Best Practice & Research Clinical Anaesthesiology

Vol. 17, No. 1, pp. 7789, 2003

doi:10.1053/bean.2002.0266, available online at http://www.elsevier.com/locate/jnlabr/ybean

Toxicity of intravenous anaesthetics

Timothy G. Short MB ChB, MD, FANZCA

Specialist Anaesthetist, Auckland Hospital, Clinical Associate Professor, School of Health Sciences,
University of Auckland

Yatin Young* MBBS, MRCP(UK), FRCA

Specialist Anaesthetist, Auckland Hospital, Clinical Senior Lecturer, School of Health Sciences,
University of Auckland

Department of Anaesthesia, Auckland Hospital, Park Road, Grafton, Auckland 1, New Zealand

Intravenous anaesthetic agents are generally remarkably safe. However, it is clear that propofol
infusion syndrome is a real, albeit rare, entity. This often lethal syndrome of metabolic acidosis,
acute cardiomyopathy and skeletal myopathy is strongly associated with infusions of propofol at
rates of 5 mg/kg/hour and greater for more than 48 hours. There is evidence to support the
hypothesis that the syndrome is caused by the failure of free fatty acid metabolism due to
inhibition of free fatty acid entry into the mitochondria and also specic sites in the mitochondrial
respiratory chain. The syndrome therefore mimics the mitochondrial myopathies. Midazolam
causes seizure-like activity in very-low-birthweight premature infants requiring the drug prior
to tracheal intubation or during prolonged positive pressure ventilation. This can be successfully
reversed with the specic benzodiazepine antagonist umazenil. Midazolam can also cause
paradoxical reactions, including increased agitation, poor co-operation and aggressive or violent
behaviour, which has been successfully managed with umazenil.

Key words: diazepam; etomidate; ketamine; midazolam; propofol; thiopentone; toxicity;

mitochondrial myopathy.

PROPOFOL

Propofol became available for commercial use in the current lipid emulsion formulation
25 years ago. Its superior properties in terms of anaesthetic recovery were immediately
recognized and its use became widespread. The drug has a remarkable safety record in
anaesthetic practice when used as an intravenous induction agent, although occasional
reports of excitatory phenomena, pancreatitis and hepatocellular toxicity have
appeared. It has also been successfully used for intravenous maintenance of anaesthesia.
The widespread use of propofol for short-term (524 hours) sedation in intensive care
units has led to an increased interest in longer-term use (472 hours). Its use in this
context, particularly at high doses (e.g. for cerebral metabolic suppression), has been
associated with a range of toxic reactions, including metabolic acidosis, rhabdomyolysis,
*Corresponding author. Tel.: +64 9 307 4949; Fax: +64 9 307 2814; E-mail: yatiny@adhb.govt.nz
15216896/03/$ - see front matter *
c 2003 Elsevier Science Ltd. All rights reserved.
78 T. G. Short and Y. Young

myocardial failure and death. The role of propofol in these reactions has been debated
vigorously in the literature.

Nervous system
Induction of anaesthesia using propofol is characteristically associated with a minimum of
involuntary movements or excitatory phenomena. However, case reports of
spontaneous movements, myoclonus and seizures have been made.16 In children,
spontaneous movements occur in 90% of patients receiving 3 mg/kg for anaesthesia
induction, but dramatically decrease at a dose of 4 mg/kg.7 Higher doses can, however,
be associated with coughing which can interfere with manual ventilation.
Generalized tonicclonic seizures induced by propofol have been described in a range
of patients. They include a patient with a history of epilepsy,2 a woman who had
previously received propofol without complications,3 and a man who received no other
drug and had no previous history of epilepsy who had a unilateral t and was later found
to have an old contralateral cerebral infarct.4 This latter patient had received no other
drugs, which is important in ascribing causality because multiple drug administration
and active pathologies have complicated most case reports of convulsions.5
Convulsions have also been reported in other patients with no history of epilepsy.6
Interestingly, a cross-over study of 20 epileptic patients undergoing cortical resection
with electrocorticogram monitoring using propofol for sedation found that propofol
had no greater proconvulsive eect than thiopentone.5 The lack of clear pattern to these
reports leads to the conclusion that the reactions cannot be predicted; the common
outcome of a lack of demonstrated long-term harm from these ts, which have all
occurred in a well-supervised environment, is reassuring.

Metabolic
In 1992, ve cases of metabolic acidosis, bradyarrythmias and fatal myocardial failure
were reported in children receiving intensive care treatment for upper respiratory tract
infections requiring positive pressure ventilation.8 The patients were aged 4 weeks to 6
years and had received average propofol infusion rates of 7.510 mg/kg/hour for 66115
hours. The total dose of propofol administered over a prolonged period was well outside
of past experience with propofol in the anaesthetic setting and the role of propofol in
causing the deaths, versus the usually ascribed sepsis or viral myocarditis, in sick patients
was intensively debated. Further cases of rhabdomyolysis and metabolic acidosis were
soon reported in patients receiving propofol for sedation in similar settings.911
Two patients admitted to intensive care units for treatment of acute asthma suered
similar problems.12 The rst was a woman aged 47 years who received an infusion of
propofol 12 mg/kg/hour for 4 days. On day two she developed haematuria, and labo-
ratory investigations showed renal insuciency with hyperkalaemic metabolic acidosis.
She died as a result of rhabdomyolysis with cardiac involvement. The second was a man
aged 41 who received propofol at rates of up to 13 mg/kg/hour for 2 days and then
developed oliguria following which the propofol was withdrawn. He was also receiving
fentanyl and low-molecular-weight heparin for deep-vein thrombosis prophylaxis. He
subsequently developed a very high creatine kinase activity of over 170 000 IU/l.
Echocardiography showed globally depressed myocardial dysfunction. He subsequently
recovered. A similar case, possibly relating to propofol, was reported in a man aged 18
years who suered multiple trauma.13 He was sedated for 4 days with propofol
530700 mg/hour. On day ve he developed a metabolic acidosis with hyperkalaemia,
 Toxicity of intravenous anaesthetics 79

his serum was lipaemic and an echocardiogram showed global hypokinesia. He

deteriorated and died shortly afterwards.
Although none of these cases provide a denitive link between propofol and the
pathology established, they presented a common clinical pattern, and unlike the original
report, occurred in patients with no known active sepsis.
Recently a retrospective cohort analysis was reported on ve adult patients with head
injuries who inexplicably suered fatal cardiac arrests in a neurosurgical intensive care
unit after the introduction of a sedation regime containing increased doses of propofol.14
The odds ratio for the development of the propofol infusion syndrome was 1.9 (95% CI
1.13.3, P 0.02) for every mg/kg/hour increase in mean propofol dose above 5 mg/kg/
hour. The authors suggested that propofol infusion at rates higher than 5 mg/kg/hour
should be discouraged for long-term sedation. Other reports of deaths in head-injured
patients reinforce this suggestion.13 An editorial review of the subject suggested that the
use of high-dose prolonged propofol infusions, dened as 44.86.0 mg/kg/hour for
44872 hours, be avoided.15 It was noted that if high-dose metabolic suppressive
treatment was required for longer than 3 days in head injury, the alternative of
barbiturate treatment should be considered. Although barbiturates are long-acting
agents that have well-known potent myocardial depressant eects of their own, and
which can be dicult to manage due to their long half-life, they have an established place
in therapy and have not been associated with similar problems.
Extensive metabolic analysis was carried out on a case of propofol infusion syndrome
occurring in a 2-year-old child. The patient received propofol at an average rate of
5.2 mg/kg/hour for 72 hours following a gunshot injury to the head.16 On the fourth
day, he became oliguric with elevated potassium, urea and creatinine, and then
developed a severe nodal bradycardia of 28 beats/minute. The propofol infusion was
stopped and an isoprenaline infusion started, but he required emergency transvenous
pacing of the heart to restore an adequate heart rate. Haemoltration was begun on the
basis of another case report suggesting that it may be successful. The acidosis cleared,
cardiovascular function was restored, and the child made a complete recovery.
Extensive metabolic analysis was performed on blood taken before commencing
haemoltration.16 Important ndings included raised malonylcarnitine, C5-acylcarni-
tine, creatine kinase, troponin T and myoglobinaemia. These ndings are consistent
with impaired fatty acid oxidation, namely, reduced mitochondrial entry of long-chain
acylcarnitine esters due to inhibition of the transport protein carnitine palmityl
transferase-1, and failure of the respiratory chain at complex II. At follow-up 9 months
later, all markers of fatty acid oxidation were normal. Previous reports of propofol
infusion syndrome have demonstrated other abnormalities of the respiratory chain
including a reduction in cytochrome C oxidase activity and decreased complex IV
activity with a reduced cytochrome oxidase ratio of 0.004. Propofol can also impair the
mitochondrial electron transport system in isolated heart preparations.
Propofol infusion syndrome mimics the mitochondrial myopathies, in which there are
specic defects in the mitochondrial respiratory chain associated with specic
mitochondrial DNA abnormalities. The clinical features of mitochondrial myopathy
result from a disturbance in lipid metabolism in cardiac and skeletal muscle.
These patients generally remain well until stressed by infection or starvation, although
subclinical biochemical abnormalities of mitochondrial transport can be demonstrated.
It has been suggested that early management of critically ill children may not include
adequate caloric intake to balance the increase in metabolic demands, and that in
susceptible children, the diversion of metabolism to fat substrates may cause propofol
infusion syndrome. It is unclear whether the dose or duration of propofol infusion alters
80 T. G. Short and Y. Young

this eect. As adults have larger carbohydrate stores and require lower doses of
propofol for sedation, this may account for the relative rarity of the syndrome in adults.
It has been suggested that adequate early carbohydrate intake may help to prevent
propofol infusion syndrome.
It is possible that the full-blown propofol infusion syndrome occurs only in those
individuals with a genetic susceptibility. Similarly, it may also be possible that more
subtle alteration in mitochondrial function is occurring in many more individuals
receiving propofol, and may explain why ICU stay is no dierent in patients sedated with
propofol-based regimens (rather than midazolam), although tracheal extubation is
signicantly earlier. Hyperlipidaemia with propofol may also result from failure of free
fatty acid metabolism and hence may be a useful early marker of the development of
the syndrome.
The proposed sites of action of propofol at the mitochondrial membrane and at the
respiratory chain are shown in Figures 1 and 2.
The use of propofol as the main or sole agent for sedation is a recent development.
Traditionally, intensive care sedation has consisted of combinations of sedatives and
opioids to achieve adequate sedation. Combinations of opioids with sedatives such as
benzodiazepines are well known for their synergy in decreasing dose requirements to
achieve hypnosis or suppression of movement to pain in the anaesthetic setting.17
These combinations also appear to decrease the incidence of spontaneous movements in
ventilated patients, which may be misinterpreted as inadequate sedation.18 Small studies
have demonstrated the safety and lack of biochemical abnormalities from use of
combination therapy. One such study demonstrated the safety of the combination of

ATP + CoA AMP + PPi

Propofol Cell cytoplasm

FFA Acyl-CoA

Carnitine
palmitoyl- Outer
Acyl-CoA transferase I Mitochondrial
Synthetase Membrane

Acyl-CoA
Carnitine Acylcarnitine
Propofol

Carnitine Carnitine Inner

palmitoyl- Acylcarnitine Mitochondrial
transferase II Translocase Membrane

CoA Carnitine Acylcarnitine

Acylcarnitine
Acyl-CoA

Figure 1. Proposed sites of inhibitory action by propofol at the mitochondrial membrane. Proposed
mechanism whereby propofol inhibits the conversion of free fatty acids to Acyl-CoA and hence failure of fatty
acid oxidation and ATP production. Failure of carbohydrate metabolism due to glycogen depletion leads to
lactic acidosis.
 Toxicity of intravenous anaesthetics 81

NADH
Complex I
NADH-ubiquinone
NAD+
oxidoreductase
CoQ
Succinate Complex II Electron path
TCA Succinate-ubiquinone
cycle oxidoreductase
Fumarate CoQ
Propofol
Complex III
Ubiquinol-cytochrome C
oxidoreductase

Cyt C
1/2 O2 + 2 H+
Propofol Complex IV
Cyt C
oxidase

H2O

Figure 2. Proposed sites of inhibitory action by propofol at the mitochondrial respiratory chain. Proposed
sites where propofol causes failure of ATP production in the mitochondrial respiratory chain.
CoQ, coenzyme Q; CytC, cytochrome C.

Practice points
Signs of possible propofol infusion syndrome
. prolonged, high propofol infusion rate, typically above 5 mg/kg/hour for
448 hours
. metabolic acidosis
. hyperkalaemia
. elevated creatinine kinase
. bradydysrhythmias
. depressed myocardial function
. rhabdomyolysis
. haematuria
. absence of other obvious clinical cause
Prevention of propofol infusion syndrome
. aggressive early feeding
Treatment of propofol infusion syndrome
. stop the infusion
. consider haemoltration to remove propofol
. consider pacing of the heart for bradycardia
. maintain ionized calcium concentration 4 1.0 mmol/l
. consider intravenous glucagon (bolus 5 mg and infusion 3 mg/hour)
General
. prolonged high-dose propofol infusion mimics the mitochondrial myopathies
. avoid prolonged infusions above 5 mg/kg/hour
82 T. G. Short and Y. Young

propofol 14 mg/kg/hour and fentanyl 15 mg/kg/hour for periods up to 2 days in nine

children requiring ventilation.19 Their liver and renal function remained normal and no
evidence of metabolic acidosis occurred. Although these combinations have not been
systematically researched on a large scale for rare side-eects, they appear to allow
adequate sedation without the need for excessive dosage of any one agent.20

. avoid use of propofol as a sole sedative agent

. benzodiazepines and opioids both signicantly reduce propofol requirements for
sedation; these drugs decrease the incidence of spontaneous movements in
sedated patients

Research agenda
. optimal sole drugs for intensive care sedation do not exist
. existing drugs are more eective when used in combination
. metabolic eects and ecacy of common drug combinations are poorly explored
. the metabolic eects of low-dose propofol infusion requires systematic study
. systematic study of mitochondrial DNA abnormalities in the critically ill is required
. animal models of mitochondrial myopathies (including cardiomyopathy) are
readily available

Hyperlipidaemia
Hyperlipidaemia has been reported in patients receiving prolonged propofol infusions
for sedation in the intensive care unit.20,21 In one study, patients had received infusion
rates of 1% propofol of 38 mg/kg/hour for 0.58 days. Propofol was their only source
of lipids and blood concentrations of triglycerides were 3.59.5 mmol/l (normal range
0.341.7). The daily lipid load was 0.61.5 g/kg/day. In the second study, triglyceride
concentrations were elevated, necessitating cessation of treatment in three of 32
patients receiving propofol sedation in the 1.56 mg/kg/hour dose range.
The doses of lipid received when infusing propofol are well below recommended
doses for parenteral nutrition in critically ill patients. The standard formulation of
propofol is a 1% emulsion in 10% intralipid. The maximum recommended infusion rate
for intralipid is usually regarded as 0.5 g/kg/hour, which is equivalent to an infusion
rate of 50 mg/kg/hour of propofol, well above clinical dosing requirements.
Nevertheless, clinically signicant quantities of propofol can be administered during
long-term infusion, and hyperlipidaemia in association with propofol infusion has been
observed during prolonged infusion in critically ill patients, particularly children and
those with impaired liver metabolism. It is also possible that the hyperlipaemia is, in
part, due to failure of lipid metabolism secondary to the eect of propofol. Both 2%
and 6% formulations of propofol have been developed in an attempt to reduce the lipid
load. These formulations have been found to be similar in terms of pharmacokinetics,
induction time, dose requirements and safety proles in small clinical trials, and to be
associated with lower lipid concentrations in patients.7,22

Cardiovascular
The cardiovascular eects of propofol given at two infusion rates in healthy patients
were examined using transthoracic echocardiography.23 Patients were randomly
 Toxicity of intravenous anaesthetics 83

assigned to receive propofol at 10 mg/s or 2 mg/s. In both groups, global and segmental
ventricular function remained unchanged. In both groups, there were markedly
reduced end-systolic quotients, presumably related to diminished afterload. In the
higher infusion rate group, there was a signicant reduction in fractional shortening,
thought to be related principally to diminished pre-load. The study conrms that, in
healthy patients, propofol has few signicant direct myocardial eects that would
account for the myocardial failure noted in propofol infusion syndrome.

Respiratory
Two cases of propofol-induced bronchoconstriction have been reported.24 Both
patients had allergic rhinitis and took antihistamines during spring, but were
otherwise healthy. Respiratory complications of propofol are rare; it was not clear
whether these were allergic reactions.

Hepatic
A case of hepatocellular injury following the use of propofol as a sole agent in a young
patient with multiple drug allergies and undergoing outpatient anaesthesia for femoral
hernia repair has been reported.25 Post-operatively the patient required re-admission to
hospital for severe nausea and vomiting with diuse abdominal tenderness.
Acute hepatitis was diagnosed on the basis of very high transaminase levels and a
prolonged prothrombin time. No viral aetiology could be demonstrated, antinuclear
antibody and smooth muscle antibody titres were not elevated, and the plasma
caeruloplasmin concentration was normal. Abdominal ultrasound was normal and did
not demonstrate gallstones. A urine examination was normal and did not show evidence
of porphyrins or porphobilinogen. Unfortunately the patient refused liver biopsy; he
recovered spontaneously.

Pancreatic
Pancreatitis is a rare complication of propofol administration, which has also generated
controversy regarding the signicance of propofol in its aetiology. A recent report noted
25 cases of pancreatitis associated with propofol reported to the Federal Drug
Administration registry, which has listed the association between propofol and
pancreatitis as `probable'.26
In one case, the propofol-induced pancreatitis recurred on re-challenge 17 days later,
prompting the suggestion that the association should be upgraded to `denite causal'.26
The patient was a female aged 51 years who had been admitted to intensive care with
pneumonia and was sedated using a propofol infusion to assist mechanical ventilation.
She received a total of 26.5 g of propofol at a maximum dose rate of 12 mg/kg/hour over a
7-day period. On diagnosis of pancreatitis, which was associated with hypertriglycer-
idaemia, the propofol infusion was stopped. In addition to elevated amylase, triglyceride
and lipase concentrations were also elevated in the blood and recovered over the next 7
days. The patient underwent a tracheotomy revision on the 17th day, during which she
received 200 mg of propofol for anaesthesia induction. Subsequently she developed
another episode of pancreatitis, this time without hypertriglyceridaemia, which
recovered over several days.
In another case, a healthy man aged 35 years developed acute pancreatitis a few hours
after a 15-minute propofol anaesthetic for laser treatment of a urethral stricture.27
84 T. G. Short and Y. Young

He required 3 weeks of respiratory and renal support in intensive care. There was no
evidence of gallstones on abdominal imaging. No defect in lipid metabolism was
demonstrated. Other reports of pancreatitis after bolus dosing for anaesthesia induction
also exist.28,29 The aetiology of this problem has not been elucidated, but a role for
propofol in causing these reactions seems increasingly likely.

Infection risk
Clusters of infection have been sporadically reported ever since the introduction of
propofol into clinical practice.3032 The Federal Drug Administration in the USA
consequently requested that manufacturers add a preservative to the ampoule to reduce
this risk. Ethylenediaminetetra-acetic acid (EDTA) and sodium metabisulphite have both
been used for this purpose. The EDTA additive has been shown not to alter the
pharmacokinetics or pharmacodynamics of the drug.33 Concerns that EDTA might bind
zinc, magnesium or calcium, aecting their homeostasis, have been allayed following a
clinical trial programme in multiple intensive care units looking into this possible side-
eect.34 There have not been reports of cluster infections occurring since introduction
of these new formulations, but notably one case of propofol infusion syndrome occurred
in a patient receiving a high dose of the sodium-metabisulphite-containing preparation
of propofol.35 The patient was a 21-year-old female who received infusion rates of up to
9 mg/kg/hour and 30 g total in the rst 48 hours of treatment. The metabisulphite-
containing preparation has a pH of 4.56.4 versus pH 7.58.0 for the EDTA-containing
preparation and the authors speculated that the low pH of the solution may have
signicantly contributed to the acid load. However, the possibility that the problem was
due to propofol infusion syndrome was not ruled out, serum lactate levels were elevated
at 14 mM during the infusion and the patient initially improved on discontinuation of
propofol. The use of sodium metabisulphite as a preservative has been criticized because
of possible allergy to the preservative, which has been associated with asthmatic
reactions when used as a preservative in other drug preparations.

Practice points
Preventing contamination of propofol
. aseptic technique should be used when handling propofol
. all ampoules and syringes of propofol are for single patient use only
. draw up and use propofol immediately on opening the ampoule
. discard unused propofol at the end of the procedure or within 6 hours of
opening it

THIOPENTONE

Toxic eects of thiopentone include local toxicity, with extravasation under the skin
being associated with severe pain and tissue necrosis, and rarely nerve damage from
direct toxicity has also been reported. Intra-arterial injection is also associated with
severe pain and arterial spasm and can cause necrosis in the territory of the artery.
Use of 2.5% solution has reduced the incidence of this problem in comparison to a 5%
solution. Severe anaphylaxis also occurs, with a reported incidence of 1:2030 000
 Toxicity of intravenous anaesthetics 85

patients, and severe skin reactions, including erythema multiforme, exanthems, toxic
epidermal necrolysis and urticaria, have also been reported.36
Recently, infusions of thiopental in the intensive care unit have been shown to cause
altered thyroid function.37 The patients had received a bolus dose of thiopental 5 mg/kg
followed by an infusion of 3 mg/kg/hour for 23 days for cerebral protection after
cardiac arrest. Free T3 concentrations fell dramatically in three of the ve patients
tested, and were associated with an increase in reverse T3 concentrations. T3
concentrations returned to normal on cessation of the infusion. It was speculated that
thiopental converts T3 to reverse T3 and may intensify euthyroid sick syndrome after
cardiac arrest.

ETOMIDATE

Etomidate has been recently reformulated in a lipid emulsion, which solves some of the
disadvantages of pain on injection and thrombophlebitis when using the original
propylene-glycol-containing preparation. The eects of long-term infusion of etomidate
in suppression of adrenocortical function are well known. The drug is also useful for
anaesthesia induction in haemodynamically unstable patients due to a lack of myocardial
depression seen with other agents combined with an increase in sympathetic tone
following bolus dose administration. A prospective randomized trial assessed
adrenocortical function following intravenous etomidate use in emergency department
patients requiring rapid-sequence induction and tracheal intubation.38 The control
group received midazolam. Use of etomidate did result in adrenocortical dysfunction
that appeared to resolve after 12 hours. The clinical signicance of this nding is unclear,
but given the common use of the drug in acutely unwell patients, it is clearly undesirable.

KETAMINE

Ketamine has found increasing favour for use in chronic pain treatment and for
refractory acute pain management. This has extended its use into long-term
administration and via novel routes. A case of focal lymphocytic vasculitis has been
reported adjacent to a catheter injection site in a patient who received intrathecal
ketamine infusion for chronic cancer pain.39 The patient was an elderly woman with a
malignant mesothelioma of the peritoneum who, along with various intravenous
therapies, received a thoracic epidural infusion of bupivacaine and morphine, and
clonidine with minor success. Satisfactory pain relief was nally achieved by adding
commercially available ketamine 1 mg/ml, which contains benzethonium chloride as a
preservative. The mean daily dose of ketamine administered intrathecally was 67 mg.
After 7 days of ketamine administration, the ketamine was discontinued due to acute
psychotic changes in the patient. No neurological decits were observed. Ten days
later, the patient passed away. Histological examination of the spinal cord at the
autopsy found focal lymphocytic vasculitis in the medullary tissue, in the nerves, and in
the leptomeninges of the thoracolumbar spinal cord. This neurotoxicity could have
been due to the preservative benzethonium chloride or the toxicity of the drug
mixture administered. As a number of other agents, including bupivacaine, morphine
and clonidine, were also given intrathecally, causality has not been proven. However,
there is much more extensive experience of intrathecal administration of these agents
without the problem being recognized.
86 T. G. Short and Y. Young

DIAZEPAM
Vascular
Inadvertent intra-arterial injection of diazepam 2.5 mg in 0.5 ml into the hand of an
8-year-old child resulted in gangrene of the 4th and 5th ngers, requiring amputation.40
This complication has been previously reported with diazepam. It appears to be caused
by the drug rather than the solvent used in the intravenous formulations.

Nervous system
Prolonged, deep sedation has been reported in ve neonates due to persistence of
diazepam metabolites.41 Persistence of the metabolite N-desmethyldiazepam was
probably responsible for the problem. This metabolite is very slowly metabolized in
term and preterm neonates due to the reduced capacity of the hepatic microsomal
enzyme uridine diphosphate glucuronyl.
Paradoxical seizures after diazepam administration have been reported in a 20-year-old
man with complex partial seizures who presented with exacerbation of his disease.42
He was taking phenytoin and sodium valproate, with plasma concentrations in the target
ranges. During a video electroencephalogram recording, the partial seizures developed
into frequent generalized seizures following diazepam 10 mg. The same response was
observed on a subsequent occasion. Such paradoxical reactions to benzodiazepines are
rare but should be considered in cases of refractory epilepsy.

MIDAZOLAM
Metabolic
Medazolam is metabolized by cytochrome CYP3A. Numerous other drugs also utilize
CYP3A, and delayed metabolism and prolonged or increased eect can occur when
the drugs are co-administered. These include the azole antifungal drugs ketaconazole,
itraconazole and uconazole, the antidepressants uoxitine and noruoxetine,
diltiazem and also grapefruit juice.4345 Itraconazole has been shown to increase the
elimination half-life of midazolam from 2.7 hours to 7.6 hours. The converse is also
true, with the CYP3A inducer rifampicin, decreasing the elimination half-life from 2.7
hours to 1 hour.46 The eect was still present, although less marked, at 4 days after
cessation of either itraconazole or rifampicin. Similarly, after acute administration, the
period of drowsiness was increased from 76 to 201 minutes with itraconazole and
decreased from 76 to 35 minutes with rifampicin. The result shows that the
pharmacokinetics and pharmacodynamics of midazolam are markedly aected by drugs
that inuence cytochrome CYP3A.

Nervous system
Involuntary epileptiform movements were described in three of six premature infants
given midazolam for sedation.47 They were born at 2426 weeks' gestation, aged 2332
days and weighed 671 g on average. They were given midazolam 100 mg/kg by slow
bolus injection and then suered from accentuated myoclonic jerks resembling clonic
seizures within 5 minutes. The abnormal movements resolved within 510 minutes.
There have also been reports of convulsions caused by midazolam in two
preterm infants.48 They were 26 and 28 weeks' gestation and were given midazolam
 Toxicity of intravenous anaesthetics 87

100 and 150 mg/kg intravenously prior to tracheal intubation. Both babies were
successfully treated with umazenil 10.0 mg/kg. The safety of midazolam in very-low-
birthweight neonates has being questioned. Infants given heavy-sedation-weight
midazolam and fentanyl combination have also been found on occasion to prolong
recovery from sedation. Signs included poor social interaction, decreased visual
attentiveness, dystonic postures and chorioathetosis, and resolved over 5 days to 4
weeks.49 While aetiology cannot be certain, the possibility that prolonged action of
midazolam is causing or exacerbating this syndrome needs to be considered. It is notable
that blood concentrations of midazolam were not measured in these patients. Failure of
acutely unwell patients to metabolize midazolam has been recorded in the past in adult
patients and could reasonably be expected to be a greater problem in neonates.50
Midazolam can cause paradoxical reactions, including increased agitation, poor co-
operation and aggressive or violent behaviour. Often other drugs are required to
continue the procedure successfully. Reversal of the phenomena by umazenil,
a benzodiazepine antagonist, has been reported in several studies.5153 In a cohort
study of 58 patients undergoing surgery under spinal or epidural anaesthesia,
umazenil titrated to a total dose of 0.10.5 mg resulted in cessation of the agitation
without reversal of sedation and without side-eects of umazenil being reported.
Care must be taken when considering the use of umazenil for reversal of
midazolam-induced agitation as these data are anecdotal and no controlled trials have
been published. Flumazenil is a specic competitive antagonist of benzodiazepines at
the benzodiazepine receptor. Its rapidly reverses benzodiazepine-induced sedation,
including that due to overdose, when it is occasionally used as a diagnostic test for the
presence of benzodiazepines. The drug reverses both agonists and inverse agonists at
the benzodiazepine receptor, an eect that possibly explains some of its unusual
properties. It has been shown to be capable of reversing paradoxical arousal after
benzodiazepines and to cause convulsions in patients dependent on benzodiazepines
for their suppression and to be anticonvulsant in other circumstances.

SUMMARY

Intravenous anaesthetic agents are usually remarkably safe, especially when given for
short periods of time. However, it is clear that propofol infusion syndrome is a real,
albeit rare, entity. This often lethal syndrome of metabolic acidosis, acute
cardiomyopathy (presenting as bradydysrhythmias and cardiac failure) and skeletal
myopathy (presenting as rhabdomyolosis, hypermyoglobinaemia and acute renal
failure) is strongly associated with infusions of propofol at rates of 5 mg/kg/hour and
greater for more than 48 hours. There is evidence to support the hypothesis that the
syndrome is caused by the failure of free fatty acid metabolism once carbohydrate
metabolism is exhausted. This failure appears to occur at the level of free fatty acid
entry into the mitochondria and at specic sites in the mitochondrial respiratory
chain. The syndrome therefore mimics the mitochondrial myopathies. The metabolic
eects and ecacy of common drug combinations are poorly explored. Systematic
study of the eects of low-dose propofol infusion is required. Systematic study of
mitochondrial DNA abnormalities in the critically ill is also required. Animal models
of mitochondrial myopathies, including cardiomyopathy, are readily available.
Midazolam has been described as causing seizure-like activity in very-low-
birthweight premature infants requiring the drug prior to tracheal intubation or
during prolonged positive pressure ventilation. This has been successfully reversed
 88 T. G. Short and Y. Young

with the specic antagonist umazenil. Midazolam can also cause paradoxical reactions,
including increased agitation, poor co-operation and aggressive or violent behaviour,
which may also be successfully managed with umazenil.

REFERENCES

1. Bragonier R, Bartle D & Langton-Hewer S. Acute dystonia in a 14-yr-old following propofol and fentanyl
anaesthesia. British Journal of Anaesthesia 2000; 84: 828829.
2. Iwasaki F, Mimura M, Yamazaki Y et al. Generalized tonic-clonic seizure induced by propofol in a patient
with epilepsy. Japanese Journal of Anesthesiology 2001; 50: 168170.
3. Harrigan PWJ, Browne SM & Quail AW. Multiple seizures following re-exposure to propofol. Anaesthesia
and Intensive Care 1996; 24: 261264.
4. Cochran D, Price W & Gwinnutt CL. Unilateral convulsion after induction of anaesthesia with propofol.
British Journal of Anaesthesia 1996; 76: 570572.
5. Sneyd JR. Propofol and epilepsy. British Journal of Anaesthesia 1999; 2: 6869.
6. Yasukawa M & Yasukawa K-I. Convulsion in two non-epileptic patients following induction of anesthesia
with propofol. Japanese Journal of Anesthesiology 1999; 48: 271274.
7. Borgeat A, Fuchs T & Tassonyi E. Induction characteristics of 2% propofol in children. British Journal of
Anaesthesia 1997; 78: 433435.
* 8. Parke TJ, Stevens JE, Rice ASC et al. Metabolic acidosis and fatal myocardial failure after propofol infusion
in children: ve case reports. British Medical Journal 1992; 305: 613616.
9. Cray SH, Robinson BH & Cox PN. Lactic academia and bradyarrythmia in a child sedated with propofol.
Critical Care Medicine 1998; 26: 20872092.
10. Hanna JP & Ramundo ML. Rhabdomyolysis and hypoxia associated with prolonged propofol infusion in
children. Neurology 1998; 50: 301303.
*11. Stelow EB, Johari VP, Smith SA et al. Propofol-associated rhabdomyolysis with cardiac involvement in
adults: chemical and anatomic ndings. Clinical Chemistry 2000; 46: 577581.
12. Perrier ND, Baerga-Varela Y & Murray MJ. Death related to propofol use in an adult patient. Critical
Care Medicine 2000; 28: 30713074.
*13. Cannon ML, Glazier SS & Bauman LA. Metabolic acidosis, rhabdomyolysis and cardiovascular collapse
after prolonged propofol infusion. Journal of Neurosurgery 2001; 95: 10531056.
*14. Cremer OL, Moons KGM, Bouman EAC et al. Long-term propofol infusion and cardiac failure in adult
head-injured patients. Lancet 2001; 357: 117118.
*15. Kelly DF. Propofol-infusion syndrome. Journal of Neurosurgery 2001; 95: 925926.
*16. Wolf A, Weir P, Segar P et al. Impaired fatty acid oxidation in propofol infusion syndrome. Lancet 2001;
357: 606607.
17. Glass PS. Anesthetic drug interactions. Anesthesiology 1998; 88: 56.
*18. Godsi L, Magee L & Park GR. Co-sedation in the critically ill. Anaesthesia 1995; 50: 10041005.
*19. Martin PH, Murthy BV & Petros AJ. Metabolic, biochemical and haemodynamic eects of infusion of
propofol for long-term sedation of children undergoing intensive care. British Journal of Anaesthesia 1997;
79: 276279.
20. Camps AC, Riera JASI, Vazquez DT et al. Midazolam and 2% propofol in long-term sedation of
traumatized, critically ill patients: ecacy and sedation. Critical Care Medicine 2000; 28: 36123619.
21. Mateu J & Barrachina F. Hypertriglyceridaemia associated with propofol administration in critically ill
patients. Intensive Care Medicine 1996; 22: 834835.
22. Knibbe CAJ, Voortman H-J, Aarts LPHJ et al. Pharmacokinetics, induction of anaesthesia and safety
characteristics of propofol 6% SAZN vs propofol 1% SAZN and Diprivan-10 after bolus injection. British
Journal of Clinical Pharmacology 1999; 47: 653660.
23. Bilotta F, Fiorani L, La Rosa I et al. Cardiovascular eects of propofol administered at two infusion rates:
a transthoracic echocardiographic study. Anaesthesia 2001; 56: 266271.
24. Nishiyama T & Hanaoka K. Propofol induced bronchconstriction: two case reports. Anesthesia and
Analgesia 2001; 93: 645646.
25. Anand K, Ramsay MA & Crippin JS. Hepatocellular injury following the administration of propofol.
Anesthesiology 2001; 95: 15231524.
*26. Kumar AN, Schwartz DE & Lim KG. Propofol-induced pancreatitis: recurrence of pancreatitis after
rechallenge. Chest 1999; 115: 11981199.
27. Betrosian AP, Balla M, Papanikolaou M et al. Postoperative pancreatitis after propofol administration.
Acta Anaesthesiologica Scandinavica 2001; 45: 1052.
 Toxicity of intravenous anaesthetics 89

28. Leisure GS, O'Flaherty J, Green L et al. Propofol and acute pancreatitis. Anesthesiology 1996; 84: 224227.
29. Wingeld TW. Pancreatitis after administration: is there a relationship? Anesthesiology 1996; 84: 236237.
30. Wachowski I, Jolly DT, Hrazdil J et al. The growth of microorganisms in propofol and mixtures of
propofol and lidocaine. Anesthesia and Analgesia 1999; 88: 209212.
31. Mehta U, Gunston GD & O'Connor N. Serious consequences to the misuse of propofol anaesthetic.
South African Medical Journal 2000; 90: 240.
32. Arduino MJ, Bland LA, McAllister SK et al. Microbial growth and endotoxin production in the
intravenous anesthetic propofol. Journal of Infection Control and Hospital Epidemiology 1991; 12: 535539.
33. Schnider TW, Minto CF & Gambus PL. The inuence of method of administration and covariates on the
pharmacokinetics of propofol in adult volunteers. Anesthesiology 1998; 88: 11701182.
34. Zaloga GP & Teres D. The safety and ecacy of propofol containing EDTA: a randomised clinical trial
programme focusing on cation and trace metal homeostasis in critically ill patients. Intensive Care
Medicine 2000; 26: S398S399.
35. Badr AE, Mychaskiw G & Eichhorn JH. Metabolic acidosis associated with a new formulation of propofol.
Anesthesiology 2001; 94: 536538.
36. Litt JZ. Drug Eruption Reference Manual 2000. New York: Parthenon Publishing Group, 2000; 555556.
37. Kotake Y, Matsumoto M & Takeda J. Thiopental intensies the euthyroid sick syndrome after
cardiopulmonary resuscitation. Clinical Journal of Anesthesia 2000; 14: 3841.
38. Schenarts CL, Burton JH & Riker RR. Adrenocortical dysfunction following etomidate induction in
emergency department patients. Academy of Emergency Medicine 2001; 8: 17.
39. Stotz M, Oehen H-P & Gerber H. Histological ndings after long-term infusion of intrathecal ketamine
for chronic pain: a case report. Journal of Pain and Symptom Management 1999; 18: 223238.
40. Derakshan MR. Amputation due to inadvertent intra-arterial diazepam injection. Iranian Journal of
Medical Science 2000; 25: 8486.
41. Peinemann F & Daldrup T. Severe and prolonged sedation in ve neonates due to persistence of
diazepam metabolites. European Journal of Pediatrics 2001; 160: 378381.
42. Al Tahan A. Paradoxical response to diazepam in complex partial status epilepticus. Archives of Medical
Research 2000; 31: 101104.
43. Von Moltke LL, Greenblatt DJ, Schmider J et al. Midazolam hydroxylation by human liver microsomes
in vitro: inhibition by uoxetine, noruoxetine and by the azole antifungal agents. Journal of Clinical
Pharmacology 1996; 36: 783791.
44. Ahonen J, Olkkola KT, Salmenpera M et al. Eect of diltiazem on midazolam and alfentanil disposition in
patients undergoing coronary artery bypass grating. Anesthesiology 1996; 85: 12461252.
45. D'Arcy PF. Grapefruit juice, midazolam and triazolam. International Pharmacy Journal 1996; 10: 223.
46. Backman JT, Kivisto KT, Olkkola KT et al. The area under the plasma concentration-time curve for oral
midazolam is 400 fold larger during treatment with itraconazole than with rifampicin. European Journal of
Clinical Pharmacology 1998; 54: 5358.
47. Waisman D, Weintraub Z, Rotschild A et al. Myoclonic movements in very low birth weight premature
infants associated with midazolam intravenous bolus administration. Pediatrics 1999; 104: 579.
48. Birrell VL, Wyllie JP & Pagan J. Midazolam causing convulsions. British Journal of Intensive Care 1999;
9: 197.
49. Bergman I, Steeves M, Burckart G et al. Reversible neurologic abnormalities with prolonged intravenous
midazolam and fentanyl administration. Journal of Pediatrics 1991; 119: 644649.
50. Shelly MP, Mendel L & Park GR. Failure of critically ill patients to metabolise midazolam. Anaesthesia
1987; 42: 619626.
*51. Weinbroum AA, Szold O, Ogorek D et al. The midazolam-induced paradox phenomenon is reversible
by umazenil. Epidemiology, patient characteristics and review of the literature. European Journal of
Anaesthesiology 2001; 18: 789797.
52. Fulton SA & Mullen KD. Completion of upper endoscopic procedures despite paradoxical reaction to
midazolam: a role for umazenil? American Journal of Gastroenterology 2000; 95: 809811.
53. Saltik IN & Ozen H. Role of umazenil for paradoxical reaction to midazolam during endoscopic
procedures in children. American Journal of Gastroenterology 2000; 95: 30113012.