Trends in Anaesthesia and Critical Care 3 (2013) 199e204

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Trends in Anaesthesia and Critical Care

journal homepage: www.elsevier.com/locate/tacc

REVIEW

Postoperative delirium and cognitive dysfunction

Laura Alcover, Rafael Badenes*, Maria Jesús Montero, Marina Soro, Francisco Javier Belda
Department of Anesthesiology and Critical Care, Hospital Clínico Universitario, Avenida Blasco Ibañez 17, 46010 Valencia, Spain

s u m m a r y
Keywords: Delirium and cognitive dysfunction are common manifestations of acute brain dysfunction, occurring in
Postoperative up to 70% of post-surgical patients. Developing postoperative delirium and postoperative cognitive
Delirium
dysfunction have long-term consequences, such as higher morbidity and mortality and increased hos-
Cognitive
Dysfunction
pital stay, and it increases the risk of dependency and institutionalisation. Despite the relevance of these
Critical cognitive disorders, the specific aetiology is still unknown, and there are many factors that have been
associated with its development. Between modifiable factors associated with the development of
Postoperative Delirium is the exposure to analgesics and hypnotics. The multicomponent interventions
for prevention and treatment have been shown to reduce the incidence and severity of episodes.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction 2. Definitions

Postoperative cognitive impairment is becoming more and 2.1. Delirium

more frequent in patients who undergo major surgery. This growth
is mainly a result of two situations following major surgery: an
increasing number of patients are admitted to intensive care units
(ICUs), and there is an older population.
Delirium, the most common form of acute brain dysfunction in
postoperative patients, affects over 80% of critically ill patients. The
presence of delirium is an independent risk factor of such adverse
outcomes as longer hospital stay,1,2,4 higher 6-month and 1-year
mortality rates,3e5 increased risk of institutionalisation,3 higher
cost,6 and long-term cognitive impairment.7
Postoperative cognitive dysfunction (POCD) is a decline in
cognitive function distinct from delirium and dementia. It is pre-
sent for weeks or months after surgery and is considered to be a
mild cognitive disorder. POCD affects many different cognitive
domains, such as memory, information processing and executive
function. It often goes unrecognised until the patient or relatives
discover difficulties with normal activities at home or at work. The
development of POCD is associated with increased mortality, risk of
leaving the labour market prematurely, and dependency on social
transfer payments.8
The aim of this review is to provide an update of both cognitive
deficits.
* Corresponding author.
E-mail addresses: alcover.laura@gmail.com (L. Alcover), rafaelbadenes@
gmail.com (R. Badenes), majemontero@gmail.com (M.J. Montero), soromarina@
gmail.com (M. Soro), fjbelda@uv.es (F.J. Belda).
Delirium is defined, accordingly to the World Health Organiza-
tion’s classification of Mental and Behavioural Disorders (ICD-10),9
as a clinical condition characterised by:
A. Altered level of consciousness, (with reduced clarity of
awareness and inattention.)
B. Disturbance of cognition, with impairment of recent memory
and disorientation (in time, place or person).
C. Psychomotor disturbances: rapid, unpredictable shifts from
hypo-activity to hyper-activity; increased reaction time;
increased or decreased flow of speech and enhanced startle
reaction.
D. Disturbance of sleep or the sleep/wake cycle as manifest by
insomnia, nocturnal worsening of symptoms and/or disturbing
dreams and nightmares.
E. Rapid onset and fluctuations of the symptoms over the course
of the day.
F. Evidence that the disturbance is caused by the direct physio-
logical consequences of a general medical condition.
Delirium has been traditionally classified according to the psy-
chomotor behaviour scale into the subtypes hyperactive, hypo-
active and mixed delirium.10 The hyperactive form is characterised
by increased psycho-motor activity and agitation. Conversely,
hypoactive delirium is characterised by reduced psycho-motor
behaviour and lethargy. Mixed forms manifest both hyperactive
and hypoactive elements unpredictably. Meagher et al.11 developed

2210-8440/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tacc.2013.03.010
200 L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204
a new scale, the Delirium Motor Subtype Scale (DMSS), focussing
only on motor features, thus allowing for the diagnosis of delirious
subjects, and their classification into the different subtypes. It has
been suggested that different motor subtypes of delirium may have
associations with different etiologies, phenomenology, treatment
responses and outcomes. The latest studies,12,13 however, have
suggested that cognitive impairments remain constant among
different types, while the disturbances of the circadian rhythm
(motor activity and sleepewake cycle) change in the different
subtypes. This last element seems to determine the different
response to treatment and outcome. Yang et al.14 found that in
patients who also suffered from dementia, the hypoactive class was
associated with a higher risk of mortality. Greater severity was
associated with high mortality, independent of psychomotor
features.
Additionally, there is another subtype, called subsyndromal
delirium (SSD), which has emerged as a condition of clinical in-
terest. It is defined as a condition in which patients have one or
more symptoms that never progress to a full diagnosis of
delirium.10 Recent studies have also demonstrated that sub-
syndromal delirium predicts a poorer outcome than does the
absence of delirium.15,16 Nevertheless, the fluctuating course of
delirium makes subsyndromal delirium difficult to diagnose.13
2.2. Postoperative cognitive dysfunction
POCD is considered to be a mild neurocognitive disorder.7 Ac-
cording to the diagnostic criteria from DSM-IV, a mild neuro-
cognitive disorder can only be diagnosed if the cognitive
disturbance does not meet the criteria for three other conditions
(delirium, dementia, or amnestic disorder), namely an exclusion
diagnosis.17 Furthermore, the diagnosis of POCD, needs to be
corroborated by the results of a battery of neurocognitive tests
(usually two or more) showing that an individual has undergone a
20% change or an absolute decline (>1 SD) from a baseline evalu-
ation, for a period of at least 2 weeks after surgery.10 The symptoms
vary from decline in memory to an inability to concentrate or
process information, and it is often the patient or the family who
recognises the problem.
View comparative between PD and POCD in Table 1.
3. Epidemiology and risk factors
3.1. Incidence and risk factors of delirium
There is a wide discrepancy in the literature regarding PD rates,
which vary between 9% and 87%.7,18e20 This is in part attributed to
Table 1
Comparative table between PD and POCD. CAM: Confusion assessment method. Nu-
DESC: Nursing delirium screening scale. DDS: Delirium detection scale. ICDSC:
Intensive care delirium screening checklist. CAM-ICU: modified CAM for ICU
patients.
PD POCD
Start Acute, 1e3 days after Subtle, 2 weeks to 2 months
surgery. after surgery.
Length Commonly self-limited, Weeks or months.
days or weeks.
Symptoms Inattention, change in Impairment of memory,
cognition, fluctuation concentration and information
over time. processing.
Diagnosis DSM-IV criteria and Failure on >2 tests on a
Scales (CAM, Nu-Desc, neuropsychological test battery.
DDS, ICDSC, CAM-ICU)
Reversibility Usually. Normally, but long-range.
the lack of standardised criteria for delirium diagnosis and vali-
dated delirium-monitoring instruments.21 In addition, hypoactive
sub-types are commonly overlooked and misdiagnosed in a surgi-
cal ward. Despite these limitations, the incidence and risk factors
appear to be strongly influenced by the type of surgery. Thus, as
described in Rudolph’s articles,22 the incidence varies depending
on the type of surgery, more frequent in abdominal surgery 5e51%,
abdominal aortic aneurysm 33e54%, coronary artery bypass graft
surgery 37e52% and hip fracture 35e65%. In 2003, a study by
Maldonado,23 based on the diagnosis of delirium by the DSM-IV
classification, obtained an incidence of 18% in surgical patients.
Although the mechanism of delirium has not been elucidated,
there has been a significant description of associated patient risk
factors.21 According to the Inouye model,24 some of these may be
considered pre-existing; that is, to patient vulnerability and to
other precipitating factors, potentially modifiable (Table 2). The
most significant risk factor for POD is dementia and cognitive
impairment. Low cognitive and brain reserve may imply greater
vulnerability to delirium.25 Other predisposing risk factors include
sensory impairment (vision and hearing), severe illness (American
Society of Anaesthesiologists classification >3), dehydration,
malnutrition and alcohol abuse.18e22,26 Vascular risk factors such as
age, tobacco use, and the need for vascular surgery were inde-
pendently associated with postoperative delirium.27 The apolipo-
protein epsilon polymer is a protein that is associated with plasma
lipoproteins. It relates especially to the central nervous system,
because its function is to redistribute and mobilise cholesterol for
repair and maintenance of myelin and neuronal membranes.
Therefore, their genetic disorder has been linked to Alzheimer’s
disease and neuronal damage after brain injury. Another postulated
link is a genetic predisposition in patients with the epsilon 4 allele
for apolipoprotein (APO E4) and a higher incidence of delirium and
POCD.28e30
Some risk factors are directly related to surgery21,22: type of
surgery (open vs laparoscopic), surgical time, blood transfusion and
emergence versus elective surgery. The relationship between
delirium and anaesthesia is unclear. There are many drugs associ-
ated with delirium, such as the benzodiazepines.19,22,31e33 The in-
formation about opioids is unclear; the literature has not shown a
direct relationship between the use of them and POD.21,32,34,35
Similarly, the role of general anaesthesia in POD is not clear.
Studies like Sieber’s36 suggest that light sedation decreases the risk
of POD versus that for general anaesthesia. Others did not find an
increased risk of general versus regional anaesthesia in POD.37,38
The different pathways of the hypnotic agents are being investi-
gated as possible causes for the differences in potential deliriogenic
action. Thus, patients anaesthetised with propofol had a higher
incidence of cognitive dysfunction compared with desflurane39 and
sevoflurane. Also, the depth of sedation influences the develop-
ment of delirium, independent of the agent used.19,40
Table 2
Risk factors for delirium.
Predisposing Precipitating
Reduced cognitive reserve: Medications (benzodiazepines,
advanced age, dementia, opioids, anticholinergics,
cognitive impairment. antiarrhythmics.)
Sensory impairment. Pain
Malnutrition. Dehydration. Hypoxaemia.
Alcohol abuse. Smoking. Electrolyte abnormalities.
Severe illness (renal impairment, Environmental changes.
pulmonary disease, atherosclerotic Sleep/wake disturbances.
disease, diabetes, atrial fibrillation.) Urinary catheter.
Apolipoprotein E4 genotype. Infection.
 L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204
3.2. Incidence and risk factors of postoperative cognitive
dysfunction
Postoperative cognitive dysfunction (POCD) is considered a mild
form of cognitive impairment.7 Its definition is more ambiguous,20
and it embraces many fields comprising the cognitive, both infor-
mation processing functions such as the executive, and especially
memory. Symptoms range from a mild memory impairment and
inability to concentrate and focus attention, and frequently the
recognition of the same by relatives when patients return to their
normal activities.8 It is difficult to establish the incidence of POCD
given the wide variability in definitions and tests used for diag-
nosis.41 There are many studies focussing on the presence of POCD
after cardiac surgery that indicate an incidence of between 30 and
80% in the first weeks and 10e60% at 3e6 months post-surgery.41
The incidence after major non-cardiac surgery is 25.8% in the first
week and 9.9% after 3 months according to the widely referenced
international study of cognitive dysfunction (International Study of
Postoperative Dysfunction, ISPOCD I).42 Recently they have con-
ducted several studies in which the incidence is significantly lower,
as performed by the Rasmussen group43 that gets data from 3.4%
(first week) and 2.8% (3 months).
The aetiology of postoperative cognitive dysfunction is considered
multifactorial,44 in which there have been implicated many variables
including the following: anaesthetic regimen used, postoperative
analgesia protocol, the admission in a hospital, level of surgical
invasiveness, response-mediated inflammatory cytokines, sleep
disturbance and consequent reduction of neurotransmitters such as
acetylcholine and adenosine (which in turn produces hyperalgesia)
and hypoperfusion and/or intraoperative hypoxia. The only risk fac-
tors independently demonstrated, however, include advanced age,
previous physical and cognitive impairment, and low educational
level.7,26,44 There is a relationship between PD and the subsequent
development of short-term POCD.45 The impact of delirium in long-
term dysfunction, however, remains under investigation.
3.3. Pathophysiology
In both entities (PD and POCD), the exact aetiology is unknown.
However, the final mechanism responsible for both would be
neuronal destruction through apoptosis, whose triggers are still in
question.46 Among the most accepted hypotheses are the
following:
 Genetic: as explained above, the expression of EPO E4 allele
increases the risk of delirium and cognitive dysfunction.28e30
 Immunological: this involves the central nervous system
response to the surgical operation itself47,48 activating the
cascade of inflammatory cytokines (such as interleukin 1 (IL1),
interleukin 6 (IL6), tumour necrosis factor alpha (TNF a) and C-
reactive protein (CRP)). By themselves, these cytokines are
capable of altering the integrity of the bloodebrain barrier
causing increased susceptibility to postoperative systemic in-
flammatory reaction, interfering with normal synaptic activity,
causing neuronal degeneration and increasing b protein S-100.
It has been demonstrated that the blood levels of these sub-
stances are elevated in patients who develop POCD or PD.49
 “Brain reserve”: this concept, described in 1993 by Statz50 and
developed in studies such as those by Monk7 and Jankowski,51
shows a greater vulnerability to cognitive dysfunction in pa-
tients with lower brain reserve.52 The brain reserve is assessed
with neurocognitive test results, educational level, the pres-
ence of brain injuries, and so forth. This hypothesis would
explain the greater tendency to have cognitive impairment in
patients with prior cerebral vascular pathology.
201
 Pharmacology: Traditionally, a neurotoxic effect has been
attributed to anaesthetics, something which has been exten-
sively studied over time.53 This effect has also been associated
with increased postoperative delirium and cognitive delay in
long-term recovery.18 Over the last few years, studies have
focussed on the potential deliriogenic effect of the substances
used such as hypnotics and sedatives, showing a great vari-
ability depending on the pharmacokinetic and pharmacody-
namic profile of each. Thus, benzodiazepines are associated
with a higher incidence of delirium and memory impairment,19
there is even a Cochrane review that recommends avoiding
their use in the treatment of delirium.54
Instead, the beneficial effect of sedation with a2 agonist drugs
such as clonidine or dexmetomidine55 is known, producing brain-
stem level changes similar to those occurring physiologically dur-
ing non-REM sleep.33
Similarly, second-generation antipsychotics, such as quetiapine
and risperidone have proved to be more effective in the prevention
and treatment of delirium than have classical antipsychotics such
as haloperidol.19 In particular, risperidone has been shown to
reduce the incidence of delirium when administered in the sub-
clinical stage without prophylactically medicating.56
Both propofol and opioids produce an increase in the incidence
of delirium directly related to the amount of drug administered.19,33
Inhaled anaesthetics are presented as a valid alternative to the
intravenous anaesthetics discussed above. This is because of a
lower incidence of postoperative cognitive dysfunction,57 when
compared with that for propofol, and a faster cognitive recovery
after anaesthesia.58 Nevertheless, recent studies have provided
mixed results. The NeuroMorfeo study conducted by Citerio et al.59
on neurosurgical patients concluded that there were no differences
in terms of neurological recovery time between inhaled or intra-
venous anaesthetics.
4. Diagnosis
Early recognition and treatment are the key to reducing the
duration, severity and adverse outcome of delirium. Recognising
delirium is often difficult; without using validation tools, less than
30% of patients with delirium are identified.60 For the diagnosis, the
DSM-IV criteria are still the current gold standard, but unfortu-
nately, it is time consuming for daily use. Moreover, this manual is
being reviewed, and a new version will be published in May 2013.
There are several rapid assessment tools used to diagnose delirium
in hospitalised patients, e.g., the Confusion Assessment Method
(CAM),61 the Nursing Delirium Screening Scale (Nu-DESC)62 and the
Delirium Detection Scale (DDS). These three scales were compared
by Radtke et al.64 against the DSM-IV. The results showed that the
Nu-DESC was the most sensitive (95%), had a high specificity (87%)
and was the least time-consuming test, while the CAM had a
sensitivity of 43% and specificity of 98%, and the DDS had scores of
14% and 99%, respectively.63 Other scales have been validated for
patients requiring critical care support, such as the Intensive Care
Delirium Screening Checklist (ICDSC) and the modified CAM for ICU
patients (CAM-ICU) which relies on nonverbal responses and can be
used with critically ill patients or the intubated.64,65 This last one is
the most frequently used, with high sensitivity and specificity.66 For
use with ICU patients, the international guidelines recommend
making a daily assessment of delirium with validated tools, because
without them the incidence is underestimated.67 Including daily
delirium monitoring in clinical practice allows for the earlier iden-
tification and treatment of PD patients.60
Regarding POCD, since it is considered a mild cognitive
impairment, the diagnosis is based on exclusion criteria as
202 L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204
established by the DSM-IV. This diagnosis uses a battery of neu-
ropsychological tests, and requires the affectation of at least two
areas of cognitive function for at least two weeks.7 It is always
compared to the patient’s baseline. Usually, it is considered diag-
nostic when there is a 20% change from a baseline evaluation for a
pre-defined number of tests (normally two or more) or an absolute
decline (>1 SD) from baselines scores.10 There is no consensus on
which tests to use in the diagnosis of POCD.68 The development and
validation of a standardised neuropsychological battery and
analytical criteria may improve the diagnosis and prevention of
POCD.
5. Management
5.1. Prevention
Preventive measures can be divided into two main groups:
multimodal and pharmacological.
The first group, the multimodal approach, is based on prevent-
ing both vulnerability and precipitating factors, as well for delirium
is a multifactorial syndrome. In 2010 the English National Clinical
Guideline Centre (NCGC)69 issued guidelines that revised the most
significant studies concerning the efficacy of a multimodal
approach. Inouye et al.70 established a multi-component inter-
vention called the Hospital Elder Life Program (HELP). They found
their strategy resulted in a significant reduction in the number and
duration of episodes of delirium in hospitalised patients. This
programme had been successfully reproduced in medical and sur-
gical wards with the same results.71e73 Even in elderly patients, it
has proven to be an effective measure.74 Bjorkelund et al.75 per-
formed a prospective study with 263 elderly hip fracture patients
and found a decrease in the incidence of delirium during hospi-
talisation of 35%. These programmes have shown their utility in
reducing costs and ICU lengths of stay.70,76,77
Regarding pharmacological measures, there have been a
growing number of studies examining different drugs. The pro-
phylactic use of haloperidol has been studied with mixed results. In
two studies,78,79 its use did not reduce delirium incidence. Two
more recent studies,80,81 however, found a decreased incidence of
PD and a shorter median length of stay in the ICU. Wang et al.81
performed a randomised, double blind, placebo-controlled trial of
non-cardiac surgery patients, and found a significant decreased
incidence of delirium between the groups (15.3% haloperidol group
vs. 23.2% placebo group). There is even a Cochrane review82 which
suggests that the prophylactic low dose of haloperidol may reduce
the severity and duration of delirium episodes and shorten the
length of hospital stay.
Other substances, such as risperidone are being investigated.
Hakim et al.56 studied the effect of treating subsyndromal delirium
with risperidone in a randomised trial and found a significantly
lower incidence of delirium (13.7% risperidone group vs. 34% pla-
cebo group). Several randomised controlled trials studying the use
of rivastigmine have demonstrated it to be ineffective at preventing
delirium nor did it decrease the duration of delirium, and it might
have increased mortality.83,84
Regarding the role of anaesthesia, there are some measures that
decrease the development of delirium. Some studies have sug-
gested a lower incidence of delirium when inhalational agents are
used compared to intravenous ones.52,57,58 While studies like that
carried out by Royse et al.36 found no difference in delirium rates
between patients anaesthetised with propofol and those with
sevoflurane. But there is a difference in early postoperative
cognitive dysfunction that was significantly higher with propofol
than with desflurane (67.5% vs. 49.4%). Another aspect to note
about anaesthesia is its depth. In the latest research, the
anaesthetic depth is correlated directly with cognitive dysfunc-
tion,85 independent of the drug used and the type of surgery.
Intraoperative monitoring of processed electroencephalogram
(EEG), such as the Bispectral Index (BIS), has been shown to
facilitate titration of anaesthetic drug delivery.86 This allows for an
improved early recovery profiles and faster emergence from
anaesthesia.87 Sieber et al.36 showed a 50% decrease in the prev-
alence of postoperative delirium when a light sedation with pro-
pofol was used versus a deep sedation, guided by the Bispectral
Index (BIS). More recently, Chan et al.88 showed a lower incidence
of delirium (15.6% vs. 24.1%) and decreased the risk of POCD at 3
months after surgery (10.2% vs. 14.7%) for their BIS-guided group
versus their control group.
5.2. Treatment
The drug most commonly used, and studied, for treatment of
delirium is haloperidol. It is recommended as the drug of choice for
the treatment of ICU delirium by the SCCM (Society of Critical Care
Medicine)89 and the APA (American Psychiatric Association).90
Common doses for ICU patients range from 4 to 20 mg/day.
Atypical antipsychotics may also be helpful for delirium treat-
ment. As discussed above, risperidone has proven effective for the
treatment of delirium, as it reduces the duration of episodes and
the length of hospital stay.56,91
Quetiapine has also been shown to be effective in reducing the
length of episodes.91
Sedation with dexmedetomidine has been studied as an option
for critical post-surgical patients. Results were positive, with a
decreased length of episodes, shorter mechanical ventilation and
decreased mortality.33,92,93
Recently, Leung et al.94 carried out a randomised, placebo-
controlled trial, using gabapentin for postoperative pain control.
They found a decreased incidence of delirium (42% placebo vs. 0%
gabapentin).
With the aim of reducing the incidence of delirium in post-
surgical units, measures should be taken to control potential risk
and precipitating factors. An example would be to avoid poly-
pharmacy in elderly patients and reduce postoperative pain. Post-
operative pain has been shown as an independent risk factor for the
development of delirium.95 Paradoxically, the overuse of analgesics
(mainly opioids) increases the risk of developing delirium.96 Other
measures like non-pharmacological sleep protocols and environ-
mental changes (e.g., lights off, creating a relaxing environment,
minimising night-time interruptions, placing a clock in view of the
patient and window protection) have proven to be useful for
reducing medication and delirium.22
6. Conclusion
Delirium is the most common form of acute brain dysfunction in
the post-surgical period since it is associated with poor outcomes
and long-term consequences (increased morbidity and mortality,
longer hospital stay and increased costs). New diagnostic, preven-
tive and management strategies have helped reduce the incidence
of PD and POCD. Identifying those patients most at risk and pre-
venting the development of PD is the most effective way to reduce
its incidence. Reducing neuroactive drug doses is especially
important for reducing the incidence, duration and severity of
delirium episodes.
Conflict of interest
The authors have no conflicts of interest to declare.
 L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204 203

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