to international destinations where an awareness of the significance of altitude-related illness is
very important. Preventive measures and a high level of awareness of the subtle onset of symptoms are essential
for anyone travelling to areas above 2500 metres (8000 feet) in altitude.

Pathophysiology of altitude illness

As we increase in altitude, the atmospheric pressure reduces (there are fewer molecules of gas per given volume)
so the amount of oxygen available to breathe is less.

Reduced oxygenation of the blood, variable (organ dependent) vasoconstriction and vasodilation, and increased
vascular fluid leakage lead to symptoms. The exact pathophysiology is not clear.

The threshold altitude for developing symptoms due to reduced oxygen availability is about 2500 metres.

Assessment of risk for altitude illness

Altitude illness can occur in any individual, and there is no certain way to predict risk. Relative risk factors
include:

rate of ascent
maximum height achieved
sleeping elevation
strenuous exertion at altitude.

Clinical presentation of altitude illness

Introduction

Altitude sickness presents as three clinical syndromes—acute mountain sickness (AMS), high altitude cerebral
oedema (HACE), and high altitude pulmonary oedema (HAPE) (see Table 17.25).

Altitude sickness syndromes (Table 17.25) [NB1]

Syndrome Features
In the setting of a recent gain in altitude, the presence of headache and at
least one of the following symptoms:

gastrointestinal (anorexia, nausea or vomiting)

acute mountain sickness (AMS)
fatigue or weakness
dizziness or lightheadedness
difficulty sleeping.

Can be considered 'end stage' or severe AMS. In the setting of a recent

gain in altitude, the presence of either:
high altitude cerebral oedema (HACE)
a change in mental status and/or ataxia in a person with AMS, or
both mental status changes and ataxia in a person without AMS.

At least two of the following symptoms:

dyspnoea at rest
cough
weakness or decreased exercise performance
chest tightness or congestion.

high altitude pulmonary oedema PLUS

(HAPE) At least two of the following signs:

crackles or wheezing in at least one lung field

central cyanosis
tachypnoea
tachycardia.

NB1: These definitions were adopted at the 1991 International Hypoxia Symposium, held at Lake Louise in Alberta, Canada.

Severity of acute mountain sickness

An estimate of the severity of acute mountain sickness (mild, moderate or severe) can be determined by
calculating the Lake Louise Score (see www.high-altitude-medicine.com/AMS-worksheet.html). If AMS is
suspected then serial measurements are more important than an absolute number in determining response to
therapeutic intervention.

Prevention of altitude illness

Gradual ascent
The best preventive strategy for altitude illness is gradual ascent to allow acclimatisation. Ideally individuals
should take two or more days to ascend to an initial 3000 metres, with subsequent increases in sleeping elevation
of no more than 500 metres each day.

Moderate-risk situations for developing AMS include when individuals above 3000 metres:

ascend and increase sleeping elevation by more than 500 metres in day
ascend by more than 2800 metres in a day
have a history of AMS and ascend by more than 2500 metres in a day.

High-risk situations for developing AMS include when individuals above 3000 metres:

ascend by more than 3500 metres in a day

have a history of AMS and ascend by more than 2800 metres in a day
ascend and increase sleeping elevation by more than 1000 metres in a day
climb very rapid ascents (eg Mt Kilimanjaro)
have a history of HAPE or HACE.

A detailed assessment of risk based on the individual patient and their ascent profile should be undertaken. Care
should be taken to counsel the patient on symptoms and signs of altitude-related illness and to be aware of what
actions to take if these occur. The best advice is to descend until symptoms resolve if there is any uncertainty and
in the absence of expert medical advice.

Prophylaxis

There is no substitute for a sensible ascent profile. However, if unavoidable, prophylactic acetazolamide should be
considered in moderate- to high-risk situations. Use:

acetazolamide 125 mg (child: 2.5 mg/kg up to 125 mg) orally, 12-hourly commencing the
day before ascent.

Continue prophylaxis until acclimatisation occurs (usually when at target altitude for 2 or 3 days) or when
commencing descent without further planned ascent. Acetazolamide is a carbonic anhydrase inhibitor and acts
mainly as a respiratory stimulant. There is a cross-reactivity with sulfonamide allergies and the most troublesome
adverse effect of acetazolamide is perioral and digital paraesthesia. Other adverse effects include anorexia,
polyuria, polydipsia, tinnitus and headache.

Dexamethasone should be used for prophylaxis of AMS only in those allergic to or intolerant of acetazolamide,
due to its greater adverse effect profile and problems with continuous use. Use:

1 dexamethasone 2 mg orally, 6-hourly commencing on the day of ascent

OR

1 dexamethasone 4 mg orally, 12-hourly commencing on the day of ascent.

Continue prophylaxis until acclimatisation occurs (usually when at target altitude for 2 or 3 days) or when
commencing descent without further planned ascent. Dexamethasone should not be used for longer than 10 days
and is not recommended as prophylaxis in children.

Nifedipine, tadalafil, sildenafil or inhaled salmeterol may also play a role in preventing HAPE in individuals with a
history of HAPE, but should only be used on specialist advice.

Treatment of altitude illness

Persons with altitude illness of any severity should stop, rest, rehydrate and consider taking simple analgesia and
antiemetic drugs. They may need to consider descent depending on the geographical circumstances and severity of
illness.

Rest and gradual ascent once symptoms settle is appropriate for mild to moderate AMS, but further ascent or re-
ascent should never be undertaken if symptoms persist. For severe AMS, descent is advised until symptoms
resolve. A careful assessment of fitness to re-ascend should be undertaken by the trek leader or medic. Fitness to
re-ascend usually involves the resolution of AMS to at least a mild severity at a lower altitude.

The primary treatment for any altitude-related illness is descent.

In the case of HACE or HAPE descent is the highest priority. Symptoms typically start to improve following
descent of 300 to 1000 metres, but may persist for a number of days in severe cases. Further ascent following this
is not advised until the patient has been medically reviewed and cleared. Temporary recovery for HACE and
HAPE victims before evacuation can be achieved with the use of a portable hyperbaric chamber, which may be
carried by larger parties. It must be emphasised that this is only a temporising measure pending evacuation. If
oxygen is available, it can be given by nasal prongs at 2 to 3 L/minute, or to raise oxygen saturation above 90% as
measured by pulse oximetry if portable monitoring is available.

Drug therapies should be used as adjuncts to the above measures for severe AMS, HACE and HAPE, and can be
continued until evacuation is achieved.

For patients with severe AMS or HACE, in adults use:

dexamethasone 8 mg orally, IV or IM for the first dose, then 4 mg 6-hourly.

In children, use:

dexamethasone 0.15 mg/kg up to 4 mg orally, IV or IM, 6-hourly.

For patients with HACE who can take oral medications, consider adding acetazolamide to dexamethasone. Use:

acetazolamide 250 mg (child: 2.5 mg/kg up to 125 mg) orally, 12-hourly.

For adults with HAPE, nifedipine may be used as an adjunctive therapy to descent, supplemental oxygen and a
portable hyperbaric chamber (optimal dosing for children in this situation is unknown). Use:

1 nifedipine controlled-release 20 mg orally, 8-hourly

OR

1 nifedipine controlled-release 30 mg orally, 12-hourly.

Dexamethasone should be added to nifedipine for patients with concurrent HAPE and HACE.

Further altitude-related considerations

Sleep disorders

Many people experience difficulties sleeping at high altitudes and prophylactic acetazolamide may help to prevent
such problems. If insomnia persists, short-term use of pharmacological therapy may be appropriate (see Insomnia:
pharmacological management).
Medical comorbidities
With the increasing popularity and accessibility of high-altitude destinations, more people with medical and
psychiatric comorbidities are contemplating travel to these areas. This often involves increased risk, and as a first
step their current specialists should be consulted about the safety of their proposed itinerary.

Pregnancy
Travel above 2500 metres in the first trimester is highly associated with miscarriage, and therefore is strongly
advised against. Little research is published in this area, but travel above 2500 metres in the second and third
trimesters is also associated with a number of adverse outcomes in pregnancy, and so also advised against unless
approved by an obstetrician. In addition, most of the medications used to treat altitude-related illness are
contraindicated in pregnancy.

Other considerations
Other risks that are common to high-altitude areas include:

cold-related illnesses such as hypothermia and frostbite

photokeratitis (snow blindness)
dehydration
heat exhaustion
sunburn
infectious diseases (eg traveller's diarrhoea, lower respiratory tract infections).

Often these areas are remote and the travel is physically demanding so careful planning is essential. This includes
medical advice on an appropriate medical kit, and general advice on appropriate clothing and eye wear (high
ultraviolet [UV] protection is recommended). It is important to be familiar with local medical services and
evacuation procedures, and appropriate medical insurance should be considered.

Key references
Altitude illness

Julian CG. High altitude during pregnancy. Clin Chest Med 2011;32(1):21–31, vii. [ ]

Luks AM. Which medications are safe and effective for improving sleep at high altitude? High Alt Med Biol.
2008;9(3):195–8. [ ]

Luks AM, McIntosh SE, Grissom CK, Auerbach PS, Rodway GW, Schoene RB, et al. Wilderness Medical Society
consensus guidelines for the prevention and treatment of acute altitude illness. Wilderness Environ Med
2010;21(2):146–55. [ ]

Maggiorini M. Prevention and treatment of high-altitude pulmonary edema. Prog Cardiovasc Dis 2010;52(6):500–6. [
]

Maggiorini M, Brunner-La Rocca HP, Peth S, Fischler M, Bohm T, Bernheim A, et al. Both tadalafil and
dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial. Ann Intern Med
2006;145(7):497–506. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Cold-related illness
Accidental hypothermia
Introduction
Hypothermia is defined as a core body temperature less than 35 °C, and may have a number of precipitating causes
(eg minor and major trauma, environmental exposure, drug intoxication, neurological events, endocrine
disturbances).

Although it is more common in colder climates, severe accidental hypothermia can occur in any location. Infants,
the elderly and the socially isolated are at higher risk.

Pathophysiology

The hypothalamus stimulates a compensatory response to cold exposure through shivering and an increase in
thyroid and catecholamine activity to stimulate heat production. Peripheral vasoconstriction redirects blood flow
from the body surface where maximum heat loss occurs.

Shivering can increase metabolic rate up to 5 times, producing increased endogenous heat, but ceases once
glycogen stores are depleted or the body temperature falls below 30 °C.

As the body core temperature lowers from the normal range there is progressive organ dysfunction, including
cardiac arrhythmias and eventual death. The level at which this occurs varies between individuals.

Clinical presentation

A core body temperature must be taken. An oesophageal probe is the most reliable method, but typically this is
only possible in a ventilated patient. Rectal or bladder probes are a less reliable alternative. Standard thermometers
often do not measure below 34 °C, and the validity of infrared tympanic thermometers has not been demonstrated
in hypothermic patients.

The presentation of hypothermia falls broadly into 3 groups based on the measured core temperature—mild,
moderate and severe hypothermia. These groups are both clinically meaningful and relate to the underlying
physiology of hypothermia.

Mild hypothermia (32 to 35 °C)

Features of mild hypothermia:

shivering, dysarthria, ataxia and apathy

skin is cool to touch
cold diuresis (hypothermic patients are often volume depleted) [Note 1]
body retains the ability to spontaneously rewarm if removed from the cold environment.

Note 1: Exposure to cold stimulates peripheral vasoconstriction to conserve heat. Shunting of circulation
centrally produces an elevation of blood pressure which in turn inhibits antidiuretic hormone (ADH or
vasopressin), increasing urine volume.

Moderate hypothermia (29 to 32 °C)

Features of moderate hypothermia:

shivering ceases, and muscle tone increases

proportionate lowering of heart rate and cardiac output
cardiac arrhythmias (slow atrial fibrillation or junctional bradycardia)
reduced ventilation due to slowing of respiratory rate
alteration of conscious state (may appear drowsy or confused, and paradoxical undressing may occur).

Severe hypothermia (less than 29 °C)

Features of severe hypothermia:

body adopts the temperature of the surrounding environment (poikilothermia) and loses the ability to
rewarm spontaneously
patient may be unconscious and areflexic, with fixed dilated pupils (ie look dead)
cardiac arrhythmia (slow atrial fibrillation progressing to ventricular fibrillation or asystole, any of which
may be precipitated by rough handling).

At temperatures below 32 °C, the patient's electrocardiogram (ECG) may show J or Osborn waves, which are an
extra positive deflection at the QRS/ST junction, most often seen in leads II and V3 to V6. Although these waves
are commonly seen in hypothermic patients and correlate with the degree of hypothermia, they are not prognostic,
and can also exist as a result of other (nonhypothermic) pathologies.

Key investigations
Multiple biochemical abnormalities can be expected in patients with moderate or severe hypothermia. In particular,
look for and treat abnormal glucose, potassium, creatine kinase, kidney function, and clotting.

Key management issues

The most important intervention is to remove the patient from the cold environment and prevent any further heat
loss. The hypothermic patient must be handled gently. Any rough handling can precipitate potentially fatal cardiac
arrhythmias. Continuous cardiac monitoring is mandatory.

Rough handling of hypothermic patients can precipitate arrhythmia and should be minimised wherever possible.

Rewarming (carried out simultaneously with resuscitative interventions) is the primary treatment for hypothermia.
Avoiding any further cooling is more important than the speed of rewarming.

A detailed resuscitative assessment is required (see the Australian Resuscitation Council website for advice). It is
important to be wary about patients whose vital signs are not consistent with the level of hypothermia, and to
always consider concomitant pathology (eg trauma, hypoglycaemia, drug intoxication) as the underlying cause for
hypothermia.

Despite advances in modern supportive care, the in-hospital mortality for patients with moderate to severe
hypothermia remains at almost 40%.

Rewarming

Passive rewarming is necessary in the treatment of all hypothermic patients, and is achieved by:

removing any wet clothing and drying the patient

placing them in a warm, wind-free environment insulated from the cold
allowing the patient to shiver
providing warm, caloric fluids to drink if tolerated.

Active external rewarming techniques include (among others):

warmed blankets or heating pads

forced warm air devices (eg Bair Hugger or Warm Touch).

For safety reasons, immersion in a warm bath should be avoided.

Active internal rewarming may be required for more significant cases of hypothermia, and includes:

warmed intravenous fluids, ideally 40 to 42 °C (a dedicated fluid warmer should be used if available but, as
a simple alternative, fluid bags stored in a blanket warmer are adequate; fluid should never be heated in a
microwave)
warmed humidified oxygen
irrigation of body cavities with warmed fluid (bladder / intraperitoneal / intrathoracic lavage)
extracorporeal blood rewarming, including cardiopulmonary bypass.

Active internal rewarming requires experienced intensive care support.

A suggested rewarming algorithm is provided in Figure 17.4.

A hypothermic patient may require intubation. This is safe if it is performed gently, and does not precipitate
ventricular fibrillation.

If ventricular fibrillation occurs, resuscitation should proceed according to standard advanced life support
protocols (see flowcharts developed by the Australian Resuscitation Council). Defibrillation is unlikely to be
effective at temperatures below 32 °C.

There are well-documented cases of complete recovery from very prolonged hypothermic cardiac arrest, and
prolonged resuscitative attempts are warranted. The patient must be rewarmed to at least 32 °C before resuscitation
efforts are ceased. If resuscitation does not result in an increase in core body temperature, specialist-level advice
should be obtained before resuscitation is ceased.

Continue resuscitation until core temperature is above 32 °C or specialist advice recommends cessation.

Most cardiac arrhythmias associated with hypothermia resolve spontaneously with rewarming. Electrolyte
concentrations may change rapidly and unpredictably with rewarming, and should be monitored closely. Any
electrolyte disturbances should be corrected.

The pharmacokinetics and pharmacodynamics of many drugs, eg adrenaline or insulin, are substantially altered or
unknown at low body temperatures.

Antiarrhythmic drugs are not indicated unless malignant arrhythmias are present. Although there is limited
evidence to support any specific drug, magnesium holds the most promise to treat ventricular arrhythmias
associated with hypothermia. Use:

magnesium sulfate 50% 5 to 10 mL (= 2.5 to 5 g or 10 to 20 mmol) (child: 0.05 mL/kg) IV

over 30 to 60 minutes.

Glucose is required as an energy substrate in all hypothermic patients. If glucose cannot be taken orally, administer
intravenously.

In adults, use:

1 glucose 10% IV by infusion through a large peripheral vein, commencing at a rate of 100
mL/hour (= 10 g/hour) and increasing until the blood glucose concentration is maintained
between 5.5 and 11 mmol/L

OR

1 glucose 50% IV by infusion through a central venous catheter, commencing at a rate of 20

mL/hour (= 10 g/hour) and increasing until the blood glucose concentration is maintained
between 5.5 and 11 mmol/L.

In children, use:

1 glucose 10% IV by infusion through a large peripheral vein at a rate of 3 to 5 mL/kg/hour

(= 5 to 8 mg/kg/minute) increasing until the blood glucose concentration is maintained
between 5.5 and 11 mmol/L

OR

1 glucose 50% IV by infusion through a central venous catheter at a maximum rate of 1

mL/kg/hour (= 8 mg/kg/minute) to maintain the blood glucose concentration between 5.5
and 11 mmol/L.

Hypothermic patients typically have intravascular volume depletion, and fluid resuscitation is required. Sodium
chloride 0.9% solution warmed to approximately 40 to 42 °C is the preferred fluid choice, and should be
administered cautiously as the patient rewarms and their intravascular space expands. A relative level of
hypotension can be normal in hypothermia—it is important to be aware of this and to regularly reassess fluid
requirements as the patient rewarms to avoid intravascular fluid overload.

Rewarming algorithm for hypothermia and cold-related illness (Figure 17.4)

Observation and disposition

The presence of concomitant trauma or illness influences disposition.

A mildly hypothermic patient can be managed as an outpatient after a period of emergency department care.

Patients with moderate or severe hypothermia need hospitalisation, and may need admission to an intensive care
unit.

Early expert advice on management and the need for transfer to a tertiary centre should be obtained for all critical
patients.

Frostbite
Frostbite is severe localised tissue injury resulting from exposure to freezing cold.

Pathophysiology
Following exposure to subfreezing conditions, formation of extracellular and intracellular ice crystals causes
instantaneous cell death. Simultaneously, release of multiple inflammatory mediators from damaged tissue
contributes further to tissue ischaemia and death. This process is exaggerated if refreezing follows partial thawing
of the tissues.

While frostbite typically occurs following exposure to cold environments, it can also occur from prolonged
exposure to ice packs—as used in the treatment of soft tissue injuries.

Clinical presentation
Frostbite can be classified as either:

superficial (areas of pale, numb skin with surrounding oedema progressing to the formation of large clear
blisters that dry out to superficial eschar), or
deep (smaller, more proximal haemorrhagic blisters that progress to eschar over a week, and may involve
 deeper tissues including muscle and bone).

Frostbite typically affects distal extremities (fingers and toes) as well as facial areas with end artery supply (ears,
nose and cheeks).

The affected person often complains of cold and numbness and, in the case of distal extremities, clumsiness. The
skin initially appears pale and waxy.

In severe cases, autoamputation may occur after a period of weeks.

Key management issues

Frostbite is a nonlethal injury. It is essential that a detailed resuscitative assessment be completed, so that more
immediately life-threatening injuries can be identified and treated (see the Australian Resuscitation Council
website for advice). Systemic hypothermia must be addressed if present.

Thawing by rewarming must not be attempted if there is a possibility that refreezing of the affected area may
occur. If a partially thawed limb is allowed to refreeze the extent of tissue damage is significantly increased.

Do not commence tissue thawing if subsequent refreezing of the tissue is a risk.

Prehospital

In the prehopsital setting:

Remove the victim from the cold environment, and remove any wet clothing.
Avoid trauma to the damaged tissue—do not walk on frostbitten feet unless absolutely necessary, and do not
rub.
If rewarming is attempted, immerse the affected area in warm (ie comfortable when applied to the back of
the hand) water, or use body heat (place fingers under axillae). Do not use stoves or fires to rewarm.

Hospital

In the hospital setting:

Immerse the affected area in warm water heated to approximately 38 to 40 °C (ie comfortable when applied
to the back of the hand) for 15 to 30 minutes until the affected tissue is pinkish and soft to the touch.
Parenteral analgesia (typically opioids) is often necessary to allow the victim to tolerate rewarming (see
Figure 1.3).
Oral nonsteroidal anti-inflammatory analgesia should be administered unless contraindicated (see Table
12.7).
Splint and elevate the affected limb, and use soft nonadherent dressings once the rewarmed skin is dry. Soft
padding should be placed between adjacent digits.
Small clear blisters should be left intact, but larger haemorrhagic bullae should be aspirated (but not
debrided). Any large bullae restricting motion at a joint should be debrided.
There is no indication for routine prophylactic antibiotics; however, if infection is apparent, parenteral
antibiotics with antipseudomonal cover should be commenced.
Early experienced surgical consultation should be obtained. Early surgical debridement should be avoided.
Delineation of viable from nonviable tissue may not be apparent until more than a week after rewarming.
Technetium scanning or magnetic resonance imaging (MRI) may be useful to predict tissue viability and
support any decision to debride tissue surgically.
Tetanus immunisation should be administered as per current guidelines (see Table 2.63).

Other potential treatments to consider following expert consultation include intra-arterial thrombolysis, papaverine
(vasodilator), and hyperbaric oxygen therapy.

Observation and disposition

Most patients with frostbite require short-term hospital admission for analgesia and wound care.

All patients with deep frostbite should be referred for specialist care and follow-up. The local specialist burn unit is
the most appropriate referral.

Victims of frostbite should be advised of the increased risk of recurrent frostbite from any re-exposure to freezing
conditions.
Other localised cold exposure injury
Introduction
There are a number of conditions that can occur following exposure to nonfreezing cold and damp environments.

Frostnip
Frostnip presents as localised paraesthesia that resolves with rewarming.

Perniosis (chilblain)
Perniosis is a localised inflammatory skin lesion that results from acute (or repetitive) exposure to nonfreezing cold
wet conditions. See Chilblains for preventive measures.

Immersion foot (trench foot)

Immersion foot presents with symptoms of pain, redness, swelling and numbness of the feet. It is a result of
damage to sympathetic nerves and small peripheral vessels after prolonged exposure to moist cold conditions. In
severe cases haemorrhagic bullae can form, and permanent tissue damage may occur.

Key references
Cold-related illness

Steele MT, Nelson MJ, Sessler DI, Fraker L, Bunney B, Watson WA, et al. Forced air speeds rewarming in accidental
hypothermia. Ann Emerg Med 1996;27(4):479–84. [ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Diving medicine
Introduction to diving medicine
Illness associated with diving can be caused by barotrauma, decompression sickness or nitrogen narcosis.

Assume any illness after diving is diving-related until proven otherwise. The Divers Emergency Service can
be contacted for advice (telephone 1800 088 200 within Australia).

For information about assessment for fitness to scuba dive (including information about those with significant
obstructive airways disease or a history of a spontaneous pneumothorax) see Fitness to scuba dive.

Barotrauma
Pathophysiology

Boyle's Law states that for a particular quantity of gas the volume is inversely proportional to the pressure.
The effect of the column of water above a diver means that 1 atmosphere of pressure is added for every 10
metres of seawater descended.

Barotrauma occurs when the pressure of an air-filled space within the body does not equilibrate with changes
in ambient pressure of the environment, and can occur either on descent or ascent.

On descent, relative under-pressurisation causes mucosal oedema, vascular engorgement and haemorrhage
within tissues. This is known as tissue ‘squeeze’. On ascent, increasing gas volume within a confined space
(relative over-pressurisation) can result in rupture of hollow organs.

Clinical presentation
Barotrauma can occur after even very short and shallow dives. The onset of symptoms is usually within 30
minutes of ascent to the surface. A history establishing the onset of symptoms in relation to the dive phase
(ascent or descent) helps to delineate syndromes.

Head and neck

Eyes: ‘facemask squeeze’ can result in subconjunctival haemorrhage, lid oedema, and skin petechiae and
bruising.

Ears: ‘ear squeeze’ develops on descent, resulting in pain and hearing loss. There may be sudden relief of
pain (and bleeding from the ear canal) if the tympanic membrane ruptures. Unilateral tympanic membrane
rupture can result in vertigo, nausea and disorientation due to caloric stimulation of cold water in the middle
ear. Inner ear damage (tinnitus, vertigo, deafness) must be excluded in all cases of middle ear trauma.

Sinuses: frontal sinus pain, headache and occasionally epistaxis may occur (‘sinus squeeze’).

Teeth/jaws: toothache, jaw pain and dislodged dental fillings may occur (‘dental squeeze’).

Pulmonary

Pneumothorax is uncommon, although more likely in the presence of underlying lung disease or previous
pneumothorax. It can present as chest pain, shortness of breath and, rarely, haemoptysis. A tension
pneumothorax can present with more severe chest pain and dyspnoea, tachycardia, hypotension, cyanosis,
and distended neck veins—and may progress to cardiovascular collapse and respiratory arrest.

Pneumomediastinum is possible, and may present with pleuritic chest pain radiating to the shoulders,
dyspnoea, coughing and dysphagia. Palpable crepitation due to subcutaneous emphysema might be found.
Tension pneumomediastinum is rare, presenting with all of the above symptoms and progressing rapidly to
severe respiratory distress and cardiovascular collapse due to increased intrathoracic pressure obstructing
venous return to the heart.
Arterial gas embolism

Barotrauma can result in bubbles of gas being forced from the alveoli, through a breech in a vessel wall into
pulmonary capillaries, and then on to the systemic circulation. Most gas bubbles distribute to the cerebral
circulation; however, essentially any organ system may be involved. The resulting symptom complex
depends on the size and location of the embolus:

cerebral emboli—stroke, coma, seizure, apnoea, death

cardiac emboli—dysrhythmia, myocardial ischaemia, sudden cardiac death
mucocutaneous emboli—cyanotic marbling of the skin and pallor of the tongue
kidney emboli—flank pain, haematuria, proteinuria, kidney impairment.

Management
Assume any illness postdiving is diving-related until proven otherwise, and seek specific advice early about
appropriate therapy and the need for transfer [Note 1].

Any patient with neurological symptoms needs urgent referral for hyperbaric oxygen therapy.

Note 1: Within Australia, the Divers Emergency Service can be contacted by telephone 1800 088 200.

Head and neck

Ear, dental and sinus barotrauma usually only requires reassurance and symptomatic management. Referral
for specialist ear, nose and throat (ENT) review should be arranged if there is suspicion of inner ear damage.

Pulmonary

All divers with chest pain or shortness of breath require a detailed assessment including 12-lead
electrocardiogram (ECG) and chest X-ray. Minimally symptomatic pneumomediastinum and small
pneumothoraces usually only require conservative management with supplemental oxygen, rest and
analgesia. Close observation and daily chest X-ray can be done to monitor spontaneous resolution.

Tension pneumothorax or tension pneumomediastinum must always be considered in a diver with severe
respiratory distress, and is managed with a midclavicular intercostal needle thoracostomy followed by formal
intercostal tube thoracostomy.

Arterial gas embolism

Arterial gas embolism is a critical emergency. While there are no randomised controlled clinical studies to
support the role of hyperbaric oxygen therapy, clinical case experience and expert consensus strongly
supports its role in this condition. Increasing the ambient pressure reduces bubble volume and facilitates
diffusion of the gas from the bubble into solution within the surrounding tissues, to be eliminated via the
lungs.

Time to recompression within a hyperbaric chamber is critical. Despite some reports of clinical improvement
in divers presenting for recompression after 24 hours, the efficacy of hyperbaric therapy diminishes over
time. Advice on hyperbaric treatment can be obtained from the Divers Emergency Service (telephone 1800
088 200 within Australia).

While awaiting transfer to a hyperbaric unit:

nurse in the supine position (not head up or head down)

administer high-flow oxygen (achieve as close to 100% oxygen saturation as possible)
rehydrate with intravenous fluids, titrating to clinical response (pulse rate, blood pressure, urine output
and mucosal moistness).

The use of adjuvant drugs such as aspirin, glucocorticoids and lidocaine is controversial, and advice should
be sought from a specialist hyperbaric service before these are given.

Disposition
The timing and method of transfer needs careful consideration of the logistics, particularly in relation to air
transport. Specific specialist advice is required from the Divers Emergency Service (telephone 1800 088 200
within Australia).

In cases of arterial gas embolism, any delay to hyperbaric treatment is associated with a worse outcome and
should be avoided.

Air travel after diving

Consideration must always be given to when a diver can safely travel by aircraft. For an asymptomatic
patient, appropriate advice is to avoid air travel after the latest dive:

for 12 hours if dives have been no more often than once daily (and have not required decompression
stops)
for 48 hours if there have been multiple dives per day, or single dives requiring decompression stops.

For a symptomatic patient, appropriate evacuation should not be delayed. Suitable aircraft cabin
pressurisation (eg to sea level) is necessary to avoid exacerbating the clinical situation.

Decompression sickness
Introduction
Henry's Law states that the amount of gas dissolved in a liquid is directly proportional to the pressure of that
gas.

Decompression sickness occurs when gas tension within tissues exceeds the ambient environmental pressure,
with formation of free gas bubbles within that tissue. These gas bubbles can cause direct mechanical effects
(by blocking vessels or damaging tissue) or activate inflammatory pathways (causing secondary adverse
effects).

Divers can develop decompression sickness after ascending from even very short dives, in deep or shallow
water, even when adhering to protocols. A strong index of suspicion must exist and decompression sickness
should be strongly considered when divers experience pain after diving.

Any neurologic symptoms after a dive are abnormal and should be attributed to decompression sickness until
proven otherwise.

Clinical presentation
The majority of divers develop symptoms within the first few hours of surfacing. It is uncommon to develop
symptoms after 12 hours.

Symptoms are determined by both the volume and location of any gas bubbles that form.

Decompression sickness is frequently classified into 2 types based on clinical presentation. Type 1
decompression sickness is typically mild and resolves with symptomatic treatment. The systemic symptoms
of type 2 decompression sickness, however, require urgent referral for recompression in a hyperbaric oxygen
chamber.

Constitutional symptoms such as lethargy, anorexia, headache and a sense of impending doom are common
with both forms.

Type 1 decompression sickness

Features of type 1 decompression sickness include:

musculoskeletal effects (‘the bends’)—characterised by localised joint pain (which is not worse with
movement) and minimal tenderness or swelling. Onset usually occurs within an hour, and pain
progressively worsens over a number of days
cutaneous effects—associated with self-limiting pruritus over the trunk and localised areas of self-
limiting skin cyanosis
lymphatic effects—present as pain, lymphadenopathy and localised oedema with follicular depressions
(peau d'orange effect).

Type 2 decompression sickness

Features of type 2 decompression sickness include:

neurological effects—most commonly affect the upper lumbar and lower thoracic spinal cord,
presenting as paraesthesia, weakness and bowel or bladder sphincter dysfunction. Can affect cranial
nerves and cerebral function, including subtle manifestations of gait, balance, memory and personality
pulmonary effects—may present with cough, chest pain, dyspnoea and haemoptysis.

Management

Where required, resuscitation should follow standard advanced life support protocols (see flowcharts
developed by the Australian Resuscitation Council).

Decompression sickness is a diagnosis made on a detailed history and clinical examination. Specific
investigations are not indicated unless there are concerns for concomitant barotrauma.

The neurological manifestations of decompression sickness can be clinically indistinguishable from those of
true arterial gas embolism, and the treatment is identical—urgent referral for hyperbaric oxygen therapy.

Hyperbaric oxygen is the treatment of choice for all forms of decompression sickness. While there are no
randomised controlled clinical studies to support the role of hyperbaric oxygen therapy, clinical case
experience and expert consensus strongly supports its role in this condition. Increasing the ambient pressure
reduces bubble volume and facilitates diffusion of the gas from any bubbles into solution within the
surrounding tissues, to be eliminated via the lungs.

Time to recompression within a hyperbaric chamber is critical, and while there are some reports of clinical
improvement in symptoms in divers presenting for recompression after 24 hours, the efficacy of hyperbaric
therapy diminishes over time. Any diver with a presumed diving-related illness should be referred to a
hyperbaric service. Advice on hyperbaric treatment can be obtained from the Divers Emergency Service
(telephone 1800 088 200 within Australia).

While awaiting transfer to a hyperbaric unit:

nurse in the supine position (not head up or head down)

administer high-flow oxygen (achieve as close to 100% oxygen saturation as possible)
rehydrate with intravenous fluids, titrating to clinical response (pulse rate, blood pressure, urine output
and mucosal moistness).

The use of adjuvant drugs such as aspirin, glucocorticoids and lidocaine is controversial, and advice should
be sought from a specialist hyperbaric service before these are given.

Nitrogen narcosis
Nitrogen narcosis is due to the increased partial pressure of nitrogen in compressed air at depth, resulting in
increased nitrogen within nervous system tissues. It usually only occurs at depths of greater than 30 metres
(100 feet).

Known as ‘rapture of the deep’, nitrogen narcosis produces changes similar to alcohol intoxication, including
impairment of intellectual performance, deterioration in judgment, and personality changes.

The risk of nitrogen narcosis increases if the diver is cold, dehydrated or has consumed alcohol in the
preceding 24 hours. The main danger is drowning as a result of impaired judgment.

Symptoms resolve rapidly after ascent.

Key references
Diving medicine

Lind F, Ohlen G, Linden V, Eriksson BM, Frostell C. Treatment with Hyperbaric Oxygen (HBO) at the Karolinska
University Hospital; 2011. [URL]

Barratt DM, Harch PG, Van Meter K. Decompression illness in divers: a review of the literature. Neurologist
2002;8(3):186–202. [ ]

Cameron P. Textbook of adult emergency medicine. 3rd ed. Edinburgh; New York: Churchill Livingstone Elsevier;
2009.

Dunn R, Dilley SJ. The emergency medicine manual. 5th edition. ed. Tennyson, SA: Venom Publishing; 2010.

Lynch JH, Bove AA. Diving medicine: a review of current evidence. J Am Board Fam Med 2009;22(4):399–407. [
]

Mitchell SJ, Doolette DJ, Wacholz CJ, Vann RD, editors. Management of mild or marginal decompression illness
in remote locations workshop proceedings. Durham, N.C: Divers Alert Network; 2005.

Van Stiegmann G, Brantigan CO, Hopeman AR. Tension pneumomediastinum. Arch Surg 1977;112(10):1212–5.
[ ]

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Electrical injury
General information on electrical injury
Most electrical injuries occur in the home or workplace. Lightning strike, while uncommon, has a high
morbidity and mortality. Exposure to electrical weapons is increasingly common, but this rarely results in any
direct complications.

Electrical injury in the home and workplace

Pathophysiology
The amount of current that flows through body tissues is the main determinant of injury. One milliampere
(mA) is generally undetectable, while 100 mA across the heart can trigger ventricular fibrillation. The voltage
and type of current, alternating current (AC) or direct current (DC), also influence the risk of injury.

Complications relating to exposure are influenced by the path of the current through the body, the duration of
exposure and the resistance of body tissues in the current path. Wet skin has 40 times less resistance to
current flow than dry skin and therefore allows a much greater current to pass through the body.

DC electricity (commonly found in high-tension power lines and vehicle electronic systems) generates a
single muscle spasm, typically throwing a victim away from the source. AC electricity (household and most
commercial electricity) stimulates tetanic muscle contraction. This causes the victim to grip onto the source,
potentially prolonging the duration of exposure and hence the risk of significant injury. The greatest risk to
human tissue from AC current is within the frequency range of 40 to 150 Hertz. Household current in
Australia is 240 volts at a frequency of 50 Hertz.

Clinical presentation

Electrical injury can occur from any of the following three mechanisms:

direct effect of the electric current

burns resulting from conversion of electric current to thermal energy
trauma from a fall.

Injuries may range from minor superficial skin burns through to severe multiorgan failure and death.

Burns can occur from the heat of current arcing across the skin or mucous membranes, or if clothing catches
fire. Superficial cutaneous burns occur virtually universally with any significant electrical current exposure,
and deep tissue injury is also common.

Bone has very high resistance to electrical current, and any bone in the current path generates significant heat.
This can result in thermal injury to surrounding muscle, and the risk of limb-threatening compartment
syndrome. Compartment syndrome is seen when increased pressure within a muscle compartment leads to
neurovascular compression and extensive tissue ischaemia and necrosis. Compartment syndrome must be
considered in the setting of severe pain and tenderness over a limb that progressively worsens over 6 to 12
hours and increases with passive movement. If pressure within the affected compartment is not released, there
is a progressive loss of sensation over the affected area. The loss of a palpable distal pulse is a very late sign,
and is typically associated with significant irreversible tissue damage. Compartment syndrome is a surgical
emergency, requiring urgent referral for decompression fasciotomy.

Compartment syndrome must be considered in the setting of severe pain and tenderness over a limb. It is a surgical
emergency.

The extent of deep tissue injury is often not obvious on first assessment, and seemingly minor entry and exit
wounds may be associated with extensive deep tissue damage. A high index of suspicion is essential to avoid
underestimating the severity of injury.
Vascular spasm and thrombosis can lead to tissue ischaemia and necrosis. The sites of entrance and exit
wounds provide a clue to the path of the current.

Extensive tissue damage can precipitate rhabdomyolysis and resultant kidney failure.

Extensive tissue damage can precipitate rhabdomyolysis (breakdown of muscle fibres and release of toxic
proteins into the bloodstream) and resultant kidney failure. Urinalysis must be performed and, because
myoglobin mimics haematuria on a dipstick urinalysis, a specific myoglobin assay is available in some
centres and can be carried out if there is any haematuria detected (see Rhabdomyolysis).

Cardiac arrhythmias are infrequent, and are usually benign and self-limiting. The risk of arrhythmia increases
if the electrical current crosses the heart. The commonest fatal arrhythmia is ventricular fibrillation.

Key management issues

In the prehospital environment, safety of the rescuer is paramount. The victim should not be approached
while there is any risk of electrical injury to the rescuer. If the electrical source cannot be turned off, electrical
cables can be removed from the victim using a nonconducting material such as timber or rubber.

The victim of a serious electrical burn has likely experienced significant trauma, and a detailed resuscitative
trauma assessment must be made. Hypotension should be considered a symptom of internal haemorrhage
until proven otherwise, and fluid resuscitation commenced.

The commonest potentially lethal arrhythmia following electrocution is ventricular fibrillation. Early
advanced life support (ALS) and defibrillation are critical for survival (see the Australian Resuscitation
Council website).

Prolonged ALS is warranted due to the higher likelihood of recovery from cardiac arrest following
electrocution relative to other causes of cardiac arrest. ALS should follow standard protocols (see flowcharts
developed by the Australian Resuscitation Council).

Deep tissue injury must be suspected in anyone with an entry and exit wound. Such patients should be
monitored closely for compartment syndrome (see Clinical presentation), hyperkalaemia, rhabdomyolysis
and kidney failure. They may require aggressive fluid resuscitation.

Damage to end organs or superficial burns are treated on their own merits.

Assessment of any patient with an electrical injury should always include an electrocardiogram (ECG). Fatal
arrhythmias typically occur at the time of the electrical insult, and delayed arrhythmias are uncommon in
otherwise healthy patients. Continued cardiac monitoring is only required if the ECG is abnormal, or if there
has been prehospital arrhythmia or loss of consciousness.

Measurement of troponin or other cardiac biomarkers is not routinely required as the clinical significance of
an elevated level is not clear and does not guide disposition decisions.

Observation and disposition

The victim of a brief, low-voltage (household) exposure who is asymptomatic and has a normal ECG can be
discharged directly.

Patients with a pacemaker or implantable defibrillator should have its function checked before they are
discharged.

Prolonged cardiac monitoring (for at least 12 hours) is only required for patients with:

high voltage exposure (more than 1000 volts)

documented ECG changes or arrhythmias (rare)
seizures or loss of consciousness.

Any patient with suspected deep tissue electrical injury should be admitted to a specialist burns or plastic
surgical unit.

Lightning strike
Introduction
Lightning can generate a direct electrical current of more than 10 million volts over a very short time period.

The mortality from lightning strike is about 30%, and three-quarters of the survivors have permanent
disability.

Clinical presentation
The very short duration of exposure often results in minimal cutaneous burns or tissue destruction.

The most frequent complications of lightning strike are cardiac arrhythmias and respiratory arrest. The
commonest initial arrhythmia following a direct strike is asystole but, unlike other causes of asystolic cardiac
arrest, the survival rate can be as high as 50% if early bystander cardiopulmonary resuscitation (CPR) is
commenced. Apnoea can be prolonged—this is not in itself a predictor of poor outcome as long as adequate
respiratory support is provided.

Lichtenberg figures (typically transient, often resolve within a couple of hours) are characteristic skin changes
that occur in about 20% of victims of lightning strike. They have a fernlike or feathering pattern, and can
provide a valuable clue to the cause of unexplained cardiac or respiratory collapse.

Keraunoparalysis is a rare transient paralysis unique to victims of lightning strike. It is thought to result from
severe vascular spasm, causing ischaemia which usually resolves within hours.

The patient may have fixed dilated pupils as a result of transient paralysis. This can be misleading to the
resuscitation medical team.

The presence of fixed dilated pupils may be transient. Resuscitation efforts should continue.

Fetal mortality is high in pregnant women who are victims of lightning strike. Urgent specialist obstetric
consultation is essential.

Lightning can also cause acute blast effects such as tympanic membrane rupture, and delayed effects such as
neuropsychiatric sequelae and cataracts.

Key management issues

Many lightning strikes are unwitnessed, and a high index of suspicion is required. The diagnosis is difficult if
the patient is unconscious or confused, but should be considered particularly if the patient has been outdoors
during an electrical storm. The presence of multiple victims, characteristic Lichtenberg figures, exploded
clothing, localised paralysis or ruptured tympanic membranes should heighten suspicion (see Clinical
presentation, above]).

Cardiac arrest following lightning strike is frequently self-limiting after a short period, while respiratory
apnoea can be prolonged. The duration of unsupported apnoea is the major determinant of survival following
lightning strike. Prolonged ventilatory support may be required.

In lightning strike, bystander CPR by itself may be lifesaving, allowing time for the heart to return
spontaneously to a perfusing rhythm. In a multicasualty situation, this means (paradoxically) that the focus of
resuscitation should be on those who appear to be dead, not those showing signs of life.

Bystander CPR and prolonged respiratory support for lightning strike victims can be lifesaving.

Resuscitation otherwise follows standard protocols (see the Australian Resuscitation Council website).

Observation and disposition

Asymptomatic patients, with a normal electrocardiogram (ECG) and no evidence of complications, can be
safely discharged from hospital. All other victims of lightning strike require admission for observation and
management of the complications.

Patients with a pacemaker or implantable defibrillator should have its function checked before they are
discharged.

Because of the risk of delayed ocular complications (cataracts) a referral for nonurgent outpatient
ophthalmology review should be provided.

Injury from electrical weapons

Introduction
Electrical weapons including dart and stun guns have been developed as nonlethal alternatives for law
enforcement and security personnel. They can be obtained and used illicitly. They deliver bursts of high-
voltage but low-amperage direct current.

The commonest device currently used in Australia and New Zealand is the Taser X26. This battery-operated
device fires 2 barbed electrodes on the end of 6.4-metre-long copper wires, delivering 50 000 volts with 1.76
joules of energy in rapid pulses over 5 seconds. This produces overwhelming pain and involuntary muscle
contraction, resulting in the subject falling to the ground.

Clinical presentation
Subjects of electrical weapon use present for the following reasons:

complications as a result of weapon use (eg primary barb strike injury, electrical injury, trauma from
falling)
medical or psychiatric illness associated with the underlying reason for the electrical weapon being
used.

Key management issues

Due to widespread implementation of these weapons among law enforcement agencies, emergency
department staff can expect to treat patients who have been subdued with an electrical weapon.

Based on available evidence, there is negligible risk of an adverse event due to the current from an electrical
weapon in an otherwise healthy individual.

An electrocardiogram (ECG) is not necessary in all patients, but may be considered in those with chest pain
and palpitations, a significant cardiac history, or multiple exposures.

Most victims of electrical weapon use have medical issues complicating their presentation (eg psychiatric
illness, drug intoxication). A detailed history and examination are required. This should focus on the events
leading up to the electrical weapon use and any trauma that may have occurred as a result of an uncontrolled
fall while being immobilised.

Injury as a result of barb strike is occasionally reported, and should be excluded.

Observation and disposition

Otherwise healthy individuals may be safely discharged following routine history and examination. There is
no requirement for cardiac monitoring.

Hospitalisation may be necessary to manage any medical issues that may have contributed to the need for use
of the electrical weapon, or to manage injuries that may result from a fall during immobilisation.

Patients with a pacemaker or implantable defibrillator should have its function checked before they are
discharged.

Key references
Electrical injury

Auerbach PS. Wilderness medicine. 5th ed. Philadelphia: Mosby Elsevier; 2007.

Bleetman A, Steyn R, Lee C. Introduction of the Taser into British policing. Implications for UK emergency
departments: an overview of electronic weaponry. Emerg Med J 2004;21(2):136–40. [ ]
Cameron P. Textbook of adult emergency medicine. 3rd ed. Edinburgh; New York: Churchill Livingstone Elsevier;
2009.

Dunn R, Dilley SJ. The emergency medicine manual. 5th edition. ed. Tennyson, SA: Venom Publishing; 2010.

Robb M, Close B, Furyk J, Aitken P. Review article: Emergency Department implications of the TASER. Emerg
Med Australas 2009;21(4):250–8. [ ]

Spies C, Trohman RG. Narrative review: Electrocution and life-threatening electrical injuries. Ann Intern Med
2006;145(7):531–7. [ ]

Published July 2012. Amended October 2014. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Heat-related illness
General information on heat-related illness
Hyperthermia is defined as a core body temperature above 37.5 °C due to a failure of normal body
thermoregulation. It is not synonymous with fever.

The severity of heat-related illness is a continuum:

Heat cramps are painful involuntary muscle spasms that can occur after prolonged exercise (more often in
nonacclimatised individuals), and are typically associated with dehydration-induced volume depletion and
significant sodium loss from sweating.
Heat exhaustion is another mild form of systemic heat illness, typically associated with volume depletion.
The body's normal heat dissipation capacity is maintained.
Heat stroke is an uncommon but life-threatening condition, where the core body temperature exceeds 40 °C
and the body's ability to dissipate heat is lost, resulting in organ system failure. Heat stroke can be
–
classic (nonexertional)—typically occurs in the elderly and those with chronic disease, who may
either have impaired normal thermoregulation or are unable to remove themselves from a hot
environment
–
exertional—occurs in individuals engaging in strenuous exercise during periods of high ambient
temperature and humidity.

Important differential diagnoses in heat-related illness

The differential diagnosis of an elevated core body temperature is wide and varied (and beyond the scope of this
chapter). It is important that, during the initial assessment of a victim of possible heat stroke, critical alternative (or
coexistent) diagnoses be actively excluded.

Sepsis is a common cause of elevated body temperature with an associated high morbidity and mortality, and can
coexist with heat stroke in some patients. Sources of infection must be considered and excluded in all cases.

Other causes of elevated core body temperature that have very different pathophysiologies, but can also progress to
heat stroke include:

neuroleptic malignant syndrome (NMS)—fever, muscular rigidity, altered mental state and autonomic
lability
serotonin toxicity—agitation, confusion, hyperreflexia, myoclonus and tachycardia
malignant hyperthermia—a genetically inherited disorder where specific triggers (anaesthetic drugs most
commonly linked) stimulate overwhelming intracellular calcium release, producing profound muscle
contraction and disordered metabolism. The hyperthermia is peripherally, rather than centrally, mediated.

Pathophysiology of heat-related illness

The body thermostat located in the hypothalamus maintains core body temperature within a narrow range. It is
able to activate a number of heat-gain and heat-loss mechanisms, largely via the autonomic nervous system.

In a normal individual, most heat is lost by radiation; however, the most important adaptive mechanism for heat
loss is evaporation. This makes heat-related illness most likely in environments with high ambient temperature and
high humidity, when environmental temperature exceeds skin temperature, and evaporative capacity is limited.

An increase in core body temperature is associated with an increase in metabolic rate and oxygen consumption. At
temperatures exceeding 40 °C there is a high risk of intracellular mechanisms becoming dysfunctional, resulting in
organ system failure and death. The major risk factors for heat-related illness are:

behavioural factors (eg athletes, children left in cars, struggling against physical restraint, inappropriate
clothing worn by the elderly)
drugs (eg anticholinergics, stimulants, phenothiazines, serotonergic drugs)
illness (eg prolonged seizures, delirium tremens, central nervous system [CNS] infections).

Clinical presentation of heat-related illness

Introduction
A core body temperature must be taken. An oesophageal probe is the most reliable method, but typically this is
only possible in a ventilated patient. Rectal or bladder probes are a less reliable alternative. The validity of infrared
tympanic thermometers has not been demonstrated in hyperthermic patients.

Heat exhaustion
Heat exhaustion usually presents at the end of a prolonged period of exertion, and may be difficult to distinguish
from heat stroke. Symptoms can include headache, nausea, vomiting, postural dizziness or collapse, and muscle
cramps.

Clinical examination may reveal tachycardia, tachypnoea and profuse sweating. Postural hypotension may be
present with mild volume depletion; more severe volume depletion can cause overt cardiovascular collapse.

The core body temperature is typically less than 40 °C.

Heat stroke
Typical clinical features of heat stroke are:

core body temperature 40 °C or greater (it is important to determine the initial prehospital temperature if
possible, because prehospital interventions may have resulted in cooling and therefore mask the diagnosis)
altered conscious state and/or abnormal neurological signs
hot, dry skin (although sweating may still be present in the exertional form).

Physical findings of heat stroke include:

cardiovascular—may appear hyperdynamic with tachycardia, dyspnoea and crackles (noncardiogenic

pulmonary oedema), flushing and warm moist peripheries; or may present in a hypodynamic state with
hypotension and cool dry underperfused peripheries
respiratory—an increase in respiratory rate and minute volume is present unless the patient is obtunded
neurological—may present with lethargy, confusion and ataxia, which can progress to a decreased conscious
state and generalised seizures
haematological—petechial haemorrhages, bruising and overt bleeding as disseminated intravascular
coagulation develops
musculoskeletal— rhabdomyolysis may present with muscle pain, and tenderness on palpation. A high index
of suspicion is necessary.

Key management issues in heat-related illness

Introduction
Mortality from heat-related illness is related to the degree of temperature elevation, the duration of hyperthermia
and the number of organ systems affected. Pre-existing co-morbidities also affect morbidity and mortality. The
clinical approach to a patient with suspected heat-related illness is summarised in Figure 17.5.

Clinical approach to a patient with suspected heat-related illness (Figure 17.5)

 NB1: Note that at the time of patient assessment the core body temperature, having previously been elevated, may have returned to normal levels.

Heat cramps and heat exhaustion

Heat cramps and heat exhaustion typically respond to rest in a supine position in a cool environment and oral
rehydration. Intravenous fluids are rarely required.

Heat stroke

Resuscitation should follow standard advanced life support protocols (see the Australian Resuscitation Council
website).

Irrespective of the cause, the primary therapy for suspected heat stroke is to remove the patient from the hot
environment and commence rapid cooling to preserve brain and nervous system function.

The aim is to actively reduce core body temperature to about 38 °C. Active cooling should be ceased at this point,
to avoid overcooling.

Cooling measures

There are a number of cooling options available, including:

evaporative cooling—spray or sponge the uncovered patient with tepid water and then fan air over the moist
skin. This is remarkably effective, noninvasive and easily performed both in the hospital and prehospital
 environment
ice packs—these can be applied to the skin, overlying vascular beds such as the groin, axillae and neck if
tolerated by a conscious patient (caution—avoid cold thermal burns, which can result from prolonged
exposure of an icepack directly to unprotected skin)
specialised cooling mats or blankets
cooled intravenous fluids (use sodium chloride 0.9% solution stored at approximately 4 °C in a standard
refrigerator)
immersion in an ice bath—this results in very rapid cooling, but it is poorly tolerated in a conscious patient,
makes patient access for interventions very difficult, and can be logistically challenging in an unconscious or
ventilated patient
cold thoracic or peritoneal lavage.

It is important to avoid shivering, because this causes heat gain. Shivering can be stopped by using titrated small
doses of intravenous benzodiazepines which suppress shivering without causing significant sedation. Use:

1 diazepam (adult and child) 0.02 mg/kg IV as an initial bolus (note that this is only 1 to 2
mg in an adult), then titrate at approximately 5-minute intervals until shivering is
suppressed

OR

1 midazolam (adult and child) 0.01 mg/kg IV as an initial bolus (note that this is only 0.5 to
1 mg in an adult), then titrate at approximately 5-minute intervals until shivering is
suppressed.

If required because of an altered conscious state, intubation and neuromuscular paralysis effectively lowers heat
generation.

Antipyretics (paracetamol, aspirin, ibuprofen) are ineffective and should not be used for the purposes of active
cooling.

Key investigations

Heat stroke of whatever aetiology can cause elevated potassium and creatine kinase concentrations, impaired
kidney function, and an abnormal blood glucose concentration—therefore, these tests should all be performed
early and monitored regularly. The risk of disseminated intravascular coagulation is high, and liver biochemistry
and a coagulation profile should be performed. Myoglobinuria may easily be mistaken for haematuria and, if
available, specific urinalysis for myoglobin should be requested if the urine dipstick is positive for blood.

Rehydration

Heat stroke is not always associated with volume depletion. Intravenous fluid should be administered cautiously,
and ideally titrated to clinical parameters such as urine output and central venous pressure.

Differential diagnosis

If central nervous system infection is a likely differential diagnosis (due to altered mental state and fever), then
treat on clinical suspicion with antibiotics and antivirals (see Empirical regimens for sepsis or septic shock,
Meningitis, and Empirical therapy for encephalitis).

Observation and patient disposition after heat-related illness

Heat exhaustion is typically treated as an outpatient, or even in the field, and inpatient hospitalisation is usually
unnecessary. Rapid recovery usually occurs. Advice on prevention of heat-related illness should be provided
before discharge, and return to competitive sport should be delayed for at least 48 hours.

Hospitalisation is always necessary for heat stroke, irrespective of the primary cause, as multiorgan failure is
common. Expert advice should be obtained early about management and the need for transfer to a tertiary centre.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Near drowning
General information on near drowning
The incidence of near drowning peaks in toddlers and young adults. Trauma, alcohol and drug intoxication,
hypoglycaemia and seizures must be considered as precipitating events, particularly in young adults.

Immersion syndrome is sudden death following immersion in cold water. It typically occurs in older
individuals and is due to vagally-mediated bradyarrhythmias, ventricular fibrillation and cardiac arrest.

Pathophysiology of near drowning

In drowning an initial period of panic and voluntary breath holding is followed by air hunger which then
triggers a reflex inspiratory effort. Water is inhaled into the upper airways resulting in aspiration (wet
drowning) or laryngospasm (dry drowning). Swallowed water is frequently vomited and can result in
pulmonary aspiration of stomach contents.

Hypoxia triggers a profound bradycardia and associated hypotension, and ultimately cardiac arrest.
Irreversible brain injury can occur within 3 minutes, but may be delayed due to the protective effects of
hypothermia if the drowning occurs in very cold water.

There is no clinical distinction between wet and dry drowning. Likewise there is no clinical distinction
between fresh and salt-water drowning.

Near drowning results in decreased lung compliance, and ventilation-perfusion mismatching with
physiological shunting. Hypoxaemia causes tissue hypoxia and diffuse organ dysfunction or death.

Clinical presentation of near drowning

Clinical presentation can vary from no symptoms to full cardiorespiratory arrest. The onset of symptoms
following a near-drowning event can be delayed—even if the patient is seemingly well at presentation, a
detailed assessment and a period of at least 6 hours of observation are required.

Fluid aspiration triggers noncardiogenic pulmonary oedema which progresses to severe acute respiratory
distress syndrome (ARDS). Patients may appear dyspnoeic and cyanosed, with audible wheeze or crackles on
auscultation.

Vomiting is very common during near-drowning events, and aspiration of stomach contents can occur.

Effects of hypoxaemia include:

cerebral—can lead to cerebral oedema, reduced consciousness and seizures

cardiac—arrhythmias (from hypoxaemia and/or hypothermia) can result in cardiovascular compromise
and cardiac arrest
acidosis—metabolic and/or respiratory acidosis is common, however significant electrolyte
disturbances are uncommon.

It is difficult to predict how any individual will fare following near drowning. Factors associated with an
improved prognosis include:

prompt initiation of, and response to, resuscitation

paediatric (as opposed to adult) near drowning
short submersion times
respiratory arrest only (ie pulse throughout)
awake, or conscious but obtunded, on arrival in the emergency department.

Key management issues in near drowning

Ventilation and oxygenation are the initial priorities—time to commencement of effective resuscitation is a
major determinant of the clinical outcome following significant near-drowning injury.

Resuscitation should follow standard advanced life support protocols (see the Australian Resuscitation
Council website). Despite successful resuscitation, 20% of near-drowning patients experience neurological
damage causing significant functional limitation. There are, however, no accurate predictors of poor outcome
at initial presentation. Prolonged resuscitation efforts are indicated and, because near-drowning victims are
frequently young and healthy, often rewarding. In the case of hypothermic near-drowning incidents,
substantial neurological recovery can occur after prolonged resuscitation.

Cervical spine injury is not commonly associated with near drowning—unless there is a strong suggestion of
risk, immobilisation of the spine should not be allowed to interfere with resuscitation interventions.

There is no indication for postural drainage or Heimlich-type manoeuvres to drain water from the lungs.

Supplemental high-flow oxygen should be administered to all patients as soon as it is available.

Noncardiogenic pulmonary oedema responds well to continuous positive airways pressure (CPAP) using
pressures of 5 to 10 cm of water, or bi-level positive airways pressure (BiPAP) with initial settings of 10 cm
of water inspiratory pressure and 5 cm of water expiratory pressure. More severe cases may require
intubation and mechanical ventilation to maintain oxygenation and to control pulmonary oedema.

Core temperature should be monitored and hypothermia actively treated (see Accidental hypothermia).

Specific drug therapies are not generally indicated. There is no evidence for the use of neuroprotective drugs
such as glucocorticoids or barbiturate infusions.

The onset of symptoms of respiratory compromise may be delayed by a number of hours. A chest X-ray is
not routinely required for drowning victims without clinical evidence of respiratory compromise, but must be
performed if any symptoms develop.

Prophylactic antibiotics are not routinely indicated unless the submersion fluid is grossly contaminated. A
wide range of organisms can colonise fluid media in which near-drowning events may occur. If considered
necessary, an antibiotic with adequate cover against water-borne organisms should be commenced. Expert
opinion should be obtained.

Blood glucose concentrations should be maintained within a narrow normal range, with the use of insulin if
necessary, to aid optimal neurological recovery.

Observation and patient disposition after near drowning

The onset of symptoms following a near drowning may be delayed. All patients require a period of
emergency department observation of 6 to 8 hours. Only those who remain completely asymptomatic can be
safely discharged home after this observation period [Note 1].

Intubated patients or those with severe respiratory compromise need to be cared for in the intensive care unit.
Those with moderate respiratory compromise need inpatient ward care.

Early expert advice on management and the need for transfer to a tertiary centre should be obtained for all
critical patients.

Note 1: Near drowning is a notifiable event in some Australian states and territories.

Key references
Near drowning

Cameron P. Textbook of adult emergency medicine. 3rd ed. Edinburgh; New York: Churchill Livingstone Elsevier;
2009.

Dunn R, Dilley SJ. The emergency medicine manual. 5th edition. ed. Tennyson, SA: Venom Publishing; 2010.

Published July 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Intravenous inotrope infusion calculations
(Appendix 17.1)
The content of this appendix was prepared by the expert writing group for Therapeutic Guidelines:
Emergency Medicine, version 1. It has not been revised for this version of Therapeutic Guidelines:
Toxicology & Wilderness.

The choice of inotrope depends on the patient's clinical condition and the available resources. Calculations
for preparations of standard inotropes are provided in Box 17.7 and Box 17.8. Noradrenaline is prepared
according to the same principles as adrenaline (see Box 17.7). Doses for inotropes used in toxicology are
given in Box 17.2.
Adrenaline intravenous infusion calculations (Box 17.7)

Use adrenaline 0.1% or 1:1000 solution which is 1 mg/mL [NB1] [NB2] [NB3].

Adults:

The standard infusion rate for adults ranges from 1 to 20 micrograms/minute (60 to 1200
micrograms/hour).

Infusion rates should be initiated at the lower end of the above ranges but can be titrated up approximately
every 3 minutes to achieve the desired effects on blood pressure and heart rate.

For 50 mL bag or syringe driver, use:

3 mg/50 mL, which gives an infusion concentration of 60 micrograms/mL.

Therefore run the infusion at 1 to 20 mL/hour to deliver 1 to 20 micrograms/minute.

For 100 mL bag, use:

6 mg/100 mL, which gives an infusion concentration of 60 micrograms/mL.

Therefore run the infusion at 1 to 20 mL/hour to deliver 1 to 20 micrograms/minute.

For 1000 mL bag, use:

6 mg/1000 mL, which gives an infusion concentration of 6 micrograms/mL.

Therefore run the infusion at 10 to 200 mL/hour to deliver 1 to 20
micrograms/minute.

Children:

The initial infusion rate for children is 0.05 to 0.1 micrograms/kg/minute (3 to 6 micrograms/kg/hour).

For child 30 kg or less, use:

0.3 mg/kg in 50 mL so that 0.5 to 1 mL/hour gives 0.05 to 0.1

micrograms/kg/minute.

For child more than 30 kg, use:

0.15 mg/kg in 50 mL so that 1 to 2 mL/hour gives 0.05 to 0.1

micrograms/kg/minute.
NB1: Adrenaline is compatible with most standard infusion solutions. In most hospital emergency departments, glucose 5% is used to
maintain consistency with use in the intensive care setting.

NB2: Adrenaline dose terminology:

Percent Ratio Concentration
0.01% 1 in 10 000 1 mg/10 mL
0.1% 1 in 1000 1 mg/mL (most commonly available)
1% 1 in 100 10 mg/mL

NB3: Noradrenaline is available as a 1:1000 solution, and the same calculations apply to its preparation and use.
 Isoprenaline intravenous infusion calculations (Box 17.8)

Isoprenaline is available as 1 mL or 5 mL ampoules of 200 micrograms/mL, which is 1 mg/5 mL [NB1].

Adults:

The standard initial infusion rate for adults ranges from 1 to 4 micrograms/minute (but may need to be
increased up to 4 times or higher to overcome beta blockade in beta-blocker poisoning).

For 50 mL bag or syringe driver, use:

3 mg/50 mL which gives an infusion concentration of 60 micrograms/mL.

Therefore run the infusion at 1 to 4 mL/hour to deliver 1 to 4 micrograms/minute.

For 100 mL bag, use:

6 mg/100 mL which gives an infusion concentration of 60 micrograms/mL.

Therefore run the infusion at 1 to 4 mL/hour to deliver 1 to 4 micrograms/minute.
NB1: Isoprenaline is compatible with most standard infusion solutions. In most hospital emergency departments, glucose 5% is used to
maintain consistency with use in the intensive care setting.

Published March 2008. Amended June 2012. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Fundamentals of ulcer and wound management
Fundamentals of ulcer and wound management
Patients with chronic or recurrent ulcers or wounds have a health condition that reduces quality of life, and
that may progress to serious medical complications and hospital admission. The prevalence of ulcers and
wounds in older patients has been estimated between 1% and 5%. For patients with diabetes or peripheral
arterial disease, complications include limb amputation and life-threatening infection.

Prevention is the best strategy. Undertake a thorough history and examination at least annually to identify and
minimise risk factors for a first wound or for wound recurrence. Some patients require more frequent review
based on their risk profile; for example, patients with a high-risk foot need to be reviewed every 3 months.
Interventions to prevent a wound include improving skin integrity, optimising the patient’s general health and
referring a patient with chronic venous insufficiency to a vascular surgeon.

If a wound does occur, the aim of management is to promote healing, minimise the likelihood of recurrence,
and reduce the impact on the patient’s quality of life. Successful treatment is predicated on an accurate
diagnosis; collaboration between the patient, healthcare professionals (including between hospital- and
community-based clinicians) and other carers is critical.

The ability to heal diminishes with age, so minor injuries in an older person have a higher risk of delayed
healing, infection, and progression to serious injury, threatening limb or life. Proactive management is
required for a person with risk factors for delayed healing (see Factors affecting wound healing).

A general framework for ulcer and wound assessment and management is provided in Table 15.1.

After implementing a wound management plan, early review—usually within a week—ensures patients can
tolerate and adhere to the plan. The duration between reviews can thereafter be extended according to wound
characteristics and progress, interventions required and patient characteristics. If patients have difficulty
adhering to a wound management plan, explore the basis for this without judgment. Patient and carer
education is essential to facilitate optimal management.

Key references
Cheung C. Older adults and ulcers: chronic wounds in the geriatric population. Adv Skin Wound Care
2010;23(1):39–44; quiz 5–6.

Steed DL. Foundations of good ulcer care. Am J Surg 1998;176(2A Suppl):20S–5S.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Assessing patients with an ulcer or wound
Introduction to assessing patients with an ulcer or wound
Assess the wound and the limb or local area, within the clinical context of the patient. This is essential to complete
the first step in wound management—establishing the aetiology of the wound. Wound management is tailored to the
mechanism of injury and cannot be undertaken without an accurate diagnosis.

Using the HEIDI acronym for holistic care, assessment and management consists of history, examination,
investigation, diagnosis and implementation of care; see Table 15.1. Regular review and reassessment of the patient
and the wound is essential.

A framework for ulcer and wound management (Table 15.1)

Activity Description
Undertake a thorough medical and medication history, including smoking status
and alcohol intake.

History Determine precipitating factors for the ulcer, and its progress.

Determine the impact (eg physical, social, financial, psychological) of the ulcer
on the patient.
Examine the patient, then the ulcer, local area and surrounding skin and tissues
Examination (use TIME framework; see Table 15.2).

Document examination findings and take photographs of the wound.

Investigations may include blood tests, wound swabs, punch or elliptical biopsy,
Investigations
imaging, and vascular assessment.
Establish an accurate aetiology and manage the underlying pathophysiology;
consider specialist referral.

Diagnosis Consider differential diagnoses, including rare and uncommon causes.

Discuss the expected prognosis and possible complications with the patient,
especially if the ulcer is not expected to heal.
Interventions are specific to the aetiology of the ulcer; consider interventions to:

correct pathophysiology
manage symptoms
address lifestyle and behavioural issues
manage factors that impair wound healing (eg inadequate nutrition).
Implementation of care
Ensure patients understand their diagnosis and prognosis, and create a plan for
review and evaluation.

Provide patient information sheets and encourage a collaborative relationship

between the patient, healthcare team and carers. Document the wound
management plan and the information provided.

Taking a history for patients with an ulcer or wound

Undertake a comprehensive medical history (including previous ulcers, surgical and social history) and medication
history (including prescription, over-the-counter and complementary and alternative medicines). Ask about the
patient’s smoking status and alcohol intake. Identify relevant comorbidities, such as those that:

limit circulation and oxygenation to skin—chronic venous insufficiency, peripheral arterial disease, heart
failure, impaired respiratory function, blood disorders (eg anaemia, polycythaemia, thrombocythaemia)
affect skin integrity—dryness, purpura, atrophy, solar exposure and skin cancer, dermatitis, allergy to topical
products (including dressings; see Previous reactions to ulcer and wound dressings), neuropathy, tinea
alter immune function—rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, HIV
impair healing—endocrine or metabolic disorders (eg diabetes mellitus, thyroid dysfunction, oestrogen
deficiency), disseminated malignancy, peripheral oedema, disorders affecting nutrition (eg malabsorption)
affect mobility or ability to self-care—poor vision, reduced hand function or range of movement, neurological
 conditions, arthritis, obesity, dementia or other cognitive or developmental disorder, major psychiatric
disorders, incontinence.

Ask patients what concerns them about their wound (eg pain, restricted mobility, swelling, exudate leakage, odour).
Also explore their physical, mental, social, spiritual and cultural wellbeing [Note 1]. Determine their financial
situation. Acknowledge and address their concerns and priorities at the initial visit and subsequent reviews.

Review the following aspects:

location (aids diagnosis [eg venous leg ulcers typically occur on the lower third of the leg] and management
[eg for patients with a foot ulcer, find out their types of footwear and if they use orthotics])
details of wound onset (spontaneous, traumatic, caused by foreign body) and duration
progress (consider if the wound is advancing appropriately through the phases of healing)
treatments already used and response.

Ask about other healthcare professionals involved and their role. Discuss changes in the management plan with all
practitioners.

Determine if the patient has previously had a chronic wound, and ask about its progression and if any investigations
(including imaging) were performed. It is also important to know whether there has been trauma, radiotherapy or
surgery in the region of the current wound.

Note 1: For comprehensive information, see: Optimising wellbeing in people living with a wound. An expert working group review. London: Wounds
International, 2012.

Tetanus-prone wounds
Tetanus vaccination is recommended as postexposure prophylaxis for a tetanus-prone wound. Tetanus-prone wounds
are any wound other than a clean, minor cut in patients without recent vaccination. For more information, see the
Australian Immunisation Handbook.

Examining patients with an ulcer or wound

General principles
Examine the patient first, then the wound and surrounding skin and local area, including joints. Examination can
begin in the waiting room, by assessing how patients stand and move, and if they are wearing appropriate footwear.

Examine the patient for:

vascular disease (chronic venous insufficiency, peripheral arterial disease, mixed vascular disease)
heart and lung disease (eg breathlessness on exertion, cyanosis, signs of right-sided heart failure [eg elevated
jugular venous pressure])
anaemia (eg pallor)
systemic infection (eg fever, tachycardia)
lymphadenopathy
peripheral oedema or lymphoedema
nutritional deficiency
dehydration
neurological disease (eg gait disturbance that influences calf muscle pump function, impaired upper limb
function, sensory or motor impairment)
arthritis.

Throughout the examination, look out for signs of:

impaired communication or cognitive function

anxiety, depressed mood or other mental health concerns
wound-related pain or distress.

Consider the patient’s standard of personal hygiene.

Examining the ulcer or wound

Assess and document the wound at the initial presentation and at each review. The wound characteristics (eg
appearance, location) aid diagnosis. The status of the wound base, the amount of exudate, and the condition of the
surrounding tissues influence the selection of appropriate therapies, including dressings.
Observing removal of the dressing provides useful information for assessing current therapy. Observe whether the
dressing adheres to the wound, if there is pain on removal, and the quantity, appearance and odour of any exudate.

Note and record the wound’s location and dimensions (measure length, width, depth). Also note and record other
important characteristics of the wound using the TIME acronym of tissue, infection/inflammation, moisture balance
and edge (see Table 15.2). Wound charts, serial tracings and photographs are used to document wound characteristics.
Photographs are also useful for communicating with other healthcare professionals; see Box 15.1. Examination and
documentation remains important at subsequent visits.

Practice points for ulcer and wound photographs (Box 15.1)

Take photographs at the initial visit, then every month (more frequently if a change is identified), and on
healing.
Explain the process and use of photos to the patient and obtain consent.
Cleanse the wound before taking a photograph.
Ensure infection control procedures are maintained (eg take gloves off before using a camera).
Use a white background to minimise shadows and glare.
Ensure adequate lighting so wound details are clear—the flash may be required.
Take the photograph from directly in front of the wound; holding the camera at an angle can distort the
wound size and shape.
Take a photo of the wound that includes a wide area of healthy tissue, so the location is clear.
Then take a close-up photo to provide more detail.
Ensure the wound measuring scale is visible in the picture (if it is causing significant glare, also take a close-
up photo without the measuring scale).
Include the date the photograph was taken (write the date on the measuring scale, or, if available, use the date
stamp function of the camera).
Take repeat photos from the same reference point as previously used.
Always consider and maintain patient privacy. Do not include identifying patient features.
Photographs must be stored appropriately and only shared professionally.

Wound characteristics summarised using the TIME acronym (Table 15.2)

Tissue refers to the ulcer base. Note the presence and approximate extent of tissue
types in the wound. This might include:

devitalised tissue (necrosis, eschar, slough)

granulation tissue (see Photo 15.1 and Photo 15.2)
Tissue hypergranulation (see Photo 15.3)
agranulation (absence of healthy granulation tissue) (see Photo 15.4)
epithelium
deeper tissues (eg bone, tendon, muscle, subcutaneous fat)
foreign material or debris.

Determine if the wound is inflamed or infected.

A superficial infection or increased bacterial burden in a wound can be indicated by the

following features:

delayed healing
increased pain
increased volume of exudate
green tinge to exudate
odour
abnormal granulation tissue (dark, bleeds easily, may be dull).

A deep infection can have any of the features above, and may include the following:
Infection/inflammation
increased wound size
increased local temperature
bone probed in base
oedema
erythema further than 2 cm from the wound margin
‘satellite’ breakdown (new areas of ulceration next to the original ulcer)
yellow or green exudate.

See also Table 15.24 for more signs and symptoms of wound infection.

Also consider noninfective causes of inflammation. Seek specialist diagnostic opinion

 if necessary.
Moisture balance refers to the amount of exudate. Note the following features:

Moisture balance quantity (none, scant, small, moderate, heavy)

type (eg serous, purulent).

The edge of the wound informs the initial diagnosis and provides information about
healing. Note whether the edge is:

flat
indistinct
Edge and periwound area
sloping
(skin within 4 cm of the
punched out
wound edge)
undermined (not attached)
hyperplastic (heaped up)
hyperkeratotic (callused skin at the edge; see Photo 15.1)
rolled or curled-under closed-wound edges (epibole).

Granulation tissue, maceration and hyperkeratosis (Photo 15.1)

Reproduced with permission from Silver Chain Group.

Healthy granulation tissue (Photo 15.2)

 Reproduced with permission from Silver Chain Group.

Hypergranulation (Photo 15.3)

Reproduced with permission from Silver Chain Group.

Agranulation (absence of healthy granulation tissue) (Photo 15.4)

 Reproduced with permission from Silver Chain Group.

Examining the surrounding skin and tissue

Examine the skin and tissue surrounding the wound, looking for:

dry or macerated skin

inflammation (heat, redness, swelling)
excoriation
oedema
collections or sinus tracts
hyperkeratosis (scaly skin).

Check whether sensation is normal, reduced, absent or altered (eg allodynia [pain on light touch]). Also look for
abnormal tissue (eg lipodermatosclerosis, scarring, radiotherapy damage).

Examining the local area

Introduction

When assessing an ulcer, examine the local area. There may be specific signs to aid diagnosis and management,
including need for referral.

Leg

For patients with a leg ulcer, examine the leg for signs of vascular disease because it is the most common cause.

Up to 80% of leg ulcers are caused by chronic venous insufficiency, indicated by:

oedema
visible varicose veins or venous flares
lipodermatosclerosis (hard skin and subcutaneous fibrotic tissue, ‘inverted champagne bottle leg’)
haemosiderin (rust-coloured) staining of the skin.

Peripheral arterial disease is indicated by:

reduced or absent lower-limb pulses

skin atrophy
pale, cold or tender foot
thin hairless skin.
Look for deformity or reduced movement of the feet or other joints. The range of motion at the ankle joint influences
the calf muscle’s function as a pump.

For information on management, see Overview of leg ulcers.

Foot

Check the foot for:

loss of protective sensation (see Assessment for peripheral neuropathy)

peripheral arterial disease (see Assessment for peripheral arterial disease)
deformity
dry atrophic skin, including over the heels—this can indicate autonomic neuropathy.

Probe foot ulcers (using a sterile metal probe) to see if there is communication with bone. Introduce the probe with
slow gentle force, assessing all extents of the ulcer. If bone can be probed through the ulcer, this indicates a high risk
of osteomyelitis, especially if the ulcer is infected.

Examine feet for callus formation—which indicates excessive local pressure—and examine heels for pressure
injuries. Assess footwear (style, fit, condition, stability, fastening) and orthotic devices.

For information on management, see Wounds on a high-risk foot.

Sacrum, buttock (ischium) or hip (trochanteric area)

When examining a person with an ulcer on the sacrum, buttock or hip, note if the ulcer is over a bony prominence.

Using a sterile probe, assess the following:

sinus tracts
communication with deeper structures, including bone
presence and extent of any cavity.

Assess support surfaces (eg mattress, chair cushion) and the techniques being used to position and reposition the
person.

For information on management, see Pressure injuries.

Investigations for patients with an ulcer or wound

Blood tests
Blood tests are not routinely required for investigation of wounds unless the aetiology of the wound is unclear or
healing is delayed. In these cases, appropriate blood tests may include:

full blood count (FBC), C-reactive protein (CRP)

electrolytes, kidney function, liver biochemistry (including albumin)
thyroid stimulating hormone (TSH)
random blood glucose concentration (or HbA1c if the patient has diabetes)
oral glucose tolerance test (OGTT)
iron studies, vitamin B12, folate, vitamin D
erythrocyte sedimentation rate (ESR)
antinuclear antibody (ANA).

Always follow up or obtain existing pathology to avoid repeating investigations that have already been performed.

Ulcer or wound swabs

Diagnose infection on clinical grounds—do not use swabs to diagnose infection. However, swabs should be used to
identify the pathogen when there is clinical suspicion of invasive infection requiring systemic therapy; see Ulcer and
wound infection.

Biopsy
Consider punch or elliptical biopsy if the wound or ulcer has an atypical appearance (eg an irregular edge, abnormal
colour and texture of tissue) or location, or has not responded to therapy. Practice points for undertaking a biopsy are
listed in Box 15.2. Liaise with a pathologist or microbiologist if an unusual cause is suspected.

Histopathology is required if malignancy or an inflammatory disorder (eg vasculitis, pyoderma) is suspected, and
may be useful in the diagnosis of some infections (eg Mycobacterium ulcerans).

Send biopsy specimens for microscopy, culture and susceptibility testing (consider whether to test for specific
organisms; see Ulcer and wound infection).

Practice points for an ulcer or wound biopsy (Box 15.2)

Biopsy specimens can be used for histopathology, microbiology and (occasionally) immunofluorescence.
Obtain biopsy specimens from several sites, including the wound edge and main wound area; usually a
specimen is taken from each quarter of the wound.
Put specimens for histopathology in formalin.
Put specimens for microbiology in sterile water or saline soaked gauze; do not wash the specimen with
antiseptic.
An adequate specimen (eg from a surgical debridement) can be cut in half to be used for microbiology and
histopathology.
A deep skin biopsy of the ulcer edge that includes normal skin is ideal for chronic ulcers with delayed
healing, to perform histology, fungal and mycobacterial culture.
If blisters are present:
take a biopsy for histopathology of the blister edge and part of the roof. A small intact blister (if
present) can provide more information than the edge of a large one
take a second biopsy from the adjacent (normal) skin for immunofluorescence to exclude inflammatory
aetiology (liaise with pathology centre for appropriate transport media).

Vascular assessment
Perform vascular assessment for patients with a lower-limb ulcer to assess circulation. Vascular assessment starts
with a detailed clinical examination as described in Examining the leg.

Venous incompetence must be identified because it can cause a wound or contribute to delayed healing.
Refer patients with a leg ulcer or a wound with delayed healing for a comprehensive venous duplex scan for
incompetence (obstruction and insufficiency). A duplex scan determines the competence of the patient’s valves and
veins. The referral must be clear, otherwise the assessment may only look for venous thrombosis (ie deep vein
thrombosis [DVT]). Ideally, scans are undertaken by an experienced laboratory; liaise with the imaging centre to
ensure the intended study is performed.

A Doppler is used to assess arterial waveforms, and to measure the ankle brachial pressure index (ABPI). The ABPI
is the ratio of the ankle systolic blood pressure to the brachial systolic blood pressure. ABPI is usually required
before compression therapy to exclude significant peripheral arterial disease; for detailed discussion, see Venous leg
ulcers, Arterial leg ulcers and Compression therapy.

Perform all scans with bandages and dressings removed. Arrangements to reapply wound dressings following the
scan may need to be made.

Other imaging
Other imaging that may be required includes:

ultrasound (to define cavities, collections or radiolucent foreign bodies)

plain X-ray (if a foreign body or osteomyelitis is suspected)
magnetic resonance imaging (MRI) of the foot or ankle, or radionuclide bone scans (if further investigation for
osteomyelitis is required).

MRI is expensive and not subsidised by Medicare. The probe-to-bone test is a much cheaper alternative for
osteomyelitis diagnosis; see Examining the foot. Do not perform MRI unless the clinical suspicion of osteomyelitis is
high but the diagnosis cannot be confirmed by other means. See also Osteomyelitis.

Differential diagnoses for ulcers or wounds

After taking a history, examining the patient and performing relevant investigations, it is essential to make an
accurate diagnosis of the aetiology of the ulcer or wound. The diagnosis dictates subsequent management.

Common ulcers and wounds discussed in this guideline are:

surgical wounds
skin tears
minor burns
 abrasions
haematomas
pressure injuries
wounds on a high-risk foot
leg ulcers.

When making a diagnosis, consider uncommon causes of ulcers, including vasculitis (see Cutaneous vasculitis),
pyoderma gangrenosum, Mycobacterium ulcerans, malignancy, necrobiosis lipoidica, calciphylaxis, lymphoedema,
radiation-induced ulcers, drugs (eg warfarin or hydroxyurea—see Medications that inhibit wound healing), syphilitic
ulcers (see Syphilis) or dermatitis artefacta.

An accurate diagnosis of the aetiology of the ulcer must be established.

Review the diagnosis and consider referral if the wound is not progressing as expected (eg a 25% reduction in wound
size of a venous leg ulcer by 4 weeks). Also address factors affecting ulcer and wound healing.

Discuss the expected prognosis and possible complications with the patient. If the ulcer is not expected to heal, a
palliative approach to wound management may be required (see Ulcers or wounds not expected to heal).

Key references
Alavi A, Niakosari F, Sibbald RG. When and how to perform a biopsy on a chronic wound. Adv Skin Wound Care
2010;23(3):132–40; quiz 41–2.

Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing to bone in infected pedal ulcers. A clinical sign of
underlying osteomyelitis in diabetic patients. JAMA 1995;273(9):721–3.

Grey JE, Enoch S, Harding KG. Wound assessment. BMJ 2006;332(7536):285–8.

International consensus. Optimising wellbeing in people living with a wound. An expert working group review. London:
Wounds International; 2012.

International Wound Infection Institute (IWII). Wound infection in clincal practice. London: Wounds International; 2016.
www.woundinfection-institute.com/resources/

Lavery LA, Armstrong DG, Peters EJ, Lipsky BA. Probe-to-bone test for diagnosing diabetic foot osteomyelitis: reliable or
relic? Diabetes Care 2007;30(2):270–4.

Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of America
clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2012;54(12):e132–73.

Middleburgh T. Biopsy of skin [internet]. 2016 [accessed August 2018]. Available from:
https://www.dermnetnz.org/topics/skin-biopsy/

O’Donnell TF, Jr., Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, et al. Management of venous leg ulcers:
clinical practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg
2014;60(2 Suppl):3S–59S.

Rayman G, Vas PR, Baker N, Taylor CG, Jr., Gooday C, Alder AI, et al. The Ipswich Touch Test: a simple and novel
method to identify inpatients with diabetes at risk of foot ulceration. Diabetes Care 2011;34(7):1517–8.

Schultz GS, Barillo DJ, Mozingo DW, Chin GA, Wound Bed Advisory Board Members. Wound bed preparation and a
brief history of TIME. Int Wound J 2004;1(1):19–32.

Schultz GS, Sibbald RG, Falanga V, Ayello EA, Dowsett C, Harding K, et al. Wound bed preparation: a systematic
approach to wound management. Wound Repair Regen 2003;11 Suppl 1:S1–28.

Steed DL. Foundations of good ulcer care. Am J Surg 1998;176(2A Suppl):20S–5S.

World Union of Wound Healing Societies. Principles of best practice: diagnostics and wounds. A consensus document.
London: Medical Education Partnership; 2008.

Wounds Australia. Wounds Australia Standards for wound prevention and management. 3rd ed Osborne Park, Western
Australia: Cambridge Media; 2016.
Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature,
interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Surgical wounds
Introduction to surgical wounds
Surgical wounds follow surgical intervention, such as excision, incision, reconstructive surgery or
debridement. Surgical wounds are generally acute wounds that heal without complication within an expected
timeframe. Surgical wounds can be classified into four types based on the potential for microbial
contamination: clean, clean-contaminated, contaminated, and dirty or infected (see Stratifying surgical
wounds based on the level of contamination).

Surgical wounds heal via:

primary intention—the open wound edges are approximated and closed with staples, sutures,
adhesives or fixation strips
secondary intention—the wound edges are left open and healing occurs from the base upwards by
granulation (new connective tissue), with wound contraction and finally re-epithelialisation
delayed primary closure—the wound is left open and later closed by primary intention.

The majority of surgical wounds heal by primary intention, typically within 14 days. Healing by secondary
intention can take weeks to months, depending on the size of the tissue deficit. The mechanism of healing
influences wound management, prognosis and risk of complications.

Wound dehiscence and surgical site infections of the skin and subcutaneous tissue are common postoperative
complications.

Prevention of surgical wound complications

Common postoperative complications are surgical site infections of the skin and subcutaneous tissue and
wound dehiscence. There are many factors that increase the risk of postoperative wound complications. For
patients undergoing elective surgery, these risk factors must be identified and addressed preoperatively.

The majority of surgical site infections are preventable. Most surgical site infections are caused by
contamination of the wound with colonising organisms.

Practice points for preventing surgical site infections are listed in Box 15.3.

Patient-related risk factors for surgical site infection include:

advanced age
malnutrition
cigarette smoking
high body mass index
diabetes (particularly postoperative hyperglycaemia)
concurrent infection at another body site
an impaired immune response.

Encourage the patient to stop smoking 4 weeks before surgery. Screen patients for risk of malnutrition using a
malnutrition screening tool [Note 1]. Refer patients to a dietitian for assessment and management if necessary.

Surgical risk factors for surgical site infection include:

inadequate sterilisation of surgical instruments

foreign material in the surgical site
microbial contamination of the surgical site
surgical drains (particularly those with open drainage)
inadequate duration of surgical scrub
inadequate skin antisepsis (see Box 15.3)
preoperative shaving (see Box 15.3)
inadequate or incorrect preoperative skin preparation (see Box 15.3)
prolonged duration of operation
inappropriate selection of antimicrobial prophylaxis
 poor operating room ventilation
poor surgical technique (failure to achieve haemostasis, failure to obliterate dead space, tissue trauma,
wound tension).

Detailed guidance on prevention of surgical site infections is provided by the World Health Organization. For
appropriate antibiotic treatment of surgical site infections, see Surgical site infection.

Wound dehiscence occurs when the edges of a closed surgical wound separate and open, exposing the wound
cavity. Dehiscence can be superficial or deep, exposing underlying structures and organs.

Risk factors for surgical wound dehiscence include:

contaminated, dirty or previously infected surgical wounds [Note 2]

surgical site infection
haematoma (or failure to achieve haemostasis)
malnutrition
excessive exudate (with or without seroma)
reduced vascular supply to the operative site
mechanical stress on the wound (patient movement, obesity, oedema, local pressure).

Practice points for preventing surgical site infection (Box 15.3)

Printable box

Preoperative phase

encourage the patient to stop smoking

screen patients for malnutrition
advise patients to wash (shower or bath) at least the day before surgery
do not routinely remove hair at the surgical site; if hair has to be removed to perform surgery, use
electric clippers with a single-use head on the day of surgery. Do not use razors for hair removal
because these increase the risk of infection
see Surgical antibiotic prophylaxis for prophylaxis regimens

Intraoperative phase

immediately before incision, prepare the skin at the surgical site using an antiseptic (aqueous or
alcohol-based) preparation; povidone-iodine or chlorhexidine are most suitable
cover surgical incisions with an appropriate dressing at the end of the operation

Postoperative phase

use an aseptic technique for changing or removing dressings

aim to keep the postoperative dressing intact, uncontaminated and dry for up to 48 hours after surgery;
if necessary, use sterile saline (sodium chloride 0.9%) for wound cleansing during this period
advise patients that they can shower 48 hours after surgery
use an appropriate dressing for surgical wounds that are healing by secondary intention (see Ulcer and
wound dressings)
avoid:
topical antimicrobial products on wounds healing by primary intention
Edinburgh University Solution of Lime (EUSOL) and gauze, moist cotton gauze, and mercuric
antiseptic solutions on wounds healing by secondary intention

For antibiotic treatment of surgical site infections, see Surgical site infection.

All stages

Provide patients and carers with clear information and advice for each stage of care. This should include the
risk factors for surgical site infection, the approaches taken to reduce the risk, how to recognise a surgical
site infection, and how they are managed.

Note 1: Ferguson M, Capra S, Bauer J, Banks M. Development of a valid and reliable malnutrition screening tool for adult acute hospital
patients. Nutrition 1999;15(6):458-64. [URL]
 Note 2: Contaminated, dirty or previously infected surgical wounds are those in which the incision encounters acute, nonpurulent inflammation,
existing infection or retained devitalised tissue; or that involve open, fresh or accidental wounds, major breaks in sterile technique, gross spillage
from the gastrointestinal tract or perforated viscera.

Assessment of surgical wounds

If a surgical wound does not heal as expected, perform a thorough assessment. The assessment should not be
limited to the wound; to identify the cause(s) of impaired healing, consider the surgical site, the reasons for
surgery, and patient characteristics. See Assessing patients with an ulcer or wound.

Specifically for surgical wounds, assessment should also include:

the type of surgery or cause of skin damage

when the surgery took place
review of any complications during the surgery.

Regular review with reassessment is important.

Management of surgical wounds

Overview of management of surgical wounds

Management of the wound is an important component of postoperative patient care. Key elements of
postoperative wound management include:

regular wound review (depending on patient risk factors and surgical risk factors)
appropriate cleansing (see Box 15.3)
appropriate dressing selection (see Dressings for surgical wounds)
early recognition and intervention for wound complications.

For 72 hours after surgery, erythema (up to 2 cm from the wound edge) and mild swelling represent a normal
inflammatory response. Surgical wounds are expected to have minimal exudate. Warning signs of surgical site
complications include erythema that persists for longer than 72 hours, heat, pain, swelling, separation of
wound edges and an unexpected amount of exudate.

Debridement of nonviable tissue and delayed primary closure are indicated for surgical wounds with minor
dehiscence.

Removal of sutures or clips at an appropriate time reduces the risk of infection, scarring and pain. As a
general guide, sutures or clips can be removed after 10 days. Removal can be earlier (eg after 5 days) for
wounds in well-vascularised areas (such as the face or neck), or later (eg 14 days) for areas with poor
vascularisation or over a joint.

For wounds that do not heal as expected, consider the factors affecting wound healing.

Dressings for surgical wounds

Cover wounds healing by primary intention for the first 48 hours. These wounds normally seal and dry out
within this period. Use a low-adherent or semipermeable island dressing (a dressing with an absorbent pad
covered by a conformable adhesive layer) for uncomplicated surgical wounds. Most postoperative wounds
heal within 7 to 14 days. Healing should coincide with the removal of clips, staples or fixation devices.

For wounds healing by secondary intention, selection of appropriate local therapy is based on assessment of
the wound and its environment. Appropriate dressing is based on the anticipated amount of discharge (ie
blood or haemoserous exudate) from the surgical site. A low-adherent island dressing is typically used.
Patients with altered coagulation profiles (eg patients taking an anticoagulant) can have significant bleeding at
the surgical site, so require a more absorbent dressing and compression.

Waterproof dressings are preferred; most currently available waterproof dressings still have adequate
permeability to minimise risk of maceration. For advice on choosing a dressing based on amount of exudate,
see Ulcer and wound dressings.

At the time of publication, there is insufficient evidence to suggest one type of dressing is superior to any
other for preventing surgical site infections, scarring or pain.

Do not use the following interventions on surgical wounds:

topical antimicrobial preparations on surgical wounds that are healing by primary intention
Edinburgh University Solution of Lime (EUSOL) antiseptic solution and gauze, or moist cotton gauze
or mercuric antiseptic solutions on surgical wounds that are healing by secondary intention.

Surgical scar prevention and management

Prevention of surgical scars
Scarring is a natural biological process of wound healing and repair. Scars develop during the maturation
phase of wound healing, when production and degradation of new collagen fibres occur. Most scars are pale
and flat; however, they can be raised and prominent due to excessive collagen and scar tissue formation. The
two main types of abnormal scars are hypertrophic and keloid scars.

Hypertrophic scars are thick scars caused by excess tension on the healing wound. They remain within the
boundaries of the wound area and may spontaneously regress over time.

Keloid scars are smooth, hard growths that extend beyond the boundaries of the wound area. They can be
uncomfortable, itchy and large. Keloid scars do not regress and may recur after excision.

Designing the skin incision to minimise tension is the most important factor in preventing an abnormal scar.

Risk factors for scars include:

improper incision design—a major risk factor for hypertrophic scars

darkly pigmented skin (eg African ethnicity)—a major risk factor for keloid scars
incisions over the shoulder, chest, upper back or earlobe
younger age—the risk of keloid scars peaks between the ages of 10 and 20 years
severe acne
history of keloid scars
family history of abnormal scarring
inadequate blood supply to the wound
inappropriate surgical technique.

Intraoperative procedures to minimise scarring include using aseptic technique, minimising skin tension,
accurate skin edge approximation and atraumatic tissue handling.

Surgical wound management to prevent scars includes:

using silicone gel sheets or silicone oil-based cream on healed wounds (not open wounds) for 1 month
in patients at high risk of scarring
removing sutures or clips at the appropriate time (see Overview of management of surgical wounds)
applying skin tape (eg Micropore) across the incision line to reduce tension for 3 months following
removal of sutures or clips.

One week after surgery, the tensile strength across the incision site is only 3% of normal (uninterrupted) skin.
This increases to 20% after 3 weeks, and reaches 80% by 3 months.

Management of surgical scars

Hypertrophic and keloid scars are suboptimal consequences of surgical wounds. Appropriate management
requires specialist advice. The following techniques may be used:

intralesional steroid injections

pressure dressings or garments (especially for burns)
radiotherapy
laser resurfacing
dermabrasion
microneedling
excision.
Pilonidal sinus excision wounds
A pilonidal sinus is a cyst or abscess in the natal or intergluteal cleft. Treatment of pilonidal sinus requires
eradication of the sinus tract, healing of the tissue deficit and prevention of recurrence. Following surgical
intervention, these wounds can be closed by primary intention (off-midline closure preferred) or left open to
heal by secondary intention. Closed wounds can be managed as for other surgical wounds.

Complications following pilonidal sinus excision include surgical site infection and wound dehiscence. The
risk factors for surgical site infection and wound dehiscence are the same as for other surgical wounds; see
Prevention of surgical wound complications. Hair removal from the wound area with tweezers or laser
epilation may be beneficial; however, shaving hair may increase the risk of recurrence.

For wounds healing by secondary intention, healing should occur from the bottom of the wound upwards, and
this must be assessed and confirmed at every dressing change. An abscess can form if the wound is
inappropriately allowed to heal across the surface.

Open wounds or wounds that have dehisced can be managed by packing with a hypertonic saline dressing (see
Table 15.22), a gelling fibre dressing or an alginate fibre dressing. Advise patients to wear firm-fitting trunks
(eg bicycle shorts) for compression.

For wounds with delayed healing, consider using a silver gelling fibre dressing (eg Aquacel Ag), topical
negative wound pressure therapy, or a silver polyurethane foam dressing (eg Biatain Ag—see Foam
dressings). Principles of packing the wound are as for cavity wounds.

Showering is encouraged to keep the wound clean; sitz baths are not routinely recommended.

Skin grafts and donor sites

Overview

A skin graft is the transplant of healthy skin from one site of a patient’s body to another. It is used to heal
wounds that cannot be closed, or when healing by secondary intention is likely to cause loss of function or
prominent scars. Two types of skin grafts are generally used: split thickness skin grafts and full thickness skin
grafts.

Split thickness skin grafts contain the epidermis and varying amounts of dermis. The transplanted tissue has
sufficient deep dermis to enable angiogenesis. Donor sites include medial or lateral thigh, buttocks, posterior
or anterior trunk and upper arm. Split thickness skin graft donor sites heal by secondary intention.

Full thickness skin grafts contain the entire dermis. These are often used where avascular tissue is exposed
(eg tendon or bone, on the face or hands, over joints). Full thickness skin grafts do not contract as much as
split thickness skin grafts because they contain more collagen. Donor sites include postauricular, preauricular,
supraclavicular, upper eyelid, scalp and inguinal areas. Full thickness skin graft donor sites heal by primary
intention.

Other types of grafting may be used in specialist settings.

Risk factors for graft failure

Risk factors for graft failure are similar to those for other surgical wounds; see Prevention of surgical wound
complications. Address factors affecting wound healing for each patient. Specific risks for skin graft failure
include:

poor wound bed preparation—ideally, the graft should be placed on a clean bed of granulation tissue
poor vascularity of the wound bed—referral to a vascular specialist may be required
haematoma or seroma under the graft—can cause separation of graft from the recipient bed, leading to
graft death
excessive patient or graft-site mobilisation—can cause dressings to move or shear against the graft,
limiting the ability of the dressing to compress the graft to the wound bed
excessive compression (more than 30 mmHg)—can impair blood flow to the graft
inadequate compression on a lower leg—can prevent graft adherence
haemorrhage
infection.

Postoperative skin graft management

Postoperative management of the graft site includes:

immobilisation of the graft site

adequate analgesia and other pain management strategies
keeping the dressing dry and intact for 5 days
assessing the site for bleeding
topical negative pressure wound therapy (ie vacuum-assisted closure [VAC]), as directed by the surgeon
encouraging the patient to stop smoking.

Follow the postoperative dressing plan if the patient has one, unless the wound is not healing as expected and
specific wound characteristics need to be addressed. See Ulcer and wound dressings for dressings based on
amount of exudate and wound characteristics.

If a plan for dressings is not in place and the wound is healing as expected, redress using a nonparaffin wound
contact layer, either with a secondary absorbent pad dressing or foam dressing, based on wound
characteristics.

Do not use adhesive dressings on the graft site because these could pull the graft off at dressing change.

Compression therapy can be used after 5 days, when revascularisation is likely to have occurred.

When removing the graft dressing:

remove staples or tie-over pack

assess whether the graft has adhered to the wound bed
trim edges of graft
look for signs of infection
assess and manage haematoma.

Postoperative management of the donor site includes:

providing adequate analgesia and other pain management strategies

leaving the site intact for 10 to 14 days (this may be longer than manufacturer recommendations for
some dressings)
keeping the site dry, including when showering
closing full-thickness donor sites with primary intention.

Replace dressings on the donor site if they become saturated. Follow the plan for dressings if one is in place;
alternatively, use an adhesive foam dressing as long as the adhesive is beyond the margins of the wound.

Key references
Introduction to surgical wounds

Australian Institute of Health and Welfare (AIHW). Australia’s hospitals 2015-16 at a glance. health services
series no. 77. Cat. no. HSE 189. Canberra: AIHW; 2017. www.aihw.gov.au/reports/hospitals/ahs-2015-16-at-a-
glance/contents/table-of-contents

Burton F. Best practice overview: surgical and trauma wounds. Wound Essentials 2006;6:98–107

Ferguson M, Capra S, Bauer J, Banks M. Development of a valid and reliable malnutrition screening tool for adult
acute hospital patients. Nutrition 1999;15(6):458–64.

Prevention of surgical wound complications

Australian Commission on Safety and Quality in Health Care (ACSQHC). Approaches to surgical site infection
surveillance. Sydney: ACSQHC; 2017. www.safetyandquality.gov.au/publications/approaches-to-surgical-site-
infection-surveillance/

Oldfield A, Burton F. Surgical wounds: why do they dehisce? Wound Essentials 2009;4:84–91.

Owens CD, Stoessel K. Surgical site infections: epidemiology, microbiology and prevention. J Hosp Infect
2008;70 Suppl 2:3–10.

Reiffel AJ, Barie PS, Spector JA. A multi-disciplinary review of the potential association between closed-suction
drains and surgical site infection. Surg Infect (Larchmt) 2013;14(3):244–69.
World Health Organization (WHO). Global guidelines for the prevention of surgical site infection. Geneva,
Switzerland: WHO; 2016. www.who.int/gpsc/ssi-prevention-guidelines/en/

Assessment of surgical wounds

Oldfield A. Assessing the open surgical wound. Wound Essentials 2010;5:48–56.

Management of surgical wounds

Dumville JC, Gray TA, Walter CJ, Sharp CA, Page T, Macefield R, et al. Dressings for the prevention of surgical
site infection. Cochrane Database Syst Rev 2016;12:CD003091.

National Institute for Health and Care Excellence (NICE). Surgical site infections: prevention and treatment.
Clinical guideline [CG74]. London: NICE; 2008. www.nice.org.uk/guidance/cg74

Yao K, Bae L, Yew WP. Post-operative wound management. Aust Fam Physician 2013;42(12):867–70.

Surgical scar prevention and management

Gold MH, Berman B, Clementoni MT, Gauglitz GG, Nahai F, Murcia C. Updated international clinical
recommendations on scar management: part 1--evaluating the evidence. Dermatol Surg 2014;40(8):817–24.

Gold MH, McGuire M, Mustoe TA, Pusic A, Sachdev M, Waibel J, et al. Updated international clinical
recommendations on scar management: part 2--algorithms for scar prevention and treatment. Dermatol Surg
2014;40(8):825–31.

Juckett G, Hartman-Adams H. Management of keloids and hypertrophic scars. Am Fam Physician

2009;80(3):253–60.

Milne J, Vowden P, Fumarola S, Leaper D. Postoperative incision management made easy. Wounds UK
2012;Suppl. 8(4):1–4.

Oakley A. Keloid and hypertropic scar [internet]. Last updated: September 2014.
www.dermnetnz.org/topics/keloids-and-hypertrophic-scar

Son D, Harijan A. Overview of surgical scar prevention and management. J Korean Med Sci 2014;29(6):751–7.

Pilonidal sinus excision wounds

Bradley L. Pilonidal sinus disease: a review. Part one. J Wound Care 2010;19(11):504–8.

Li Y. Evidence summary. Pilonidal sinus: wound management by primary intent. Adelaide: The Joanna Briggs
Institute; 2017.

McCallum IJ, King PM, Bruce J. Healing by primary closure versus open healing after surgery for pilonidal sinus:
systematic review and meta-analysis. BMJ 2008;336(7649):868–71.

Whiteley I, Keshava A. Management of complicated sacrococcygeal pilonidal sinus disease. Wound Prac Res
2017;25(2):103–112.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Skin tears
Introduction to skin tears
Skin tears are acute wounds caused by shear, friction or blunt force, resulting in separation of skin layers. Skin
tears occur most commonly in older patients due to:

impaired anchoring of the epidermis and dermis

reduced hydration and elasticity of skin.

Tears vary in depth and by the amount of tissue loss. Classification systems are available to guide assessment
and management (see Assessment of skin tears).

Risk factors and prevention of skin tears

The risk of skin tears is higher in aged skin, though general health and mobility are also contributing factors.
A validated risk assessment tool for skin tears is not available; risk factors are divided into modifiable and
nonmodifiable categories.

Modifiable risk factors include:

oedema
inadequate nutrition
dehydration
dry skin
medications (corticosteroids, or drugs that contribute to falls or impair balance)
mobility equipment (eg lifters, frames, wheelchairs).

Nonmodifiable risk factors include:

advanced age
history of skin tear
haematoma
impaired mobility
dementia.

Healthcare facilities should develop and implement protocols to optimise patient handling and minimise skin
damage during care. Skin tears can be prevented by implementing general preventive measures and
addressing patient risk factors. General preventive measures include:

protecting fragile skin with moisturiser (eg QV Cream or Alpha Keri lotion, applied twice a day) and
protective garments (eg tubular retention sleeves, stockings, long sleeves or trousers)
drying skin thoroughly (by patting, not rubbing) after washing
careful application and removal of dressings.

Assessment of skin tears

For a structured ulcer and wound assessment, see Assessing patients with an ulcer or wound.

When assessing a skin tear, it can help to classify the tear using a validated classification system. The
International Skin Tear Advisory Panel (ISTAP) published their validated Skin Tear Classification System in
2013. The ISTAP skin tear classification is described in Table 15.3.

For skin tears, document the wound characteristics, classification, size and presence of infection.

Interventions for skin tears

Initial management of skin tears
Initial management of a skin tear depends on the degree of tissue trauma. Ensure that any separated tissue is
replaced anatomically, if possible.

Clean and dress the skin tear carefully to avoid causing further damage. Other management strategies include:

providing analgesia
controlling bleeding (which can be profuse initially) using pressure; an alginate dressing can be used to
stop bleeding, but should not be used as the primary dressing (see Dressings for skin tears)
cleansing the wound with potable water or sterile saline (sodium chloride 0.9%). If the wound is
extensively contaminated, consider using a noncytotoxic antiseptic (see Cleansing and debridement)
expelling subflap haematoma—if viable flap tissue remains, gently roll a gloved finger, moistened
cotton bud or the smooth edge of plastic forceps on top of the flap
debriding a nonviable flap
gently replacing the tissue flap over the wound, avoiding tension on the flap
applying an appropriate dressing (see Dressings for skin tears)
reviewing the need for tetanus vaccination (see Tetanus-prone wounds)
supporting the limb using a tubular support bandage, if not contraindicated; see Compression therapy.

Oedema can delay healing—managing oedema is important, especially on the lower limb.

Limbs with skin tears should be supported with appropriate compression, applied carefully to minimise shear.
Local oedema occurs with all wounds, and can impair healing. Appropriate limb support can prevent a skin
tear developing into a chronic wound.

Dressings for skin tears

Appropriate dressings for skin tears are described in Table 15.3. The dressing must not cause further trauma to
the wound on either application or removal, and should provide a moist wound environment, manage exudate
and minimise pain. The most common approach is to use a silicone-based dressing. A small amount of an
amorphous hydrogel dressing can be added to the wound bed if the wound area is at risk of drying out.

Use a dressing suitable for fragile skin.

Avoid:

alginate dressings as primary dressings on bleeding wounds—these can adhere to the wound
skin closure strips (eg Steri-Strips, tapes)—because of the risk of damage on removal
suturing or stapling—because the skin tissue is too fragile.

Use a cohesive or tubular retention bandage to retain dressings. Cyanoacrylate skin glue (eg Leukosan,
Dermabond, Marathon) is an option for ISTAP type 1 and 2 skin tears, but require skill and knowledge to use
appropriately.

After applying an appropriate dressing, using a felt-tip pen, mark the dressing with:

the date of application

an indication of how to remove the dressing to avoid disturbing the skin flap, if present; see Photo 15.5.

Mark the dressing to indicate how it should be removed.

Review the dressing after 24 hours to assess exudate management—look for exudate strikethrough on the
back and edges of the dressing. If a skin flap is present, aim to leave the dressing in place for at least 5 days so
the flap can reconnect. Silicone mesh dressings can be left in place for 2 weeks.

How to mark a dressing for a skin tear (Photo 15.5)

Classification of skin tears and appropriate dressings (Table 15.3)

ISTAP classification Definition Appropriate dressing [NB1]

Type 1 skin tear

Silicone foam dressing, or a silicone

mesh (ie a silicone wound contact
No skin loss: layer) with a secondary dressing
linear or flap tear appropriate to the expected amount of
that can be exudate (see Ulcer and wound
repositioned to dressings).
cover the wound
bed Skin glue may be used by experienced
practitioners to approximate wound
edges.

Type 2 skin tear

Partial flap loss: Silicone foam dressing, or silicone

 the flap cannot be mesh (ie a silicone wound contact
repositioned to layer) with a secondary dressing
fully cover the appropriate to the amount of exudate
wound (see Ulcer and wound dressings).

Type 3 skin tear

No need to protect skin flap, so choose

Total flap loss:
a dressing based on wound
exposing the
characteristics (see Ulcer and wound
entire wound bed
dressings).

ISTAP = International Skin Tear Advisory Panel

NB1: Limbs with skin tears should be supported with appropriate compression, applied carefully to minimise shear.

Complications and review of skin tears

Monitor carefully for infection of the skin tear and loss of skin flap viability. As an acute wound, significant
improvement is expected within 7 to 14 days. If healing is not progressing as expected, seek specialist advice
for further assessment. Always identify and address the factors affecting wound healing and consider referral
for management of comorbidities.

Skin tear management can be complicated by:

patient interference with the dressing

injury during dressing changes.

Avoid unnecessarily frequent dressing changes because this can cause pain, disrupt healing, inconvenience the
patient, and be expensive.

Other complications related to a skin tear include:

maceration of the surrounding skin

persistent bleeding
conversion into a chronic ulcer.

Key references
Baranoski S, LeBlanc K, Gloeckner M. CE: Preventing, assessing, and managing skin tears: a clinical review. Am
J Nurs 2016;116(11):24–30.

Carville K, Leslie G, Osseiran-Moisson R, Newall N, Lewin G. The effectiveness of a twice-daily skin-moisturising

regimen for reducing the incidence of skin tears. Int Wound J 2014;11(4):446–53.

Edwards H, Courtney M, Chang AM, Finlayson K, Gibb M, Parker C. Promoting healthy skin: A self-directed
learning resourec for residential aged care workers (web based interactive DVD). Brisbane: Queensland
University of Technology; 2010. http://promoting-healthy-skin.qut.edu.au/m1_resources.html

LeBlanc K, Baranoski S. Skin tears: Finally recognized. Adv Skin Wound Care 2017;30(2):62–3.

LeBlanc K, Baranoski S, Christensen D, Langemo D, Sammon MA, Edwards K, et al. International Skin Tear
Advisory Panel: a tool kit to aid in the prevention, assessment, and treatment of skin tears using a Simplified
Classification System (c). Adv Skin Wound Care 2013;26(10):459–76; quiz 77–8.

Munro EL, Hickling DF, Williams DM, Bell JJ. Malnutrition is independently associated with skin tears in hospital
inpatient setting-findings of a 6-year point prevalence audit. Int Wound J 2018.

Sussman G, Golding M. Skin tears: should the emphasis be only their management?. Wound Prac Res
2011;19(2):66–71.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Minor burns
Introduction to minor burns
Burns can be classified as minor if they do not meet the criteria for referral in Box 15.4. Minor burns can
usually be managed in the community. According to the Victorian Adult Burns Service, a minor burn is
defined as:

superficial in depth (eg painful, moist, brisk capillary return)

less than 10% total body surface area in adults and less than 5% total body surface area in children.

Infected burns or burns that are not healing as expected may require referral for specialist management.
Contact the referral centre to discuss appropriate treatment or dressings for transfer. The Australian and New
Zealand Burn Association has contacts for referral centres.

Criteria for referral of a burn to a specialist centre (Box 15.4)

The Australian and New Zealand Burn Association criteria for referral of a burns patient to a specialist
centre are:

burns greater than 10% total body surface area in adults

burns greater than 5% total body surface area in children
full thickness burns greater than 5% total body surface area
burns to the face, hands, feet, genitals, perineum, major joints and circumferential limb or chest
burns with inhalation injury
electrical burns
chemical burns
burns in patients with pre-existing illness
burns associated with major trauma
burns at the extremes of age—young children and the elderly
burns in women who are pregnant
intentional burns (assault and self-inflicted).

Prevention of minor burns

Flame injuries are the most common cause of burns in adults. Flame injuries often involve open fires for
camping and cooking or use of accelerants for barbecue. They most commonly occur in young males.

The most common cause of burns in children is scalding. Simple measures to prevent scalding include placing
saucepan handles towards the stove, moving objects that a child could use to climb up to a stove, and placing
hot items out of reach.

Assessment of minor burns

Accurate assessment of a burn ensures the patient receives appropriate management. Patients that meet criteria
in Box 15.4 require referral to a specialist centre—contact the referral centre to discuss appropriate treatment
or dressings for transfer.

Patients that meet criteria in Box 15.4 require referral to a specialist centre.

Determine the percentage of total body surface area affected and burn depth (see Table 15.4). For a structured
wound assessment, see Assessing patients with an ulcer or wound.

For adults or children over 10 years old, the Wallace Rule of Nines (see Figure 15.1) can be used to estimate
the total body surface area affected. For children younger than 10 years old, the modified Lund and Browder
chart is recommended. Both these tools are available online. For patients of any age, the surface area of their
palm and fingers is approximately 1% of total body surface area.

Discuss how the burn occurred. Consider if the burn is self-inflicted or the result of neglect or abuse.

Wallace Rule of Nines for burns assessment in patients over 10 years old (Figure 15.1)

Reproduced with permission from Hyland EJ, Connolly SM, Fox JA, Harvey JG. Minor burn management: potions and lotions. Aust Prescr
2015;38:124-7.

Presentation, treatment and expected healing outcomes for burns (Table 15.4)

Printable table

Depth Presentation Treatment Healing

timeframe and
outcome
Cool showers or compress to manage warmth
Epidermis is damaged but and pain. Ensure adequate hydration and
intact, appears pink/red and moisturise skin. 10 to 12 days
Epidermal painful. without
If pain is significant use a hydrogel to soothe scarring.
Example: sunburn and provide analgesia. A secondary dressing is
generally not needed.
Provide first aid and analgesia. Ensure adequate
hydration. Deroof blisters and debride as
Epidermis and top part of the required. 7 to 21 days.
dermis (papillary) is painful,
pink and moist, and often Significant exudate is often produced in the first Scarring is
72 hours. unlikely, unless
blistered with peeling skin.
Superficial Wound base blanches to the burn
converts to a
dermal pressure. Appropriate dressings include a silicone foam deeper injury.
dressing and, if contaminated, silver-based Pigment
Example: water scald, longer dressings (eg Acticoat or AquacelAg; see Table changes may
flash burn 15.22). If there is minimal exudate, use a occur.
moisture retention dressing (eg a clear acrylic
dressing; see Table 15.16).

Provide first aid and analgesia. Ensure adequate

hydration.
Affects epidermis down to mid
dermis. Significant exudate is often produced in the first 14 to 21 days.
72 hours.
Mid Sluggish capillary return. Scarring can
dermal Appropriate dressings include silver-based occur if healing
Less painful than epidermal or dressings (eg Acticoat or AquacelAg; see Table takes longer
superficial dermal burns and 15.22). than 3 weeks.
appears dark pink to red.
Consider referral to a specialist burns centre—
grafting may be required.
Epidermis and lower dermis Provide first aid and analgesia. Ensure adequate
(reticular) mottled pink or hydration. Debride damaged or nonviable
white (variable); slow capillary tissue. Longer than 3
return to nonblanching (ie the weeks.
Deep skin colour does not change Appropriate dressings include silver-based
dermal when pressed). dressings (eg Acticoat or AquacelAg; see Table Expect scarring
15.22). and pigment
Due to dulled sensation, may changes.
present as discomfort or feeling Consider referral to a specialist burns centre—
of pressure rather than pain. grafting may be required.
The majority of patients with a full thickness
burn require referral to a specialist burns centre
(see Box 15.4); full thickness burns greater than
1 cm require surgical intervention.

Burn extends through all layers, Provide first aid and analgesia. Ensure adequate Longer than 3
hydration. If necessary, provide resuscitation
possibly including muscle and weeks.
Full bone. May be mottled, dry, and systemic supportive management. Observe
thickness translucent, black, pale or for complications. Expect scarring
leathery in appearance. No and pigment
Cleansing and topical management may be
sensation. Does not blanche. changes.
required, as directed by referral hospital.

Full thickness burns that do not meet criteria for

referral may be managed in the community
with cleansing and debridement—seek advice
from a burns centre.

Interventions for minor burns

First aid is essential to cool the burn and prevent conversion to a deeper injury. Cool the burn with running
water (ideally at 15°C) for 20 minutes. This is effective for up to 3 hours after the burn occurred. Do not apply
ice because this can cause further injury. If using a hose or tap, consider the likely temperature of the water—
allow the water to run until it reaches an appropriate temperature. If there is limited water or access, consider:

spraying with cool water

sponging with a wet cloth (ensure the cloth remains cool)
using a water gel product (eg an antiseptic hydrogel such as Burnaid) in adults.

Cool the burn with running water (ideally at 15°C) for 20 minutes.

Cooling can be associated with hypothermia. Keep the patient warm (cover nonaffected areas) and observe for
signs of hypothermia. Cut away adhered or constrictive clothing and remove jewellery from the burn area.

Initial management of a minor burn also consists of:

 providing adequate analgesia
ensuring adequate hydration
cleansing with potable water, or if available, 0.1% aqueous chlorhexidine or saline (0.9% sodium
chloride)
removing foreign material and loose or nonviable skin or tissue
deroofing blisters (see Box 15.5)
removing hair in and around the burn to a 2 cm radius
reviewing the need for tetanus vaccination (see Tetanus-prone wounds).

Deroofing blisters allows assessment of burn depth, removal of nonviable tissue and, in tense blisters, relief of
pain.

Practice points for deroofing blisters (Box 15.5)

obtain consent
provide adequate analgesia
take photograph before and after deroofing
to deroof, use:
moist gauze rubbed across the blister, for thin-walled blisters
sterile forceps and scissors, for thick-walled blisters
choose an appropriate dressing

Treatment of burns depends on thickness and is detailed in Table 15.4. Information sheets for clinicians and
patients are available from the Victorian Adult Burns Service and the Australian and New Zealand
Burn Association.

For burns on a limb, manage oedema with limb elevation and appropriate support (eg gentle compression).

Although silver dressings are recommended for contaminated or infected burns, silver sulfadiazine cream is
not. It may delay healing compared to other antiseptics, it only provides antimicrobial activity for
approximately 8 hours, and it impedes reassessment of the wound. For these reasons, it is only considered
appropriate when silver dressings are not available.

Review of minor burns

Review patients with a minor burn within 24 to 48 hours. Emotional support of the patient and their family is
often required. If healing is not progressing as expected (eg after 14 days), refer to a wound specialist or burns
service.

Antibiotics are not required unless there is clinical infection; see Ulcer and wound infection.

Key references
Agency for Clinical Innovation. Clinical guideline: minor burn management. 4th ed. Chatswood, NSW: Statewide
Burn Injury Service; 2017. www.aci.health.nsw.gov.au/resources/burn-injury

Australian and New Zealand Burn Association (ANZBA). Initial management of small burns. ANZBA; In press.
https://anzba.org.au/?s=initial+management+of+small+burns

Cuttle L, Pearn J, McMillan JR, Kimble RM. A review of first aid treatments for burn injuries. Burns
2009;35(6):768–75.

Hyland EJ, Connolly SM, Fox JA, Harvey JG. Minor burn management: potions and lotions. Aust Prescr
2015;38(4):124–7.

Maitz P, Harish V. How to treat: burns [Internet]. Australian Doctor. Last Updated: 15 April 2016. Available from:
www.howtotreat.com.au/how-to-treat?field_category_target_id=All&page=11

Norman G, Christie J, Liu Z, Westby MJ, Jefferies JM, Hudson T, et al. Antiseptics for burns. Cochrane Database
Syst Rev 2017;7:CD011821.

Victorian Adult Burns Service, Alfred Health. Minor burns [Internet]. Melbourne, Australia; Accessed August 2018.
www.vicburns.org.au/minor-burns/

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Abrasions
Overview of abrasions
Abrasions are caused by friction, shear and force, causing trauma to the skin. Abrasions are usually partial
thickness; these heal by regeneration. Scarring may occur if the injury extends deeper into the dermis.
Abrasions commonly follow a fall from a bike or skateboard; the body moves across the ground,
compromising skin integrity (see Photo 15.6).

Abrasions are common injuries in active children and adults. They typically occur on the extremities and
exposed skin. Skin loses some of its elasticity, strength and hydration over time, which can predispose older
adults to injury.

Example of an abrasion (Photo 15.6)

Prevention of abrasions
To prevent abrasions, advise patients to wear appropriate protective clothing when participating in sport or
outdoor activities. This reduces the physical force on exposed skin during a fall or accident.

Assessment of abrasions
For a structured review of a wound, see Assessing patients with an ulcer or wound.

Ensure haemostasis and undertake a primary survey. The primary survey consists of assessing danger,
response, airway, breathing and circulation to identify life-threatening injuries. After the primary survey,
undertake a secondary survey (ask about details of the accident and undertake a detailed patient assessment)
to determine the extent, depth and implications of the injury. Assess the patient for bruises, haematomas and
fractures.

Contamination of the wound with dirt or soil is common; knowing when, how and why the injury occurred
assists in treatment and prevention strategies. If contaminants cannot be easily removed (eg gravel), refer to a
plastic surgeon.

Interventions for abrasions

First aid includes providing adequate analgesia and cleansing the wound with antiseptic (eg povidone-iodine,
polyhexamethylene biguanide [PHMB]); see Cleansing and debridement.

Review the need for tetanus vaccination; see Tetanus-prone wounds.

For abrasions that are significantly contaminated, see Post-traumatic wound infections for antibiotic
prophylaxis.

Choose a dressing based on patient characteristics and preference, and wound characteristics and progression;
see Ulcer and wound dressings.

Review of abrasions
An abrasion is normally a minor injury. Severity depends on the extent and depth of the wound, and the
general health of the patient. Expect significant improvement within 7 days. If this does not occur, consider
factors affecting wound healing, optimise patient comorbidities, and consider referral for further assessment.

Key references
Lowe DO, Knowles SR, Weber EA, Railton CJ, Shear NH. Povidone-iodine-induced burn: case report and review
of the literature. Pharmacotherapy 2006;26(11):1641–5.

Nahlieli O, Baruchin AM, Levi D, Shapira Y, Yoffe B. Povidone-iodine related burns. Burns 2001;27(2):185–8.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Haematomas
Overview of haematomas
A haematoma is an abnormal collection of blood outside a blood vessel, causing swelling (see Photo 15.7). A
bruise or contusion is bleeding underneath the skin without swelling.

This topic covers subcutaneous haematomas on the skin and underlying structures. Haematoma can occur at
other locations (eg subdural haematoma). Pretibial injury refers to injuries affecting the medial, lateral and
anterior sections of the tibia, often associated with haematoma.

Haematoma severity depends on its extent and depth, as well as the general health of the patient. Trauma is
the most common cause of a haematoma—for example, bumping into furniture, falling, or closing a car door
on a limb. When the vessel is damaged, blood leaks into the surrounding tissue and coagulates or clots. Major
haematomas may occur as a result of a shearing injury, with separation of the skin and subcutaneous tissue
from muscle fascia.

Haematomas can cause tissue necrosis.

Untreated haematomas or those that extend into underlying structures can cause tissue necrosis. Pressure
from the haematoma restricts blood flow into the dermal and subdermal tissues, and causes local oedema and
inflammation. Large haematomas form into a hard mass if blood is trapped in the tissue space.

Example of a haematoma (Photo 15.7)

Risk factors for haematomas
Treatment with anticoagulants is considered the most significant risk factor for haematoma, but other
medications (eg corticosteroids), medical conditions (eg altered coagulation profile) and advanced age are
also risk factors. Educate patients taking an anticoagulant to avoid activities that could cause trauma.

Assessment of haematomas
If the haematoma was caused by trauma, assess the patient for other injuries. Undertake a comprehensive
clinical assessment (see Assessing patients with an ulcer or wound), including a thorough medication history.

Compartment syndrome may occur (particularly in a limb) if bleeding, secondary oedema and inflammation
are significant. This is a medical emergency because blood supply is restricted; immediate management is
required.

Accurate assessment of the size of the haematoma guides therapy. A common mistake is to underestimate the
size and depth of the haematoma. Determine the depth and extent of the haematoma by:

palpating the area

assessing the range of motion
assessing distal circulation
identifying severity of pain.

The location of the haematoma is important—haematomas over a joint require specialist management. Assess
the haematoma for signs of infection.

The colour of the haematoma changes over time, initially appearing as a purple/blue colour, then progressing
to yellow/green as it resolves.
Depending on size, location (eg over the airway) and progression, haematomas may require investigations
such as ultrasound, plain X-ray, computed tomography (CT) scan or magnetic resonance imaging (MRI) to
guide interventions.

Interventions for haematomas

Minor (small) haematomas will resolve over time with minimal intervention. If on a limb, they may require
compression to decrease local swelling and aid absorption of fluid.

Treatment for a minor haematoma includes:

rest, ice, compression and elevation (RICE)

adequate analgesia
monitoring for complications (eg extension).

Refer patients with systemic symptoms or with a haematoma that is:

large
tense
painful
infected
over a joint or airway
expanding.

The best method for evacuation of a haematoma is incision and drainage, undertaken by a competent
practitioner. The skin over a haematoma can be thin, tense, hypoxic or necrosed, so the incision should be
made at the periphery. The clot can be removed with irrigation, lavage or low-frequency ultrasound
debridement. Some patients require skin grafting.

Refer patients with arterial or venous disease to a vascular surgeon; see Venous leg ulcers.

Review the need for tetanus vaccination; see Tetanus-prone wounds.

Selection of an appropriate dressing is based on the haematoma depth, location, amount of exudate,
interventions needed, and patient preference.

Review the patient’s current medications to identify any that promote bleeding (including nonprescribed
medications). If the patient is taking an anticoagulant and the haematoma is expanding, seek advice about
whether medication can be stopped.

Review of haematomas
Early assessment of severity and implementation of appropriate management reduce morbidity and mortality,
especially in an older person. Consider referral to a specialist if there is significant pain or reduced mobility,
or if signs of systemic or local infection develop; see Ulcer or wound infection.

If wound healing is slower than expected, review and address factors affecting wound healing.

Key references
Dunkin C, Elfleet D, Ling CA, Brown TL. A step-by-step guide to classifying and managing pretibial injuries. Nurs
Times 2003;99(21):58–61.

Marsden AK. Pretibial injuries: a common pitfall. Br Med J (Clin Res Ed) 1983;286(6367):800–1.

Pagan M, Hunter J. Lower leg haematomas: Potential for complications in older people. Wound Prac Res
2011;19(1):21–8.

Thompson-McHale S. Haematomas: management and treatment. Wound Essentials 2015;10(1):24–8.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Pressure injuries
Introduction to pressure injuries
Pressure injury is localised tissue damage usually over a bony prominence from pressure (causing tissue compression), often in
combination with shear (causing tissue deformation). Pressure injury is caused by prolonged pressure on the skin or tissues
from an underlying surface. Chair or bed surfaces cause the majority of pressure injuries. Devices such as casts and splints,
tubing, straps and clothing can also cause pressure injury.

Additional pathologies contributing to a pressure injury include reperfusion injury (tissue damage as blood flow returns after a
period of ischaemia) and extremes of skin moisture and temperature (the microclimate) at the point of contact with a surface.

Primary risk factors for a pressure injury include reduced mobility (eg inability to change body position independently), or
reduced sensory perception (either from reduced sensation or reduced conscious state).

Secondary risk factors for a pressure injury include macerated or moist skin (eg from incontinence), advanced age,
malnutrition, poor perfusion and oxygenation, severe illness, increased body temperature, shear (sliding) forces and friction.

Common sites of pressure injury include the area over the sacrum, ischial tuberosities, greater trochanters, heels and malleoli.
Pressure injury can also occur on other areas, including the back of the head (occiput), vertebral spinous processes, ears, elbows
and toes.

Timely assessment and intervention is crucial in pressure injury prevention and management.

Preventing pressure injuries

Most pressure injuries are preventable. All healthcare professionals and service providers play a role in preventing pressure
injuries.

Most pressure injuries are preventable.

Assess patients for their risk of developing a pressure injury. An example of a validated risk assessment tool is the PURPOSE-
T (Pressure Ulcer Risk Primary or Secondary Evaluation Tool), which covers screening and full assessment. Undertake a
validated risk assessment within 8 hours of admission to a healthcare setting (or on the first visit for those in residential aged-
care facilities or receiving home-based care). Repeat risk assessment is required; frequency depends on the patient's clinical
condition. Follow the policies of the health service provider in relation to pressure injury risk assessment and documentation.

Patients confined to bed or who have severely limited mobility are at risk of a pressure injury.

Patients confined to bed or who have severely limited mobility are at risk of a pressure injury.

Prevention strategies are developed and implemented based on risks. Strategies include:

regular patient repositioning (also consider the weight of blankets on toes, feet, heels)
using slide sheets and materials that decrease friction
using mechanical aids (eg lifters) as required for patient transfer
using an appropriate support surface
regular skin inspection
using a pH-appropriate skin cleanser and moisturiser
implementing a continence management plan
using barrier creams and ointments
implementing a nutritional support plan
using prophylactic dressings (eg a multilayer adhesive silicone foam dressing)
avoiding the use of heating devices (hot water bottles, heating pads) directly on skin.

Assessment of pressure injuries

For a structured assessment framework, see Assessing patients with an ulcer or wound. Service providers generally require that
pressure injuries are reported on a risk or incident management system.

A classification system is used to stage a pressure injury based on the depth and type of tissue damage. There are currently six
pressure injury stages; for diagrams and photographs, see Table 15.5. Pressure injury development may not progress through
consecutive stages; full thickness pressure injury (ie stage III or IV) can occur without any preceding external signs if caused
by deep tissue ischaemia.

Pressure injury stages are:

 ▪Stage I—intact skin with nonblanchable erythema [Note 1]. In patients with dark skin the pressure injury may be a
different colour from the surrounding skin.
▪Stage II—partial thickness loss of dermis. A shallow wound with a red/pink wound bed but no slough or bruising. Can
also present as an intact or ruptured serum-filled blister.
▪Stage III—full thickness tissue loss. Subcutaneous fat may be visible, but bone, muscle or tendon is not visible or
palpable. Slough (if present) does not obscure the depth of tissue loss. Undermining or tunnelling can be present.
▪Stage IV—full thickness tissue loss with exposed or palpable bone, muscle or tendon. May have slough or eschar on
areas of the wound bed. Undermining or tunnelling is often present.
▪Unstageable (depth unknown)—full thickness tissue loss where the wound bed is covered by nonviable tissue (slough,
necrosis, eschar) that obscures the depth of the wound. Until enough nonviable tissue is removed, the stage of the
pressure injury cannot be determined [Note 2].
▪Suspected deep tissue injury (depth unknown)—an area of intact skin, purple or maroon in colour, or a blood-filled
blister. Indicates damage to underlying soft tissue from pressure or shear. Deep tissue injury can be difficult to detect in
patients with dark skin tones.

This classification system is used for initial assessment of pressure injuries. It is not used for staging pressure injury healing, or
to describe skin tears, moisture or incontinence associated lesions, or mucous membrane injury.

Stage III or IV pressure injuries can form a cavity, including undermining, tunnelling, sinus, or fistula. Assess cavities using a
sterile probe, or with careful palpation (wear sterile gloves), to determine the depth and extent of the cavity. Exposed bone can
indicate osteomyelitis.

Assess the pressure injury characteristics using the TIME framework (see Table 15.2).

Infection is suggested by profuse, purulent or malodorous discharge; increasing pain; signs of inflammation; or wound
increasing in size—see Ulcer and wound infection. Patients with pressure injury are at risk of systemic infection, which
requires urgent medical review and management.

Vascular assessment is recommended for patients with pressure injury of the lower limb or extremities.

Pressure injury stages: diagrams and photographs (Table 15.5)

Classification Cross-sectional diagram Photograph

Stage I:
nonblanchable
erythema

Stage II:
partial
thickness skin
loss
Stage III: full
thickness skin
loss

Stage IV: full

thickness
tissue loss

Unstageable:
depth
unknown

Suspected
deep tissue
injury: depth
unknown
Stage II photograph reproduced with permission from NPUAP.org. Copyright 2011 Gordian Medical, Inc. dba American Medical Technologies. All other images
reproduced with permission of Wounds Australia. All rights reserved.

Note 1: In nonblanchable erythema, the skin colour does not change when pressed.

Note 2: Stable dry eschar (adherent, intact, without erythema or fluctuance) on the heel or foot serves as the body's natural biological cover and should not be removed.

Interventions for pressure injuries

Principles of managing pressure injuries
Pressure injury reporting and management requirements are covered by the National Safety and Quality Health Service
Standards [Note 3]. Pressure injury is associated with significant morbidity and mortality. Timely intervention prevents adverse
effects of pressure injury. Adverse effects from a pressure injury include pain, increased cost to the patient and the health
system, increased length of hospital stay, prolonged home or community care, loss of income, loss of functioning and reduced
quality of life. Occasionally, pressure injury can lead to sepsis and death.

Timely intervention prevents adverse effects of pressure injury.

After undertaking a full assessment, create an individualised management plan. Management is based on:

the likelihood of healing

minimising pressure and shear
managing the wound characteristics
optimising nutritional status and general health (see Other interventions for pressure injuries).

Refer to an appropriate specialist if:

the patient is systemically unwell

there is rapidly spreading or extensive necrosis
a fistula develops
specialist intervention is needed (eg pressure seating clinic, wheelchair prescription, equipment, sharp debridement or
surgery).

Maintain prevention strategies—see Preventing pressure injuries.

Note 3: Full standard is available here. A factsheet for clinicians is available here.

Determine likelihood of healing

Determining the likelihood of healing allows realistic goals to be set and indicates the need for referral to a specialist service.
Healing is dependent on the patient's general health, wound characteristics, availability of resources, and the patient's ability
and commitment to participate in the plan. If a pressure injury is not expected to heal, the priority of care is the patient's quality
of life and symptom management (as determined by the patient or their family). For management of pressure injury in patients
receiving palliative care, see Pressure ulcers in palliative care.

Minimise pressure and shear

Minimising pressure and shear is a major component in managing pressure injury. Encourage patients to move frequently, if
able.

For patients in bed, the head of the bed should not be elevated more than 30 degrees. If this is unavoidable, ensure that the
patient's knees are bent (by either positioning the bed or using pillows). If the patient needs to lie on their side, use a 30 degrees
lateral position to reduce pressure on the trochanter (hip).

Methods to minimise pressure include:

using an appropriate support surface for the bed, chair, trolley or table
offloading pressure (pressure redistribution) from the patient's heels, regardless of the surface on which they are resting
avoiding long periods of sitting out of bed
careful patient positioning (avoid positioning a patient on an existing pressure injury; use at least two different positions
to avoid development of an additional pressure injury).

Support surfaces manage pressure by distributing the patient's body weight evenly over the surface, or eliminating pressure
intermittently. They include mattress overlays or replacement systems, integrated bed systems, and seat cushions. Support
surfaces can be reactive or active. Reactive support surfaces can adapt to a pressure load and conform to the patient's body
shape. Active surfaces typically cycle air in and out to periodically reduce tissue pressure and shear over body segments.

Support surfaces that are not recommended include ring (doughnut) cushions, nonmedical grade sheepskins, fluid-filled gloves
and intravenous fluid bags.

Manage the pressure injury characteristics

Debride nonviable tissue unless contraindicated. Exposed bone may require antibiotic therapy for osteomyelitis, and surgical
intervention; seek expert advice. Use wound dressings to maintain optimal moisture balance; see Ulcer and wound dressings.
Pressure injury is most commonly managed conservatively with healing by secondary intention. Plastic surgery for flap
reconstruction is needed for some patients with pressure injury.

Other interventions for pressure injuries

Optimise the patient's general health to facilitate healing of pressure injury and improve the effectiveness of local wound
therapies. Factors affecting ulcer and wound healing must be addressed. Ensure the patient is hydrated and well nourished.
Adequate protein and energy intake is important; patients with stage III and IV pressure injury may require protein and other
nutritional supplements–consider referral to a dietitian. After optimising protein and energy intake, consider adding arginine.
Arginine (at a dose of 4.5 to 9 g daily) may be beneficial for healing pressure injuries that are stage II or more.

Additional management may include:

adequate analgesia
incontinence management
optimising skin condition
use of advanced or biophysical therapies (eg negative pressure wound therapy, ultrasound, electrical stimulation)
rehabilitation programs (to improve physical functioning and strength)
optimising management of comorbidities (consider specialist referral).

Review of pressure injuries

Assess wound progress at least weekly and adjust the management plan as required depending on the patient and wound
characteristics. If the wound is not healing, review the diagnosis, ensure pressure to the area has been eliminated, and address
the factors affecting ulcer and wound healing (eg nutrition, infection, oedema).

Referral may be required if the injury is not progressing, or deteriorating despite optimal care. Consider referral to a vascular
specialist for patients with vascular disease.

Key references
Australian Commission on Safety and Quality in Health Care (ACSQHC). Safety and quality improvement guide standard 8:
preventing and managing pressure injuries (October 2012). Sydney: ACSQHC; 2012.
www.safetyandquality.gov.au/publications/safety-and-quality-improvement-guide-standard-8-preventing-and-managing-pressure-
injuries-october-2012/

Australian Wound Management Association. Pan Pacific guideline for the prevention and management of pressure injury (2012).
Osborne Park, WA: Cambridge Media; 2012.

Coleman S, Smith IL, McGinnis E, Keen J, Muir D, Wilson L, et al. Clinical evaluation of a new pressure ulcer risk assessment
instrument, the Pressure Ulcer Risk Primary or Secondary Evaluation Tool (PURPOSE T). J Adv Nurs 2018;74(2):407–24.

Gillespie BM, Chaboyer WP, McInnes E, Kent B, Whitty JA, Thalib L. Repositioning for pressure ulcer prevention in adults.
Cochrane Database Syst Rev 2014;(4):CD009958.

Huang L, Woo KY, Liu LB, Wen RJ, Hu AL, Shi CG. Dressings for preventing pressure ulcers: A meta-analysis. Adv Skin Wound
Care 2015;28(6):267–73.

Keast DH, Parslow N, Houghton PE, Norton L, Fraser C. Best practice recommendations for the prevention and treatment of
pressure ulcers: update 2006. Adv Skin Wound Care 2007;20(8):447–60; quiz 61–2.

Langer G, Fink A. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database Syst Rev 2014;
(6):CD003216.

Leigh B, Desneves K, Rafferty J, Pearce L, King S, Woodward MC, et al. The effect of different doses of an arginine-containing
supplement on the healing of pressure ulcers. J Wound Care 2012;21(3):150–6.

McInnes E, Jammali-Blasi A, Bell-Syer SE, Dumville JC, Middleton V, Cullum N. Support surfaces for pressure ulcer prevention.
Cochrane Database Syst Rev 2015;(9):CD001735.

Moore ZE, Cowman S. Repositioning for treating pressure ulcers. Cochrane Database Syst Rev 2015;1:CD006898.

Moore ZE, Webster J. Dressings and topical agents for preventing pressure ulcers. Cochrane Database Syst Rev 2013;
(8):CD009362.

National Institute for Health and Care Excellence (NICE). Pressure ulcers: prevention and management. London: NICE; 2014.
www.nice.org.uk/guidance/CG179
National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance.
Prevention and treatment of pressure ulcers: Clinical practice guideline. Perth, Australia: Cambridge Media; 2014.

Romanelli M, Mastronicola D. The role of wound-bed preparation in managing chronic pressure ulcers. J Wound Care
2002;11(8):305–10.

Santamaria N, Gerdtz M, Kapp S, Wilson L, Gefen A. A randomised controlled trial of the clinical effectiveness of multi-layer silicone
foam dressings for the prevention of pressure injuries in high-risk aged care residents: The Border III Trial. Int Wound J
2018;15(3):482–90.

Santamaria N, Gerdtz M, Sage S, McCann J, Freeman A, Vassiliou T, et al. A randomised controlled trial of the effectiveness of soft
silicone multi-layered foam dressings in the prevention of sacral and heel pressure ulcers in trauma and critically ill patients: the
border trial. Int Wound J 2015;12(3):302–8.

Strachan V. PUPPS3––Pressure ulcer point prevalence survey: statewide report 2006. Melbourne, Victoria: State of Victoria,
Department of Human Services; 2006. www2.health.vic.gov.au/about/publications/researchandreports/pressure-ulcer-prevalence-
survey

Wounds Australia. Application of aseptic technique in wound dressing procedure: a consensus document. Osborne Park, Western
Australia. Cambridge Media: [in press] 2018.

Wounds Australia. Standards for Wound Prevention and Management. 3rd edition Osborne Park Western Australia: Cambridge
Media; 2016.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and
distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Wounds on a high-risk foot
Introduction to wounds on a high-risk foot
A high-risk foot is a foot at high risk of amputation, ulceration or infection due to complications from a
chronic disease. A high-risk foot is diagnosed in people with two or more risk factors (neuropathy, peripheral
arterial disease, foot deformity), or a current or previous foot wound or amputation.

Diabetes is the most common condition placing the foot at high risk. Foot disease is the leading cause of
hospitalisation for people with diabetes, and is the most common cause of nontraumatic lower-limb wounds
and amputation. A foot wound in a patient with diabetes often occurs as a result of a complex combination of
peripheral neuropathy, peripheral arterial disease and infection.

Foot disease is the leading cause of hospitalisation for people with diabetes.

Other chronic conditions such as rheumatoid arthritis, peripheral arterial disease, scleroderma and gout can
place the foot at risk of a wound or amputation. These conditions (and diabetes) share a common pathway to
ulceration, namely joint deformity, reduced peripheral arterial blood flow, and reduced pain perception. Foot
deformity, decreased pain perception and gait changes also contribute to abnormal pressures on the foot or
toes causing calluses or corns. If a callus or corn is not appropriately managed in a high-risk foot, skin
breakdown and ulceration can occur; early referral to a podiatrist is recommended.

For advice on routine foot care and monitoring in diabetes, see Foot care for patients with diabetes.

Prevention of wounds on a high-risk foot

Wounds on a high-risk foot are often preventable. Preventive care for patients with a high-risk foot includes:

education about appropriate foot care (see Box 15.6)

appropriate footwear advice (see Box 15.7)
treatment of calluses, corns, blisters or foot injuries
treatment of ingrown or thickened toenails
treatment of fungal infections in the skin or toenails
offloading abnormal pressure under the foot
care from a multidisciplinary team
a chronic disease management plan.

If appropriate retail footwear is not available, consider prescribing medical grade footwear. Footwear should
be professionally fitted if possible, particularly in patients who have peripheral neuropathy.

Patients with high-risk feet (without a current foot wound), should perform daily self-checks, and professional
foot examination should occur at least every 3 to 6 months. Always examine the patient's bare feet (ie with
shoes and socks removed). A daily foot care checklist is available from Diabetic Foot Australia for patients to
encourage appropriate foot care.
Advice for patients about foot care (Box 15.6)

Patient information sheet

check feet every day for cuts, blisters, ingrowing toenails or changes in skin colour; use a mirror if
required
avoid walking barefoot, or in thin-soled shoes (eg slippers) or socks
wash and dry your feet every day, especially between toes
moisturise feet on the top and bottom, but not between toes
cut toenails straight across and file nail edges, if possible
wear appropriate footwear as recommended by a healthcare professional
protect your feet from hot and cold; avoid using external heat sources (eg heaters) to warm feet
elevate feet when sitting

Advice for patients about footwear (Box 15.7)

Patient information sheet

Shoes that support and protect your feet are recommended. Shoes should:

completely enclose the feet

be longer than the longest toe by 1 to 2 cm when standing
be deep enough to allow toes to move freely, avoiding pressure on the front of the foot
be wide enough to accommodate the foot shape
have a heel height of less than 2.5 cm
have laces or adjustable straps that fasten the shoe securely to the foot; the foot should not slide within
the shoe
be made of comfortable material (eg leather) that lets the feet breathe
not have seams on the inside
be reviewed (preferably by your healthcare provider) and replaced regularly.

Wear seamless cotton socks to avoid friction and absorb moisture. Change socks daily.

Footwear may need to be different if you have a foot wound—check with your healthcare provider.

Assessment of wounds on a high-risk foot

Introduction
Early and frequent assessment of patients with a high-risk foot wound is essential. Appropriate assessment
and management minimises the risk of wound deterioration, further wounds or amputation.

For structured advice on examination, see Foot examination. Assess for peripheral neuropathy and peripheral
arterial disease. Review current footwear for suitability, fit and wear, and consider whether pressure
redistribution can be accommodated within the shoe.

Patients with peripheral neuropathy often have loss of sensation, so are unable to detect damage or discomfort
to their feet and are less likely to take appropriate action to prevent tissue damage. Patients with peripheral
neuropathy must be educated about foot care (see Box 15.6) and appropriate footwear (see Box 15.7), and be
reviewed by a podiatrist.

If the patient has diabetes, check for hyperglycaemia or poor vision as these may affect the management plan.

Assessment for peripheral neuropathy

Introduction

Peripheral neuropathy is one of the major contributors to foot wounds. Peripheral neuropathy can involve
damage to:
 sensory nerves, causing reduced temperature, touch and pain sensation
motor nerves, causing foot deformity from altered foot biomechanics
autonomic nerves, causing reduced skin quality and changes to peripheral vascular function.

See Causes, classification and types of peripheral neuropathy for a comprehensive list of causes of peripheral
neuropathy.

For management of patients found to have peripheral neuropathy, see Interventions for wounds on a high-risk
foot.

10 gram monofilament test

A calibrated 10 gram monofilament is an objective, simple instrument used to screen the foot for loss of
protective sensation. There is disagreement in the literature about the accuracy and method of application of
this test. This test should be considered in conjunction with the overall neurological examination and clinical
review.

The process for sensory examination using a calibrated 10 gram monofilament is:

▪Perform in a quiet and relaxed setting.

▪Demonstrate buckling of the 10 gram monofilament on the patient's hand so they know what to expect.
▪Position the patient so they can't see when and where the monofilament is applied, or ask them to close
their eyes.
▪Ask the patient to tell you if they feel the monofilament, and where they feel it (left or right foot).
▪Apply the monofilament perpendicular to the skin surface to at least four sites on each foot (see Figure
15.2). Do not put the monofilament on a wound, callus, scar or necrotic tissue. Do not let the
monofilament slide across the skin or make repetitive contact at the test site. Each site can be tested up
to three times if the patient does not respond.
▪Apply sufficient force to make the monofilament bend or buckle (see Photo 15.8). When the
monofilament bends, its tip is exerting a pressure of 10 grams.
▪The total time taken to touch the skin, make contact, and remove the monofilament should be
approximately 2 to 3 seconds.

Peripheral neuropathy testing sites on the sole of the foot (Figure 15.2)

Adapted with permission from NHS Highland Diabetes Guidelines Group. Use of 10 gram monofilament in screening the diabetic foot; 2011.

Screening using a 10 gram monofilament (Photo 15.8)

 Photo courtesy of Medical Illustration Department, The Royal Melbourne Hospital.

If a patient cannot detect the pressure of the monofilament at any one of the sites, this may indicate peripheral
neuropathy and loss of protective sensation [Note 1]. For patients with suspected peripheral neuropathy,
undertake a neurological exam for further assessment.

If the patient can detect the monofilament at all sites, they have adequate sensation. Consider an alternative
cause for the wound (eg peripheral arterial disease).

It is important to use a properly calibrated monofilament so that 10 grams of linear pressure is applied. For
practice points about care of a monofilament, see Box 15.8. Clinics screening more than 10 patients per day
require more than one 10 gram monofilament.

Practice points for care of a monofilament (Box 15.8)

if a monofilament is bent or damaged, replace it

if used daily, replace monofilament every 6 months
if used less than daily, replace monofilament every 12 months
disposable monofilaments are preferred

Note 1: Loss of protective sensation is not equivalent to absence of sensation.

Ipswich touch test

If a calibrated 10 gram monofilament isn't available, the Ipswich touch test may be used. The Ipswich touch
test is conducted by lightly touching the first, third, and fifth toes, and the dorsum of the hallux, for 1 to 2
seconds. The patient has their eyes shut and announces if they feel the touch. If they cannot feel the touch at
any of the sites, this strongly suggests sensory neuropathy.

Assessment for peripheral arterial disease

Screening for peripheral arterial disease is an essential part of high-risk foot wound assessment. To screen for
peripheral arterial disease:

palpate pedal pulses (dorsalis pedis, posterior tibial)

auscultate for femoral artery bruit
look for signs of ischaemia (cold, pale extremities; thin hairless skin)
ask about symptoms of intermittent claudication (note these may be absent in patients with neuropathy)
check for history of cardiovascular or vascular disease.
Auscultation for femoral artery bruits can indicate significant arterial disease or occlusion. An inability to
palpate pedal pulses is associated with peripheral arterial disease and the risk of amputation. However,
palpable pulses alone do not reliably exclude peripheral arterial disease, so consider more advanced vascular
assessment techniques.

Handheld Doppler waveform evaluation can be used to evaluate pedal pulses. The 8 MHz Doppler probe
should be used when evaluating pedal waveforms. Abnormal waveforms have high accuracy for detecting
peripheral arterial disease. Abnormal Doppler waveforms typically sound unclear, have low volume and only
one phase. Normal waveforms are loud, clear and have two to three phases.

If peripheral arterial disease is suspected, consider pressure measurement (ie ankle brachial pressure index
[ABPI], toe brachial pressure index [TBPI] or toe pressure) to assess arterial perfusion and determine if
vascular referral is required. See Table 15.6.

Interpret ABPI with caution in patients older than 75 years and those with kidney disease or diabetes. In such
patients, ABPI can be artificially inflated by arterial calcification. An ABPI within the normal range in a
patient with a strong clinical presentation for peripheral arterial disease does not exclude peripheral arterial
disease. Measuring the toe pressure or TBPI is useful for patients with an ABPI greater than 1.3, or if the
ABPI result does not fit within the clinical context of the patient, or for patients who do not respond to therapy
as expected.

Interpretation of lower-limb pressure measurements (Table 15.6)

Less than 0.9: indicative of peripheral arterial disease

0.9 up to 1.3: normal

ABPI
Greater than 1.3: indicative of calcification; further testing required for
peripheral arterial disease
Less than 0.7: indicative of peripheral arterial disease
TBPI
Greater than or equal to 0.7: normal
Less than 30 mmHg: unlikely to heal

30 to 50 mmHg: poor healing capacity

Toe pressure Less than 96 mmHg: indicative of peripheral arterial disease in general
population

Less than 97 mmHg: indicative of peripheral arterial disease in diabetes

population
ABPI = ankle brachial pressure index; TBPI = toe brachial pressure index

For management of patients with peripheral arterial disease, see Interventions for wounds on a high-risk foot.

Assessment of foot deformity

Foot deformity, especially in combination with peripheral neuropathy, can lead to abnormally high pressures
on the foot, predisposing it to a wound.

Assess the foot for deformities, including:

hallux abducto valgus (bunions)

claw or hammer toes
bony prominences
Charcot foot deformity
congenital abnormalities.

Deformity may also occur as a result of surgical intervention. Rheumatoid arthritis, gout, diabetes and other
conditions that cause peripheral neuropathy commonly lead to changes in foot shape and deformity.

Assessment for infection

Always assess high-risk foot wounds for infection; see Ulcer and wound infection. Signs of infection are often
subtle in patients who have diabetes or are significantly immunocompromised, and these patients can
deteriorate rapidly. Collect wound swabs to identify the pathogen and guide antibiotic therapy. Thorough
assessment and close monitoring is important. See also Diabetic foot infection.

If an infection is identified, investigate for osteomyelitis. A simple and accurate technique is to probe for bone
(see Foot examination). Assess for osteomyelitis and infection at the initial presentation of a foot wound, and
at regular intervals in a chronic foot wound. Consider an X-ray to assist with the identification of
osteomyelitis; however, it can take up to 4 weeks for bony changes due to osteomyelitis to be visible on X-ray.
For more information on diagnosis and management of osteomyelitis, see Osteomyelitis.

Interventions for wounds on a high-risk foot

A foot wound in a patient with a high-risk foot can result in amputation so requires prompt management.
Interventions for high-risk foot wounds include:

pressure redistribution (see Table 15.7)

treating infection (see Ulcer and wound infection)
wound cleansing and debridement
management of ischaemia
use of appropriate wound dressings.

Ideally, patients with a high-risk foot wound are managed by a specialised multidisciplinary team (usually
comprising of medical, surgical, podiatry, wound care, orthotic and footwear specialists). For patients in rural
areas who may not have access to a specialist foot clinic, liaise with the closest clinic (telehealth review may
be an option).

Interventions for high-risk foot wounds depend on the aetiology of the wound. Patients with a combination of
peripheral neuropathy, peripheral arterial disease and foot deformity are at highest risk of amputation and
require earlier and more comprehensive interventions.

Consider pressure redistribution strategies when developing a management plan for foot wounds.

For foot wounds in patients with peripheral neuropathy, redistribution of pressure (pressure offloading) is
essential for wound healing. Pressure redistribution must be considered when developing a management plan
for any foot wound.

Basic pressure redistribution involves:

encouraging patients to rest

avoiding weight-bearing activities in the affected area
using offloading devices; see Table 15.7.

Pressure offloading devices are specialised and need appropriately trained therapists (usually a podiatrist or
orthotist) to fit them and advise on their use. Patients may incur a cost.

Peripheral neuropathy is frequently irreversible and progressive. Ensure regular review and educate about foot
care and footwear (see Box 15.6 and Box 15.7). Referral to a neurologist may be useful if the peripheral
neuropathy is treatable. If the cause of neuropathy is diabetes, blood glucose control can limit progression.

If foot deformity is contributing to the development or chronicity of a wound, invasive interventions may also
be required; see Table 15.8.

When foot wounds have an ischaemic component (ie patients with peripheral arterial disease), refer to a
vascular specialist for revascularisation—manage as for Arterial leg ulcers. Risk factor modification and
ongoing monitoring is required; see Intermittent claudication.

Pressure redistribution strategies (Table 15.7)

Nonremovable:

total contact cast

instant total contact cast (iTCC)

Removable:

Charcot restraint orthotic walker (CROW)

removable cast walker
 soft boots or pressure relief shoes
felt padding
orthoses
pressure-relieving ankle foot orthotic (PRAFO or MPO)
medical grade footwear

total contact cast

Efficacy and features
Other considerations
very effective (gold standard)
time consuming to apply
application requires expertise
falls risk (especially in older, visually impaired or
disabled patients)
contraindicated in patients with peripheral arterial
disease or infection
requires replacement every 1 to 2 weeks
expensive

instant total contact cast (iTCC)

(a removable cast walker is made nonremovable using plaster or similar material)

outcomes likely similar to a total contact cast
can have pop-out insole for pressure relief,
Efficacy and features
orthoses or padding

minimal expertise required for application

Other considerations
enables weight bearing
falls risk (especially in older, visually impaired or
disabled patients)
caution with infected wounds due to limited
ability to monitor progression of infection

Charcot restraint orthotic walker (CROW)

good pressure redistribution
custom moulded for optimal redistribution
Efficacy and features allows for walking
longer-term device (good for unstable Charcot or
recalcitrant wounds)

patient can remove

Other considerations
high one-off cost
availability is limited by the requirement for
expertise to fit and modify
falls risk (especially in older, visually impaired or
disabled patients)

removable cast walker


Efficacy and features
Other considerations
soft boots or pressure relief shoes
Efficacy and features
Other considerations
felt padding
good pressure redistribution
can have pop-out insole for pressure relief,
orthoses or felt offloading
patient can remove
initial cost and ongoing cost of liners
requires some expertise to fit and modify for each
patient
limited sizes—caution in obesity or patients with
wide feet (foot may not fit and device can break
with excess weight)
the height of the boot can cause uneven limb
length (this can be overcome with an ‘even-up’
device on the opposite shoe)
not as effective at offloading as devices that
immobilise the ankle
lightweight
easy for patients to walk in
easy to apply and remove
can have pop-out insole for pressure relief,
orthoses or felt offloading
limited sizes
need some training to fit correctly
low cost
wear out quickly
poor compliance due to ease of removal
inexpensive
readily available
Efficacy and features
Other considerations
orthoses
Efficacy and features
Other considerations
pressure-relieving ankle foot orthotic (PRAFO or MPO)
Efficacy and features
Other considerations
medical grade footwear
Efficacy and features
Other considerations
Invasive interventions for high-risk foot wounds (Table 15.8)
can be applied to shoes and boots, or directly to
the foot
requires clinician expertise
risk of skin trauma with incorrect placement
only for short-term use (after 3 days it loses
efficacy)
low cost
good for preventing wound recurrence after
healing
need expert fitting and regular monitoring because
foot shape may change in patients with diabetes,
gout or rheumatoid arthritis
high cost (usually annual replacement needed)
usually used in combination with extra depth and
width footwear, or custom footwear—adds to cost
needs expertise to manufacture appropriately
wound needs to be completely healed before
prescription and fitting of orthoses
removes pressure from the entire heel
can be used in ambulant patients as well as bed-
bound patients
limited sizes—may not fit large feet or feet with
significant deformities
increased risk of falls
not always well tolerated by patients, especially if
used bilaterally
not effective for Achilles wounds (adds pressure
to Achilles)
protective; aims to prevent trauma caused by
footwear
can accommodate offloading devices such as
orthoses or felt padding
accommodates most foot deformities
expensive
poor aesthetic
in cases of severe foot deformity, a custom-made
shoe may be required
Intervention (specialist)
surgical correction
(orthopaedic specialist)
Description Rationale and considerations
Achilles lengthening
surgery
tenotomy (tendon release)
shortening of the Achilles tendon
occurs frequently due to motor
neuropathy; lengthening can reduce
forefoot pressures and reduce
incidence of wounds
tenotomy is used to correct
musculoskeletal deformities that can
lead to abnormal pressures in the
foot
patient needs adequate blood supply
and to be suitable for surgery
normally a lengthy period of non–
weight bearing in a cast after surgery

patient needs to be suitable for

aggressive debridement
surgery; generally performed under
of devitalised tissue under
surgical debridement general anaesthesia
anaesthesia
(orthopaedic specialist or in wounds with osteomyelitis, can
incision and drainage of
vascular surgeon) produce bone fragments that delay
pus
wound healing

reduces plantar pressure

effective for removal of
reduces bacterial burden
nonviable tissue from
caution in patients with peripheral
conservative sharp wound
arterial disease
callus removal using a
debridement (podiatrist or clinician should be experienced or
scalpel
wound specialist) competent in debridement
low-frequency ultrasound
cost effective
debridement
reduces time to healing

Review of patients with wounds on a high-risk foot

Review patients with a current foot wound, or who are at high risk of a foot wound regularly. Frequency of
review and wound care varies from daily to weekly based on patient characteristics, wound characteristics and
progression, and the environment. For patients with diabetes and an infected foot wound, close monitoring (eg
daily) is required initially as patients can deteriorate rapidly.

Factors that influence wound healing in the foot include vascular supply, infection, glycaemic control,
nutrition, smoking, deformity, and adherence with pressure redistribution strategies. Regular review should
address the factors affecting ulcer and wound healing.

If a wound is not improving, or is deteriorating after 2 weeks, referral and involvement of a specialised
multidisciplinary team should be considered (see Interventions for wounds on a high-risk foot). Depending on
the aetiology of the wound, consider wider specialist review (including vascular, orthopaedic, endocrinology,
rheumatology).

Key references
Armstrong DG, Cohen K, Courric S, Bharara M, Marston W. Diabetic foot ulcers and vascular insufficiency: our
population has changed, but our methods have not. J Diabetes Sci Technol 2011;5(6):1591–5.

Baraz S, Zarea K, Shahbazian HB, Latifi SM. Comparison of the accuracy of monofilament testing at various
points of feet in peripheral diabetic neuropathy screening. J Diabetes Metab Disord 2014;13(1):19.

Brownrigg JR, Hinchliffe RJ, Apelqvist J, Boyko EJ, Fitridge R, Mills JL, et al. Effectiveness of bedside
investigations to diagnose peripheral artery disease among people with diabetes mellitus: a systematic review.
Diabetes Metab Res Rev 2016;32 Suppl 1:119–27.

Commonwealth of Australia. National evidence-based guideline on prevention, identification and management of

foot complications in diabetes (part of the guidelines on management of type 2 diabetes). Melbourne, Australia;
2011.
Firth J, Hale C, Helliwell P, Hill J, Nelson EA. The prevalence of foot ulceration in patients with rheumatoid
arthritis. Arthritis Rheum 2008;59(2):200–5.

Frykberg RG. Epidemiology of the diabetic foot: ulcerations and amputations. Adv Wound Care 1999;12(3):139–
41.

Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. 2016 AHA/ACC
guideline on the management of patients with lower extremity peripheral artery disease: A report of the American
College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation
2017;135(12):e726–e79.

Hennion DR, Siano KA. Diagnosis and treatment of peripheral arterial disease. Am Fam Physician
2013;88(5):306–10.

Kerr M, Rayman G, Jeffcoate WJ. Cost of diabetic foot disease to the National Health Service in England. Diabet
Med 2014;31(12):1498–504.

Kinlay S. Management of critical limb ischemia. Circ Cardiovasc Interv 2016;9(2):e001946.

Lam K, van Asten SA, Nguyen T, La Fontaine J, Lavery LA. Diagnostic sccuracy of probe to bone to detect
osteomyelitis in the diabetic foot: A systematic review. Clin Infect Dis 2016;63(7):944–8.

Lewis J, Lipp A. Pressure-relieving interventions for treating diabetic foot ulcers. Cochrane Database Syst Rev
2013;(1):CD002302.

Lipsky BA, Aragon-Sanchez J, Diggle M, Embil J, Kono S, Lavery L, et al. IWGDF guidance on the diagnosis and
management of foot infections in persons with diabetes. Diabetes Metab Res Rev 2016;32 Suppl 1:45–74.

Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, et al. 2012 Infectious Diseases Society of
America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis
2012;54(12):e132–73.

McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, et al. The independent contributions of
diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care 1995;18(2):216–
9.

Menke NB, Ward KR, Witten TM, Bonchev DG, Diegelmann RF. Impaired wound healing. Clin Dermatol
2007;25(1):19–25.

National Institute for Health and Care Excellence (NICE). Diabetic foot problems: prevention and management
[NG19]. London; 2015. www.nice.org.uk/guidance/ng19

Nube V, Bolton T, Chua E, Yue D. Osteomyelitis in the diabetic foot: what lies beneath. Primary Intention
2007;15(2):49–50.

Ouriel K. Peripheral arterial disease. Lancet 2001;358(9289):1257–64.

Payne CB. Diabetes-related lower-limb amputations in Australia. Med J Aust 2000;173(7):352–4.

Pomposelli FB, Jr., Jepsen SJ, Gibbons GW, Campbell DR, Freeman DV, Miller A, et al. Efficacy of the dorsal
pedal bypass for limb salvage in diabetic patients: short-term observations. J Vasc Surg 1990;11(6):745–51;
discussion 51–2.

Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A, Bakker K, et al. High prevalence of ischaemia, infection
and serious comorbidity in patients with diabetic foot disease in Europe. Baseline results from the Eurodiale study.
Diabetologia 2007;50(1):18–25.

Rayman G, Vas PR, Baker N, Taylor CG, Jr., Gooday C, Alder AI, et al. The Ipswich Touch Test: a simple and
novel method to identify inpatients with diabetes at risk of foot ulceration. Diabetes Care 2011;34(7):1517–8.
Rome K, Erikson K, Otene C, Sahid H, Sangster K, Gow P. Clinical characteristics of foot ulceration in people with
chronic gout. Int Wound J 2016;13(2):209–15.

Saap LJ, Falanga V. Debridement performance index and its correlation with complete closure of diabetic foot
ulcers. Wound Repair Regen 2002;10(6):354–9.

Schaper NC, Van Netten JJ, Apelqvist J, Lipsky BA, Bakker K, International Working Group on the Diabetic Foot.
Prevention and management of foot problems in diabetes: a summary guidance for daily practice 2015, based on
the IWGDF guidance documents. Diabetes Metab Res Rev 2016;32 Suppl 1:7–15.

Sonter JA, Ho A, Chuter VH. The predictive capacity of toe blood pressure and the toe brachial index for foot
wound healing and amputation: A systematic review and meta-analysis [online]. Wound PracRes 2014;22(4):208–
20.

Tehan PE, Barwick AL, Sebastian M, Chuter VH. Diagnostic accuracy of resting systolic toe pressure for
diagnosis of peripheral arterial disease in people with and without diabetes: a cross-sectional retrospective case-
control study. J Foot Ankle Res 2017;10:58.

Tehan PE, Bray A, Chuter VH. Non-invasive vascular assessment in the foot with diabetes: sensitivity and
specificity of the ankle brachial index, toe brachial index and continuous wave Doppler for detecting peripheral
arterial disease. J Diabetes Complications 2016;30(1):155–60.

van Netten JJ, Price PE, Lavery LA, Monteiro-Soares M, Rasmussen A, Jubiz Y, et al. Prevention of foot ulcers in
the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32 Suppl 1:84–98.

Williams DT, Harding KG, Price P. An evaluation of the efficacy of methods used in screening for lower-limb
arterial disease in diabetes. Diabetes Care 2005;28(9):2206–10.

Young MJ, Breddy JL, Veves A, Boulton AJ. The prediction of diabetic neuropathic foot ulceration using vibration
perception thresholds. A prospective study. Diabetes Care 1994;17(6):557–60.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Overview of leg ulcers
Overview of leg ulcers
The most common type of leg ulcers are venous leg ulcers, which account for up to 80%. Ulcers due to
peripheral arterial disease are less common, representing approximately 15%. Mixed arterial and venous leg
ulcers occur in 10 to 15% of patients. Leg ulcers unrelated to arterial or venous disease (eg malignancy,
vasculitis, pyoderma gangrenosum, traumatic or drug-induced ulcers) account for approximately 5%.

For patients with a leg ulcer, undertake a thorough assessment with history and physical examination to
identify features of venous or arterial disease (see Table 15.9 and Assessing patients with an ulcer or wound).
Consider uncommon causes of leg ulcers, including malignancy (see Differential diagnoses for ulcers or
wounds).

Educate patients about the cause of the ulcer, the treatment plan (including patient participation), and how to
prevent recurrence.

An overview of leg ulcer assessment and compression therapy is provided in Figure 15.6.

Determining the vascular cause of a leg ulcer (Table 15.9)

Cause Common Common examination findings Common ulcer features

medical
history
varicose veins

oedema
located on lower third of the leg
varicose veins venous flares

Venous disease thrombosis shallow, poorly defined edges

haemosiderin staining (dark purple or that are usually sloping
(venous rusty skin discolouration of lower legs)
incompetence leg fracture
granulating and sloughy base
or obstruction) features of lipodermatosclerosis (‘inverted
right-sided
champagne bottle leg’) heavy exudate with maceration
heart failure
and hyperkeratotic skin
pain: if present may be relieved with leg
elevation, aggravated by lowering the leg;
often occurs later in the day
intermittent
claudication

peripheral
arterial disease
signs of ischaemia (cold, pale extremities,
myocardial hair loss or nail changes)
infarction
pallor on leg elevation located on toes, bony
stroke prominences, sides of feet, heel
redness on dependence (legs down or
atrial dangling) punched out edges
Arterial fibrillation
disease
femoral bruit sloughy base or covered by
heart valve eschar
disease absence of one or more pedal pulses
minimal exudate
aneurysmal pain: common; may be aggravated by leg
disease elevation and relieved by lowering the leg
over the side of the bed
hypertension
 smoker

kidney disease

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Venous leg ulcers
Introduction to venous leg ulcers
Venous leg ulcers are the most common type of leg ulcer. Venous ulcers are caused by venous valve incompetence, venous
obstruction and calf muscle pump insufficiency (either alone or in combination), resulting in venous stasis and venous
hypertension. The impaired circulation increases the risk of an ulcer and reduces the ability to heal.

Determining the cause of a leg ulcer is essential to guide management; see Table 15.9 for advice on determining the vascular
cause of a leg ulcer. An overview of assessment and management of venous leg ulcers is provided in Figure 15.3.

Patient education is an important part of management [Note 1]. Patients are more likely to participate in therapy if they
understand why it is necessary. Patient education is also essential in preventing venous leg ulcer recurrence. Topics for
education include:

the pathophysiology of venous disease and venous leg ulceration

leg ulcer assessment techniques
the role of the foot and calf pump
the role of compression therapy or biomechanical alternatives
devices and appliances that can assist in the application and removal of compression garments
skin care
strategies to prevent recurrence (eg ongoing compression therapy, nutrition, leg elevation, exercise).

Patients with diabetes require early specialist involvement as they can deteriorate rapidly and standard assessment techniques
may be unreliable.

Note 1: Patient information sheets are available from Wounds Australia [registration required].

Prevention of an initial venous leg ulcer

To reduce the risk of a venous leg ulcer, advise patients to:

optimise their nutritional status—see Nutrition

lose weight, for patients who are overweight or obese
avoid prolonged standing or sitting
optimise comorbidities (especially blood glucose concentration in patients with diabetes)
stimulate calf muscle pump function with exercises—see Exercise
elevate legs to 90 degrees (to the level of the hips) when sitting
moisturise skin on lower limbs to improve skin integrity—see Skin care for venous dermatitis
use compression to prevent deep vein thrombosis and improve venous return.

Preventing venous hypertension is the key management strategy in preventing a venous leg ulcer. Early referral to a vascular
or venous specialist to correct venous insufficiency is an important strategy to prevent leg ulceration. Refer patients at
increased risk:

male patients with varicose veins

patients with diabetes and varicose veins
patients with a previous serious leg injury (eg broken leg, burn, stab or gunshot wound, crush injury) and varicose veins
patients with symptomatic varicose veins (pain, aching, discomfort, swelling, heaviness and itching)
patients with skin changes on the lower limb likely related to chronic venous insufficiency (eg pigmentation, eczema)
patients with superficial vein thrombosis (hard, painful veins) and suspected venous incompetence.

Progression of venous disease from varicose veins to chronic venous insufficiency is associated with the following:

female gender
age older than 70 years
body mass index (BMI) more than 25 kg/m2
elevated blood pressure.

Assessment of venous leg ulcers

For a structured approach to assessing patients with a leg ulcer, see Assessing patients with an ulcer or wound. For an
overview of assessment and management of a venous leg ulcer, see Figure 15.3.

Overview of assessment and management of venous leg ulcers (Figure 15.3)

 ABPI = ankle brachial pressure index

NB1: Perform ABPI if the patient has impaired peripheral sensation or features of arterial disease (see Arterial leg ulcers).

NB2: Standard ulcer care is wound debridement and cleansing, diagnosing and minimising oedema, treating infection (if present), and optimising moisture balance.

NB3: An ABPI above 1.3 does not exclude arterial disease because arteries can be calcified and noncompressible.

A patient with a venous leg ulcer may have the following clinical features:

history of varicose veins or thrombosis

oedema or pain that is worse at the end of the day
venous flares, haemosiderin staining (dark purple or rusty skin discolouration of lower legs), or lipodermatosclerosis
(‘inverted champagne bottle leg’ with hard skin and subcutaneous tissues).

Pain occurring from a venous leg ulcer may be reduced by elevation and aggravated by lowering the leg. If pain is a dominant
feature of the ulcer, assess for infection, oedema, or concurrent arterial disease.

A venous leg ulcer is shown in Photo 15.9. A venous leg ulcer may have the following features:

location—‘gaiter area’ (lower third of the leg [medial or lateral])

edge—usually sloping and may be irregular (shallow, poorly defined edges)
base—usually granulating and sloughy
exudate—usually heavy, with maceration and hyperkeratotic skin.

A venous leg ulcer can occur above or below the malleoli, so imaging should include the inframalleolar region.

Features of the surrounding skin include:

‘atrophie blanche’ (pale scarring with stippled telangiectasia)

venous dermatitis (eg erythema, weeping, scaling).

Example of a venous leg ulcer (Photo 15.9)

Patients with a leg ulcer must have a comprehensive venous duplex scan of the lower limb by an experienced laboratory to
assess venous insufficiency and diagnose obstruction.

Investigate patients with a leg ulcer for peripheral arterial disease to determine suitability for compression therapy. Assess for
femoral artery bruit and pedal pulses (dorsalis pedis and posterior tibial), and calculate the ankle brachial pressure index
(ABPI). If femoral artery bruit is absent and pedal pulses are all normal, ABPI may be omitted if the patient has intact
peripheral sensation, adequate cognition to report a complication, and no clinical features that suggest arterial impairment.
Record examination findings in the patient notes. See Figure 15.3 and ABPI for more information.

Interventions for venous leg ulcers

Introduction
Standard ulcer care includes:

wound cleansing and debridement

diagnosing and minimising oedema (see Oedema and ulcer and wound healing)
treating infection, if present (see Ulcer and wound infection)
optimising wound moisture balance (see Ulcer and wound dressings).

The cornerstone of treatment is correction of venous hypertension. Evidence shows that patients with venous leg ulcers who
have prompt specialist endovenous intervention have accelerated healing [Note 2]. This is the most cost effective way to
manage a venous leg ulcer. Patients with a venous leg ulcer should be immediately referred to a specialist vascular service.

Compression therapy is recommended as an adjunctive therapy to vascular intervention.

Other interventions include optimising nutrition, managing pain, leg elevation, a structured exercise program, skin care and
pharmacological therapies. Also address the factors affecting ulcer and wound healing.

Note 2: Gohel MS, Heatley F, Liu X, Bradbury A, Bulbulia R, Cullum N, et al. A randomized trial of early endovenous ablation in venous ulceration. N Engl J Med
2018;378(22):2105-14. [URL]

Endovenous intervention and surgery

Early referral to a vascular specialist is strongly recommended for patients with a venous leg ulcer. The aim of vascular
intervention is to assist ulcer healing and reduce recurrence. First-line endovenous therapy is endothermal ablation, including
endovenous laser and radiofrequency ablation. Endothermal ablation can be used for both axial and perforator vein reflux.
Second-line therapy is ultrasound guided foam sclerotherapy. Third-line therapy is open surgery.

Early referral to a vascular specialist is strongly recommended for patients with a venous leg ulcer.
Patients with chronic venous disease and proximal obstruction (inferior vena cava or iliac) should be considered for
angioplasty and stent recanalisation to aid healing and prevent recurrence of venous leg ulcers; seek specialist advice.

Compression therapy
Compression therapy is recommended to promote ulcer healing and reduce ulcer recurrence. Aim for class III compression
(defined in this guideline as 30 to 40 mmHg). If class III compression is not tolerated, class II compression (20 to 29 mmHg)
can be used. Patients often need to start with a lower level of compression (eg a 3-layer tubular bandage) and increase to class
III compression when tolerated.

Compression class II or III must be prescribed by an appropriately trained healthcare professional to avoid damage to the
limb; see Compression therapy. Frequent review of patients is required, especially at initiation.

Standards of compression vary internationally. For simplicity, classes of compression have been defined in this guideline as
shown in Box 15.11.

Nutrition

Adequate nutrition is important to promote wound healing. The majority of patients with venous leg ulcers are overweight or
obese; however, these patients are still at risk of malnutrition.

Ask patients about their diet and assess for deficiencies; dietary intakes of omega-3 fatty acids, vitamin C and zinc may be
low.

Encourage patients to eat a wholefood, balanced diet, including fish at least twice a week, at least five serves of vegetables a
day, and healthy fats (eg avocado, extra virgin olive oil, a handful of nuts). Patients may require referral to a dietitian for
comprehensive nutritional assessment.

If a micronutrient deficiency is identified, it should be corrected. Vitamin D, flavonoids and folic acid supplements have been
associated with beneficial effects on ulcer healing.

Encourage weight loss for patients who are overweight or obese to facilitate mobility (see Exercise) and reduce venous
hypertension.

Pain management
Managing pain is important to facilitate walking (which maintains calf muscle pump function) and compression therapy, and
to improve the patient's wellbeing.

Create an individual pain management plan; see Ulcer and wound pain.

Ulcer pain often improves with a reduction in limb oedema and wound exudate. For management of oedema, see Oedema and
ulcer and wound healing. For exudate management, see Ulcer or wound moisture balance.

Leg elevation
Leg elevation aids venous return, and reduces pain and oedema in some patients. During periods of inactivity, elevate the legs
so the ankles are higher than the heart, taking into account the patient's lifestyle and physical limitations. If the patient's legs
cannot be elevated above the level of the heart, raise to approximately 90 degrees (eg level with the hips) when sitting.

Exercise
Encourage regular exercise (eg walking or plantar flexing the foot) to maintain calf muscle pump function. Improved calf
muscle pump function reduces venous pooling and improves venous return. Ankle exercises to improve mobility, or
biomechanical stimulation (eg Veinoplus), can be used to improve calf muscle pump function. Lifestyle counselling and
structured exercise programs reduce duration of leg ulcers and their recurrence.

Skin care for venous dermatitis

Skin care of the lower limb is essential to maintain skin integrity and minimise the risk of further ulceration.

Dermatitis on the legs is common in patients with ulcers, especially venous leg ulcers. Contributing factors include dryness
and irritants (eg soap, antiseptics). Allergic contact dermatitis from dressings and topical medications may also occur (see
Previous reactions to ulcer and wound dressings). Common allergens include preservatives in creams, rubber accelerants in
elastic dressings and topical antibiotics. Specific allergen identification is facilitated by patch testing, which is undertaken by
a dermatologist (see Contact dermatitis).

Dermatitis varies in severity. Milder forms may have a dry, scaly appearance with superficial cracking of the skin; more
severe forms have a moist, intensely erythematous, appearance with oozing, weeping and crusting. Contact dermatitis often
presents with a well-demarcated, sharply cut-off rash on the area in contact with the allergen or irritant.

Treating venous dermatitis around a wound may reduce the risk of infection (including cellulitis) and promote ulcer healing.
Encourage skin care (see Box 15.9).
Skin care for intact skin around an ulcer (Box 15.9)

cleanse with a pH-appropriate skin cleanser (avoid soap)

use products without fragrance or preservatives
avoid frequently changing skin products
to protect skin in the shower, apply an emollient (see Table 4.6) to skin before showering (it will wash off)
shower in potable water or wash the leg using a dedicated bowl of potable water
wipe the leg with a moist cloth
gently pat the leg dry (avoid rubbing) with a clean towel
apply moisturiser (in the direction of hair growth) after showering to maintain healthy skin

Treat venous dermatitis with a simple emollient (eg a paraffin-containing ointment), applied at least daily. Continue even after
the ulcer is healed. A moderately potent topical corticosteroid in an ointment base (eg betamethasone dipropionate 0.05%
ointment) should be applied liberally to all areas of dermatitis at each dressing change until the skin is completely clear.
Emollients can be applied on top of the corticosteroid. For milder presentations, a weaker topical corticosteroid such as
triamcinolone acetonide 0.02% ointment could be used—hydrocortisone 1% ointment is inadequate. Topical corticosteroids
can be applied safely over cracked or broken skin, and should be applied up to (and including) the edge of an ulcer. Also
consider using zinc paste bandages.

Excessive ulcer exudate can lead to skin irritation, maceration and delayed healing—choose dressings that appropriately
manage ulcer exudate (see Ulcer and wound dressings).

For advice on cleansing the wound, see Cleansing and debridement.

Pharmacological therapies
Oxpentifylline (pentoxifylline) may be considered as an adjunctive therapy for patients with ulcers that have not healed
despite optimal therapy, with specialist advice. Oxpentifylline is not registered by the Australian Therapeutic Goods
Administration (TGA) for treatment of venous leg ulcers. It has significant precautions and drug interactions.

Good-quality evidence to support the use of micronised purified flavonoid fraction (MPFF) for venous leg ulcers is lacking,
and this product is not readily available in Australia.

Low-dose aspirin has not been shown to improve healing of venous leg ulcers.

Review of venous leg ulcers

If compression therapy is initiated, review patients within 24 to 48 hours to ensure they can tolerate therapy (see Compression
therapy).

Ideally, review patients with a leg ulcer weekly. If healing is not progressing as expected, despite best practice management
(including appropriate endovascular intervention):

consider the factors affecting ulcer and wound healing

optimise management of comorbidities (eg heart failure, diabetes)
review the diagnosis (see Differential diagnoses for ulcers or wounds)
refer back to the vascular specialist.

Risk factors for delayed healing of venous leg ulcers include:

patients with mixed venous and arterial disease

ulcer bigger than 5 cm2
ulceration for longer than 6 months
presence of popliteal reflux
decreased limb mobility
history of venous ligation or stripping
history of hip or knee replacement
fibrin over more than 50% of the wound
unusual limb shape
poor skin condition.

Preventing recurrence of venous leg ulcers

Historically, recurrence of a venous leg ulcer has been common—most patients had multiple episodes. With improved access
to optimal vein care (eg endovenous interventions), it is expected that venous leg ulcer recurrences will significantly reduce.
Factors associated with recurrence include a history of deep vein thrombosis, failure to correct venous hypertension or a
previous large ulcer.

The mainstay of preventive treatment is correction of venous hypertension. Long-term compression therapy is still
recommended for patients with obstruction or deep venous insufficiency, use class III compression (defined in this guideline
as 30 to 40 mmHg). For other patients, use class II compression (20 to 29 mmHg). If patients do not tolerate this level of
compression, options include using a lower grade of compression, a combination of low compression stockings, a
biomechanical device (eg Veinoplus) or long-term compression bandaging (elastic or inelastic).

Key references
Introduction to venous leg ulcers

Labropoulos N, Manalo D, Patel NP, Tiongson J, Pryor L, Giannoukas AD. Uncommon leg ulcers in the lower extremity. J Vasc
Surg 2007;45(3):568–73.

O'Donnell TF, Jr., Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, et al. Management of venous leg ulcers: clinical
practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg 2014;60(2 Suppl):3S–
59S.

Simon DA, Dix FP, McCollum CN. Management of venous leg ulcers. BMJ 2004;328(7452):1358–62.

van Gent WB, Wilschut ED, Wittens C. Management of venous ulcer disease. BMJ 2010;341:c6045.

Prevention of an initial venous leg ulcer

National Institute for Health and Clinical Excellence (NICE). Varicose veins: diagnosis and management. London: NICE; 2013.
www.nice.org.uk/guidance/cg168

Pannier F, Rabe E. Progression of chronic venous disorders: results from the Bonn Vein Study [conference abstract]. J Vasc Surg
2011;53(1):254–5.

Interventions for venous leg ulcers

Barber GA, Weller CD, Gibson SJ. Effects and associations of nutrition in patients with venous leg ulcers: A systematic review. J
Adv Nurs 2018;74(4):774–87.

Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, et al. Comparison of surgery and compression with
compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet 2004;363(9424):1854–9.

Gohel MS, Heatley F, Liu X, Bradbury A, Bulbulia R, Cullum N, et al. A randomized trial of early endovenous ablation in venous
ulceration. N Engl J Med 2018;378(22):2105–14.

Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev
2012;12:CD001733.

Jull A, Wadham A, Bullen C, Parag V, Kerse N, Waters J. Low dose aspirin as adjuvant treatment for venous leg ulceration:
pragmatic, randomised, double blind, placebo controlled trial (Aspirin4VLU). BMJ 2017;359:j5157.

Klonizakis M, Tew GA, Gumber A, Crank H, King B, Middleton G, et al. Supervised exercise training as an adjunct therapy for
venous leg ulcers: a randomized controlled feasibility trial. Br J Dermatol 2018;178(5):1072–82.

Loden M. Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders. Am J Clin Dermatol
2003;4(11):771–88.

National Health and Medical Research Council (NHMRC). Australian Dietary Guidelines. Canberra: NHMRC; 2013.

Norman G, Westby MJ, Rithalia AD, Stubbs N, Soares MO, Dumville JC. Dressings and topical agents for treating venous leg
ulcers. Cochrane Database Syst Rev 2018;6:CD012583.

O'Donnell TF, Jr., Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, et al. Management of venous leg ulcers: clinical
practice guidelines of the Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg 2014;60(2 Suppl):3S–
59S.

O'Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev
2012;11:CD000265.

Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic venous leg ulcers: a national clinical guideline [SIGN
120]. Edinburgh: SIGN; 2010.

Wittens C, Davies AH, Baekgaard N, Broholm R, Cavezzi A, Chastanet S, et al. Editor's choice - management of chronic venous
disease: clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg
2015;49(6):678–737.

Preventing recurrence of venous leg ulcers

Finlayson K, Edwards H, Courtney M. Factors associated with recurrence of venous leg ulcers: a survey and retrospective chart
review. Int J Nurs Stud 2009;46(8):1071–8.

Franks PJ, Oldroyd MI, Dickson D, Sharp EJ, Moffatt CJ. Risk factors for leg ulcer recurrence: a randomized trial of two types of
compression stocking. Age Ageing 1995;24(6):490–4.

Nelson EA, Bell-Syer SE. Compression for preventing recurrence of venous ulcers. Cochrane Database Syst Rev 2014;
(9):CD002303.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and
distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Arterial leg ulcers
Introduction to arterial leg ulcers
Arterial leg ulcers are caused by peripheral arterial disease. Peripheral arterial disease is atherosclerotic disease of
the arteries in the extremities. Peripheral arterial disease affects 10 to 25% of people older than 55 years.
Although the majority of patients are asymptomatic and never require revascularisation, patients with peripheral
arterial disease have three times the risk of all-cause mortality and six times the risk of death from coronary artery
disease.

A clinical assessment, including history and physical examination (with emphasis on peripheral pulse palpation),
detects peripheral arterial disease in most cases. Arterial leg ulcers can be spontaneous or associated with trauma.

Determining the cause of a leg ulcer is essential to guide management; see Table 15.9 for advice on determining
the vascular cause of a leg ulcer. An overview of assessment and management of arterial leg ulcers is provided in
Figure 15.4.

The majority of arterial ulcers are on the foot. Management of arterial foot ulcers is the same as for arterial leg
ulcers. See also Wounds on a high-risk foot.

Prevention of arterial leg ulcers

There is limited evidence to inform prevention strategies for arterial ulcers. Ensure optimal management of
peripheral arterial disease (eg an exercise program, foot care [see Box 15.6], cardiovascular risk modification);
see Intermittent claudication. Measure ankle brachial pressure index (ABPI) every 6 to 12 months to assess
progression of peripheral arterial disease.

Assessment of arterial leg ulcers

For a structured approach to assessing patients with a leg ulcer, see Assessing patients with an ulcer or wound and
Figure 15.4.

Overview of assessment and management of arterial leg ulcers (Figure 15.4)

ABPI = ankle brachial pressure index

NB1: Refer patients for a comprehensive venous duplex scan because most leg ulcers are caused by venous disease.

NB2: Standard ulcer care is wound debridement and cleansing, diagnosing and minimising oedema, treating infection (if present), and optimising
moisture balance.
A patient with an arterial leg ulcer may have the following clinical features:

history of vascular disease (cardiac, cerebral, peripheral)

signs of ischaemia (cold, pale extremities; thin hairless skin)
pallor on elevation, redness on dependency
abnormal ankle brachial pressure index (ABPI) (usually less than 0.9, but ABPI may be artificially inflated
because arteries are calcified and noncompressible—most commonly from diabetes or kidney disease).

Leg ulcers due to peripheral arterial disease are often painful—pain is aggravated by elevation and relieved by
lowering the leg (eg over the side of the bed).

An arterial leg ulcer is shown in Photo 15.10. An arterial leg ulcer may have the following features:

location—usually toes, bony prominences, sides of feet, heel

edge—punched out
base—sloughy or covered by eschar
exudate—minimal.

In severe cases, an arterial ulcer may be associated with gangrene.

Example of an arterial leg ulcer (Photo 15.10)

Assess patients with peripheral arterial disease for signs of haemodynamic compromise. Palpation of peripheral
arterial pedal pulses (dorsalis pedis and posterior tibial) and auscultation for a femoral artery bruit has a high
positive predictive value (93.8%) for the detection of peripheral arterial disease. If femoral bruit is absent and
peripheral pedal pulses are present in both lower limbs, the patient is unlikely to have peripheral arterial disease.

Measuring the ABPI accurately detects peripheral arterial disease in most patients and provides prognostic
information (see Vascular assessment and ABPI). An ABPI less than 0.9 indicates peripheral arterial disease.

Patients with an arterial leg ulcer and an ankle pressure less than 60 mmHg or an ABPI 0.5 or less have a
threatened limb (see Critical limb ischaemia) and need urgent assessment by a vascular specialist. Patients with
diabetes require early specialist referral as they may have critical limb ischaemia at higher ankle pressures due to
the presence of neuropathy and infection.
For patients with an ABPI less than 0.9, undertake an arterial duplex scan to assess the anatomy of disease.

An ABPI higher than 1.3 does not exclude arterial disease because arteries can be calcified and noncompressible,
most commonly due to diabetes, age over 75 years and kidney disease. For patients with an ABPI greater than 1.3,
a toe pressure or toe brachial pressure index (TBPI) can be used to assess for arterial disease and likelihood of
wound healing—see Table 15.6 for interpretation.

Refer patients with a leg ulcer for a comprehensive venous duplex scan to detect venous insufficiency because
most leg ulcers are caused by venous disease, and chronic venous insufficiency can delay healing.

Interventions for arterial leg ulcers

Introduction
Standard ulcer care includes:

wound cleansing and debridement

diagnosing and minimising oedema (see Oedema and ulcer and wound healing)
treating infection, if present (see Ulcer and wound infection)
optimising wound moisture balance (see Ulcer and wound dressings).

Refer patients to a vascular specialist for consideration of revascularisation. Promote cardiovascular risk
modification, and monitor progress. Encourage patients to stop smoking, and optimise management of
comorbidities (especially diabetes, hypertension, hyperlipidaemia, obesity). Advise patients to care for the
surrounding skin (see Skin care) and assess the patient’s diet for nutritional deficiencies (see Nutrition).

Compression is not routinely indicated for patients with an arterial leg ulcer because it may further restrict blood
flow. However, it may be used by an appropriately trained healthcare professional for patients with mixed arterial
and venous disease, or who have another indication for compression (eg oedema), as long as the patient is
monitored regularly. See Compression therapy.

Ulcer dressing
In patients with arterial leg ulcers, no dressing has been shown to improve wound healing over any other dressing.
See Ulcer and wound dressings for advice on selecting an appropriate dressing.

Stable dry eschar (adherent, intact, without erythema or fluctuance) on the heel or foot serves as natural biological
cover and should not be removed. However, if eschar becomes loose, soggy, malodourous or starts to ooze or
separate from the edge, it should be removed.

Revascularisation

If peripheral arterial disease is detected, refer to a vascular specialist for revascularisation and assessment of
lower-limb perfusion. Conservative measures can be undertaken while the patient is waiting for specialist review,
but the referral must be made as soon as an arterial leg ulcer is diagnosed.

Peripheral arterial reconstructive surgery (open or endovascular) has a small but definite risk of severe
complications, is costly, and should not be performed unless there is a clear indication (eg critical limb
ischaemia).

Pain management
Pain is common in patients with arterial leg ulcers, and may be exacerbated by dressing changes. Prescribe
analgesia if required; see Ulcer and wound pain.

Footwear

Ill-fitting footwear may create pressure areas that lead to further ulceration. Advise patients to wear well-fitting,
closed footwear. Practice points for footwear are provided in Box 15.7. Refer to a podiatrist or orthotist if
specialised footwear is required. For patients with peripheral arterial disease and a foot wound, see Wounds on a
high-risk foot.

Pharmacological therapies
Oxpentifylline (pentoxifylline) and cilostazol may improve wound healing. Drugs used to reduce vascular events
in patients with peripheral arterial disease (eg lipid-lowering drugs, drugs to reduce blood pressure, antiplatelet
drugs) and vasodilators (eg calcium channel blockers, prostanoids) do not promote wound healing.

Review of arterial leg ulcers

Patients can deteriorate rapidly, so frequent review is needed initially (up to daily if compression is used). Regular
review (including monitoring for progression of arterial disease and cardiovascular risks) is needed. Frequency of
review depends on patient characteristics, and wound characteristics and progression. Risk factor modification
includes smoking cessation, diet modification, and exercise.

Educate patients to check their ulcer and advise their healthcare professional of any complications (eg worsening
pain or exudate).

If the ulcer is not healing as expected:

address the factors affecting ulcer and wound healing

refer to a specialist for management or assessment of arterial or venous disease
optimise management of comorbidities (eg heart failure, diabetes)
review the diagnosis (see Differential diagnoses for ulcers or wounds).

Key references
Introduction to arterial leg ulcers

Mohler ER, 3rd. Peripheral arterial disease: identification and implications. Arch Intern Med 2003;163(19):2306–14.

Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society consensus for the
management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007;33 Suppl 1: S1–75.

Norman PE, Eikelboom JW, Hankey GJ. Peripheral arterial disease: prognostic significance and prevention of
atherothrombotic complications. Med J Aust 2004;181(3):150–4.

Prevention of arterial leg ulcers

Hopf HW, Ueno C, Aslam R, Dardik A, Fife C, Grant L, et al. Guidelines for the prevention of lower extremity arterial
ulcers. Wound Repair Regen 2008;16(2):175–88.

Assessment of arterial leg ulcers

Armstrong DW, Tobin C, Matangi MF. The accuracy of the physical examination for the detection of lower extremity
peripheral arterial disease. Can J Cardiol 2010;26(10):e346–50.

Halliday A, Bax JJ. The 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in
collaboration with the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2018;55(3):301–2.

Mills JLSr., Conte MS, Armstrong DG, Pomposelli FB, Schanzer A, Sidawy AN, et al. The Society for Vascular
Surgery lower extremity threatened limb classification system: risk stratification based on wound, ischemia, and foot
infection (WIfI). J Vasc Surg 2014;59(1):220–34 e1-2.

Interventions for arterial leg ulcers

Forster R, Pagnamenta F. Dressings and topical agents for arterial leg ulcers. Cochrane Database Syst Rev 2015;
(6):CD001836.

Federman DG, Ladiiznski B, Dardik A, Kelly M, Shapshak D, Ueno CM, et al. Wound Healing Society 2014 update on
guidelines for arterial ulcers. Wound Repair Regen 2016;24(1):127–35.

Grey JE, Harding KG, Enoch S. Venous and arterial leg ulcers. BMJ 2006;332(7537):347–50.

Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen therapy for chronic
wounds. Cochrane Database Syst Rev 2015;(6):CD004123.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)
Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Mixed venous and arterial leg ulcers
Mixed venous and arterial leg ulcers
Mixed venous and arterial leg ulcers can occur; 10 to 15% of patients with a venous leg ulcer also have
peripheral arterial disease. The venous or arterial components may be unrecognised. Undertake a structured
assessment—see Assessing patients with an ulcer or wound.

Assess for venous and arterial disease; see Table 15.9. Although features of both are present, one may
dominate. Manage as directed by the patient’s dominant clinical features (see Venous leg ulcers or Arterial
leg ulcers).

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Leg ulcers not caused by venous or arterial disease
Leg ulcers not caused by venous or arterial disease
Leg ulcers are not always caused by venous or arterial disease. When a vascular cause has been excluded,
other causes of ulcers include autoimmune disease, malignancy, and trauma; see Differential diagnoses for
ulcers or wounds. An overview of management is provided in Figure 15.5.

Diagnose the cause of leg oedema and manage before interventions are undertaken; see Oedema and ulcer and
wound healing.

Assessment for venous insufficiency is required because venous leg ulcers are the most common type and
because venous insufficiency can contribute to delayed healing. Refer for a comprehensive venous duplex
scan by an experienced laboratory if significant improvement in ulcer healing has not occurred within 2 to 4
weeks. For other causes of delayed healing, see Factors affecting ulcer and wound healing.

Wound biopsy is recommended for leg ulcers that do not improve with optimal therapy after 4 weeks of
treatment, and for ulcers with atypical features (eg an irregular edge, abnormal colour and texture) or
distribution.

Overview of management of leg ulcers in patients without features of venous or arterial

disease (Figure 15.5)

NB1: Standard ulcer care is wound debridement and cleansing, diagnosing and minimising oedema, treating infection (if present), and
optimising moisture balance.
Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Compression therapy
Introduction to compression therapy
This topic provides information on compression therapy for the treatment of venous leg ulcers. Although compression is used for other indications
(eg lymphoedema), target compression levels differ to those used for venous leg ulcers. Patients with a venous leg ulcer should be referred for
correction of venous hypertension; see Venous leg ulcers.

Compression therapy is used as adjunctive therapy for venous leg ulcers to aid ulcer healing. It may also assist in prevention. Compression therapy
results in:

reduced blood pressure in the superficial venous system

improved venous return by increasing flow velocity in the deep veins
reduced oedema from decreased venous hypertension
enhanced lymphatic function.

Sustained graduated compression is the most effective way to achieve therapeutic results. The optimal compression is higher at the ankle, gradually
reducing towards the knee. The amount of pressure delivered depends on the design of the compression system and the size and shape of the patient’s
limb. Efficacy of compression therapy is enhanced by walking (ie using the calf muscle pump).

Compression therapy must only be prescribed by an appropriately trained healthcare professional. Examples of compression therapy include
compression bandages, compression stockings, wrap systems and biomechanical devices.

Compression therapy must be prescribed by an appropriately trained healthcare professional.

Standards of compression vary internationally. For simplicity, classes of compression are defined in this guideline as shown in Box 15.11.

Precautions for use of compression therapy

Compression therapy is not appropriate for all patients. Compression should be used with caution in people with peripheral arterial disease (see
Ankle brachial pressure index [ABPI]). Failure to diagnose arterial disease can result in unsafe use of compression therapy, potentially causing tissue
damage. Only trained healthcare professionals should prescribe compression therapy.

Before applying compression therapy, complete a comprehensive wound assessment and select an appropriate wound dressing to use under
compression.

Precautions of compression therapy include:

poor skin condition—delicate skin can be damaged by high pressure and shear forces during application of compression
abnormal limb shape—sub-bandage pressure is altered by limb shape
ulcer over bony prominences—these areas are at risk of pressure injury, so extra padding may be required
peripheral neuropathy—absent protective responses increase the risk of skin damage
heart failure—when compression bandaging is applied, large amounts of fluid may be returned quickly from the legs to the heart. Educate
patients to report symptoms of worsening heart failure (eg shortness of breath when lying flat, or waking up gasping for breath)
spinal cord injury—if patients have reduced sensation and ability to report complications, ensure adequate monitoring
clinical infection (including cellulitis)—compression may be too painful, so consider reducing or delaying until the infection has resolved.

Provide patients with information about their condition, and ensure patients understand the risks and benefits of compression. Education can improve
adherence to compression therapy. A patient information sheet on compression therapy is available (see Box 15.12). Patients or their carers must be
able to report problems, including:

numbness
pain
change in skin colour (blue, dusky) of their toes or foot
shortness of breath.

Review the patient 24 to 48 hours after starting compression therapy to assess tolerance.

Review the patient to assess tolerance and complications 24 to 48 hours after starting compression therapy. Worsening pain following application of
compression can indicate trauma or ischaemia. If this occurs, remove compression, review the limb and consider urgent referral if ischaemia is
present.

Assessment before compression therapy

Overview
Before applying compression therapy, a comprehensive assessment is required to ensure an accurate diagnosis and exclude significant arterial disease
(see Assessing patients with an ulcer or wound and Overview of leg ulcers). Undertake clinical assessment of the patient and an ankle brachial
pressure index (ABPI).

If ABPI measurement is not available, compression may be used—with close monitoring—if the patient has palpable pedal pulses (dorsalis pedis
and posterior tibial), no femoral artery bruit, intact peripheral sensation, adequate cognition to report a complication, and no clinical features that
suggest peripheral arterial disease.

Ankle brachial pressure index (ABPI)

The ABPI is the ratio of the ankle systolic blood pressure to the brachial systolic blood pressure. ABPI is measured using a sphygmomanometer and
handheld Doppler device. ABPI measurement is available in specialised wound clinics, community nursing services, podiatry services, some primary
care settings and vascular practices. A video showing how to undertake an ABPI is available here.
An ABPI less than 0.9 indicates peripheral arterial disease. An ABPI between 0.9 and 1.3 is considered normal (ie the patient does not have
peripheral arterial disease). Although the APBI is a useful noninvasive diagnostic test for objective assessment of arterial disease, it cannot be used
for patients with calcified vessels (eg in patients with diabetes, kidney disease, age over 75 years). Calcified arteries are noncompressible, causing an
artificially inflated arterial systolic blood pressure and subsequently elevating the ABPI. For patients with an ABPI above 1.3, or if the ABPI result
does not fit within the clinical context of the patient, a toe pressure or toe brachial pressure index may be useful; see Assessment for peripheral
arterial disease. An arterial duplex scan may be useful when clinical assessment suggests arterial impairment, and referral to a vascular specialist may
be necessary; see Arterial leg ulcers.

The APBI guides compression therapy for venous leg ulcers. ABPI values used for compression therapy are different to those used to diagnose
peripheral arterial disease. International expert consensus on correlating the ABPI to levels of compression for venous leg ulcers is lacking. However,
general rules for selecting compression therapy based on the ABPI are [Note 1]:

for any ABPI, if pedal pulses are not palpable—do not apply compression and seek expert advice
ABPI 0.5 or less—compression is contraindicated (see Figure 15.4)
ABPI above 0.5 up to 0.8—use class II compression with frequent monitoring, or class I if frequent monitoring is not possible
ABPI above 0.8 up to 1.3—use class III compression, or lower if not tolerated
ABPI above 1.3—further assessment is required; seek specialist advice.

Repeat ABPI regularly (eg 6 monthly) as part of a thorough clinical review in patients with nonhealing ulcers to exclude progression of arterial
disease.

Note 1: Classes of compression are shown in Box 15.11.

Guide to starting compression therapy

Undertake the following before prescribing compression therapy:

diagnose the aetiology of the ulcer (see Overview of leg ulcers)

identify any precautions for use of compression therapy
educate patient and carers (see Box 15.12)
discuss the cost
refer to vascular specialist (see Venous leg ulcers).

Practice points for applying compression are shown in Box 15.10.

Class III compression is recommended for venous leg ulcers. However, a lower class of compression (ie class II) may be needed initially if the ulcer
is inflamed and painful and higher levels of compression are not tolerated. A practical approach to implementing compression therapy is to start with
a three-layer elastic tubular system. This compression system is low cost, facilitates frequent dressing changes and is well tolerated; see Long-stretch
bandages. When ulcer pain and inflammation have improved (ie with standard ulcer care) and the ulcer is suitable for a weekly dressing, switch to
class III compression. Continue class III compression with weekly changes until the wound has healed, then switch to compression hosiery for
maintenance compression therapy.

Practice points for applying compression (Box 15.10)

follow manufacturer’s instructions

online resources (eg instructional videos) are available for some brands
contact the company representative—onsite training or other resources may be available
practicing improves competence
apply compression from the base of the toes to just below the knee
if using bandages, start at the toes and apply up the leg
generally the heel is included, unless otherwise specified by the manufacturer
if applying bandages, position the foot at 90 degrees during application

Types of compression therapy

Overview
Standards of compression vary internationally. For simplicity, classes of compression are defined in this guideline as shown in Box 15.11.

Definition of compression classes used in this guideline (Box 15.11)

class I provides less than 20 mmHg of compression at the ankle

class II provides 20 to 29 mmHg of compression at the ankle
class III provides 30 to 40 mmHg of compression at the ankle

Examples of compression therapy include compression bandages, compression stockings, wrap systems and biomechanical devices. In general, a
pressure of 30 to 40 mmHg at the ankle, reducing by 50% below the knee is considered optimal for treating venous disease. Therefore, for treatment
of a venous leg ulcer, class III compression is recommended, though patient comorbidities (particularly peripheral arterial disease, cognition) and
tolerability of compression must be considered; see Venous leg ulcers and Precautions for use of compression therapy.

For use of compression for other indications, seek specialist advice.

The amount of compression provided depends on the design of the compression system, the shape of the limb and the skill and technique of the
person applying the compression. An overview of compression systems in provided in Table 15.10. Graduated compression therapy is summarised in
Figure 15.6.

Overview of compression systems (Table 15.10)

Compression system Stiffness Examples [NB1] Comments

Has almost no ability to stretch. Produces higher working pressures than
Short-stretch Comprilan, Tensolan, Lastolan, long-stretch bandages.
(inelastic) high
Coban 2, Coban 2 Lite
bandaging Can be a single- or multilayer product that produces high working
pressures and low resting pressures. Most beneficial for mobile patients.
Has high extensibility. Produces lower working pressures than short-
stretch bandages. Often used for immobile patients because it provides
compression when patient is at rest.
Long-stretch Setopress, Surepress, Tensopress,
low Can be a single- or multilayer product. If multiple layers are used,
(elastic) bandaging Eloflex
stiffness increases due to friction between the layers.

A 3-layer tubular system is useful for a patient’s first compression

regimen, due to low cost and good tolerability.
Multicomponent Profore, Veno 4, PutterPro2, Comprised of both short- and long-stretch components. Often used for
high
bandages UrgoK2 immobile patients.
Generally used for prevention of a first ulcer or recurrence. The amount
Medical grade of compression depends on the product. Needs to be individually fitted.
Sigvaris, Elvarex, Elvarex Plus,
compression hosiery medium
Elvarex Soft, Jobst, Venosan Do not confuse with single-layer support stockings or antiembolic
(stockings)
stockings, which do not provide therapeutic compression.
Available as elastic or inelastic products. Generally have a flexible spine
with multiple overlapping bands secured with a loop and hook (ie Velcro)
medium to Circaid Juxtafit, Easywrap, fastener.
Compression wraps
high Readywrap, FarrowWrap
Useful for patients who have difficulty applying and removing
compression hosiery.
LX9 Compression Pump, Hydroven Continuous, intermittent or sequential cycles of compression, delivered
Pneumatic
variable 3, Compress DL2002D Sequential by a boot inflated with air.
compression
Compression Pump Can be easier to tolerate than bandages.
NB1: Brand examples are not exhaustive and are provided for illustrative purposes only; inclusion of a product in this table does not imply endorsement by the Ulcer and Wound Expert Group.

Overview of leg ulcer assessment and compression therapy (Figure 15.6) [NB1]

ABPI = ankle brachial pressure index

NB1: Patients may need to use a lower class of compression (ie class II compression) initially for tolerability, and escalate to class III compression as pain and inflammation resolve.

Adapted with permission from Royal Melbourne Hospital Royal Park Chronic Wound Service, 2005.

Compression bandages

Overview

A variety of compression bandaging systems are available, in single- or multilayer products, made of long-stretch (elastic) or short-stretch (inelastic)
components. Multicomponent systems combine both long- and short-stretch components. An overview of compression systems is provided in Table
15.10. International consensus on types and grades of compression bandaging is lacking.

Ideally, the first application of compression bandages is undertaken in the morning when there is less oedema. Bandages are generally applied in a
spiral or figure-of-eight pattern, according to the manufacturer’s instructions. Always apply a layer of padding underneath the compression bandage,
unless the first layer is a padding layer.

Apply compression bandages from the base of the toe to the just below the knee. Once compression therapy is established, it is usually worn
continuously (ie 24 hours a day) and changed weekly, depending on wound and patient characteristics. If exudate leaks through the bandage, adjust
the primary and secondary dressings to be more absorbent and consider more frequent dressing changes (see Ulcer and wound dressings). When
choosing a dressing or padding layer, remember that these can increase the total limb circumference. Increased limb circumference can change the
effectiveness of the compression, and increase exudate. Choose a dressing or padding sufficient to absorb exudate with minimal bulk. Compression
bandages should only be washed and reused according to the manufacturer’s instructions.

A patient information sheet on compression therapy is available—see Box 15.12.

Short-stretch bandages

Short-stretch (inelastic) bandages remain rigid when the calf muscle expands on movement, creating a high working pressure. When the patient is
resting, a marked decrease in compression occurs. The higher pressure exerted when the patient is mobile creates a massaging effect and helps the
calf muscle pump with venous return. As limb oedema reduces, particularly in the first week of compression therapy, short-stretch bandages may
become loose and require more frequent changes.

Long-stretch bandages

Long-stretch (elastic) bandages produce lower working pressures than short-stretch bandages.

Long-stretch bandages are useful in patients who are immobile because they provide compression while the patient is at rest.

Although tubular support bandages are not technically compression bandages, when combined in a three-layer system they provide adequate
compression for ulcer healing. A three-layer elastic tubular system is useful as the patient’s first compression regimen due to low cost and comfort.
The low cost and ease of application facilitates frequent wound review. A three-layer tubular system is created by applying three different lengths
(long—toe to knee, medium—toe to calf, short—toe to malleolus) of bandage on top of each other to create a pressure gradient. The bandages should
be of parallel design. Ideally, tubular bandages are for single use only.

Multicomponent compression bandage

A multicomponent compression bandage contains both long- and short-stretch components. Multiple layers increase the pressure applied by the
bandage and its stiffness.

Check the patient’s ankle circumference before applying these bandage systems, because many are designed for an ankle circumference between 18
and 25 cm. Follow the manufacturer’s instructions.

Pneumatic pump compression

Pneumatic pump compression is a mechanical method of delivering compression to swollen limbs. This technique has been used to treat venous leg
ulcers and limb swelling due to lymphoedema. Pressure is applied via a boot that is inflated by a machine. Pressure can be applied continuously,
intermittently, or in sequential cycles. For some patients it may be easier and more comfortable than bandages. It is generally used multiple times a
day, not continuously. Intermittent pneumatic compression can be considered if other compression options are not available, cannot be used, or have
not facilitated healing despite prolonged use.

Antiembolic stockings
Antiembolic stockings are not used to treat or prevent venous leg ulcers. They are only useful for patients in the supine position, and do not apply
sufficient compression.

Information for patients using compression therapy

An information sheet for patients using compression therapy is provided in Box 15.12.
Compression therapy—patient information sheet (Box 15.12)

Patient information sheet

Your health professional has recommended the following compression therapy as part of your treatment plan.

Class of compression prescribed_______________________(mmHg)

Product name___________________________________________________________________________

Size or style ____________________________________________________________________________

Type of compression: bandage / hosiery / tubular system / other____________________________________

To be applied by_____________________________when (how often)______________________________

To be worn: daytime only / day and night / other instructions:______________________________________

Benefits of compression

Compression therapy for venous leg ulcers improves the chance of healing and encourages faster healing. It also reduces the risk of another ulcer
forming, and controls swelling. Other symptoms (such as heaviness or aching in the legs, tingling or burning in the feet) may also improve with
compression therapy.

Risks of compression

When you start compression therapy, you may experience some discomfort as it starts to work—this is not unusual.

However, look out for the following:

pain, especially over bony areas such as shins or ankles

colour change of the toes, especially if they become pale or blue
tingling or numbness, especially in the toes or feet
increased pain or severe tightness at night.

If you have any of the above, contact a health professional immediately. If this is not possible, remove the compression at once and see a health
professional as soon as possible.

Other problems that may occur include:

shortness of breath when lying flat, or waking gasping for breath

skin damage
excessive ooze from the ulcer.

If any of the above occur, contact your treating health professional as soon as possible.

If any problems occur, contact (person or organisation)__________________________________________

(phone number)___________________________(other contact details)_____________________________

(days and times available)__________________________________________________________________

Key references
Aboyans V, Criqui MH, Abraham P, Allison MA, Creager MA, Diehm C, et al. Measurement and interpretation of the ankle-brachial index: a scientific
statement from the American Heart Association. Circulation 2012;126(24):2890–2909.

Annells M, O’Neill J, Flowers C. Compression bandaging for venous leg ulcers: the essentialness of a willing patient. J Clin Nurs 2008;17(3):350–9.

Ashby RL, Gabe R, Ali S, Saramago P, Chuang LH, Adderley U, et al. VenUS IV (Venous leg Ulcer Study IV) - compression hosiery compared with
compression bandaging in the treatment of venous leg ulcers: a randomised controlled trial, mixed-treatment comparison and decision-analytic model.
Health Technol Assess 2014;18(57):1–293, v-vi.

Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med 2006;355(5):488–98.

Donnelly R, Emslie-Smith AM, Gardner ID, Morris AD. ABC of arterial and venous disease: vascular complications of diabetes. BMJ
2000;320(7241):1062–6.

Donnelly R, Hinwood D, London NJ. ABC of arterial and venous disease. Non-invasive methods of arterial and venous assessment. BMJ
2000;320(7236):698–701.

Dowsett C. Treatment and prevention of recurrence of venous leg ulcers using RAL hosiery. Wounds UK. 2011;7(1): 115–9.

Franks PJ, Barker J, Collier M, Gethin G, Haesler E, Jawien A, et al. Management of patients with venous leg ulcers: Challenges and current best
practice. J Wound Care 2016;25 Suppl 6:S1–S67.

Gottrup F, Apelqvist J, Price PEuropean Wound Management Association Patient Outcome Group. Outcomes in controlled and comparative studies on
non-healing wounds: recommendations to improve the quality of evidence in wound management. J Wound Care 2010;19(6):237–68.

Grey JE, Harding KG, Enoch S. Venous and arterial leg ulcers. BMJ 2006;332(7537):347–50.

Hafner J, Botonakis I, Burg G. A comparison of multilayer bandage systems during rest, exercise, and over 2 days of wear time. Arch Dermatol
2000;136(7):857–63.
Harding, K, Dowsett C, Fias L, Jelnes R, Mosti G, Öien R, et al. Simplifying venous leg ulcer management. Consensus recommendations. London:
Wounds International, 2015.

Mosti G, Mattaliano V, Partsch H. Inelastic compression increases venous ejection fraction more than elastic bandages in patients with superficial venous
reflux. Phlebology 2008;23(6):287–94.

Mosti G, Mattaliano R, Polignano R, Masina M. Compression therapy in the treatment of leg ulcers. Acta Vulnologica 2009;7(3):1–43.

Newall N, Miller C, Lewin G, Kapp S, Gliddon T, Carville K, et al. Nurses’ experiences of participating in a randomised controlled trial (RCT) in the
community. Wound Prac Res 2009;17(1):24–34.

O’Donnell TF, Jr., Passman MA, Marston WA, Ennis WJ, Dalsing M, Kistner RL, et al. Management of venous leg ulcers: clinical practice guidelines of the
Society for Vascular Surgery (R) and the American Venous Forum. J Vasc Surg 2014;60(2 Suppl):3S–59S.

O’Meara S, Cullum N, Nelson EA, Dumville JC. Compression for venous leg ulcers. Cochrane Database Syst Rev 2012;11:CD000265.

Partsch H, Mortimer P. Compression for leg wounds. Br J Dermatol 2015;173(2):359–69.

Rowland J. Intermittent pump versus compression bandages in the treatment of venous leg ulcers. Aust N Z J Surg 2000;70(2):110–3.

Royal College of Nursing (RCN). Clinical practice guidelines: the management of patients with venous leg ulcers. Audit protocool. London: RCN, 2010.
www.rcn.org.uk/professional-development/publications/pub-001269

Scottish Intercollegiate Guidelines Network (SIGN). Management of chronic venous leg ulcers:, a national clinical guideline [SIGN 120]. Edinburgh: SIGN;
2010.

Sibley RC3rd, Reis SP, MacFarlane JJ, Reddick MA, Kalva SP, Sutphin PD. Noninvasive physiologic vascular studies: a guide to diagnosing peripheral
arterial disease. Radiographics 2017;37(1):346–57.

Singer AJ, Tassiopoulos A, Kirsner RS. Evaluation and management of lower-extremity ulcers. N Engl J Med 2017;377(16):1559–67.

Todd M. Compression bandaging: types and skills used in practical application. Br J Nurs 2011;20(11):681–2, 4, 6–7.

Vowden K, Vowden P. Effective compression therapy. Wound Essentials 2012;7(2).

Weller CD, Evans SM, Staples MP, Aldons P, McNeil JJ. Randomized clinical trial of three-layer tubular bandaging system for venous leg ulcers. Wound
Repair Regen 2012;20(6):822–9.

Weller CD, Jolley D, McNeil J. Sub-bandage pressure difference of tubular form and short-stretch compression bandages: in vivo randomised controlled
trial. Wound Practice and Research 2010;18(2):100–5.

Weller C, Jolley D, Wolfe R, Myers K, McNeil J. Effect of elasticity on subbandage pressure of three layer tubular compression bandages in healthy
volunteers: a RCT. J Wound Care 2010;19(10):417, 20–3.

Wittens C, Davies AH, Baekgaard N, Broholm R, Cavezzi A, Chastanet S, et al. Editor’schoice - management of chronic venous disease: clinical practice
guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg 2015;49(6):678–737.

Wound Healing and Management Node Group. Recommended practice: Ankle-Brachial Pressure Index (ABPI) using hand-held Doppler ultrasound.
Wound Prac Res 2014;22(2):102–3.

Wounds International. Compression in venous leg ulcers. a WUWHS consensus document. London: Wounds International, 2009.

Wounds International. Principles of compression in venous disease: a practitioner’s guide to treatment and prevention of venous leg ulcers. London:
Wounds International; 2013.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world literature, interpreted and distilled by Australia's most
eminent and respected experts. © Therapeutic Guidelines Ltd
Cleansing and debridement
Cleansing the ulcer or wound
Introduction
Ulcer or wound cleansing is a fundamental element of wound management. Cleansing aims to remove debris,
contaminants, bacteria, nonviable tissue (dead or dying) and excess exudate from the wound bed and
surrounding skin. This creates an optimal environment for wound healing.

Wounds should be adequately cleansed initially and at every dressing change. Wounds should be cleansed
before collecting swabs (see Ulcer or wound swabs). Cleansing agents should be warmed to body temperature
for use.

Chronic wounds require cleansing because they produce exudate and slough, and because particulate matter
from dressings, products of cell turnover and bacteria can contaminate the wound. Over time, a biofilm may
develop and impair wound healing.

Biofilms cannot be seen. They consist of aggregates of bacteria encased in polysaccharides, which are
impenetrable to the host’s immune system. Biofilms are extremely difficult to eradicate; surgical or
mechanical wound debridement is often required. After adequate debridement, re-establishment of a biofilm
may be minimised by use of a noncytotoxic antiseptic solution.

For information about identifying and treating wound infection, see Ulcer and wound infection.

Always educate the patient or their carer about how to cleanse the wound; patient information sheets are
available [Note 1].

Note 1: Available from Wounds Australia [registration required].

Cleansing solutions

Ideally, use sterile solutions (eg 0.9% sodium chloride, Hartmann solution or Ringer lactate) for standard
wound cleansing. Alternatively, potable water can be used if sterile solutions are not readily available.

Antiseptic solutions can be used if the wound is dirty or clinically infected. Aqueous-based chlorhexidine, or
povidone-iodine solution, are preferred due to efficacy. After 5 minutes, wash off the chlorhexidine or
povidone-iodine. Avoid dripping and pooling of povidone-iodine. Additionally, do not apply povidone-iodine
under an occlusive dressing or device.

Noncytotoxic antiseptic solutions, for example polyhexamethylene biguanide (PHMB, Prontosan), octenidine
dihydrochloride (Octenilin), and hypochlorous acid and sodium hypochlorite (Microdacyn) are available,
though there is limited clinical evidence to support routine use. Noncytotoxic antiseptics should not be
washed off because the onset of action is slower and cytotoxicity is not a concern.

Cytotoxic antiseptics (eg hydrogen peroxide and sodium hypochlorite [including EUSOL]) are not
recommended.

For venous leg ulcers that are progressing as expected, there is no high-level evidence to support routine use
of povidone-iodine, chlorhexidine, sodium hypochlorite (including dilute solutions), peroxide-based
preparations, ethacridine lactate, chloramphenicol, framycetin or mupirocin.

In general, topical antibiotics are not recommended because they have no demonstrated effect on healing and
can promote antimicrobial resistance; see Ulcer and wound infection.

Overview of wound debridement

Debridement is an important step in preparing the wound bed for healing, and to facilitate dressing efficacy.
Debridement describes methods that facilitate removal of necrotic (dead) tissue, metabolic waste, fibrin and
foreign material from a wound. Necrotic tissue impairs wound healing by stimulating inflammation and
delaying granulation and epithelialisation. Debridement removes senescent cells (that are no longer dividing)
from the wound bed and nonmigratory cells from the wound edge. It can help manage infection by removing
infected tissue from the wound bed.

Necrotic tissue can be removed using autolytic, sharp, surgical, mechanical (ie hydrosurgical, ultrasound),
biological or enzymatic debridement. There is insufficient evidence to conclude that one method of debriding
is superior to another. Selective methods of debridement are generally preferred because they only remove
necrotic tissue. For some wounds, more than one method of debridement may be appropriate.

The most appropriate debridement method is determined by many factors, including:

the patient’s setting (eg in the community compared to in hospital)

the patient’s wishes, concerns and medical history
the wound (consider pain, pathophysiology, size, depth, position, amount of exudate, the wound tissue,
potential for bleeding, risk of infection)
the skill and knowledge of the clinician and available resources
the cost of the procedure.

Debridement is not indicated in some instances, and sometimes specialist referral may be required; see Box
15.13. If stable dry eschar (adherent, intact, without erythema or fluctuance) is present, debridement should
not be undertaken until arterial flow has been ensured or re-established.

When not to debride an ulcer or wound (Box 15.13)

Do not debride:

stable dry eschar (unless there is adequate perfusion to the area)

wounds with an inflammatory pathology (eg pyoderma gangrenosum)
wounds with a prosthetic implant (requires specialist surgical assessment)
wounds associated with congenital malformation, suspected or confirmed malignancy or if standard
anatomy has been altered (requires specialist surgical assessment)
lower-limb wounds in patients with arterial disease (requires specialist vascular assessment).

Debride the following with caution (usually performed by a specialist):

extensive necrotic tissue

wounds on the hands or face
wounds with exposed bone.

Practitioners undertaking debridement should ensure they have appropriate competency.

Autolytic wound debridement

Autolytic debridement is the most common method of debridement. With this method, the body’s cells and
enzymes break down and remove devitalised tissue. This process is facilitated by a moist wound environment.
As a certain amount of exudate is needed, maceration of tissue surrounding the wound can occur. Autolytic
debridement is noninvasive and selective, but it can be slow. It can be particularly useful for patients if sharp
debridement is not available or inappropriate.

Do not induce autolytic debridement for clinically infected wounds, or for patients with a high risk of
anaerobic infection (eg patients with diabetes or extensive necrotic tissue), or with ischaemia of a limb or
digit.

Conservative sharp wound debridement

Sharp wound debridement facilitates selective removal of dead tissue using sharp, sterile instruments (eg
scalpel, scissors, curette).

Conservative sharp debridement can be performed at the bedside. An anaesthetic agent may not be required
because the margin of necrotic tissue is not exceeded. However, topical anaesthetics may be needed for
cleansing or dressing removal before debridement.

More extensive sharp debridement exposes healthy tissue and requires topical local anaesthetic agents (eg
eutectic mixture of local anaesthetics [EMLA 5%], lidocaine).

Although this method has similar risks to surgical debridement, the magnitude of the risk is smaller.

Surgical wound debridement

Surgical debridement is usually performed in an operating theatre, using regional or general anaesthetic.
Increasingly, it is being performed with topical or directly infiltrated local anaesthetic. Surgical wound
debridement is indicated for wounds with extensive necrotic tissue, or to control infection (eg for severe
cellulitis or osteomyelitis).

This method of debridement is the most rapid and highly selective. However, the degree of expertise required
increases the cost and limits availability. Surgical debridement has an increased risk of pain, bleeding,
infection (including bloodstream infection) and damage to underlying structures, including tendon sheaths and
nerves. There are also risks associated with the anaesthesia. Caution is required for patients with a high risk of
bleeding (eg those with clotting disorders or taking an anticoagulant) and in patients with diabetes or
peripheral arterial disease.

Mechanical wound debridement

Mechanical debridement physically removes debris from the wound bed. Methods include whirlpool therapy,
pulsed lavage, ultrasound, debridement pads, open-weave gauze, blunt curettage, hydrosurgical debridement
and wet-to-dry dressings.

Pain from mechanical debridement may be alleviated with topical local anaesthetics (eg eutectic mixture of
local anaesthetics [EMLA 5%], lidocaine).

Dressing debridement uses wet-to-dry or sodium chloride soaked gauze dressings. It is not recommended
because it is associated with an increased risk of infection, damage to granulation tissue (because it is
nonselective), prolonged inflammation, and maceration around the wound.

Hydrosurgical debridement
Hydrosurgical debridement uses a high-pressure saline jet to remove necrotic tissue. A small randomised
controlled trial compared hydrosurgical debridement (Versajet) with sharp debridement for patients with
venous leg ulcers and diabetic foot ulcers. Despite reporting shorter procedural time for the Versajet system,
no overall benefit in healing rates was found [Note 2].

Given the uncertain relationship between debridement and healing, it is not possible to routinely recommend
hydrosurgical debridement at the time of writing.

Note 2: Caputo WJ, Beggs DJ, DeFede JL, Simm L, Dharma H. A prospective randomised controlled clinical trial comparing hydrosurgery
debridement with conventional surgical debridement in lower extremity ulcers. Int Wound J 2008;5(2):288–94. [URL]

Ultrasound debridement
Low-frequency ultrasound (approximately 30 kHz) can be safely employed as local treatment of chronic
venous leg ulcers. In a randomised trial, low-frequency ultrasound was beneficial for wound size reduction
compared to conventional wound therapy [Note 3]. It may be a treatment option in venous leg ulcers
refractory to conventional management. Ultrasound debridement has been used for wound cleansing, and to
remove biofilm in wounds on ischaemic limbs, diabetic foot wounds and for patients not suitable for surgery.
However, evidence to support its routine use is not available.

Note 3: Gibbons GW, Orgill DP, Serena TE, Novoung A, O’Connell JB, Li WW, et al. A prospective, randomized, controlled trial comparing the
effects of noncontact, low-frequency ultrasound to standard care in healing venous leg ulcers. Ostomy Wound Manage 2015;61(1):16–29.
[URL]
Biological wound debridement
In biological debridement, larvae (pathogen-free maggots of the green bottle fly Lucilia sericata) are applied
to the wound bed. This therapy was compared with hydrogel dressings in a large randomised controlled trial
and demonstrated significantly faster debridement, but did not find faster ulcer healing or increased rates of
healing [Note 4].

Note 4: Dumville JC, Worthy G, Bland JM, Cullum N, Dowson C, Iglesias C, et al. Larval therapy for leg ulcers (VenUS II): randomised
controlled trial. BMJ 2009;338:b773. [URL]

Enzymatic wound debridement

Enzymatic debridement is topical application of an exogenous enzyme to the wound bed, to facilitate a host
response. Topical enzyme agents may be derived from plants, animals or microbes. At the time of publication,
no enzymatic dressings are available in Australia.

Key references
Ayello EA, Cuddigan JE. Debridement: controlling the necrotic/cellular burden. Adv Skin Wound Care
2004;17(2):66–75; quiz 6–8.

Baranoski S, Ayello EA. Wound debridement. In: Wound care essentials. 2nd ed. Ambler, PA: Lippincott Williams
& Wilkins; 2008.

Bellingeri A, Falciani F, Traspedini P, Moscatelli A, Russo A, Tino G, et al. Effect of a wound cleansing solution on
wound bed preparation and inflammation in chronic wounds: a single-blind RCT. J Wound Care 2016;25(3):160,
2–6, 8.

Bianchi T, Wolcott RD, Peghetti A, Leaper D, Cutting K, Polignano R, et al. Recommendations for the
management of biofilm: a consensus document. J Wound Care 2016;25(6):305–17.

Briggs M, Nelson EA, Martyn-St James M. Topical agents or dressings for pain in venous leg ulcers. Cochrane
Database Syst Rev 2012;11:CD001177.

Caputo WJ, Beggs DJ, DeFede JL, Simm L, Dharma H. A prospective randomised controlled clinical trial
comparing hydrosurgery debridement with conventional surgical debridement in lower extremity ulcers. Int Wound
J 2008;5(2):288–94.

Dumville JC, Worthy G, Bland JM, Cullum N, Dowson C, Iglesias C, et al. Larval therapy for leg ulcers (VenUS II):
randomised controlled trial. BMJ 2009;338:b773.

Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al. VenUS II: a randomised controlled
trial of larval therapy in the management of leg ulcers. Health Technol Assess 2009;13(55):1–182, iii-iv. .

Dynamic Quality Improvement Programme, Royal College of Nursing (RCN) Institute. The management of
patients with venous leg ulcers. Audit protocol [Clinical practice guidelines]. London: RCN; 2000.
www.rcn.org.uk/professional-development/publications/pub-001269

Ennis WJ, Valdes W, Gainer M, Meneses P. Evaluation of clinical effectiveness of MIST ultrasound therapy for the
healing of chronic wounds. Adv Skin Wound Care 2006;19(8):437–46.

Gethin G, Cowman S, Kolbach DN. Debridement for venous leg ulcers. Cochrane Database Syst Rev 2015;
(9):CD008599.

Gibbons GW, Orgill DP, Serena TE, Novoung A, O’Connell JB, Li WW, et al. A prospective, randomized,
controlled trial comparing the effects of noncontact, low-frequency ultrasound to standard care in healing venous
leg ulcers. Ostomy Wound Manage 2015;61(1):16–29.

Gottrup F, Apelqvist J, Bjarnsholt T, Cooper R, Moore Z, Peters EJ, et al. EWMA document: Antimicrobials and
non-healing wounds. Evidence, controversies and suggestions. J Wound Care 2013;22(5 Suppl):S1–89.
Gray D, Acton C, Chadwick P, Fumarola S, Leaper, D, Morris C, et al. Consensus guidance for the use of
debridement techniques in the UK. Wounds UK 2010;6(4).

Hopf HW, Ueno C, Aslam R, Burnand K, Fife C, Grant L, et al. Guidelines for the treatment of arterial insufficiency
ulcers. Wound Repair Regen 2006;14(6):693–710.

Johani K, Malone M, Jensen SO, Dickson HG, Gosbell IB, Hu H, et al. Evaluation of short exposure times of
antimicrobial wound solutions against microbial biofilms: from in vitro to in vivo. J Antimicrob Chemother
2018;73(2):494–502.

Kirshen C, Woo K, Ayello EA, Sibbald RG. Debridement: a vital component of wound bed preparation. Adv Skin
Wound Care 2006;19(9):506–17; quiz 17–9.

McLain NEM, Moore ZEH. Wound cleansing for treating venous leg ulcers Cochrane Database Syst Rev 2015;
(4):CD011675.

Moffatt C, Morison MJ, Pina E. Wound bed preparation for venous leg ulcers. In: European Wound Management
Association. Wound bed preparation in practice [Position document]. London: Medical Education Partnership Ltd;
2004. p. 12–7. http://ewma.org/resources/for-professionals/ewma-documents-and-joint-publications/ewma-
position-documents-2002-2008/

O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for
venous leg ulcers. Cochrane Database Syst Rev 2014;(1):CD003557.

Stanisic MM, Provo BJ, Larson DL, Kloth LC. Wound debridement with 25 kHz ultrasound. Adv Skin Wound Care
2005;18(9):484–90.

Uhlemann C, Heinig B, Wollina U. Therapeutic ultrasound in lower extremity wound management. Int J Low
Extrem Wounds 2003;2(3):152–7.

Whitney J, Phillips L, Aslam R, Barbul A, Gottrup F, Gould L, et al. Guidelines for the treatment of pressure ulcers.
Wound Repair Regen 2006;14(6):663–79.

Williams D, Enoch S, Miller D, Harris K, Price P, Harding KG. Effect of sharp debridement using curette on
recalcitrant nonhealing venous leg ulcers: a concurrently controlled, prospective cohort study. Wound Repair
Regen 2005;13(2):131–7.

World Union of Wound Healing Societies. Principles of best practice: wound exudate and the role of dressings
[consensus document]. London: Medical Education Partnership; 2007.

Wound Healing and Management Node Group. Evidence summary: Wound management: debridement - wet-to-
dry moistened gauze. Wound Prac Res 2013;21(4):190–2.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Ulcer and wound dressings
Introduction to ulcer and wound dressings
A wound dressing is a product intended for application to a wound. This is not limited to dressing pads, and
can include tulle, films, gels, bandages and pumps.

Wound dressings are used to:

optimise the wound environment

cover and protect the area
minimise contamination and infection
provide comfort
facilitate the patient’s needs (eg allow showering).

Dressings do not heal wounds.

Dressings do not heal wounds. The aetiology of the wound must be accurately diagnosed, and the patient must
have the physiologic capacity for tissue repair (eg adequate blood supply); see Fundamentals of ulcer and
wound management. Additionally, factors impairing wound healing (eg venous hypertension, smoking,
oedema, pressure) must be addressed; see Factors affecting ulcer and wound healing and Venous leg ulcers.

Before choosing a dressing, assess the wound characteristics using the TIME acronym (see Table 15.2).
Wounds should be cleansed at each dressing change, and if nonviable tissue is present, consider debridement
(see Cleansing and debridement). For clinically infected wounds, see Ulcer and wound infection.

The primary consideration when selecting a dressing is exudate management because maintaining an
appropriate moisture balance optimises healing. Within each class of dressing, there is little evidence to
recommend one dressing over another.

Secondary considerations when selecting a dressing include:

the aetiology and pathophysiology of the wound

the prognosis
patient preference
the wound tissue (eg need for autolytic debridement of nonviable tissue)
presence or risk of infection
wound depth
skin condition (both prior to wounding, and the skin surrounding the wound)
wound-related pain (including pain when applying and removing dressings).

Occasionally, multiple layers of dressings are required. The dressing in contact with the wound is the primary
dressing. If a dressing is placed over this, it is called the secondary dressing. More than two layers of
dressings are generally not necessary. The choice of dressing and the frequency of dressing changes is known
as the dressing regimen. Patients may request dressing change at the first sign of strikethrough, but this is
often not necessary.

Healthcare professionals must understand how to use the dressings they recommend. This includes the
following: functionality; clinical indications; technique for application and removal; when the dressing should
be changed; the expected behaviour of the dressing when in use; and any precautions and contraindications. If
there is uncertainty about the dressing or how it is used, seek specialist advice or contact the manufacturer.

Educate patients and carers about how to manage the dressing. Inform patients and carers about:

the expected wear time (ie duration between dressing changes)

what to do if the dressing becomes dislodged, contaminated or leaks
the expected dressing appearance during the wear time
managing the dressing while showering or bathing
what to report to a healthcare professional (eg increased pain, exudate volume, odour)
who will change dressings and when
 if the patient or carer is to change dressings, how to change the dressing and where to purchase
dressings.

How to navigate this topic

This topic details the considerations for choosing a dressing, including:

moisture balance
cost
previous reactions to a dressing
retaining a dressing
protecting skin around the wound.

Dressings for specific ulcer or wound characteristics are also discussed, including:

cavity wounds
infected wounds
malodorous wounds
wounds with hypergranulation tissue
painful wounds.

Guides to choosing an ulcer or wound dressing are provided. See:

Table 15.11 for an overview of appropriate wound dressings based on the wound characteristics
Table 15.23 for advice on how to choose a new dressing after a dressing change.

Considerations for choosing a dressing

Ulcer or wound moisture balance
Optimal wound healing is achieved by maintaining an appropriate moisture balance. An optimally moist
wound environment facilitates autolytic debridement and stimulates granulation tissue. Excessive moisture or
exudate can lead to leakage and soiling, formation of unhealthy granulation tissue, and maceration of the
surrounding skin (which impairs epithelialisation). Insufficient moisture or exudate can result in a dry wound
bed, delayed autolysis, or the dressing adhering to the wound.

Moisture can be controlled by the choice of dressing and the frequency of dressing changes (the dressing
regimen). For information about choosing a dressing based on wound characteristics, see Table 15.11 and
Dressings for specific ulcer or wound characteristics.

Assessment of wound moisture includes identifying the type of exudate and describing its characteristics.
Normal (serous) exudate is clear or a pale amber colour, with a watery consistency. Other types of exudate
include haemoserous (sanguineous), haemopurulent, seropurulent, and purulent. The main factors to assess
when describing exudate are colour, quantity, and consistency. Record the volume of exudate as none, scant,
small, moderate or heavy in clinical notes. Persistent excessive amounts of exudate require investigation (eg
inadequate therapy for venous leg ulcers).

Reassess the dressing regimen at each dressing change.

To determine if a wound dressing regimen is appropriate, assess the dressing in situ and on removal (ie before
discarding the dressing or cleansing the wound). Wound moisture levels vary over time, and the
appropriateness of the dressing regimen should be reassessed at every dressing change. This includes
reviewing the degree of dressing saturation, its absorbency capacity, and the duration in situ. However, unless
there is a clear problem (eg pain, excessive exudate; see Table 15.23), do not alter the dressing regimen.
Ideally, a dressing regimen should remain constant for at least 2 weeks.

Cost of dressings
Ideally, a wound dressing regimen is based on cost-per-outcome rather than cost-per-dressing. Although basic
dressings are often cheaper per item, they can prolong healing. Specialised dressings are often more expensive
and are sometimes continued for prolonged periods without clinical benefit.

Healthcare professionals recommending and using dressings should be aware of the cost. Patient expense
must be considered in the management plan and discussed with the patient. Educate patients and carers about
the dressings, and how to care for them to avoid waste.

For wounds that are unlikely to heal (where the goal is maintenance or palliation), consider using basic
dressings and minimising dressing changes.

Many dressings do not need to be changed until they are at least 75% saturated. Reduce unnecessary dressing
changes and choose the appropriate dressing for the amount of wound exudate.

For eligible Department of Veterans Affairs (DVA) cardholders, many dressings for chronic wounds are
available on the Repatriation Schedule of Pharmaceutical Benefits Scheme (RPBS). Refer to the PBS website
for more information.

Previous reactions to ulcer and wound dressings

Many patients report allergies to wound dressings. Skin redness underneath the dressing can occur for many
reasons (eg accumulation of moisture under the dressing, infection); allergy should not be assumed. Dressings
can cause irritant contact dermatitis or allergic contact dermatitis; see Contact dermatitis. Topical antibiotics
can be sensitising agents, especially with prolonged use, resulting in an allergic dermatitis after repeated
exposure. Poor skin condition and using creams or ointments under a dressing also increase the risk of an
adverse reaction. Medical adhesive–related skin injury can also occur; see Retaining ulcer and wound
dressings.

Accurate diagnosis of the cause of skin redness is important. If patients are considered allergic to a dressing,
their options will be restricted. See Box 15.14 for alternative causes of redness. If patients report an allergy to
a dressing, ask about the reaction, the previous wound characteristics and use of other dressings to determine
the likelihood of allergy. Specialist review (by an immunologist or dermatologist) may be required.

Retaining ulcer and wound dressings

Nonadhesive dressings can be held in place using tapes and film dressings, but these may cause medical
adhesive–related skin injury on removal. Skin injury occurs as superficial layers of skin are removed by the
adhesive. If the skin is fragile and adhesive fixation is required, consider using a tape or film dressing with a
silicone adhesive. Nonadhesive options can also be used; these include tubular or cohesive bandages. Crepe
bandages are not recommended as a fixation method because they are bulky, can have a tourniquet effect and
lose elasticity.

Protecting skin around the wound

Consider the skin around the wound when selecting a dressing. Use a dressing or retention system that does
not cause further damage to tissue. Tissue damage can be caused by excessive exudate or moisture on the skin
around the wound. This is managed by using a dressing that is appropriate to the amount of exudate (see Table
15.11).

Regular washing of intact skin around the wound using a pH-appropriate cleanser is recommended (see Box
15.9). Wipes that leave a protective polymer film on the skin can be considered, though these are not
recommended for use under dressings with a silicone contact layer.

Avoid medical adhesive–related skin injury. Choose dressings that will not adhere to the wound. Remove
dressings carefully; avoid harshly pulling dressings off. If a dressing has adhered to the wound, soaking the
dressing with a solution containing a surfactant or softening agent (eg Prontosan, Octenilin) for at least 10
minutes can assist with removal.

Dressings for specific ulcer or wound characteristics

Introduction

This section provides advice for:

cavity wounds
infected wounds
malodorous wounds
wounds with hypergranulation tissue
painful wounds.
For advice about dressings for fragile skin, extensive wounds, dry wounds, moist wounds and wet wounds,
see Table 15.11.

Cavity wounds

Assess the dimensions and characteristics of a cavity wound to determine management.

Wounds with dead space (ie cavity wounds) usually require packing. Packing a cavity wound aims to
encourage healing from the base. If the wound heals across the surface, pockets can form that can become an
abscess.

Wound packing should loosely fill dead space. Considerations include:

whether the wound base is entirely visible

cavity depth
exudate quantity and consistency
location
aetiology.

Packing a wound can lead to adverse outcomes including putting pressure on tissues (which prevents healing
and may cause tissue damage), impeding exudate drainage, and retention of packing material. Generally
fistulae are not packed. Other wounds in which packing may be inappropriate include narrow sinus tracts
(where packing prevents drainage of fluid), or wounds with undermining (where tissue surfaces are close
together and packing may produce excessive pressure).

If packing is appropriate, use a dressing that does not lose its integrity when saturated, and can be removed in
one piece without causing tissue trauma. Always leave a ‘tail’ of dressing outside the wound.

For cavity wounds with low exudate, consider an impregnated hydrogel dressing.

For cavity wounds with moderate to heavy exudate, consider a gelling fibre, hydrocapillary action dressing
(see Table 15.22), or a non-film backed foam covered with an absorbent pad dressing.

Specialised cavity dressings also exist.

At each dressing change, document anything removed from or put into the wound.

Infected wounds

All chronic wounds contain bacteria. This can represent normal flora, colonisation or infection (see Table
15.24).

For clinically infected wounds, collect a wound swab using the Levine technique. For management of infected
wounds, see Ulcer and wound infection.

Antimicrobial dressings are listed in Table 15.22. Assess the efficacy of antimicrobial dressings after 2 weeks.
If clinical signs of infection have not improved, or there are no signs of healing, consider an alternative
antimicrobial dressing, the need for systemic antibiotic therapy, and other factors affecting ulcer and wound
healing. Specialist advice or review may be required. Antimicrobial dressings are usually not continued for
prolonged periods.

Malodorous wounds

Malodour can be caused by a number of factors, such as infection, exudate or necrotic tissue. Always address
the cause of odour, if possible. For management of infection, see Ulcer and wound infection.

Local management strategies include topical metronidazole gel (use 0.75% gel applied to wound once or
twice daily at dressing change) and a foam dressing (including charcoal-containing foam), gauze soaked in an
antimicrobial solution, or an antimicrobial dressing. More frequent dressing changes and wound
cleansing also reduce odour.

Mechanical or sharp debridement to remove necrotic tissue may be indicated.

If the cause of the odour is unable to be managed (eg a malignant wound), consider a dressing containing
activated charcoal to adsorb odour. See Table 15.22 for examples.
Wounds with hypergranulation tissue

Hypergranulation is abnormal tissue that interferes with epithelialisation. It bleeds easily, is soft and spongy,
and exceeds the wound margins. Hypergranulation often occurs in an excessively moist wound, and can be
associated with covert infection or chronic inflammation.

Treatment options include hypertonic saline gauze, or foam dressings with silver (eg Biatain Ag; see Table
15.22). Silver nitrate can be effective for small areas of hypergranulation tissue; however, silver nitrate is
caustic, so should only be used short term. Alternatively, consider removal of hypergranulation tissue by
mechanical or sharp debridement.

Hypergranulation tissue can be a sign of a malignant wound, so wound and patient history, and clinical
presentation are important. Undertake a biopsy (for histopathology) of hypergranulation tissue that does not
respond to standard treatment or for wounds with an atypical appearance.

Painful wounds

Careful dressing selection can reduce pain and anxiety at dressing changes, and reduce the risk of tissue
trauma. Dressings with silicone are often comfortable and can be removed with minimal trauma. This includes
foams with a silicone contact surface or a silicone wound contact layer. Silicone wound contact layers can be
left in situ for up to 14 days, with more frequent changes of the secondary dressing. For dry wounds, a sheet
hydrogel can provide moisture and comfort to the wound.

If a dressing is adhered to the wound, soaking the dressing with a solution containing a surfactant or softening
agent (eg Prontosan, Octenilin) for at least 10 minutes can assist with removal.

See also Ulcer and wound pain.

Guide to choosing an ulcer or wound dressing

Dressings are classified according to functionality. Some dressings have multiple functions. Match the wound
characteristics to the function of the wound dressing; see Table 15.11. At a minimum, primary care providers
should keep dressings that perform each of the functions listed in Table 15.11. These can be used on the
majority of wounds.

Some wounds require specialised dressings to be used for a defined period of time to manage a specific issue.
Specialised dressings are listed in Table 15.22 [Note 1]. Primary care providers may need to also keep and be
familiar with more specialised dressings based on common presentations in the local patient population. For
example, cadexomer iodine (Iodosorb) dressings for wounds with nonviable tissue, or zinc paste dressings for
venous dermatitis.

Advice about dressings is provided separately for specific ulcer or wound characteristics:

cavity wounds
infected wounds
malodorous wounds
wounds with hypergranulation tissue
painful wounds.

For advice on how to choose a new dressing after a dressing change, see Table 15.23.

Overview of appropriate wound dressings based on wound characteristics (Table 15.11)

Wound characteristic Dressing function Appropriate dressing type

wound contact layer or tulle

Fragile skin or extensive wound protection low-adherent dressings

thin foam dressings

Dry wound (no or minimal
hydration hydrogel dressings
exudate)
semipermeable film dressings

Moist wound (low exudate) moisture retention hydrocolloid and other polymer
dressings

Wet wound (moderate exudate)
thin foam dressings
foam dressings
moderate absorption
absorbent pad dressings
super-absorbent pad dressings

Wet wound (heavy exudate) high absorption alginate fibre dressings

gelling fibre dressings

Wound contact layer or tulle (Table 15.12)

Function Protection
Encourages epithelialisation and protects fragile tissue. Can be used for
Indication wounds unlikely to heal or extensive wounds. Silicone mesh generally
recommended for skin tears.
Available as silicone mesh, hydrocolloid/petroleum mesh, triglyceride
mesh, petrolatum, paraffin mesh.
Variants
Available impregnated with an antimicrobial (including povidone-iodine,
chlorhexidine, silver, honey)—antimicrobial dressings are not routinely
required.
Paraffin mesh is not routinely recommended as it can adhere to the wound
Precautions bed and does not absorb exudate. Additionally, paraffin mesh is not
permeable to water vapour or exudate, so can cause maceration.
Paraffin tulle is not recommended first line (can adhere to wound and cause
maceration, as above); nonparaffin tulle is preferred.

Wound contact layers are not absorptive, so the secondary dressing needs to
be matched to the amount of wound exudate.
Comments
Generally dressings require overlap onto the surrounding skin of at least 2
cm.

A silicone mesh is usually left on for 7 to 14 days (check manufacturer’s

recommendations for maximum wear time).
Silicone: Mepitel, Silflex

Hydrocolloid/petroleum: UrgoTul

Triglyceride: Atrauman
Examples Petrolatum: Adaptic, Cuticerin

Paraffin: Jelonet

Antimicrobial: Bactrigras (chlorhexidine), Inadine (povidone-iodine),

UrgoTul Ag/Silver

Low-adherent dressings (Table 15.13)

Function Protection
Primary or secondary dressing on dry wounds or wounds with minimal
exudate.
Indications
Absorb minimal exudate; useful for surgical wounds.
Available as cotton acrylic fibres and knitted viscose, nonadhesive sheets or
island dressings with a fabric or film adhesive border.
Variants
Usually constructed with low-adherent perforated plastic film that allows
passage of exudate from the wound bed into the fibre.
If applied directly to an open wound they can adhere to the wound bed and
cause trauma on removal.
Precautions
Not suitable for wounds with moderate to heavy exudate.
Comments Nonadhesive variants need to be secured with tape or a bandage.
Examples Melolin, Cutilin, Telfa, Primapore

Semipermeable film dressings (Table 15.14)

Function Moisture retention

Primary dressing over superficial, low exudate wounds.
Indications
Fixation over nonadhesive dressings.
Available as a thin polyurethane membrane coated with a layer of acrylic
adhesive. Available with a silicone adhesive for fragile skin.
Variants
Can be used for fixation for a range of nonadhesive dressings including
low-adherent dressings, foam dressings, absorbent pads or sheet hydrogels.
Not suitable for infected wounds or wounds with moderate to heavy
exudate.
Precautions
Variants with acrylic adhesive may cause trauma to fragile or compromised
skin.
Permeable to gas and vapour, waterproof and impermeable to bacteria.

Cannot absorb exudate if used alone.

Comments
Overlap onto the surrounding skin by at least 2 cm. Change the dressing
every 5 to 7 days, more often if exudate is pooling under dressing.
Acrylic adhesive: OpSite, Tegaderm, Mefilm
Examples
Silicone adhesive: Mepitel Film, OpSite Flexifix Gentle

Hydrogel dressings (Table 15.15)

Function Hydration
Adds moisture to dry wounds and aids autolytic debridement.

May be used for skin tears if there is a risk of the wound drying out.
Indications
Can be used as first aid for minor burns for adults in specific circumstances
only, or as a dressing for epidermal burns; see Table 15.4.
Available as amorphous (that have no shape) dressings, sheet dressings or
impregnated dressings (eg gauze saturated with an amorphous hydrogel).

Amorphous hydrogels vary in consistency and composition (eg some

contain preservatives). Some are available with an antimicrobial (including
polyhexamethylene biguanide [PHMB], hypochlorous acid with sodium
Variants
hypochlorite or octenidine)—antimicrobial dressings are not routinely
required.

Sheet hydrogels can be adhesive or nonadhesive; nonadhesive variants can

be combined with a secondary adhesive film dressing. Sheet hydrogel is
preferred for use on flat or shallow wounds.
Not for use if debridement is contraindicated (eg on stable dry eschar of the
heel).
Precautions
Avoid on wounds with moderate to heavy exudate.
All are primary dressings. Amorphous and impregnated dressings require a
secondary dressing that doesn’t absorb the gel or allow it to dry out (an
occlusive dressing is recommended).

Comments Reduces risk of desiccation to structures (eg exposed bone or tendon).

Amorphous and impregnated hydrogels are usually only applied to the

wound. Sheet hydrogels require overlap onto the surrounding skin of at
least 2 cm. Generally dressings should be changed every 3 to 7 days.
Amorphous hydrogel: SoloSite, DuoDERM Hydroactive Gel, Hydrosorb
 Gel, Normlgel

Sheet hydrogel: Hydrosorb

Examples
Impregnated hydrogel: Intrasite Conformable, Kendall Hydrogel
Impregnated Gauze

Antimicrobial amorphous hydrogel: Prontosan Wound Gel X, Octenilin

Wound Gel, Microdacyn Hydrogel, Flaminal

Hydrocolloid and other polymer dressings (Table 15.16)

Function Moisture retention

Used as a primary dressing for moist wounds with low exudate. Maintains
the moisture level of wounds and encourages epithelialisation. Used for flat
or shallow wounds. Can assist with autolytic debridement.
Indication
Thin hydrocolloid dressings can be used for skin protection around the
wound for patients using topical negative pressure wound therapy.
Hydrocolloid dressings are available as sheet, paste and gel dressings; other
polymer dressings include hydropolymers and acrylic dressings.
Variants
Ability to retain moisture depends on the composition of the dressing and
film backing.
Hydrocolloid dressings should be avoided on wounds with infection, sinus
Precautions tracts or heavy exudate.

Do not use hydrocolloid dressings on the plantar surface of the foot.

Hydrocolloids form a gel in contact with exudate. Other polymer dressings
absorb exudate into the matrix of the dressing.

Generally a primary dressing. Can sometimes be used as a secondary

dressing. Usually adhesive dressings.
Comments
Overlap onto the surrounding skin by at least 2 cm. Change the dressing
every 3 to 7 days.

Applying warmth to the dressing before and after application can enhance
dressing conformation and adhesion.
Hydrocolloid sheet: Comfeel Plus, DuoDERM, REPLICARE

Hydrocolloid paste: DuoDERM Paste

Examples Hydrocolloid gel: DuoDERM Hydroactive Gel

Hydropolymer: Leukomed Control, Tielle

Acrylic: Tegaderm Absorbent

Foam dressings (Table 15.17)

Function Moderate absorption and protection

Foam dressings are widely used; they absorb excess exudate while
maintaining a moist wound bed.
Indication Used as a primary or secondary dressing for wounds with low to moderate
exudate, depending on foam thickness. They also provide thermal
insulation, protection and cushioning.
Composition, construction and mode of action vary. Available with or
without adhesive (composition of adhesives varies).

Foam thickness usually reflects absorptive capacity.

Variants Available with various contact surfaces (including silicone or hydrogel) and
shapes (for specific anatomical locations). Foams without a film backing are
used for cavity wounds.
 Specific products available to manage thick or viscous exudate, or
impregnated with an antimicrobial (including polyhexamethylene biguanide
[PHMB], silver)—antimicrobial dressings are not routinely required.
Usually avoid on very dry wounds. If used alone, foams do not facilitate
autolytic debridement, but may provide skin protection.
Precautions
Provides protection but not offloading.
Primary or secondary dressing. A secondary dressing is not required for
types with a film backing. Overlap onto the surrounding skin by at least 2
cm.

Change the dressing every 2 to 7 days, when approximately 75% saturated.

Comments
If using an adhesive variant, applying warmth to the dressing before and
after application can enhance dressing conformation and adhesion.

If used for skin graft management, adhesive must be beyond the margins of
the wound.
Nonadhesive foam: Allevyn, Biatain Non-Adhesive, Lyofoam Max

Adhesive foam: Tielle Plus, Allevyn Adhesive, Biatain Adhesive

Silicone coated nonadhesive foam: Mepilex, Mepilex XT

Examples
Silicone coated adhesive foam: Mepilex Border, Allevyn Gentle Border,
Biatain Silicone

Antimicrobial foam: Biatain Ag Non-Adhesive, Allevyn Ag, Mepilex Ag,

AMD foam

Absorbent pad dressings (Table 15.18)

Function Moderate absorption

Absorbs excess exudate. Used for wounds unlikely to heal, extensive
Indication
wounds, and surgical wounds if moderate amounts of exudate are likely.
Composition and construction vary; the absorbent layer is usually cellulose
pulp.
Variants
Usually nonadhesive.
Can become adherent if applied directly to a wound.
Precautions
Some do not retain exudate well within the structure of the dressing, so can
become soggy.
Generally used as a secondary dressing; often used over a wound contact
layer or fibre dressing. Fixation is usually required.
Comments
Change the dressing every 2 to 7 days when approximately 75% saturated.
Overlap onto the surrounding skin by at least 2 cm.
Examples Mesorb, Zetuvit, Exu-Dry

Super-absorbent pad dressings (Table 15.19)

Function High absorption

Absorb large amounts of exudate. Used for wet wounds with heavy exudate,
Indication
extensive wounds, or those unlikely to heal.
Composition and construction vary. Some have water-repellent backings to
reduce wetness from strikethrough.
Variants
Specialised shapes are available.

Usually nonadhesive.
Avoid on dry wounds or wounds with minimal exudate.
Precautions
May adhere to wound if directly applied.
 Generally used as a secondary dressing over a wound contact layer or fibre
dressing.
Comments Overlap dressing onto the surrounding skin by at least 2 cm.

Fixation is usually required.

Change the dressing when approximately 75% saturated.

Examples Mextra Superabsorbent, Zetuvit Plus, Cutimed Sorbion Sachet, Relevo

Alginate fibre dressings (Table 15.20)

Function High absorption

Absorbs excess exudate. Used for wet wounds with heavy exudate or cavity
Indication wounds. Can be useful for achieving haemostasis for bleeding wounds (see
'Precautions' below).
Composition varies. Some are soft-gelling and can break up when saturated,
others are firm-gelling and maintain structure when saturated.
Variants
Available as sheets, rope or ribbon. Some are impregnated with an
antimicrobial (including silver)—antimicrobial dressings are not routinely
required.
Avoid on dry or low exudate wounds.

Avoid in cavity wounds if the entire base is not visible.

Precautions While alginate fibre dressings can help stop bleeding, if they dry out they
can become adherent and cause trauma on removal. Not all alginates
provide haemostasis, it depends on calcium concentration.

Dressings must be removed from the wound; they are not biodegradable.
Used as a primary dressing; a secondary dressing is required.

The entire dressing must be removed at each dressing change.

Comments
Should be fitted to wound size.

Change the dressing when saturated, usually every 1 to 3 days.

Nonantimicrobial alginate: Biatain Alginate, Algisite M, Sorbsan
Examples
Antimicrobial alginate: Melgisorb Ag, Silvercel Non-Adherent

Gelling fibre dressings (Table 15.21)

Function High absorption

Indication Absorbs excess exudate. Used for cavity wounds.
Available as sheets, rope or ribbon. Available impregnated with an
antimicrobial (including silver)—antimicrobial dressings are not routinely
required.
Variants
Some have a ‘high wet strength’ so are suitable for cavity wounds even if
the base of the wound is not visible.
Avoid on dry or low exudate wounds. The entire dressing must be removed
Precautions
at each dressing change.
Used as a primary dressing; a secondary dressing is required.

Overlap onto the surrounding skin by 1 cm because the dressing will shrink
Comments
slightly as it absorbs exudate.

Change the dressing when saturated, usually every 1 to 3 days.

Examples AQUACEL Extra, DURAFIBER, Exufiber

Specialised ulcer and wound dressings (Table 15.22) [NB1]

Product type Function Example [NB2]
Tissue (enhance autolytic debridement)
Cleanse moderate to heavily exuding
Hypertonic saline gauze wounds with sloughy tissue. Can be Mesalt, Curasalt
used on hypergranulation tissue.
Hydro-responsive wound Cleansing and absorbing action for
HydroClean plus
dressings dry to moderate exudate wounds.
Infection and inflammation (treat wound infection, manage high bacterial load or manage chronic
inflammation)
Silver: Acticoat, Biatain Ag Non-
Adhesive, Mepilex Ag, Aquacel Ag,
Silvercel Non-Adherent, Melgisorb Ag,
Flamazine

Iodine: Inadine, Iodosorb

Topical antimicrobial
dressings Honey: Activon, Algivon

(Antimicrobial dressing Aim to treat infection, and prevent Polyhexamethylene biguanide (PHMB):
variants are available as infection in high-risk patients (eg Kendall AMD foam, Kerlix AMD Gauze,
wound contact burns). Prontosan range
layers, foam dressings,
Some dressings also have secondary Hypochlorous acid with sodium
hydrogel
functions (eg absorption, hydration). hypochlorite: Microdacyn Hydrogel
dressings, alginate fibre
dressings, and gelling fibre Octenidine: Octenilin Wound Gel
dressings)
Alginogels: Flaminal Hydro, Flaminal
Forte

Dialkylcarbamoyl chloride (DACC)

coated (a hydrophobic coating designed
to bind bacteria): Sorbact
Absorb odour. Some dressings also
Activated charcoal
have secondary functions (eg CarboFLEX, Carbonet, Actisorb Plus
dressings
antimicrobial).
Aim to reduce excess proteases from
Protease modulator matrix Promogran Matrix Wound Dressing,
nonhealing wounds, manage
dressings Promogran Prisma, UrgoStart
recurrent local infections.
Moisture (manage excessive exudate)
Appliance dressings
Contain excess exudate. ConvaTec Little Ones
(wound pouch)
Reduce oedema, promote venous Coban 2, Putter Pro 2, Profore, Veno4,
Compression therapy
return, and support venous valves. SurePress, Tensolan
Hydrocapillary action Draw out and retain exudate in
Vacutex
dressings dressing.
Wound edge (promote wound contraction and granulation or encourage epithelialisation and treat skin
conditions)
Negative pressure wound
Remove excess exudate, promote
therapy (NPWT) (also
contraction and formation of Vacuum-assisted closure (VAC), Renasys
known as topical negative
granulation tissue, and fill cavities.
pressure therapy [TNPT])
Promote epithelialisation, treat
Zinc paste bandages Zipzoc, Viscopaste, Gelocast
eczema and dermatitis, protect skin.
NB1: Brief information is provided because these dressings are specialised. These dressings should only be initiated by healthcare professionals
familiar with their indications and precautions.
NB2: Brand examples are not exhaustive and are provided for illustrative purposes only; inclusion of a product in this table does not imply
endorsement by the Ulcer and Wound Expert Group.

Choosing a new dressing after a dressing change (Table 15.23)

Factor Assessment Recommendation

Educate patient about avoiding activities
Had the dressing lifted, shifted,
 degraded, been worn away,
Dressing integrity become contaminated or been
damaged?
Was the exudate contained
within the dressing?
How saturated was the
dressing?
Exudate volume
Was the exudate taken up into If the dressing was fairly dry, less frequent
the dressing effectively?
Was the whole dressing wet, or might be required.
were some areas still dry?
What was the colour of the
exudate?
Exudate colour and
Was the exudate thick?
consistency
Had the dressing adhered to the might be too absorptive for the level of
wound?
that compromise dressing integrity.
Consider a more robust fixation system or
a more adhesive dressing.
If exudate was pooled on the wound or
dressing, consider changing to a dressing
that can effectively absorb or remove the
exudate.
If the dressing was completely saturated,
consider more frequent dressing changes, a
larger dressing or a more absorbent
dressing.
dressing changes or a less absorbent
dressing or a moisture retention dressing
If exudate was leaking from the dressing
but on removal areas of the dressing are
dry, reconsider the positioning of the
dressing.
Thickened or discoloured exudate might
indicate wound infection; manage
infection as for Ulcer and wound infection.
If the dressing adhered to the wound or
required soaking for removal, the dressing
exudate, or the dressing type was not
suitable for direct contact with a wound.

Note 1: The Department of Veterans Affairs (DVA) website also provides a detailed guide to wound dressings.

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McNichol L, Bianchi J. Medical adhesive-related skin injuries (MARSI) made easy. Wounds UK 2016;12(4):1–4.

National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure
Injury Alliance. Prevention and treatment of pressure ulcers: clinical practice guideline. Perth, Australia:
Cambridge Media; 2014.

Norman G, Christie J, Liu Z, Westby MJ, Jefferies JM, Hudson T, et al. Antiseptics for burns. Cochrane Database
Syst Rev 2017;7:CD011821.

Norman G, Dumville JC, Moore ZE, Tanner J, Christie J, Goto S. Antibiotics and antiseptics for pressure ulcers.
Cochrane Database Syst Rev 2016;4:CD011586.

O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for
venous leg ulcers. Cochrane Database Syst Rev 2014;(1):CD003557.

O’Meara S, Richardson R, Lipsky BA. Topical and systemic antimicrobial therapy for venous leg ulcers. JAMA
2014;311(24):2534–5.

Storm-Versloot MN, Vos CG, Ubbink DT, Vermeulen H. Topical silver for preventing wound infection. Cochrane
Database Syst Rev 2010;(3):CD006478.

Terrill P, Sussman G, Bailey M. Absorption of blood by moist wound healing dressings. Primary Intention
2003;11(1):3–17.

Vermeulen H, Ubbink D, Goossens A, de Vos R, Legemate D. Dressings and topical agents for surgical wounds
healing by secondary intention. Cochrane Database Syst Rev 2004;(2):CD003554.

Vermeulen H, van Hattem JM, Storm-Versloot MN, Ubbink DT. Topical silver for treating infected wounds.
Cochrane Database Syst Rev 2007;(1):CD005486.

Wasiak J, Cleland H, Campbell F, Spinks A. Dressings for superficial and partial thickness burns. Cochrane
Database Syst Rev 2013;(3):CD002106.

Weller C, Sussman G. Wound dressings update. J Pharm Pract Res 2006;36(4):318–24.

Woodward M. Healing wounds in older people. Medicine Today 2011;12(4):41–50.

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Wounds Australia. Standards for wound prevention and management. 3rd ed Osborne Park, Western Australia:
Cambridge Media; 2016.

Published January 2019. Amended April 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Factors affecting ulcer and wound healing
Overview of factors affecting ulcer and wound healing
Most ulcers and wounds heal after correcting the underlying pathology and optimising the environment (eg
adequate cleansing, perfusion, pressure redistribution, debridement, exudate management).

If wounds do not heal as expected, consider:

infection
oedema
nutritional status
smoking
medications
the general health of the patient (ensure optimal management of comorbidities).

Other considerations include:

managing pain
the need for specialist referral
the setting of care (hospital admission may be useful)
skin grafting.

Ulcer and wound infection

Introduction

If ulcers or wounds become infected, healing can be delayed. Although ulcers can occur due to a primary
infectious disease, more often ulcers with a noninfectious cause develop a secondary infection.

The wound infection continuum is a guide for when to initiate topical and systemic antimicrobial management
strategies (see Figure 15.7). Signs and symptoms of each stage of wound infection are provided in Table 15.24.

The wound infection continuum (Figure 15.7)

Adapted with permission from: International Wound Infection Institute (IWII). Wound infection in clinical practice. Wounds International; 2016.
Signs and symptoms of wound infection (Table 15.24)

Local infection Spreading infection Systemic infection

Ulcer or wound features:

increased size (with or

Overt signs of local
Covert (subtle) signs of local without erythema)
infection:
infection: lymphangitis
erythema crepitus
hypergranulation wound breakdown or
warmth fever
(excessive tissue) dehiscence with or without
swelling tachycardia
bleeding, delicate satellite lesions.
purulent hypotension
granulation tissue
exudate other signs of
epithelial bridging and Patient features:
new or sepsis
pocketing in granulation
worsening pain malaise, lethargy or
tissue
new or general deterioration in
wound breakdown
worsening health
delayed wound healing.
malodour. loss of appetite
inflammation or swelling
of lymph nodes.

Do not use systemic antimicrobials unless the wound is clinically infected.

Redness on a patient's leg is commonly misdiagnosed as cellulitis—consider differential diagnoses; see Box
15.14.

Common causes of a red leg (Box 15.14)

venous dermatitis
allergic contact dermatitis (eg from a dressing)
irritant contact dermatitis (eg from exudate or the dressing)
other dermatitis
superficial thrombophlebitis
cellulitis
superficial fungal infections
cutaneous drug reaction
erythema nodosum
erythromelalgia

All chronic wounds are contaminated either by transient or commensal micro-organisms that live on the skin or
have been introduced (eg during injury). Routine use of topical antiseptics, antibiotics or antimicrobial dressings
for healing ulcers or wounds is not recommended. However, when clinical infection occurs, intervention may be
warranted.

Signs of local wound infection can be covert or overt (see Table 15.24). Covert (subtle) signs of infection can
develop into overt signs of infection (see Figure 15.7). Use antiseptics for local infection (eg polyhexamethylene
biguanide [PHMB], octenidine dihydrochloride, chlorhexidine, povidone-iodine). Chlorhexidine and povidone-
iodine must be washed off after 5 minutes to avoid cytotoxicity; see Cleansing and debridement.

For spreading or systemic infection, systemic antibiotics in addition to topical management strategies are
recommended (see Systemic antimicrobial therapy). Debridement (if not contraindicated) should be undertaken
in combination with antibiotics to disrupt biofilm and impair reformation. Appropriate surgical intervention is
important in management of deep soft tissue infections for source control.

The practice of using antibiotic therapy alone to promote healing by decreasing bacterial burden is not
recommended. A combination of debridement, wound cleansing and appropriate dressing selection is essential
(see Ulcer and wound dressings).

Ulcer or wound swabs

To diagnose wound infection, a combination of clinical assessment (see Table 15.24), microbiological
investigations, blood tests and imaging may be required. If indicated, collect wound swab for culture before
starting antibiotic therapy. Indications for standard wound culture are:
 wounds with overt signs and symptoms of infection, or signs of spreading or systemic infection (see Table
15.24)
infected wounds that have failed to respond or are deteriorating, despite empirical antimicrobial treatment
for surveillance of drug-resistant bacteria as directed by local protocols
to determine appropriateness of surgery, if the presence of certain bacteria would prevent a surgical
procedure (eg beta-haemolytic streptococci in wounds before skin grafting).

If a wound culture is indicated, the Levine technique is recommended. Wound culture enables accurate
identification of pathogens and appropriate adjustment (ie de-escalation) of antibiotic therapy.

The Levine technique is:

cleanse and debride the wound (do not use antiseptic solutions)
moisten culture tip with sterile 0.9% sodium chloride (especially for dry wounds)
inform the patient that this procedure may cause discomfort
specimen should be obtained from the cleanest area of the wound (avoid slough or necrotic tissue)
firmly press swab tip into wound and rotate for 5 seconds (apply sufficient pressure so that tissue fluid is
produced)
place swab into culture container using sterile technique
label container appropriately.

Consider the need for special stains or culture (eg mycobacterial or fungal organisms), and for Mycobacterium
ulcerans polymerase chain reaction if Buruli ulcer is suspected. See Biospy.

Once the swab is obtained, the sample should be immediately sent to the laboratory. Information to be provided
with the specimen includes:

wound details (eg anatomical location, duration, aetiology)

patient details (eg demographics, significant comorbidities)
clinical indication for the swab (eg signs and symptoms, suspected pathogen)
current or recent antibiotic use.

If osteomyelitis is suspected, bone biopsy is recommended to identify deep wound pathogens; soft tissue or sinus
tract specimens do not always predict pathogens in bone. For information about assessing patients for
osteomyelitis, see Foot examination and Osteomyelitis.

Topical antimicrobial therapy

Topical antimicrobial therapy includes topical antibiotics, antifungals or antiseptics. Antiseptics are disinfectants
used to kill or inhibit the growth of micro-organisms, and can be nonselective and cytotoxic. Topical antibiotics
also kill or inhibit the growth of bacteria, but generally have a narrower spectrum of activity and are more likely
to cause bacterial resistance. Topical antifungals disrupt proliferation of fungus.

Topical antimicrobial therapies include:

silver dressings (foam, alginate, gelling fibre, nanocrystalline, carboxymethylcellulose)

iodine solution and dressings (povidone-iodine, cadexomer iodine)
sterile medical grade honey (gel, dressing) [Note 1]
alginogels (ie Flaminal range)
bacteria-binding dressings (eg Sorbact range)
antiseptic or surfactant solutions for cleansing, and gels for dressings.

Use antiseptics (eg chlorhexidine, povidone-iodine, polyhexamethylene biguanide [PHMB], octenidine

dihydrochloride) for local infection (either covert or overt; see Table 15.24) or dirty wounds. See Cleansing and
debridement for more information.

Topical antibiotics are not routinely recommended.

Topical antibiotics (eg creams or ointments) are not recommended because they can be sensitising agents, have
no demonstrated effect on healing, and promote antimicrobial resistance. An exception is topical metronidazole
gel for the management of malodorous wounds. Topical antibiotics intended for intact skin, or use in eyes or ears
(eg chloramphenicol) are inappropriate for use on the exposed tissue of a wound.

If an antimicrobial dressing is used, choice should be based on the amount of exudate, patient allergies or
sensitivities, affordability, access and evidence of efficacy. Currently, limited evidence exists to suggest one
antimicrobial dressing has greater clinical efficacy than another. Current evidence suggests that cadexomer iodine
may speed healing of infected venous leg ulcers compared with standard care; honey may speed healing of
infected surgical wounds compared with an antiseptic and gauze.

Antimicrobial dressings should be used for the shortest time possible, and in addition to standard ulcer care and
interventions (eg cleansing and debridement, pressure offloading). Review the patient 2 weeks after starting a
dressing regimen. If signs of infection have resolved, change to a nonantimicrobial dressing based on the wound
characteristics (see Ulcer and wound dressings). If signs of infection remain, ensure adequate cleansing and
debridement. Consider either continuing with the current dressing regimen for another 2 weeks, or referring for
further investigations and treatment, especially if infection is worsening. Usually, silver-based dressings are used
for 2 weeks (per manufacturer's instructions).

Antimicrobial dressings should be used for the shortest time possible.

Theoretical concerns exist about systemic iodine absorption from iodine-based dressings. Use these dressings
with caution in children younger than 6 months, for durations longer than 1 week, or for extensive open wounds.

Note 1: Only medical grade honey should be used on wounds; nonmedical grade honey can contain spores and has variable antimicrobial activity.

Systemic antimicrobial therapy

Although use of systemic antimicrobials for chronic wounds is common, they should not be used unless there are
clinical signs of spreading or systemic infection. Systemic antimicrobials should always be used in combination
with optimal local wound management, including adequate cleansing and debridement. The choice of
antimicrobial should be based on the suspected pathogen, location of infection, patient characteristics (recent
hospitalisation, previous microbiology, colonisation with a multidrug-resistant organism) and severity of
infection.

Only use systemic antimicrobials for chronic wounds if clinically indicated and in combination with optimal local wound
management.

Virulent or difficult-to-treat bacteria include resistant strains of Staphylococcus aureus, beta-haemolytic

streptococci, and (in certain circumstances) Pseudomonas aeruginosa. For treatment recommendations, see
Directed therapy for bloodstream infections, including sepsis and septic shock, Diabetic foot infection, Cellulitis
and erysipelas and Osteomyelitis.

The route of antibiotic therapy is based on severity of infection, bioavailability of the antibiotic, penetration of
the antibiotic to the site of infection and susceptibility of the pathogen. Use oral therapy for mild infections.
Intravenous therapy may be required for severe infections or if penetration at the site of infection is limited (eg
for osteomyelitis, diabetic foot infection in a patient with peripheral arterial disease).

The duration of antibiotic therapy depends on the organism isolated, the location of infection, type of wound and
patient's comorbidities. Principles of antimicrobial stewardship should always be maintained.

Oedema and ulcer and wound healing

Oedema requires accurate diagnosis and management because it can be detrimental to wound healing. Patients
with oedema have excess fluid and protein in the interstitial space, potentially leading to increased risk of
infection, reduced circulation, inflammation, inhibition of growth factors, lymphorrhoea (leakage of lymph fluid)
and maceration.

Oedema may be caused or worsened by heart failure, renal or liver impairment, limb dependency (having legs
down or dangling; eg in patients with limited mobility), venous insufficiency, protein deficiency, lymphoedema or
acute trauma.

Oedema may be drug induced; always take a thorough medication history. Common drug causes of oedema
include:

calcium channel blockers (particularly dihydropyridines, eg amlodipine)

alpha2 agonists (eg clonidine)
corticosteroids
sex hormones (eg oestrogen, progesterone, tamoxifen)
chemotherapy drugs
nonsteroidal anti-inflammatory drugs (NSAIDs)
 glitazones (eg pioglitazone)
pramipexole
pregabalin.

If a drug cause is likely, consider if the drug can be stopped or the dose modified to improve or resolve oedema.

Reducing oedema improves wound healing. Management is specific to the cause of oedema and may include
compression, elevation of the limb, movement, manual lymphatic drainage, medication alteration and complete
decongestive therapy. Some of these approaches reduce fluid loss into the interstitium (eg compression therapy)
as well as increasing lymphatic reabsorption.

Nutrition and ulcer and wound healing

Patients with a wound should be screened for malnutrition as part of their clinical review. Malnutrition is
common in people with chronic wounds, and is often not recognised. If identified, malnutrition should be treated,
despite limited evidence that this is beneficial for wound healing.

Protein and energy requirements are higher for patients with chronic wounds. Ensure patients are meeting their
intake requirements—protein and calorie supplements may be required, consider referral to a dietitian. Even
patients with a high body mass index (BMI) can be malnourished. At the time of writing, there is no evidence to
support enteral nutrition (eg percutaneous endoscopic gastrostomy [PEG] or nasogastric feeding) for wound
healing. Any identified micronutrient deficiency should be treated; however, there is little evidence that
nutritional therapy (including routine vitamin C or zinc supplements in patients without deficiency) is of benefit.

There is increasing evidence that supplements containing arginine promote healing of stage II to IV pressure
injuries, but they do not have proven efficacy for other wounds.

General dietary advice is provided in the Australian Dietary Guidelines, available here.

Smoking and ulcer and wound healing

Cigarette smoking is a risk factor for impaired wound healing and wound infection. Smoking impairs circulation
and immune function, and disrupts inflammatory processes. Identify if the patient is a smoker, and encourage
them to stop at every review. See Smoking cessation.

Medications and ulcer and wound healing

Introduction
Medication (whether prescribed or over-the-counter) can affect wound healing, either by inhibiting wound
healing or promoting wound healing.

Undertake a comprehensive medication review to identify medications that affect wound healing (see
Medications that inhibit ulcer and wound healing). Medications and their adverse effects can increase the risk of
developing a wound. For example, sedating medication increases the risk of pressure injury, and medication that
causes nausea may affect nutritional status. Medication excipients (eg ointment or cream bases) can affect the
wound environment and impair healing.

Many topical products (including crushed tablets and other powders) are used off-label for wound management
without supporting evidence and with a limited understanding of risk. The inactive vehicle in topical products
may delay rather than promote healing. Always consider the potential harm to the patient as well as the potential
benefit.

Medications that inhibit ulcer and wound healing

A number of commonly prescribed medications can delay wound healing. The mechanisms for this vary and can
be dose-related. Mechanisms include:

inhibition of growth factor or cytokines (eg corticosteroids, colchicine)

destruction of replicating cells (eg antineoplastic drugs, leflunomide)
causing oedema.

Some medications can cause wounds. Hydroxyurea is associated with ulcer formation (usually on the tips of the
malleoli), via dermal atrophy and the formation of microthrombi. Warfarin can cause skin necrosis. Nicorandil
can cause dose-dependent skin ulceration, which generally resolves when the medication is stopped.
If possible, stop the causative medication or reduce its dose. Before adjusting medication, consider the severity of
the underlying condition and the need to taper doses (eg corticosteroids). If stopping the medication poses an
unacceptable risk to the patient so wound healing is unlikely, the goal of wound management may need to change
(see Ulcers or wounds not expected to heal). If the medication profile changes and wound healing becomes
possible, revert to a curative goal.

Medications that promote ulcer and wound healing

A number of medications can promote wound healing. They fall into two main groups—those that manage the
pathology of the wound (eg antibiotics for a clinically infected wound), and those that stimulate wound healing
(usually by actions outside the licensed indication).

There is evidence that doxycycline has anti-inflammatory effects—as a result it has been used off-label for
vasculitis and vasculitic ulcers, particularly to avoid use of corticosteroids. Do not use systemic antibiotics to
promote wound healing in the absence of clinical infection.

Oxpentifylline (pentoxifylline) can help maintain vascular patency—it is sometimes used off-label by specialists
as adjunctive therapy to improve healing in chronic wounds.

Several other medications (eg phenytoin, retinoids, some immunosuppressants) have demonstrated benefit for
healing in specific wound types. However, potential harms outweigh benefits for most patients. These
medications are not appropriate outside of the specialist setting.

Ulcer and wound pain

Introduction
Assessing and managing wound-related pain is important—inadequately controlled pain delays wound healing
and causes patient suffering. Assume the wound is painful (because wound pain is so common), unless the patient
indicates otherwise. The risk of a wound being painful increases the longer it remains unhealed.

Nociceptive and neuropathic pain often coexist in wound-related pain. Nociceptive pain is caused by stimulation
of peripheral pain receptors. Neuropathic pain is due to dysfunction within the nervous system, and is commonly
described as burning, tingling, or like an electric shock.

Pain can develop in response to repeated painful stimuli (eg dressing changes). It may be triggered by light touch,
exposure or air movement over a wound. On examination, altered sensation or allodynia (pain on light touch)
may be detected.

The first step in pain management is to understand the nature of the pain and when it occurs. The most effective
approach is multifactorial. This involves modifying precipitating and relieving factors, using analgesia, and
addressing psychological and social factors. Communication and collaboration with the patient and others
involved in their care, is important. Reassess and evaluate pain management strategies regularly, and adjust
strategies accordingly.

Certain types of wound pain need specific management, such as inflammatory ulcers (eg vasculitic ulcer,
pyoderma gangrenosum) and those that are clinically infected (see Ulcer and wound infection). Seek urgent
opinion from a vascular specialist for ulcers on an ischaemic limb.

Assessment of ulcer and wound pain

See Table 15.25 for an overview of assessing wound-related pain.

There are many validated pain rating scales, including numerical, visual analogue, faces, verbal, and
observational (for use when a patient has poor cognition or communication). See Pain assessment tools for
examples. Use the same scale at each assessment to monitor the patient's response to the pain management plan.

Assessing and managing wound-related pain (Table 15.25)

1. Assess pain
history (timing, location, quality, triggers, relievers, severity, impact)
examination (including observing patient's behaviour)
review patient's pain diary if possible
review response to therapy

2. Determine type of pain based on pain circumstances

Background pain Incident pain (breakthrough pain Procedural pain
caused by a specific activity)
Identify and manage causes of Precipitated by:
background pain: Precipitated by:
tape or dressing removal or
ischaemia (requires urgent movement application
referral) contact exposure of wound to air
infection pressure wound cleansing or handling
inflammation. dressing movement while in situ debridement
elevating or lowering the limb. compression therapy.

3. Create management plan

Local management
Consider: Systemic management
cleansing Pharmacological therapy:
using a dressing that
causes minimal pain on
removal
whether the patient would
prefer to remove the Nonpharmacological therapy:
dressing
reducing frequency of
dressing changes
optimising moisture
balance of wound
managing oedema
avoiding local pressure.
Procedures: prepare, plan, prevent
pain
Undertake the following:
explain procedure and obtain
consent
involve patient in planning
analgesics provide systemic analgesia 30
adjuvant analgesics. minutes before procedure
use topical analgesia 30 to 40
minutes before procedure
exercise and physiotherapy rate pain before, during and
psychological therapy after procedure
social and environmental use a quiet, warm room; ensure
modification. patient is comfortable
use warmed solutions
minimise exposure time
monitor patient's verbal, facial
and body responses.

Treatment of ulcer and wound pain

A multidisciplinary approach to management is required for treating wound-related pain. For details, see Table
15.25. It includes:

pharmacological management—using systemic analgesics, adjuvant analgesics and topical analgesics (eg
lidocaine, tetracaine)
nonpharmacological management—attending to physical, social, and psychological effects of pain
local management—using dressings that minimise pain on removal and avoid prolonged exposure and
handling.

Involve patients and carers in decision-making. Advise patients it is important to report worsening pain.

Provide verbal and written information about recommended management—this applies to wound care in general,
and analgesia in particular. Also provide information about the pain management plan to other healthcare
professionals. Refer patients with persistent pain despite optimal management for further investigation or
specialised therapies.

When to refer a patient with an ulcer or wound

Specialist health practitioners and wound clinics are vital resources for wound management. Referral to these
services is indicated at diagnosis or soon after (early referral) for some wound types.

Patients requiring early referral include those with:

rapidly deteriorating wounds

large or complex wounds
wounds that could lead to amputation
vascular leg ulcers (early referral for vascular intervention is strongly recommended; see Venous leg
ulcers or Arterial leg ulcers)
wounds likely to require specialised therapies (eg pressure redistribution, topical negative pressure,
hyperbaric oxygen)
wounds with atypical appearance (eg irregular edge, abnormal colour and texture of tissue) or location.
Other patients requiring referral include those with:

wounds that are not healing despite best practice

wounds that recur without an obvious cause
persistent wound pain despite optimal management
multiple comorbidities.

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Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd
Ulcers or wounds not expected to heal
Introduction to ulcers or wounds not expected to heal
After a thorough assessment, it may be determined that a wound is not going to heal. This is challenging for
two reasons—it is difficult to choose a clinical approach, and it is difficult to help patients understand that
healing may not occur. A palliative approach focuses on symptom management (exudate, odour, pain).

Wounds may not heal for a certain period (while other factors are influencing their capacity to heal [eg a
course of chemotherapy]), or may never heal.

For information about palliative care and malignant wounds, see Cutaneous malignant wounds in palliative
care.

Choice of dressings for ulcers or wounds not expected to heal

As with all wounds, selection of appropriate dressings is based on assessment of the patient, the wound and
its environment (see Ulcer and wound dressings). However, when a wound is not expected to heal, two
factors have increased influence on dressing selection. Firstly, patient comfort and convenience are priorities
—both in relation to the type of dressing selected, and the frequency and timing of dressing changes.
Secondly, the ongoing cost of wound dressings (see Cost of dressings).

For appropriate dressings to manage odour, see Malodorous wounds.

Pain management for ulcers or wounds not expected to heal

Appropriate dressings can reduce the pain of a wound (including a pressure injury) and control exudate.
Nonadhesive dressings are less likely to cause pain or local trauma to patients with fragile and sensitive
wounds during dressing changes (see Painful wounds).

Adequate doses of analgesia, which may include opioids, are required and may be administered orally,
subcutaneously or via transdermal patch.

Pain from dressing changes can be minimised as shown in Table 15.25. Rarely, other measures (such as using
ketamine, midazolam or chlorpromazine) may be necessary, with expert advice. See also Ulcer and
wound pain.

Managing bleeding for ulcers or wounds not expected to heal

Bleeding from nonhealing wounds can be managed in the short term with localised pressure, and in the
longer term by stopping (if possible) any systemic drugs that promote bleeding. If the bleeding is minor,
topical alginate dressings may help because they have haemostatic properties. However, alginate dressings
must be removed before they dry out. Silver nitrate can be used to cauterise spot bleeding.

If bleeding is related to dressing adherence, use a nonadhesive wound contact layer.

Published January 2019. © Therapeutic Guidelines Ltd (eTG March 2020 edition)

Therapeutic Guidelines Limited (www.tg.org.au) is an independent not-for-profit organisation dedicated to deriving guidelines for therapy from the latest world
literature, interpreted and distilled by Australia's most eminent and respected experts. © Therapeutic Guidelines Ltd