Seminars in Cardiothoracic and

Delirium in Intensive Vascular Anesthesia

14(2) 141147
The Author(s) 2010
Care Unit Patients Reprints and permission: http://www.
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1089253210371495
http://scv.sagepub.com

M. M. J. van Eijk, MD,1 and A. J. C. Slooter, MD, PhD1

Abstract
Delirium is defined as a disturbance of consciousness with cognitive changes or perceptual disturbances, which has
developed over a short period of time, and is caused by a medical condition or a postsurgical state. Although historically
dismissed as an inconvenient and transient problem, recent studies have reported that delirium is associated with more
complications, increased length of hospital stay, and higher mortality. Although delirium is a prevalent condition after
cardiothoracic surgery and in the intensive care unit (ICU), the condition appears to be largely underdiagnosed. Several
detection tools have been developed for routine monitoring of delirium by nonpsychiatric personnel in the ICU, such
as the Confusion Assessment Method for the Intensive Care Unit and the Intensive Care Delirium Screening Checklist.
Management includes treatment of underlying disorders, nonpharmacological measures and symptomatic drug therapy.
There is a need for well-designed randomized, double-blind, placebo-controlled trials on drug treatment.

Keywords
delirium, intensive care unit, critically ill

Introduction disturbance of consciousness with cognitive changes or

Delirium has been observed in cardiothoracic surgical
patients since the introduction of open-heart surgery in the
mid 1950s. Postcardiotomy delirium usually develops on
day 2 after surgery,1 but can also be seen in the intensive
care unit (ICU), particularly if the patients have a longer
postoperative ICU stay than anticipated. Delirium in the
ICU was, until recently, referred to as ICU psychosis or
simply the ICU syndrome.2 Most physicians and nurses
regarded delirium as an inconvenient problem, both for the
patient and for personnel, but certainly not life threatening
and completely reversible after successful treatment of the
underlying disorder. Since the end of the previous century,
patients are being sedated in the ICU for shorter periods
and less profoundly,3 and subsequently, delirium appears
to be a more commonly observed condition. It is expected
that the frequency of delirium in the ICU will further rise
because of the aging of the population and an increase in
the proportion of elderly ICU patients.4 Furthermore,
adverse consequences of delirium are being increasingly
recognized. These include more complications, increased
ICU length of stay and mortality, as well as impaired cog-
nitive function following discharge from the hospital.5-8
perceptual disturbances, which has developed over a short
period of time, and caused by a general medical condition
(Table 1).9 Three subtypes of delirium have been
described10: (a) the hyperactive type, characterized by
high vigilance, restlessness, aggression, and strong emo-
tions, such as rage or fear; (b) the hypoactive type associ-
ated with low vigilance, slow or absent speech, and apathy;
and (c) the mixed type; in this third subtype, episodes with
characteristics of the hypoactive and hyperactive types
alternate. Although these subtypes are described in numer-
ous publications, a uniform definition is lacking. More-
over, in these articles, classifications were based on brief
observations, whereas delirium and its symptoms often
fluctuate over time.10
The frequency of delirium after heart surgery varies,
depending on the type of operation (valve replacement
patients seem to be at higher risk) and the method used for
diagnosing the disease. Frequencies ranging from 3% to
72% have been reported.11 The reported incidence of delir-
ium in the ICU also shows enormous variation (16% to
89%), depending on the population studied (the so-called
1
University Medical Center Utrecht, Utrecht, The Netherlands

Definition and Frequency
Delirium is defined by the Diagnostic and Statistical Man-
ual of Mental Disorders, Fourth Edition (DSM-IV) as a
Corresponding Author:
A. J. C. Slooter, Department of Intensive Care, University Medical
Center Utrecht, Room: F06.149, P.O. 85500, 3508 GA Utrecht, The
Netherlands
Email: a.slooter-3@umcutrecht.nl
142 Seminars in Cardiothoracic and Vascular Anesthesia 14(2)
Table 1. Diagnostic Criteria for Delirium According to the
DSM-IV9
Disturbance of consciousness (that is, reduced clarity of
awareness of the environment, with reduced ability to focus,
sustain, or shift attention)
A change in cognition (such as memory deficit, disorientation,
language disturbance) or the development of a perceptual
disturbance that is not better accounted for by a preexisting
established or evolving dementia
The disturbance developed over a short period of time (usually
hours to days) and tends to fluctuate during the course of
the day
There is evidence from the history, physical examination, or
laboratory findings that the disturbance is caused by the direct
physiological consequences of a general medical condition
case-mix) and sedation practices.5,6,12-18 The hypoactive
form of delirium is particularly likely to remain unnoticed,
if there is no routine method of screening for delirium.19
Furthermore, diagnostic tools and opinions differ. For
example, a patient in whom anesthesia has just been
stopped after surgery, may fulfill DSM-IV criteria for
delirium, but will not be regarded by most physicians as
delirious. In addition, variations in protocols used to pre-
vent and treat delirium may explain differences in the
observed frequency.5,6,12-18
Etiology
Despite its common occurrence and clinical impact, the
etiology of delirium remains poorly understood. To date,
central cholinergic deficiency is the leading hypothesized
mechanism for delirium.20 After heart surgery, other mech-
anisms may play a role as well, especially cerebral mico-
rembolization during cardiopulmonary bypass.21 Other
hypotheses that are not mutually exclusive, include dopa-
mine excess, inflammation, and chronic stress. In septic
patients, encephalopathy may result from microcirculation
disorders due to microthrombosis and endothelial swelling,
breakdown of the bloodbrain barrier as well as microglial
activation.22,23
The cholinergic deficiency hypothesis is supported by
several lines of evidence.20 First, acetylcholine plays a piv-
otal role in attention and consciousness. It focuses awareness
by modulating sensory and cognitive input. Irregularities
in these brain functions are core symptoms of delirium,
including inattention, disorganized thinking, and percep-
tual disturbances. Second, delirium may occur after
administration of agents that impair cholinergic function
or in conditions associated with cholinergic deficit.24 Fur-
thermore, the administration of cholinesterase inhibitors
may decrease the duration of delirium.25,26
Clinical studies showed that delirium in ICU patients is
almost always a multifactorial disorder,15,27-29 and that it is
usually impossible to assign one particular cause for delir-
ium in a particular patient. Multiple risk factors have been
identified in non-ICU patients, on average 11 (standard
deviation 4) of these risk factors were observed at the
same time in delirious ICU patients.30 Frequently reported
risk factors for the development of delirium are advanced
age, preexisting cognitive decline, comorbidities, ill phys-
ical condition, alcohol abuse or withdrawal, the use of
benzodiazepines or opiates, and liver and renal fail-
ure.15,27-29 Furthermore, the ICU environment itself may
play a role in the development of delirium. Being in a
room without orientation points, with continuous light,
and personnel working around the clock may be stressful
and may induce delirium. It is currently unclear which of
these risk factors contribute most to the burden of ICU
delirium.
Diagnosis
Delirium may be difficult to diagnose in intubated and
mechanically ventilated patients in whom cognitive test-
ing is a challenge. The key characteristics are an altered
level of consciousness with reduced ability to focus, sus-
tain, or shift attention, and fluctuation during the day.
Signs of concomitant Wernicke encephalopathy (with the
classical triad of confusion, ocular abnormalitiessuch as
nystagmus, palsy of ocular muscles and pupil abnormalities
and ataxia) should be sought.31 Ataxia may be difficult to
determine in bedridden patients with changes in mental
status. The majority of delirium patients, particularly
those with predominantly hypoactive episodes, are not
recognized by ICU physicians.19 An evaluation by a neu-
rologist, neurophysiologist, psychiatrist, or clinical geri-
atrician is regarded as the gold standard for a diagnosis
of delirium but usually requires active consultation by an
intensivist.
Because of the under diagnosis of delirium, various
tools have been developed for standardized delirium test-
ing by ICU nurses. One instrument is the Confusion
Assessment Method for the Intensive Care Unit (CAM-
ICU), which uses 4 criteria for the diagnosis of delirium32:
(a) change in cognition, (b) acute onset or fluctuating
course, (c) disordered attention, and (d) disorganized
thinking (see Figure 1). There is also the Richmond Seda-
tion and Agitation Score (RASS) to quantify the level of
consciousness (Table 2). For the CAM-ICU, 95% sensitiv-
ity and 98% specificity have been described, when com-
pared with the final diagnosis of a neurophysiologist,
clinical geriatrician, or psychiatrist.32 The Intensive Care
Delirium Screening Checklist (ICDSC), an 8-item screen-
ing instrument based on the DSM-IV criteria, has also
van Eijk and Slooter 143

Feature 1: Acute Onset or Fluctuating Course Positive Negative

Positive if you answer yes to either 1A or 1B

1A: is the patient different than his/her baseline mental status? Yes No
or
1B: has the patient had any fluctuation in mental status in the past 24 hours as evi-
dence by fluctuation on a sedation scale (e.g. RASS), GCS, or previous delirium
assessment?

Feature 2: Inattention Positive Negative

Positive is either score for 2A or 2B is less than 8. Attempt the ASE letters first. If the
patient is able to perform this test and the score is clear, record this score and move to
feature 3. If the patient is unable to perform this test or the score is unclear, then per-
form the ASE Pictures. If you perform both tests, use the ASE Pictures to score the
Feature.

2A: ASE Letters: record score (enter NT for not tested) Score (out of 10): _______

Directions: Say to the patient: I am going to read you a series of 10 letters. Whenever
you hear the letter A, indicate by squeezing my hand. Read letter form the following
letter list in a normal tone.
S AV E A H A A RT
Scoring: Errors are counted when patient fails to squeeze on the letter A and what
when the patient squeezes on any letter other than A.

2B: ASE Picture. record score (enter NT for not tested) Score (out of 10): _______
Directions are included on the picture packets.

Feature 3: Disorganized Thinking Positive Negative

Positive if combined score is less than 4

3A: Yes/No Questions Combined Score (3A+3B):

(use either Set A or Set B, alternate on consecutive days if necessary): _____ (out of 5)
Set A
1. Will a stone float on water?
2. Are there fish in the sea?
3. Does one pound weigh more than two pounds?
4. Can you use a hammer to pound a nail?

Set B
1. Will a leaf float on water?
2. Are there elephants in the sea?
3. Do two pound weigh more than one pound?
4. Can you use a hammer to cut wood?

Score ____ (patient earns 1 point for each correct answer out of 4)

3B: Command
Say to patient: Hold up this many fingers (Examiner holds two fingers in front of
patient). Now do the same thing with the other hand (Not repeating the number of
fingers). If patient is unable to mover both arms, for the second part of the command
ask patient Add one more finger.

Score _____ (Patient earns 1 point if able to successfully complete the entire com-
mand)

Feature 4: Altered Level of Consciousness Positive Negative

Positive if Actual RASS score is anything other than 0 (zero)

Overall CAM-ICU (feature 1 and 2 and either Feature 3 or 4) Positive Negative

Figure 1. Confusion Assessment Method adapted for the Intensive Care Unit (CAM-ICU)
144 Seminars in Cardiothoracic and Vascular Anesthesia 14(2)

Table 2. Richmond Agitation and Sedation Scale (RASS)

Score Term Description

+4 Combative Overtly combative, violent, immediate danger to staff

+3 Very agitated Pulls or removes tube(s) or catheter(s); aggressive
+2 Agitated Frequent nonpurposeful movement, fights ventilator
+1 Restless Anxious but movements not aggressive vigorous
0 Alert and calm

}
-1 Drowsy Not fully alert, but has sustained awakening (eye opening,/eye contact) to voice
(10 seconds) Verbal
-2 Light sedation Briefly awakens with eye contact to voice (<10 seconds) stimulation
-3 Moderate sedation Movement or eye opening to voice (but no eye contact)
-4
-5
Deep sedation
Unarousable
No response to voice, but movement or eye opening to physical stimulation
No response to voice or physical stimulation }Physical
stimulation

been developed for use in ICU patients. For the ICDSC,
64% specificity and 99% sensitivity have been reported in
comparison with the evaluation by a psychiatrist.14
In a direct comparison of the CAM-ICU and the
ICDSC within the same population of mixed ICU patients,
and an independent gold standard assessment by a neu-
rologist, geriatrician, or psychiatrist, the CAM-ICU
showed higher sensitivity than the ICDSC (64% vs 43%).
However, for both tests, considerably lower sensitivity
(CAM-ICU 64%; ICDSC 43%) and specificity (CAM-
ICU 88%; ICDSC 95%) were found than in the original
articles.19 Furthermore, in the studies described above, the
CAM-ICU and the ICDSC were administered by a limited
number of research nurses. The diagnostic value of these
instruments as administered by the clinically assigned
nurse is currently unclear, but is estimated by many inten-
sivists to be much lower.
Prevention
Nonpharmacological measures such as frequent orienta-
tion and noise reduction, appeared to prevent delirium in
non-ICU patients.33,34 However, this could not be con-
firmed in another study on 1925 medical patients.35 The
use of ear-plugs increased the duration of rapid eye move-
ment (REM) sleep in healthy volunteers who were exposed
to ICU noise.36 It is unclear whether these simple measures
are effective in ICU patients who are exposed to many
more factors that can induce delirium, but this seems to be
plausible and has no negative side effects. Early physical
therapy was recently shown to decrease duration (median
2.0 vs 4.0 days) of delirium in a randomized clinical trial
on 104 mechanically ventilated ICU patients.37 In the same
trial, early physical therapy was shown to improve the risk
of return to independent functional status at hospital dis-
charge (odds ratio 2.7, 95% confidence interval 1.2-6.1).
Currently, 5 randomized, double-blind, placebo-controlled
trials have been published on pharmacological prevention
of delirium.38 In the largest study on 430 elderly hip-
surgery patients, the use of prophylactic haloperidol was
found to have a beneficial effect on secondary endpoints,
the severity and duration of delirium, but not on the pri-
mary endpoint, the incidence of delirium.39 Recently, a
randomized placebo-controlled trial compared the use of
haloperidol or ziprasodine with a placebo in high-risk ICU
patients. No differences in clinical relevant outcomes were
found, but this trial may have lacked statistical power (n =
101).40 Prophylaxis of ICU delirium using the cholinester-
ase inhibitor rivastigmine is currently being investigated
in a randomized clinical trial (RCT; ClinicalTrials.gov
Identifier: NCT00835159). In another recent RCT, no ben-
efit of rivastigmine in postcardiothoracic surgical patients
was found,26 although the study was underpowered (n =
120) and the method of diagnosing delirium was unclear.
Treatment
Treatment of delirium starts with nonpharmacological
measures and management of modifiable precipitating dis-
orders. The patients medication list should be critically
reviewed as to whether drugs with anticholinergic side
effects (such as rifampin) may be tapered. As outlined
above, the strength of the relationships between the most
modifiable risk factors and delirium is currently unknown.
As delirium-inducing medication has presumably been
started for a certain indication, it may therefore be unclear
whether a delirious patient will in the end benefit from
ceasing this drug or will deteriorate because of the under-
lying disease. Patients suspected of having concomitant
Wernickes encephalopathy, including patients with previ-
ous alcohol abuse and/or malnutrition, should be treated
with parenteral thiamine.31
van Eijk and Slooter 145
For symptomatic treatment of delirium, the American
Psychiatric Association (APA) and the Society of Critical
Care Medicine (SCCM), recommend the use of the typical
antipsychotic haloperidol as the drug of first choice.41,42
According to these guidelines, haloperidol 0.5 to 5.0 mg
once or twice a day should be administered to a delirious
patient, and in cases of severe agitation, additional halo-
peridol up to 20 mg per day.41,42 It should be noted that the
APA and SCCM recommendations are not supported by
findings of one randomized double-blind placebo-controlled
clinical trial.38
In a double-blind RCT in 30 AIDS patients on halo-
peridol, chlorpromazine, and lorazepam, it was found that
low-dose antipsychotics reduced the symptoms of delir-
ium, whereas lorazepam alone was ineffective and associ-
ated with treatment-limiting adverse effects.43 In a RCT of
175 delirious dementia patients, haloperidol and olanzap-
ine improved the rate of response, compared with the con-
trol group without drug treatment.38 Haloperidol was as
effective as the atypical antipsychotic drug olazapine in an
RCT of 73 ICU patients.44 The use of olazapine, however,
tended to be associated with less side effects.44
The most frequent side effects of haloperidol are extra
pyramidal signs, such as Parkinsonism, dystonia, and
akathisia. It is important to differentiate akathisia, defined
as unpleasant sensations with an inability to remain motion-
less, as a side effect of haloperidol from restlessness as a
feature of delirium. Torsades des pointes (polymorphic
ventricular tachycardia) and malignant neuroleptic syn-
drome occur rarely.45,46 In older patients, higher mortality
and an increased risk of stroke have been described for
both typical and atypical antipsychotic drugs. However,
these studies were conducted in long-term users, and may
not be applicable to short-term treatment of patients with
delirium. Several attempts have been made to find other
antipsychotics with fewer side effects. In one small (n = 36)
placebo-controlled RCT, the atypical antipsychotic que-
tiapine (Seroquel) was used in addition to haloperidol in
delirious ICU patients,47 and a decreased duration of delir-
ium (1.0 vs 4.5 days) was found. Further studies with dif-
ferent antipsychotics should be performed, especially in
comparison with haloperidol.
Other drugs used to treat delirious ICU patients include
the central a2 agonist clonidine, especially in patients with
sympathetic overactivity.48 Recent studies showed that the
frequency of delirium decreased significantly when
another a2 agonist, dexmedetomidine, was used for seda-
tion, instead of lorazepam or midazolam.49,50 Furthermore,
in a recent pilot trial, dexmedetomidine was associated
with shorter mechanical ventilation times in hyperactive
delirious ICU patients compared with haloperidol (19.9 vs
42.5 hours).51 Although this was only a pilot trial (n = 20),
and no blinding was provided, it may be a promising new
approach to the treatment of delirium in the ICU. Other
drugs in the treatment of delirium are cholinesterase inhib-
itors such as rivastigmine,52,53 melatonin,54 and methyl-
phenidate, an amphetamine-like substance, particularly in
the hypoactive subtype.55
The majority of the analgesic and sedative drugs pre-
scribed to ICU patients (such as benzodiazepines and opi-
ates) may also induce or prolong delirium.28 Benzodiazepines
are agonists of the g-aminobutyric acid-A (GABA-A) recep-
tor, which results in a decrease in the level of consciousness
and a shortening of REM sleep, both risk factors for the
development of delirium. Stopping all psychoactive medi-
cation may in some cases terminate delirium.
Pharmacological treatment tends to be focused on
patients with predominantly hyperactive episodes at risk
of injury of themselves or others. Drug therapy in hypoac-
tive delirium is more controversial. Haloperidol has a
sedating effect, which is unwanted in hypoactive delirium.
Patients with hypoactive delirium can still experience
unpleasant psychiatric symptoms, such as delusions. The
aforementioned guidelines do not specifically give advice
regarding the treatment of hypoactive delirium.
The multifactorial nature of delirium complicates stud-
ies on drug prevention and therapy. Obviously, there is a
need to improve our understanding of the pathophysiology
of delirium and the efficacy of specific drugs in delirium
subtypes and subgroups.
Prognosis
ICU delirium has an unfavorable prognosis. Mortality in
ICU patients who experienced an episode of delirium dur-
ing their ICU stay was found to be higher than in ICU
patients who were never delirious (64% vs 34%)5. Deliri-
ous ICU patients remained 1 to 2 days longer on the ICU
on average, were discharged more frequently to a nursing
home, were less self supporting, and at increased risk of
dementia.7,8
An important issue in these studies is that the set of con-
founding risk factors for delirium, such as age, comorbid-
ity, and severity of illness, are also known risk factors for
worse outcome. Although in the aforementioned studies,
adjustments were made for age, comorbidity, and severity
of illness, these factors were assessed at ICU admission
only,56 and scores for disease severity and comorbidity may
have lacked detail. The observed association between delir-
ium and adverse outcomes may therefore be subject to con-
founding factors.57 It is plausible though that delirium is an
independent risk factor for worse prognosis, because delir-
ium is associated with more frequent complications, such
as auto-extubation and falls. Furthermore, the balanced
interaction between the central nervous system and the
immune system may be disturbed in delirium. Excess pro-
inflammatory mediators entering the brain may cause dys-
function of the autonomic nervous and neuroendocrine
146 Seminars in Cardiothoracic and Vascular Anesthesia 14(2)
systems, which may alter immunity in a vicious circle
resulting in metabolic derangements and organ failure.22
Because of the longer stays and increased number of
complications, delirium increases costs. In the only study on
this issue, median ICU costs for delirious and nondelirious
patients were $22 346 and $13 332, respectively; median
hospital costs were $41836 and $27106, respectively.58
Conclusion
Delirium is a frequent problem after cardiac surgery and in
the ICU. Because of the high complication rate, worse
prognosis, and increased costs, there is a need for further
studies on prevention and treatment of delirium.
Declaration of Conflicting Interests
The author(s) declared no conflicts of interest with respect to the
authorship and/or publication of this article.
Funding
The author(s) received no financial support for the research and/
or authorship of this article.
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