You are on page 1of 6

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

Contents lists available at SciVerse ScienceDirect

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 Delirium is defined, accordingly to the World Health Organiza-
increasing number of patients are admitted to intensive care units tion’s classification of Mental and Behavioural Disorders (ICD-10),9
(ICUs), and there is an older population. as a clinical condition characterised by:
Delirium, the most common form of acute brain dysfunction in
postoperative patients, affects over 80% of critically ill patients. The A. Altered level of consciousness, (with reduced clarity of
presence of delirium is an independent risk factor of such adverse awareness and inattention.)
outcomes as longer hospital stay,1,2,4 higher 6-month and 1-year B. Disturbance of cognition, with impairment of recent memory
mortality rates,3e5 increased risk of institutionalisation,3 higher and disorientation (in time, place or person).
cost,6 and long-term cognitive impairment.7 C. Psychomotor disturbances: rapid, unpredictable shifts from
Postoperative cognitive dysfunction (POCD) is a decline in hypo-activity to hyper-activity; increased reaction time;
cognitive function distinct from delirium and dementia. It is pre- increased or decreased flow of speech and enhanced startle
sent for weeks or months after surgery and is considered to be a reaction.
mild cognitive disorder. POCD affects many different cognitive D. Disturbance of sleep or the sleep/wake cycle as manifest by
domains, such as memory, information processing and executive insomnia, nocturnal worsening of symptoms and/or disturbing
function. It often goes unrecognised until the patient or relatives dreams and nightmares.
discover difficulties with normal activities at home or at work. The E. Rapid onset and fluctuations of the symptoms over the course
development of POCD is associated with increased mortality, risk of of the day.
leaving the labour market prematurely, and dependency on social F. Evidence that the disturbance is caused by the direct physio-
transfer payments.8 logical consequences of a general medical condition.
The aim of this review is to provide an update of both cognitive
deficits. 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,
* Corresponding author.
E-mail addresses: alcover.laura@gmail.com (L. Alcover), rafaelbadenes@
hypoactive delirium is characterised by reduced psycho-motor
gmail.com (R. Badenes), majemontero@gmail.com (M.J. Montero), soromarina@ behaviour and lethargy. Mixed forms manifest both hyperactive
gmail.com (M. Soro), fjbelda@uv.es (F.J. Belda). 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 the lack of standardised criteria for delirium diagnosis and vali-
only on motor features, thus allowing for the diagnosis of delirious dated delirium-monitoring instruments.21 In addition, hypoactive
subjects, and their classification into the different subtypes. It has sub-types are commonly overlooked and misdiagnosed in a surgi-
been suggested that different motor subtypes of delirium may have cal ward. Despite these limitations, the incidence and risk factors
associations with different etiologies, phenomenology, treatment appear to be strongly influenced by the type of surgery. Thus, as
responses and outcomes. The latest studies,12,13 however, have described in Rudolph’s articles,22 the incidence varies depending
suggested that cognitive impairments remain constant among on the type of surgery, more frequent in abdominal surgery 5e51%,
different types, while the disturbances of the circadian rhythm abdominal aortic aneurysm 33e54%, coronary artery bypass graft
(motor activity and sleepewake cycle) change in the different surgery 37e52% and hip fracture 35e65%. In 2003, a study by
subtypes. This last element seems to determine the different Maldonado,23 based on the diagnosis of delirium by the DSM-IV
response to treatment and outcome. Yang et al.14 found that in classification, obtained an incidence of 18% in surgical patients.
patients who also suffered from dementia, the hypoactive class was Although the mechanism of delirium has not been elucidated,
associated with a higher risk of mortality. Greater severity was there has been a significant description of associated patient risk
associated with high mortality, independent of psychomotor factors.21 According to the Inouye model,24 some of these may be
features. considered pre-existing; that is, to patient vulnerability and to
Additionally, there is another subtype, called subsyndromal other precipitating factors, potentially modifiable (Table 2). The
delirium (SSD), which has emerged as a condition of clinical in- most significant risk factor for POD is dementia and cognitive
terest. It is defined as a condition in which patients have one or impairment. Low cognitive and brain reserve may imply greater
more symptoms that never progress to a full diagnosis of vulnerability to delirium.25 Other predisposing risk factors include
delirium.10 Recent studies have also demonstrated that sub- sensory impairment (vision and hearing), severe illness (American
syndromal delirium predicts a poorer outcome than does the Society of Anaesthesiologists classification >3), dehydration,
absence of delirium.15,16 Nevertheless, the fluctuating course of malnutrition and alcohol abuse.18e22,26 Vascular risk factors such as
delirium makes subsyndromal delirium difficult to diagnose.13 age, tobacco use, and the need for vascular surgery were inde-
pendently associated with postoperative delirium.27 The apolipo-
2.2. Postoperative cognitive dysfunction protein epsilon polymer is a protein that is associated with plasma
lipoproteins. It relates especially to the central nervous system,
POCD is considered to be a mild neurocognitive disorder.7 Ac- because its function is to redistribute and mobilise cholesterol for
cording to the diagnostic criteria from DSM-IV, a mild neuro- repair and maintenance of myelin and neuronal membranes.
cognitive disorder can only be diagnosed if the cognitive Therefore, their genetic disorder has been linked to Alzheimer’s
disturbance does not meet the criteria for three other conditions disease and neuronal damage after brain injury. Another postulated
(delirium, dementia, or amnestic disorder), namely an exclusion link is a genetic predisposition in patients with the epsilon 4 allele
diagnosis.17 Furthermore, the diagnosis of POCD, needs to be for apolipoprotein (APO E4) and a higher incidence of delirium and
corroborated by the results of a battery of neurocognitive tests POCD.28e30
(usually two or more) showing that an individual has undergone a Some risk factors are directly related to surgery21,22: type of
20% change or an absolute decline (>1 SD) from a baseline evalu- surgery (open vs laparoscopic), surgical time, blood transfusion and
ation, for a period of at least 2 weeks after surgery.10 The symptoms emergence versus elective surgery. The relationship between
vary from decline in memory to an inability to concentrate or delirium and anaesthesia is unclear. There are many drugs associ-
process information, and it is often the patient or the family who ated with delirium, such as the benzodiazepines.19,22,31e33 The in-
recognises the problem. formation about opioids is unclear; the literature has not shown a
View comparative between PD and POCD in Table 1. direct relationship between the use of them and POD.21,32,34,35
Similarly, the role of general anaesthesia in POD is not clear.
3. Epidemiology and risk factors Studies like Sieber’s36 suggest that light sedation decreases the risk
of POD versus that for general anaesthesia. Others did not find an
3.1. Incidence and risk factors of delirium increased risk of general versus regional anaesthesia in POD.37,38
The different pathways of the hypnotic agents are being investi-
There is a wide discrepancy in the literature regarding PD rates, gated as possible causes for the differences in potential deliriogenic
which vary between 9% and 87%.7,18e20 This is in part attributed to 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-
Table 1 ment of delirium, independent of the agent used.19,40
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. Table 2
Risk factors for delirium.
PD POCD
Predisposing Precipitating
Start Acute, 1e3 days after Subtle, 2 weeks to 2 months
surgery. after surgery. Reduced cognitive reserve: Medications (benzodiazepines,
Length Commonly self-limited, Weeks or months. advanced age, dementia, opioids, anticholinergics,
days or weeks. cognitive impairment. antiarrhythmics.)
Symptoms Inattention, change in Impairment of memory, Sensory impairment. Pain
cognition, fluctuation concentration and information Malnutrition. Dehydration. Hypoxaemia.
over time. processing. Alcohol abuse. Smoking. Electrolyte abnormalities.
Diagnosis DSM-IV criteria and Failure on >2 tests on a Severe illness (renal impairment, Environmental changes.
Scales (CAM, Nu-Desc, neuropsychological test battery. pulmonary disease, atherosclerotic Sleep/wake disturbances.
DDS, ICDSC, CAM-ICU) disease, diabetes, atrial fibrillation.) Urinary catheter.
Reversibility Usually. Normally, but long-range. Apolipoprotein E4 genotype. Infection.
L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204 201

3.2. Incidence and risk factors of postoperative cognitive  Pharmacology: Traditionally, a neurotoxic effect has been
dysfunction attributed to anaesthetics, something which has been exten-
sively studied over time.53 This effect has also been associated
Postoperative cognitive dysfunction (POCD) is considered a mild with increased postoperative delirium and cognitive delay in
form of cognitive impairment.7 Its definition is more ambiguous,20 long-term recovery.18 Over the last few years, studies have
and it embraces many fields comprising the cognitive, both infor- focussed on the potential deliriogenic effect of the substances
mation processing functions such as the executive, and especially used such as hypnotics and sedatives, showing a great vari-
memory. Symptoms range from a mild memory impairment and ability depending on the pharmacokinetic and pharmacody-
inability to concentrate and focus attention, and frequently the namic profile of each. Thus, benzodiazepines are associated
recognition of the same by relatives when patients return to their with a higher incidence of delirium and memory impairment,19
normal activities.8 It is difficult to establish the incidence of POCD there is even a Cochrane review that recommends avoiding
given the wide variability in definitions and tests used for diag- their use in the treatment of delirium.54
nosis.41 There are many studies focussing on the presence of POCD
after cardiac surgery that indicate an incidence of between 30 and Instead, the beneficial effect of sedation with a2 agonist drugs
80% in the first weeks and 10e60% at 3e6 months post-surgery.41 such as clonidine or dexmetomidine55 is known, producing brain-
The incidence after major non-cardiac surgery is 25.8% in the first stem level changes similar to those occurring physiologically dur-
week and 9.9% after 3 months according to the widely referenced ing non-REM sleep.33
international study of cognitive dysfunction (International Study of Similarly, second-generation antipsychotics, such as quetiapine
Postoperative Dysfunction, ISPOCD I).42 Recently they have con- and risperidone have proved to be more effective in the prevention
ducted several studies in which the incidence is significantly lower, and treatment of delirium than have classical antipsychotics such
as performed by the Rasmussen group43 that gets data from 3.4% as haloperidol.19 In particular, risperidone has been shown to
(first week) and 2.8% (3 months). reduce the incidence of delirium when administered in the sub-
The aetiology of postoperative cognitive dysfunction is considered clinical stage without prophylactically medicating.56
multifactorial,44 in which there have been implicated many variables Both propofol and opioids produce an increase in the incidence
including the following: anaesthetic regimen used, postoperative of delirium directly related to the amount of drug administered.19,33
analgesia protocol, the admission in a hospital, level of surgical Inhaled anaesthetics are presented as a valid alternative to the
invasiveness, response-mediated inflammatory cytokines, sleep intravenous anaesthetics discussed above. This is because of a
disturbance and consequent reduction of neurotransmitters such as lower incidence of postoperative cognitive dysfunction,57 when
acetylcholine and adenosine (which in turn produces hyperalgesia) compared with that for propofol, and a faster cognitive recovery
and hypoperfusion and/or intraoperative hypoxia. The only risk fac- after anaesthesia.58 Nevertheless, recent studies have provided
tors independently demonstrated, however, include advanced age, mixed results. The NeuroMorfeo study conducted by Citerio et al.59
previous physical and cognitive impairment, and low educational on neurosurgical patients concluded that there were no differences
level.7,26,44 There is a relationship between PD and the subsequent in terms of neurological recovery time between inhaled or intra-
development of short-term POCD.45 The impact of delirium in long- venous anaesthetics.
term dysfunction, however, remains under investigation.
4. Diagnosis
3.3. Pathophysiology
Early recognition and treatment are the key to reducing the
In both entities (PD and POCD), the exact aetiology is unknown. duration, severity and adverse outcome of delirium. Recognising
However, the final mechanism responsible for both would be delirium is often difficult; without using validation tools, less than
neuronal destruction through apoptosis, whose triggers are still in 30% of patients with delirium are identified.60 For the diagnosis, the
question.46 Among the most accepted hypotheses are the DSM-IV criteria are still the current gold standard, but unfortu-
following: nately, it is time consuming for daily use. Moreover, this manual is
being reviewed, and a new version will be published in May 2013.
 Genetic: as explained above, the expression of EPO E4 allele There are several rapid assessment tools used to diagnose delirium
increases the risk of delirium and cognitive dysfunction.28e30 in hospitalised patients, e.g., the Confusion Assessment Method
 Immunological: this involves the central nervous system (CAM),61 the Nursing Delirium Screening Scale (Nu-DESC)62 and the
response to the surgical operation itself47,48 activating the Delirium Detection Scale (DDS). These three scales were compared
cascade of inflammatory cytokines (such as interleukin 1 (IL1), by Radtke et al.64 against the DSM-IV. The results showed that the
interleukin 6 (IL6), tumour necrosis factor alpha (TNF a) and C- Nu-DESC was the most sensitive (95%), had a high specificity (87%)
reactive protein (CRP)). By themselves, these cytokines are and was the least time-consuming test, while the CAM had a
capable of altering the integrity of the bloodebrain barrier sensitivity of 43% and specificity of 98%, and the DDS had scores of
causing increased susceptibility to postoperative systemic in- 14% and 99%, respectively.63 Other scales have been validated for
flammatory reaction, interfering with normal synaptic activity, patients requiring critical care support, such as the Intensive Care
causing neuronal degeneration and increasing b protein S-100. Delirium Screening Checklist (ICDSC) and the modified CAM for ICU
It has been demonstrated that the blood levels of these sub- patients (CAM-ICU) which relies on nonverbal responses and can be
stances are elevated in patients who develop POCD or PD.49 used with critically ill patients or the intubated.64,65 This last one is
 “Brain reserve”: this concept, described in 1993 by Statz50 and the most frequently used, with high sensitivity and specificity.66 For
developed in studies such as those by Monk7 and Jankowski,51 use with ICU patients, the international guidelines recommend
shows a greater vulnerability to cognitive dysfunction in pa- making a daily assessment of delirium with validated tools, because
tients with lower brain reserve.52 The brain reserve is assessed without them the incidence is underestimated.67 Including daily
with neurocognitive test results, educational level, the pres- delirium monitoring in clinical practice allows for the earlier iden-
ence of brain injuries, and so forth. This hypothesis would tification and treatment of PD patients.60
explain the greater tendency to have cognitive impairment in Regarding POCD, since it is considered a mild cognitive
patients with prior cerebral vascular pathology. 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- anaesthetic depth is correlated directly with cognitive dysfunc-
ropsychological tests, and requires the affectation of at least two tion,85 independent of the drug used and the type of surgery.
areas of cognitive function for at least two weeks.7 It is always Intraoperative monitoring of processed electroencephalogram
compared to the patient’s baseline. Usually, it is considered diag- (EEG), such as the Bispectral Index (BIS), has been shown to
nostic when there is a 20% change from a baseline evaluation for a facilitate titration of anaesthetic drug delivery.86 This allows for an
pre-defined number of tests (normally two or more) or an absolute improved early recovery profiles and faster emergence from
decline (>1 SD) from baselines scores.10 There is no consensus on anaesthesia.87 Sieber et al.36 showed a 50% decrease in the prev-
which tests to use in the diagnosis of POCD.68 The development and alence of postoperative delirium when a light sedation with pro-
validation of a standardised neuropsychological battery and pofol was used versus a deep sedation, guided by the Bispectral
analytical criteria may improve the diagnosis and prevention of Index (BIS). More recently, Chan et al.88 showed a lower incidence
POCD. 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
5. Management versus their control group.

5.1. Prevention 5.2. Treatment

Preventive measures can be divided into two main groups: The drug most commonly used, and studied, for treatment of
multimodal and pharmacological. delirium is haloperidol. It is recommended as the drug of choice for
The first group, the multimodal approach, is based on prevent- the treatment of ICU delirium by the SCCM (Society of Critical Care
ing both vulnerability and precipitating factors, as well for delirium Medicine)89 and the APA (American Psychiatric Association).90
is a multifactorial syndrome. In 2010 the English National Clinical Common doses for ICU patients range from 4 to 20 mg/day.
Guideline Centre (NCGC)69 issued guidelines that revised the most Atypical antipsychotics may also be helpful for delirium treat-
significant studies concerning the efficacy of a multimodal ment. As discussed above, risperidone has proven effective for the
approach. Inouye et al.70 established a multi-component inter- treatment of delirium, as it reduces the duration of episodes and
vention called the Hospital Elder Life Program (HELP). They found the length of hospital stay.56,91
their strategy resulted in a significant reduction in the number and Quetiapine has also been shown to be effective in reducing the
duration of episodes of delirium in hospitalised patients. This length of episodes.91
programme had been successfully reproduced in medical and sur- Sedation with dexmedetomidine has been studied as an option
gical wards with the same results.71e73 Even in elderly patients, it for critical post-surgical patients. Results were positive, with a
has proven to be an effective measure.74 Bjorkelund et al.75 per- decreased length of episodes, shorter mechanical ventilation and
formed a prospective study with 263 elderly hip fracture patients decreased mortality.33,92,93
and found a decrease in the incidence of delirium during hospi- Recently, Leung et al.94 carried out a randomised, placebo-
talisation of 35%. These programmes have shown their utility in controlled trial, using gabapentin for postoperative pain control.
reducing costs and ICU lengths of stay.70,76,77 They found a decreased incidence of delirium (42% placebo vs. 0%
Regarding pharmacological measures, there have been a gabapentin).
growing number of studies examining different drugs. The pro- With the aim of reducing the incidence of delirium in post-
phylactic use of haloperidol has been studied with mixed results. In surgical units, measures should be taken to control potential risk
two studies,78,79 its use did not reduce delirium incidence. Two and precipitating factors. An example would be to avoid poly-
more recent studies,80,81 however, found a decreased incidence of pharmacy in elderly patients and reduce postoperative pain. Post-
PD and a shorter median length of stay in the ICU. Wang et al.81 operative pain has been shown as an independent risk factor for the
performed a randomised, double blind, placebo-controlled trial of development of delirium.95 Paradoxically, the overuse of analgesics
non-cardiac surgery patients, and found a significant decreased (mainly opioids) increases the risk of developing delirium.96 Other
incidence of delirium between the groups (15.3% haloperidol group measures like non-pharmacological sleep protocols and environ-
vs. 23.2% placebo group). There is even a Cochrane review82 which mental changes (e.g., lights off, creating a relaxing environment,
suggests that the prophylactic low dose of haloperidol may reduce minimising night-time interruptions, placing a clock in view of the
the severity and duration of delirium episodes and shorten the patient and window protection) have proven to be useful for
length of hospital stay. reducing medication and delirium.22
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 6. Conclusion
lower incidence of delirium (13.7% risperidone group vs. 34% pla-
cebo group). Several randomised controlled trials studying the use Delirium is the most common form of acute brain dysfunction in
of rivastigmine have demonstrated it to be ineffective at preventing the post-surgical period since it is associated with poor outcomes
delirium nor did it decrease the duration of delirium, and it might and long-term consequences (increased morbidity and mortality,
have increased mortality.83,84 longer hospital stay and increased costs). New diagnostic, preven-
Regarding the role of anaesthesia, there are some measures that tive and management strategies have helped reduce the incidence
decrease the development of delirium. Some studies have sug- of PD and POCD. Identifying those patients most at risk and pre-
gested a lower incidence of delirium when inhalational agents are venting the development of PD is the most effective way to reduce
used compared to intravenous ones.52,57,58 While studies like that its incidence. Reducing neuroactive drug doses is especially
carried out by Royse et al.36 found no difference in delirium rates important for reducing the incidence, duration and severity of
between patients anaesthetised with propofol and those with delirium episodes.
sevoflurane. But there is a difference in early postoperative
cognitive dysfunction that was significantly higher with propofol Conflict of interest
than with desflurane (67.5% vs. 49.4%). Another aspect to note
about anaesthesia is its depth. In the latest research, the The authors have no conflicts of interest to declare.
L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204 203

References dysfunction in patients undergoing coronary artery bypass graft surgery. J


Cardiovasc Surg 2006;47:451e6.
31. Marcantonio ER, Juarez G, Goldman L, Mangione CM, Ludwig LE, Lind L, et al.
1. Ely EW, Gautam S, Margolin R, Francis J, May L, Speroff T, et al. The impact of
The Relationship of Postoperative Delirium With Psychoactive Medications.
delirium in the intensive care unit on hospital length of stay. Intensive Care Med
JAMA 1994;19:1518e22.
2001;27:1892e900.
32. Alldred DP. Avoid benzodiazepines and opioids in people at risk of delirium.
2. Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, Ely EW. Inten-
Evid Based Med 2011 Mar 15. [Epub ahead of print].
sive care unit delirium is an independent predictor of longer hospital stay:
33. Sanders RD, Maze M. Contribution of sedative-hypnotic agents to delirium via
a prospective analysis of 261 non-ventilated patients. Crit Care 2005;9:
modulation of the sleep pathway. Can J Anaesth 2011;58:149e56.
375e81.
34. Sieber FE, Mears S, Lee H, Gottschalk A. Postoperative opioid consumption and
3. Witlox J, Eurelings LSM, de Jonghe JFM, Kalisvaart KJ, Eikelenboom P, van
its relationship to cognitive function in older adults with hip fracture. J Am
Gool WA. Delirium in elderly patients and the risk of postdischarge mortality,
Geriatr Soc 2011;59:2256e62.
institutionalization and demencia. JAMA 2010;304:443e51.
35. Fong HK, Sands LP, Leung JM. The Role of Postoperative Analgesia in Delirium
4. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell Jr FE, et al.
and Cognitive Decline in Elderly Patients: A Systematic Review. Anesth Analg
Delirium as a predictor of mortality in mechanically ventilated patients in the
2006;102:1255e66.
intensive care unit. JAMA 2004;291:1753e62.
36. Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, et al.
5. Lin SM, Liu CY, Wang CH, Lin HC, Huang CD, Huang PY, et al. The impact of
Sedation depht during spinal anesthesia and the development of postoperative
delirium on the survival of mechanically ventilated patients. Crit Care Med
delirium in elderly patients undergoing hip fracture repair. Mayo Clin Proc
2004;32:2254e9.
2010;85:18e26.
6. Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, Stiles RA, et al.
37. Mason SE, Noel-Storr A, Ritchie CW. The impact of general and regional
Costs associated with delirium in mechanically ventilated patients. Crit Care
anesthesia on the incidence of post-operative cognitive dysfunction and post-
Med 2004;32:955e62.
operative delirium: a systematic review with meta-analysis. J Alzheimers Dis
7. Monk TG, Price CC. Postoperative cognitive disorders. Current Opinion Critical
2010;22:67e79.
Care 2011;17:376e81.
38. Bryson GL, Wyand A. Evidence-based clinincal update: general anesthesia and
8. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. ISPOCD Group.
the risk of delirium and postoperative cognitive dysfunction. Can J Anesth
Long-term Consequences of Postoperative cognitive dysfunction. Anesthesi-
2006;53:669e77.
ology 2009;110:548e55.
39. Royse CF, Andrews DT, Newman SN, Stygall J, Williams Z, Pang J, et al. The in-
9. The ICD-10 Classification of Mental and Behavioural Disorders. Geneve: World
fluence of propofol or desflurane on postoperative cognitive dysfunction in pa-
Health Organizaition; 1993.
tients undergoing coronary artery bypass surgery. Anaesthesia 2011;66:455e64.
10. Morandi A, Pandharipande PP, Jackson JC, Bellelli G, Trabucchi M, Ely EW.
40. Steinmetz J, Funder KS, Bf Dahl, Rasmussen LS. Depth of anaesthesia and post-
Understanding terminology of delirium and long term cognitive impairment in
operative cognitive dusfunction. Acta Anaesthesiol Scand 2010;54:162e8.
critically ill patients. Best Practice and Reserch Clinical Anesthesiology 2012;26:
41. Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS. ISPOCD Group.
267e76.
Long-term Consequences of Postoperative cognitive dysfunction. Anesthesi-
11. Meagher DJ, Moran M, Raju B, Leonard M, Donnelly S, Saunders J, et al. A new
ology 2009;110:548e55.
databased motor subtype schema for delirium. J Neuropsychiatry Clin Neurosci
42. Rasmussen LS. Postoperative cognitive dysfunction: incidence and prevention.
2008;20:185e93.
Best Pract Res Clin Anaesthesiol 2006;20:315e30.
12. Meagher DJ, Leonard M, Donnelly S, Conroy M, Adamis D, Trzepacz PT. A
43. Moller JT, Cluitmans P, Rasmussen LS, Houx P, Rasmussen LS, Canet J, et al.
longitudinal study of motor subtypes in delirium: relationship with other
Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study.
phenomenology, etiology, medication exposure and prognosis. J Psychosom Res.
ISPOCD investigators. International Study of Post-Operative Cognitive
2011;71:395e403.
Dysfunction. Lancet 1998;351:857e61.
13. Blazer DG, Van Niuuwenhuizen AO. Evidence for the diagnostic criteria of
44. Rasmussen LS, Larsen K, Hous P, Skovgaard LT, Hanning CD, Moller JT. ISPOCD
delirium: an update. Curr Opin Psychiatry 2012;25:239e43.
group. The assessment of postoperative cognitive function. Acta Anaes-
14. Yang FM, Marcantonio ER, Inouye SK, Kiely DK, Rudolph JL, Fearing MA, et al.
thesiologica Scandinavica 2001;45:275e89.
Phenomenological subtypes of delirium in older persons: patterns, prevalence
45. Krenk L, Rasmussen LS, Kehlet H. New insights into the pathophysiology of
and prognosis. Psychosomatics 2009;50:248e54.
postoperative cognitive dysfunction. Acta Anaesthesiol Scand 2010;54:951e6.
15. Cole MG, McCusker J, Voyer P, Monette J, Champoux N, Ciampi A, et al. Sub-
46. Rudolph JL, Marcantonio ER, Culley DJ, Silversteins JH, Rasmussen LS. Delirium
syndromal delirium in older longterm care residents: incidence, risk factors,
is associated with early postoperative cognitive dysfunction. Anaesthesia
and outcomes. J Am Geriatr Soc 2011;59:1829e36.
2008;63:941e7.
16. Ouimet S, Riker R, Bergeron N, Cossette M, Kavanagh B, Skrobik Y. Sub-
47. Cottrell JE, Hartung J. Developmental disability in the Young and post-
syndromal delirium in the ICU: evidence for a disease spectrum. Intensive Care
operative cognitive dusfuction in the elderly after anesthesia and surgery:
Med 2007;33:1007e13.
do data justify changing clinical practice? Mount Sinai Journal of Medicine
17. American Psychiatric Association. Diagnostic criteria from DSM-IV-TR. Wash-
2012;79:75e94.
ington, D.C.: American Psychiatric Association; 2000.
48. Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW, et al.
18. Whitlock EL, Vannucci A, Avidan MS. Postoperative delirium. Minerva Anes-
Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol
tesiology 2011;77:448e56.
Sci Med 2008;63:184e9.
19. Guenter U, Radtke FM. Delirium in the postanaesthesia period. Current Opinion
49. Cunnigham C. Systemic inflammation and delirium: important co-factors in the
in Anesthesiology 2011;24:670e5.
prosgression of dementia. Biochem. Soc. Trans. 2011;39:945e53.
20. Krenk L, Rasmussen LS. Postoperative delirium and postoperative congnitive
50. Li YC, Xi CH, An YF, Dong WH, Zhou M. Perioperative inflammatory response
dysfunction in the elderly- what are the differences. Miverva Anestesiology
and protein S-100 b cincentrations- relationship with post-operative cognitive
2011;77:742e9.
dysfunction in elderly patients. Acta Anaesthesiol Scand 2012;56:595e600.
21. Vasilevskis EE, Han JH, Hughes CG, Ely EW. Epidemiology and risk factors for
51. Staz P. Brain reserve capacity on symptom onset after brain injury: a formulation
delirium across hospital settings. Best Practice&Reserch Clinical Anaesthesiology
and review of evidence for thershold theory. Neuropsychology 1993;7:273e5.
2012;26:277e87.
52. Jankowski C, Mr Trenerry, Cook DJ, Buenvenida SL, Stevens SR, Schroeder DR,
22. Rudolph JL, Marcantonio E. Postoperative delirium: acute change with long-
et al. Cognitive and functional predictors and sequelae of postoperative
term implications. Anesthesia Analgesia 2011;112:1202e11.
delirium in elderly patients undergoing elective joint arthroplasty. Anesthesia
23. Maldonado JR, Dhami N, Wise L. Clinical implications of the recognition and
Analgesia 2011;112:1186e93.
management of delirium in general medical and surgical wards. Psychosomatics
53. Schoen J, Husemann L, Tiemeyer C, Lueloh A, Sedemund-Adib B, Berger KU,
2003;44:157e8.
et al. Cognitive function afer sevoflurane vs propofol based anaesthesia for on-
24. Inouye SK. Predisposing and precipitating factors for delirium in hospitalized
pump cardiac surgery: a randomized controlled trial. British Journal of Anaes-
older patients. Dement Geriatr Cogn Disord 1999;10:393e400.
thesia 2011;106:840e50.
25. Jones RN, Fong TG, Metzger E, Tulebaev S, Yang FM, Alsop DC, et al. Aging, brain
54. Hudson AE, Hemmings HC. Are anaesthetics toxic to brain? British Journal of
disease and reserve: implications for delirium. Am J Geriatri Psychiatry 2010;18:
Anesthesia 2011;107:30e7.
117e27.
55. Lonergan E, Luxenberg J, Areosa Sastre A. Benzodiazepines for delirium.
26. Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction. Br J
Cochrane Database Syst. Rev 2009;7. CD006379.
Anaesth 2009;103:41e6.
56. Hoy SM, Keating GM. Dexmedetomidine. A Review of its Use for Sedation in
27. Rudoplh JL, Jones RN, Rasmussen LS. Independent vascular and cognitive risk
Mechanically Ventilated Patients in an Intensive Care Setting and for Proce-
factors for postoperative delirium. Am J Medicine 2007;120:807e13.
dural Sedation. Drugs 2011;71:1481e501.
28. Leung JM, Sands LP, Wang Y. Apolipoprotein E e4 allele increases the risk of
57. Sanders RD, Mervyn M. Contribution of sedative-hypnotic agents to delirium
early postoperative delirium in older patients undergoing noncardiac surgery.
via modulation of the sleep pathway. Can J Anesth 2011;58:149e56.
Anesthesiology 2007;107:406e11.
58. Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for sub-
29. Ely EW, Girard TD, Shintani AK, Jackson JC, Gordon SM, Thomason JW, et al.
syndromal delirium after on-pump cardiac surgery in the elderly. Anesthesi-
Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in
ology 2012;116:987e97.
critically ill patients. Crit Care Med 2007;35:112e7.
59. Kadoi Y, Goto F. Sevoflurane anesthesia did not affect postoperative cognitive
30. Lelis RG, Krieger JE, Pereira AC, Schmidt AP, Carmona MJ, Oliveira SA, et al.
dysfunction in patients undergoing coronary artery bypass graft surgery. J
Apolipoprotein E4 genotype increases the risk of postoperative cognitive
Anesth 2007;21:330e5.
204 L. Alcover et al. / Trends in Anaesthesia and Critical Care 3 (2013) 199e204

60. Rörtgen D, Kloos J, Fries M, Grottke O, Rex S, Rossaint R, et al. Comparison of 79. Akunne A, Murphy L, Young J. Cost-effectiveness of a multi-component in-
aerly cognitive function and recovery after desflurane or sevoflurane anes- terventions to prevent delirium in older people admitted to medical wards. Age
thesia in the elderly: a doubled-blinded randomized controlled trial. British Aging 2012;41:285e91.
Journal of Anesthesia 2010;104:167e74. 80. Kalisvaart KJ, de Jonghe JF, Bogaards MJ, Vreeswijk R, Egberts TC, Burger BJ,
61. Citerio G, Pesenti A, Latini R, Masson S, Barlera S, Gaspari F, et al. A multicentre, et al. Haloperidol prophylaxis for elderly hip-surgery patients at risk for
randomised, open-label, controlled trial evaluating equivalence of inhalational delirium: a randomized placebo-controlled study. J Am Geriatr Soc 2005
and intravenous anesthesia during elective craniotomy. Eur Journal Anaes- Oct;53(10):1658e66.
thesiol 2012;29:371e9. 81. Vochteloo AJ, Moerman S, van der Burg BL, de Boo M, de Vries MR, Niesten DD,
62. Mistraletti G, Pelosi P, Mantovani E, Berardino M, Gregoretti C. Delirium: et al. Delirium risk screening and haloperidol prophylaxis program in hip
clinical approach and prevention. Best Practice and Reserch Clinical Anaes- fracture patients is a helpful tool in identifying high-risk patients, but does not
thesiology 2012;26:311e26. reduce the incidence of delirium. BMC Geriatr 2011;11:39.
63. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying 82. Van der Boogaard M, Schoonhosen L, Van Achterberg T, Van der Hooven JG,
confusion: the confusion assessment method. A new method for detection of Pickkers P. Haloperidol prophylaxis in critically ill patients with a high risk for
delirium. Ann Intern Med 1990 Dec 15;113(12):941e8. delirium. Crit Care 2013;17:R9. (Epub ahead of print).
64. Gaudreau JD, Gagnon P, Harel F, Tremblay A, Roy MA. Fast, systematic, and 83. Wang W, Li HL, Wang DX, Zhu X, Li SL, Yao GQ, et al. Haloperidol prophylaxis
continuous delirium assessment in hospitalized patients: the nursing delirium decreases delirium incidence in elderly patients after noncardiac surgery: a
screening scale. J Pain Symptom Manage 2005;29:368e75. randomized controlled trial. Crit Care Med 2012;40:731e9.
65. Radtke FM, Franck M, Schneider M, Luetz A, Seeling M, Heinz A, et al. Com- 84. Siddiqi N, Stockdale R, Britton AM, Holmes J. Interventions for preventing
parison of three scores to screen for delirium in the recovery room. Br J Anaesth delirium in hospitalised patients. Cochrane Database Syst Rev 2007;18.
2008 Sep;101(3):338e43. CD005563.
66. Ely EW, Inouye SK, Bernard GR, Gordon S, Francis J, May L, et al. Delirium in 85. Hakim SM, Othman AI, Naoum DO. Early treatment with risperidone for sub-
mechanically ventilated patients: validity and reliability of the confusion syndromal delirium after on-pump cardiac surgery in the elderly. Anesthesi-
assessment method for the intensive care unit (CAM-ICU). Jama 2001 Dec ology 2012;116:987e97.
5;286(21):2703e10. 86. van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, et al.
67. Guenter U, Popp J, Koecher L, Muders T, Wrigge H, Ely EW, et al. Validity and Effect of rivastigmine as an adjunct to usual care with haloperidol on duration
Reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU of delirium and mortality in critically ill patients: a multicentre, double-blind,
patients. J Crit Care 2010;25:144e51. placebo-controlled randomised trial. Lancet 2010;27:1829e37.
68. Shim JJ, Leung JM. An update on delirium in the postoperative setting: pre- 87. Gamberini M, Bolliger D, Lurati Buse GA, Burkhart CS, Grapow M, Gagneux A,
vention, diagnosis and management. Best Practice and Reserch Clinical Anaes- et al. Rivastigmine for the prevention of postoperative delirium in elderly
thesiology 2012;26:327e34. patients undergoing elective cardiac surgeryea randomized controlled trial.
69. Young J, Murthy L, Westby M, Akunne A, O’Mahony R. Guideline Development Crit Care Med 2009;37:1762e8.
Group. Diagnosis, prevention, and management of delirium: summary of NICE 88. Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is
guidance. BMJ 2010;341:3704. independent of type of surgery and anesthetic. Anesthesia Analgesia 2011;112:
70. Rudolph JL, Schreiber KA, Culley DJ, McGlinchey RE, Crosby G, Levitsky S, 1179e85.
et al. Measurement of post-operative cognitive dysfunction after cardiac 89. Liu SS. Effects of Bispectral Index monitoring on ambulatory anesthesia: a
surgery: a systematic review. Acta Anaesthesiologica Scandinavica 2010;54: meta-analysis of randomized controlled trials and a cost analysis. Anesthesi-
663e77. ology 2004;101:311e5.
71. NCGC N. DELIRIUM: diagnosis, prevention and management. Acute and chronic 90. Leslie K, Myles PS, Forbes A, Chan MT, Short TG, Swallow SK. Recovery from
conditions 2010. bispectral index guided anaesthesia in a large randomized controlled trial of
72. Rubin FH, Williams JT, Lescisin DA, Mook WJ, Hassan S, Inouye SK. Replicating patients at high risk of awareness. Anaesth Intensive Care 2005;33:443e51.
the Hospital Elder Life Program in a Community Hospital and Demonstrating 91. Chan MTV, Cheng BCP, Lee TMC, Gin T, CODA Trial Group. BIS-guided anes-
Effectiveness Using Quality Improvement Methodology. Journal of the American thesia decreases post-operative delirium and cognitive decline. J Neurosurg
Geriatrics Society 2006;54:969e74. Anesthesiol 2013;25:33e42.
73. Deschodt M, Braes T, Flamaing J, Detroyer E, Broos P, Haentjens P, et al. Pre- 92. Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, et al. Clinical
venting delirium in older adults with recent hip fracture through multidisci- practice guidelines for the sustained use of sedatives and analgesics in the
plinary geriatric consultation. J Am. Geriatr Soc 2012;60:733e9. critically ill adult. Crit Care Med 2002;30:119e41.
74. Rubin FH, Neal K, Fenlon K, Hassan S, Inouye SK. Sustainability and scalability 93. American Psychiatric Association. Practice guideline for the treatment of pa-
of the hospital Elder life program at a community hospital. J AM Geriatr Soc. tients with delirium. Am J Psychiatry 1999;156:1e20.
2011;59:359e65. 94. Yang J, Choi W, Ko YH, Joe SH, Han C, Kim YK. Bright light therapy as an
75. Chen CC, Lin MT, Tien YW, Yen CJ, Huang GH, Inouye SK. Modified hospital adjunctive treatment with risperidone in patients with delirium: a random-
Elder life program: effects on abdominal surgery patients. J Am Geriatr Soc ized, open, parallel group study. Gen Hosp Psychiatry 2012;34:546e51.
2011;213:245e52. 95. Pandharipande P, Pun B, Herr D, Girard T, Miller R, Thompson J, Shintani A,
76. Marcantonio ER, Flacker JM, Wright RJ, Resnick NM. Reducing delirium after Maze M, Bernard G, Ely E. Double blind randomized controlled trial comparing
hip fracture: a randomized trial. J Am Geriatr Soc 2001;49:516e22. dexmedetomidine vs. lorazepam to reduce duration of delirium and coma in
77. Bjorkelund KB, Hommel A, Thorngren KG, Gustafson L, Larsson S, Lundberg D. mechanically ventilated (MV) patients. Am J Respir Crit Care Med 2007;175:
Reducing delirium in elderly patients with hip fracture: a multi-factorial A508.
intervention study. Acta Anaesthesiol Scand 2010;54:678e88. 96. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al.
78. Brummel NE, Girard TD. Preventing delirium in the intensive care unit. Crit Dexmedetomidine vs midazolam for sedation of critically ill patients: a ran-
Care Clin 2013;29:51e65. domized trial. Jama 2009;301:489e99.