INTENSIVE CARE
Pain, agitation and
delirium in the intensive
care unit
Christopher McGovern
Richard Cowan
Richard Appleton
Barbara Miles
Abstract
Pain, agitation and delirium are common during critical illness and are
associated with many adverse consequences. A key aim of critical
care is the facilitation of a calm, comfortable patient who can interact
with their family and staff. Intensive care unit (ICU) patients frequently
have pain from a variety of sources, many of which are not readily
appreciated or actively managed. This article explores the challenges
of assessing pain in the ICU and outlines methods that can be used to
better identify and manage pain in this patient group. Agitation in ICU
is often multifactorial, with many of its sources under-recognized. We
will discuss the potential reasons that ICU patients become agitated,
methods for measuring agitation and the actions that can be taken
to alleviate it. Although the use of sedative and anxiolytic drugs is
common in the ICU, their use is not without risks. This article will
outline these risks, the variety of drugs available and how to use
these drugs to a targeted effect. We will also explore delirium, its
risk factors, precipitants and associated morbidity and mortality.
This article will discuss how to diagnose delirium and the methods
used to prevent and manage it.
Keywords Agitation; analgesia; delirium; pain; sedation
RCOA Matrix map (Level, Column and Cell): 1A02, 1D01, 1D02, 2C05,
3C00
Admission to the intensive care unit (ICU) follows the primary
insult of the patient’s underlying illness. The secondary insult of
the interventions and care required to support them in ICU then
follows. Pain, agitation and delirium often coexist in critically
unwell patients and can exacerbate each other, contributing to
Christopher McGovern MBChB MCEM FRCA FFICM is a Specialist
Trainee Registrar in Anaesthetics and Intensive Care Medicine in the
West of Scotland, UK. Conflicts of interest: none declared.
Richard Cowan MBChB(Hons) MRCP(UK) FRCA FFICM is a Consultant in
Anaesthetics and Intensive Care Medicine at Glasgow Royal
Infirmary, UK. Conflicts of interest: none declared.
Richard Appleton MBChB FRCA FFICM is a Consultant in Anaesthetics
and Critical Care at the Queen Elizabeth University Hospital,
Glasgow, UK. Conflicts of interest: none declared.
Barbara Miles MBChB FRCA FFICM is a Consultant in Anaesthetics and
Intensive Care Medicine at Glasgow Royal Infirmary, Glasgow, UK.
Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
Learning objectives
After reading this article, you should be able to:
C outline the reasons patients experience pain in ICU
C describe methods used to assess pain in ICU
C explain why patients experience agitation in ICU
C describe strategies used to optimize sedative drug use
C define delirium and identify its precipitants
C outline a management strategy for a delirious patient
further physiological derangement and injury. Analgesic, anxio-
lytic and sedative medications are frequently used to alleviate
any distress from these insults. Non-pharmacological measures
combined with these drugs should be used as part of a bespoke,
patient-centred and multi-faceted care package to ensure that
pain, agitation and delirium are minimized in ICU patients.
Pain
Pain is defined as an unpleasant sensory and emotional experi-
ence associated with actual or potential tissue damage or
described in terms of such damage. It is a common problem in
ICU, with interventional pain being reported in around 50% of
patients and, perhaps more importantly, pain at rest being re-
ported in 30e50% of patients.1
There is no clear difference in pain levels between surgical
and medical patients. Some studies have demonstrated that
medical patients experience greater pain intensity than surgical,
potentially due to less analgesic use as there is no surgical
wound. Patients frequently report pain as a significant part of
their ICU recollection after ICU discharge.
Pain and the stress response are associated with detrimental
physiological consequences including increased stress hormone
production, vasoconstriction, increased catabolism with
impaired tissue perfusion and wound healing. These conse-
quences can extend beyond short term physiological sequelae to
persisting psychological problems such as chronic pain and post-
traumatic stress disorder (PTSD).
Why are ICU patients in pain?
Pain in the ICU population can be divided into procedural pain
and pain at rest.
Procedural pain: Multiple procedures common to the intensive
care environment can be painful, e.g. vascular line or drain
insertion, wound care and patient repositioning. Many such
procedures may be carried out without additional analgesia.
Tracheal suctioning, commonly reported as a source of pain and
distress by patients, is often performed without additional
analgesia.
Pain at rest: Rest pain in the trauma or surgical population is
easily attributed to wounds, fractures or the site of surgery.
However, other common sources of pain can be related to
indwelling lines, tubes and catheters, gastrointestinal discomfort
(from ileus, spasm or constipation) or musculoskeletal pain from
immobility or pressure areas.
799 Ó 2021 Published by Elsevier Ltd.
 INTENSIVE CARE
Assessing pain
Given the subjective nature of pain, the gold standard method for
pain assessment is using a validated self-reporting measure such
as the numerical rating scale with a visual support (NRS-V).
Unfortunately, given the nature of critical illness, the use of
sedative medications and high incidence of delirium, patients are
often unable to use self-reporting tools to allow assessment of
their pain. Hence, the identification of pain relies on surrogate
markers such as observations made at the bedside.
Tools such as the Critical Care Pain Observation Tool (CPOT)2
have been developed which detect the presence of pain by
assessing and scoring patient-centred features:

facial expression:
 relaxed expression (0 points), some facial muscle ten-
sion e.g. frowning (1 point) or grimacing (2 points)

body movements
 absence of movement (0 points), cautious or protective
movements (1 point) or restless and agitated e.g. pulling
tube, thrashing (2 points)

muscle tension
 relaxed muscle tone (0 points), resistance to movements
(1 point) or rigidity (2 points)

ventilation OR vocalization
 tolerating invasive ventilation (0 points), coughing (1
point) or significant asynchrony (2 points)
 normal tone and voice (0 points), sighing (1 point),
crying (2 points).
The maximum score is 8 with a score >2 indicating the
presence of pain that should trigger interventions or further
analgesia. Such scales have been found to be reliable and valid
across the wide variety of patient groups encountered in the ICU.
Although CPOT does not accurately reflect the severity of pain
in the same way a self-reported scale does, it is useful in iden-
tifying the presence of pain and the effectiveness of analgesic
interventions.
Haemodynamic changes such as hypertension or tachycardia
have not been found to be reliable methods of assessing pain in
critical care, although any change should prompt an assessment
of a patient’s pain.
Managing pain
Given the high incidence of pain in the ICU population, many
papers and guidelines recommend an analgesia-based sedation,
or ‘analgosedation’, approach to managing ICU patients.3 This
approach prioritizes analgesia over sedation or hypnosis, with
the aim of having a comfortable, lucid and interactive patient.
This approach has demonstrated a reduction in the use of hyp-
notic agents, duration of mechanical ventilation and ICU length
of stay.
Opioids remain the mainstay of analgesia in critical care due to
their potent analgesic and antitussive effects. These drugs act as
agonists with varying affinities for mu, kappa and delta opioid
receptors. Some examples include morphine, fentanyl, alfentanil
and remifentanil.
Each drug has its advantages and disadvantages surrounding
metabolism, potency, titratability and cost. Side effects common
to all opioids include respiratory depression, constipation and
ileus, hypotension, pruritis, nausea, delirium, tolerance and
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
withdrawal phenomena. The choice of opioid will depend on
staff familiarity, local practice and patient factors such as renal
function and underlying pathology.
Given the drive towards analgesia based sedative regimes,
drugs such as remifentanil have gained favour due to their easy
titratability as an infusion and context insensitive half-life. This
allows the rapid delivery of potent analgesia during procedures
or painful interventions, as well as a reliable and quick reduction
in plasma levels upon discontinuing the infusion. This rapid
offset of remifentanil means that an alternative analgesic plan
should be considered before stopping an infusion.
Paracetamol is a commonly used simple analgesic. When used
as an adjunct to opioids, it has an opioid sparing effect. This
finding has been echoed in some small studies carried out in
critical care, showing improved patient pain experience and
reduced opioid use. Paracetamol has also been investigated for
its antipyretic effects in sepsis, and although it does not alter
outcomes, it does appear to be safe.
As with any drug in the critically ill, the pharmacokinetics of
paracetamol can be unpredictable and should be used with
caution in patients with liver impairment or those of low body
mass. Paracetamol administration is also associated with a
modest fall in blood pressure.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as
ibuprofen and diclofenac have a side effect profile that often
limits their use within critical care. They are associated with
renal impairment, gastrointestinal irritation, bronchoconstriction
and impaired platelet function.
Some studies have demonstrated a reduction in opioid con-
sumption when adjuvant NSAIDs are used. However, they
should be used with caution in the critically ill and only in
selected circumstances such as young patients with little or no
co-morbidities.
Regional analgesia: Drugs such as lignocaine and bupivicaine
are most commonly used to provide regional analgesia via
epidural or peripheral nerve catheters. Other methods of
administration include local infiltration, single-shot nerve blocks
or the use of topical patches.
The benefit of epidural analgesia has been demonstrated in
major abdominal aortic surgery, with improved pain control,
reduced myocardial infarction, reduced respiratory failure,
reduced duration of mechanical ventilation and length of ICU
stay. However, the use of techniques such as rectus sheath
catheters may also be effective, with potential benefits such as
earlier mobilization, more acceptable risk profile and fewer
haemodynamic changes compared to epidural analgesia. How-
ever, a robust evidence base for this technique is so far lacking,
with results from studies such as the TERSC trial awaited.4
Regional techniques such as thoracic epidural, paravertebral
and intercostal blocks have been used to manage pain from
traumatic rib fractures. Theoretically such regional techniques
could reduce opioid use, improve respiratory function and
reduce respiratory complication. More recently the use of erector
spinae plane (ESP) and serratus anterior plane blocks have
become more widespread, with ESP blocks having only been
described as recently as 2016. As such, the evidence base for
800 Ó 2021 Published by Elsevier Ltd.
 INTENSIVE CARE
their use is so far lacking, but many centres have incorporated
such techniques into routine practice.
Intravenous lignocaine infusions have been used as an adju-
vant analgesic in the perioperative period. However, this method
has not been investigated in the intensive care population. Given
the unpredictable pharmacokinetics and potential for neurolog-
ical and cardiovascular toxicity, the safety of such a technique in
critically ill patients is yet to be demonstrated.
Neuropathic pain medication: Multiple drugs exist for use in
acute and chronic neuropathic pain including gabapentin,
amitriptyline, carbamazepine and pregabalin. These agents may
be used not only to improve analgesia, but also to minimize
opioid requirements, improve sleep and symptoms of anxiety
and perhaps reduce the likelihood of developing chronic pain,
especially in conditions such as Guillain-Barre syndrome and
spinal cord injury. However, there is little evidence surrounding
this broad and varied class of drugs in critically ill patients. Their,
safety profile and effectiveness in ICU is largely unknown.
Other analgesic drugs: Given the overlap of effects, other drugs
with analgesic properties including alpha-2 agonists and
N-methyl-d-aspartate (NMDA) antagonists will be discussed later
in this article.
Agitation
Anxiety and agitation are commonly experienced by patients in
intensive care. The incidence of agitation in the ICU population is
reported between 50 and 70%, occurring either at the time of
admission or developing several days following admission.5
The reasons for agitation are frequently multifactorial. Drug
and alcohol withdrawal or toxicity, delirium or an underlying
psychiatric disorder can be causative factors. Underlying central
nervous system pathology, such as brain injury or meningoen-
cephalitis, can also cause agitation.
Being confined to bed in ICU in unfamiliar surroundings with
unfamiliar faces can exacerbate anxiety. Pain and unpleasant
stimuli such as loud noises, monitor alarms and bright lights can
disturb and fragment sleep, further aggravating anxiety. Other
stressors may include financial worries, concerns for their family
or simply the fear associated with critical illness, recovery or death.
Managing agitation
Managing agitation involves searching for underlying causes or
exacerbating factors and addressing them, targeting the goal of a
calm, lucid, cooperative and interactive patient. Specific efforts
should be made to regularly orientate and reassure patients
regarding their environment, treatment and progress. Should this
prove insufficient, then the mainstay of treatment is sedative or
anxiolytic medication.
The use of sedative medications in the management of
agitation should be targeted towards a specific end-point. Mul-
tiple papers and guidelines exist with the aim of improving
sedative practice in critical care, such as the ‘eCASH’ (early
Comfort using Analgesia, minimal Sedatives and maximal Hu-
mane care) concept,6 detailed in Figure 1.18
Such guidelines advocate a holistic, patient-centred approach
to sedation in combination with targeted analgesia, good sleep
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
hygiene, environmental optimization, early mobilization and
family engagement in patient care. Holistic, non-pharmacological
measures include reducing nighttime light and noise, using ear-
plugs and eye masks to promote sleep and restricting medical
interventions to daylight hours. Sedative drugs should be
continually reassessed and used at their lowest effective dose.
Measuring agitation and sedation
Several tools are available for monitoring the levels of sedation at
the bedside. These can be used to track fluctuations over time
and guide interventions to help achieve an optimal level of
sedation. The ideal tool for measuring sedation should be easy to
use, easy to interpret and have good inter-user reliability.
One of the most common tools used is the Richmond Agitation
eSedation Scale (RASS)7 which categorizes patients from the
most deeply sedated e5 (unable to rouse) to the most agitated þ4
(combative), with zero representing an alert and calm patient. RASS
and other scales have been validated in ICU and their use is rec-
ommended in the Pain Agitation and Delirium (PAD) guidelines.3
Beyond clinical bedside measures of sedation, other more
objective measures of sedation depth include evoked potentials,
oesophageal pressure monitors, heart rate variability monitors
and electroencephalograms. Although these are classically used
as depth of anaesthesia monitors, they may also be useful ad-
juncts in the ICU.
Processed electroencephalograms such as the Bispectral Index
(BIS) monitor may add diagnostic value when looking for cerebral
hypoxia, seizure activity, changes in cerebral oxygen consumption
and cerebral perfusion. Some studies have demonstrated good
correlation between BIS levels and RASS scores. They should,
however, be used with caution due to potential interference from
electromyogram (EMG) signals, the pathophysiological changes of
critical illness, changes in core temperature and multiple drugs
including catecholamines and ketamine.
The use of such monitors is not universal practice but they may
be useful in selected patient groups, such as those requiring deep
sedation during neuromuscular blockade or anaesthesia for pain-
ful procedures at the bedside (e.g. percutaneous tracheostomy).
Titrating sedatives
When using sedative medications to provide anxiolysis or com-
fort, strategies should be in place to ensure the lowest effective
dose is used. Two broad methods exist as interventions to
minimize and optimize sedative use in the ICU.
Sedation breaks: A daily sedation interruption, or ‘sedation
break’, involves temporary discontinuation of sedative infusions
to assess the patient’s underlying neurological condition and
ongoing need for further sedation. This approach has been
combined with spontaneous breathing trials and physiotherapy
sessions to wean patients from mechanical ventilation and has-
ten recovery. Studies of this approach show that it reduces
duration of mechanical ventilation, length of ICU stay and need
for CT brain imaging.
Some caution must be exercised when using this approach as
some studies have demonstrated an increased risk of self extuba-
tion (but not an increased rate of re-intubation). Patients with
certain pathologies, at least initially, are likely to be excluded from
sedation breaks and a pragmatic approach should be taken to
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 INTENSIVE CARE
The eCASH concept
18
Copyright 2002 E Wesley Ely MD. MPH & Vanderbilt University, all rights reserved.
Figure 1
weigh the risks and benefits of such a technique in these groups
(e.g patients with raised intracranial pressure, unstable spinal
fractures, multiple complex injuries or airway pathology).
Sedation protocols: Algorithms or protocols can be used to
titrate sedative drugs to a specified target using a validated
sedation scale. Medical or nursing staff continuously adjust
sedative medications based on the frequent assessment of a pa-
tient’s depth of sedation or the presence of agitation.
Evidence exists supporting the use of such an approach and this
method is recommended by multiple review articles and guidelines.3
Currently, no evidence exists to definitively say which seda-
tion practice is superior to the other.8 What is more important is
the evolving culture behind sedation, with a shift away from a
norm of deep sedation to targeting a comfortable, lucid and
interactive patient.
Risks of sedation
There is mounting evidence that deep sedation, even in the
earliest stages of admission to critical care, is associated with
prolonged periods of mechanical ventilation, prolonged ICU stay
and an increased risk of death.9
Other risks of over-sedation include critical illness neuropathy and
myopathy, cardiovascular and respiratory depression, increased rates
of delirium, immune suppression, ileus and long-term sequelae such
as cognitive decline and post-traumatic stress disorder.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
Besides the risks of too much sedation, too little sedation may
also be associated with harm. This may include physical injury to
the patient or loss of medical devices such as the endotracheal
tube. Concerns have also been raised over increased levels of
awareness during a patient’s stay, resulting in distress and lasting
psychological harm. Several studies have demonstrated that
increased awareness does not result in psychological harm.
What drugs to use
Sedatives are usually combined with analgesics, namely opioids.
Consideration should be given to each drug’s pharmacokinetic
and pharmacodynamic properties, especially in the context of
critical illness and possible hepatic or renal impairment. Drugs
given as infusions can accumulate and the adverse side effects of
many drugs can be more pronounced in critically ill patients.
The choice of sedative agent will often depend on local policy,
physician preference, cost and familiarity. A wide variety exists:
Propofol (2,6-diisopropylphenol) acts at GABA receptors and is
easily titratable when used as an infusion. Studies comparing
propofol to benzodiazepines have found improved outcomes
such as reduced duration of mechanical ventilation, reduced time
in ICU and improved survival rates.
It has the disadvantages of cardiorespiratory depression and
the risk of the rare but potentially fatal propofol infusion syn-
drome (PRIS). PRIS is likely due to mitochondrial dysfunction
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 INTENSIVE CARE
and its presentation is hugely variable. Features may include
liver impairment, metabolic acidosis, rhabdomyolysis and
hypertriglyceridaemia. The dose should not exceed 4mg/kg/h,
although cases of PRIS have been reported at lower doses.
Alpha-2 agonists: Dexmedetomidine and clonidine are alpha-2
agonists with both sedative and analgesic effects. Common side
effects include hypotension and bradycardia, occasionally asys-
tole and, in the case of dexmedetomidine, reports of pyrexia. Due
to their minimal respiratory depression and their potential to
reduce or even treat delirium, there has been increased interest in
their use over recent years.
Dexmedetomidine is a highly selective alpha-2 receptor
agonist and acts independently of the GABA-mediated activity
unlike many other sedatives. Its main site of action is the pons,
inhibiting noradrenaline release and causing the release of
various inhibitory neurotransmitters. It is claimed that its effects
more closely resemble physiological sleep and allow for a more
comfortable, lucid and interactive patient.
Multiple studies looking at the potential of dexmedetomidine
have been carried out. The MIDEX and PRODEX studies
demonstrated dexmedetomidine to be non-inferior to both pro-
pofol and midazolam.10 The DahLIA trial found an increase in
ventilator free hours and shorter duration of delirium when
dexmedetomidine was added to standard sedation therapy in
patients with hyperactive delirium.11 The DESIRE trial found no
difference in mortality or ventilator-free days in patients with
sepsis or pancreatitis managed with dexmedetomidine versus
propofol or midazolam.12 The SPICE-3 trial found no difference
in 90-day mortality in patients managed with dexmedetomidine
compared to usual care, with 74% of patients in the intervention
group requiring the addition of propofol and/or a benzodiaze-
pine to meet sedation targets.13
Clonidine is less alpha-2 receptor specific than dexmedetomi-
dine and has been less extensively studied as a sedative in ICU. A
recent systematic review found that it may play a role as an
adjuvant sedative medication with narcotic sparing properties.
Benzodiazepines: There are various drugs in this class including
midazolam, lorazepam and diazepam, each varying in their po-
tency, duration of action and pharmacokinetic properties. They
are generally inexpensive with minimal cardiovascular effects
but are respiratory depressants with risks of accumulation in
liver and renal impairment.
Once a mainstay of sedative practice in ICU, the use of ben-
zodiazepines has declined in recent years due to evidence of an
increased risk of delirium with their use. They remain first-line
drugs for treating seizures, alcohol withdrawal and recreational
drug toxicity.
Ketamine is an NMDA receptor antagonist. It has analgesic and
sedative properties though also produces sympathetic stimula-
tion with the associated effects of bronchodilation, increased
cerebral blood flow and increased intracranial pressure. Due to
the potential for distressing hallucinations and nightmares, it is
usually given with an additional sedative agent and reserved as
an adjunct for managing life threatening asthma or patients with
complex pain problems.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
Thiopental is a barbiturate that is rarely used as a maintenance
sedative agent due to its long context sensitive half-life and
problems with life threatening effects on plasma potassium levels
when given as an infusion. It remains a therapeutic option for
refractory raised intracranial pressure and status epilepticus.
Antipsychotic agents: There are a number of agents in this class
including haloperidol, quetiapine and olanzapine. Haloperidol
has received the greatest study. It is used both as a sedative agent
and as a specific treatment for delirium and agitation. There is
evidence that sedation with a regime of haloperidol and propofol
reduces sedative use when compared to midazolam and propo-
fol. Although there is limited evidence that haloperidol reduces
the rate or duration of delirium, it remains a suitable option for
treating acute agitation.
Antipsychotic agents are associated with extrapyramidal side
effects and cardiac conduction abnormalities, namely QT pro-
longation. QT prolongation is common in critically ill patients
and can lead to life-threatening arrhythmias.
Volatile agents: Although common place in the theatre setting,
inhalational agents such as sevoflurane and desflurane are rarely
used in the ICU. Equipment such as the AnaConDaÔ allow the
addition of volatile agent to an ICU ventilator circuit. Small
studies have demonstrated this approach as feasible and the re-
sults of larger studies are awaited.
Other indications for sedative drugs
Sedative medications can be used for specific purposes beyond
anxiolysis and improving patient comfort.
Sleep: Critical illness and intensive care admission can result in
fragmented sleep and a disruption of circadian rhythm. Poor
sleep is associated with adverse sequelae such as delirium,
impaired immunity and increased stress hormone production.
Multiple studies have been carried out looking at the impact of
several drugs to promote sleep and maintain a physiological
sleepewake cycle. There is insufficient evidence to support the
routine use of these medications at present.
End of life care: Providing effective palliative care is an impor-
tant element of critical care. Sedative medications are commonly
used to provide comfort and relieve distress or anxiety in the
dying patient.
Cultural and geographical variations exist regarding the legal
and ethical issues surrounding end of life care practice. The
overarching principle should be that sedative drugs are used to
provide comfort and symptom relief to patients in their final days
and hours.
Anaesthesia: Many sedative drugs such as propofol can be
titrated to higher doses to achieve anaesthesia. This may be
desirable for patients undergoing surgical procedures or when
muscle relaxant infusions are being used.
Reducing cerebral metabolic rate: Some sedative medications
act to reduce cerebral oxygen consumption, making them useful
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 INTENSIVE CARE

The Confusion Assessment Method for ICU (CAM-ICU).6 Reproduced under the creative commons attribution non-commercial 4.0
international license (https://creativecommons.org/licenses/by-nc/4.0/).

Figure 2

adjuncts in the treatment of traumatic brain injury or in the
prevention of secondary brain injury following cardiac arrest.
Seizure treatment: Benzodiazepines remain the first-line treat-
ment for the management of seizure activity. Other sedatives
such as propofol and ketamine have anti-seizure activity and
barbiturates such as thiopental can be used in the management of
refractory status epilepticus.
Drug withdrawal and toxicity: Benzodiazepines are commonly
used in the management of toxicity from illicit drug use or
alcohol withdrawal. Of note, patients taking long-term benzodi-
azepines, whether prescribed or recreational, should be managed
cautiously as sudden discontinuation may result in withdrawal
symptoms or seizures.
Delirium
Delirium is a common syndrome associated with critical illness.
It presents as an acute change in mental status with inattention
and cognitive dysfunction. The severity of delirium tends to
fluctuate through the day, often being worse at night.
Large reviews suggest that around one-third of all ICU pa-
tients are delirious.14 This proportion rises in ventilated pa-
tients where an incidence of up to 80% has been found. The
presence of delirium is an independent risk factor for an
increased length of stay in ICU and hospital, persisting cogni-
tive impairment after ICU and increased mortality. Each addi-
tional day a patient spends with delirium increases their risk of
these adverse events.
Delirium can be classified into hyperactive, hypoactive and
mixed phenotypes. Patients with hyperactive delirium are
agitated, restless and sometimes combative. Hypoactive delirium
can be harder to recognize with predominantly features of leth-
argy and inattention. Patients with mixed delirium fluctuate be-
tween hypoactive and hyperactive states.
The exact pathophysiology of delirium is poorly understood,
with an imbalance of central neurotransmitters including
dopamine and acetylcholine being postulated as the underlying
cause.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12 804 Ó 2021 Published by Elsevier Ltd.
 INTENSIVE CARE
THINK: an aide-memoire mnemonic
T Toxic Situations e heart failure, shock,
dehydration, new organ failure, drugs
H Hypoxaemia
I Infection, Inflammation, Immobility
N Non-pharmacological interventions
K Kþ (Potassium) and other electrolytes
Table 1
Risk factors for delirium
Patient factors such as increasing age, chronic drug or alcohol
use, hearing or visual impairment, existing cognitive dysfunction
and malnutrition predispose to delirium.
Within the hospital setting, modifiable precipitating factors
are also present. These include the use of various drugs common
to the ICU, e.g. steroids, sedatives, anticholinergics and opioids.
Other risk factors for delirium include illness severity, sleep
disturbance, electrolyte abnormalities and general anaesthesia.
Diagnosing delirium
Hyperactive delirium is usually easy to recognize, but hypoactive
forms of delirium are associated with the same morbidity and
mortality. In order to detect such delirium validated screening
tools can be used.
The most commonly used include the Confusion Assessment
Method for ICU (CAM-ICU) (Figure 2) and the Intensive Care
Delirium Screening Checklist (ICDSC), both of which have been
recommended by the American Society of Critical Care Medicine
(SCCM). Both of these tools use sedation scales such as RASS and
SedationeAgitation Scale (SAS) to detect altered levels of con-
sciousness as well as tests of inattention, disorientation and
cognition. The ICDSC also incorporates questions that look for
features of psychosis, hallucinations, psychomotor disturbance,
sleep cycle disruption and symptom fluctuation.
Managing delirium
The management of delirium involves treating the underlying
precipitating acute illness, minimizing modifiable risk factors
and using non-pharmacological and pharmacological treatments.
Given the wide variety of precipitants, various mnemonics exist
as an aide-memoire such as THINK (Table 1).
Non-pharmacological interventions to both prevent and
manage delirium have been advocated by interventions such as
the ABCDEF bundle.15 This includes interventions to address
pain, implementing spontaneous awakening and breathing trials,
minimizing the use of deliriogenic drugs, mobilizing patients
early and encouraging family engagement with the patient. Ef-
forts should be made to maintain a healthy sleep cycle with
appropriate lighting and minimal noise or interventions at
nighttime. Patients should be orientated to time and place using
bedside clocks, information boards and visual or hearing aids
should be provided when needed.
Pharmacological management
Specific pharmacological interventions such as anti-psychotics
and hypnotics have been used to manage delirium, especially
when agitation is the dominant feature. There is little evidence to
ANAESTHESIA AND INTENSIVE CARE MEDICINE 22:12
suggest that anti-psychotic medications prevent delirium but they
are commonly used in the management of agitation.
Melatonin is a naturally occurring hormone produced in the
pineal gland. It plays an important role in the regulation of
circadian rhythm with additional antioxidant and anti-
inflammatory properties. Synthetic melatonin has been used in
the intensive care setting with the aim of improving circadian
rhythm and the sleepewake cycle which are often disturbed in
critical illness. Current evidence fails to show any significant
benefit in the routine use of melatonin. Further trials are awaited.
Small studies of dexmedetomidine as a sedative infusion have
shown an association with reduced levels and length of delirium.
However, the comparator control groups received benzodiaze-
pines which have been shown to be an independent risk factor
for developing delirium. Larger studies such as SPICE-3 have
demonstrated small improvements in days free from coma or
delirium and ventilator free days with use of dexmedetomidine.
Other studies such as MENDS-2 found no difference in days free
from delirium, ventilator free days or global cognition at
6 months.16
Other specific therapies aimed at neurotransmitter targets
such as acetylcholine have been studied using the anticholines-
terase drug rivastigmine. This study was abandoned early as
preliminary results suggested that rivastigmine therapy was futile
and potentially harmful. Statins have also been investigated due
to their anti-inflammatory effects, but studies such as MODUS
have so far shown that they have no benefit.17 A
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