Jozef Bledowski, M.D.

Alex Trutia, M.D.

A Review of
Pharmacologic Management
and Prevention Strategies
for Delirium in the
Intensive Care Unit
Background: The prevalence of delirium has been estimated at anywhere between 10% and 30% in general medical patients
and in upwards of 80% in patients who are admitted to an intensive care unit (ICU). Given the high prevalence of delirium in
the ICU population, it should not be surprising that a large percentage of psychiatric consults arise from this setting. While the
mainstay of pharmacologic management of delirium centers on neuroleptic medications, such as haloperidol, recent studies using
alternate agents have shown varying levels of promise. Objective: Our purpose is to outline the major prospective studies looking
at the efficacy of pharmacologic management and prevention strategies for delirium exclusively in adult ICU patients. Both
conventional and novel pharmacotherapeutic interventions are discussed. Method: Articles were obtained using the MED-
LINE/PUBMED database looking specifically at pharmacologic interventions for delirium in the intensive care unit. A search
was performed using the key words-“delirium,” “intensive care unit,” “treatment,” and “prophylaxis.” The authors limited their
search to prospective studies, specifically randomized trials (both placebo-controlled and non-controlled) in the adult ICU
population, and eliminated retrospective and observational studies. Relevant citations from the previously mentioned articles
were also included in the review. Conclusion: There is a plethora of studies on pharmacologic management strategies in general
medical patients with delirium. Findings from these studies are often extrapolated to the ICU population; however, when
looking at studies limited to ICU patients with delirium, there are far fewer credible prospective studies.

(Reprinted with permission from Psychosomatics, 2012; 53:203–211)

Delirium prevalence is estimated at 10%–30% in
general medical population and as high as 80% in
the ICU population. Given these statistics, it is not
surprising that a large percentage, if not a majority,
of delirium consults arise from the critical care set-
ting. Definitive treatment of delirium in any setting
centers on the correction of underlying physiologic
and iatrogenic insults; however, the pathogenesis of
delirium is often multifactorial and definitive pre-
cipitants are not always known. As a result, psychiatric
consultants are often asked to suggest pharmaco-
logic management strategies for the delirious patient
while simultaneously addressing predisposing and
precipitating risk factors. The higher incidence of
morbidity (including injury to self and staff as well
as long-term cognitive impairment) and mortality
(3-fold increase in 6-month mortality) in ICU pa-
tients with delirium underscores the importance of
early identification and treatment.1 With delirium
often comes the added burden of prolonged me-
chanical ventilation and extended hospitalization.
This leads to significantly increased risks for noso-
comial infection and an increase in overall health-
care costs.
To underscore the importance of addressing de-
lirium in the ICU, a recent study by Heymann and
colleagues showed that in a cohort of 204 ICU
patients, treating delirium within the first 24 hours

568 Fall 2013, Vol. XI, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY

of onset significantly reduced mortality (3-fold higher
rate of mortality in the delayed treatment group vs.
immediate treatment group).2 Studies such as these
highlight the necessity for vigilance in identifying
and treating delirium in the ICU setting and pro-
mote moving away from the archaic notion that
delirium is a transient, benign process, with no long-
term sequelae.
The purpose of this review is to familiarize the
reader with the major prospective clinical trials that
have looked at pharmacologic interventions for
delirium in the adult ICU population (Table 1).
Studies in non-ICU patients were excluded in an
attempt to minimize confounding variables that are
inherent when generalizing findings between very
different study populations. Furthermore, this re-
view serves as an update of the current evidence
and rationale behind using various pharmacologic
agents for the management of delirium in the
ICU.
ANTIPSYCHOTICS
Antipsychotics are currently the mainstay of
pharmacotherapy for the management of delirium in
most settings. They are thought to exert their in-
fluence primarily via dopaminergic blockade as it
relates to the dopamine excess/acetylcholine de-
ficiency hypothesis of delirium pathophysiology.3
There is also some evidence that antipsychotics, in
particular haloperidol, may also impart a neuro-
protective effect by proposed s-1 receptor antago-
nism, which helps attenuate oxidative stress that
then leads to neuronal damage in delirium.4 Fur-
thermore, there are studies showing that anti-
psychotics may also function as immunomodulators
via indirect antagonism of IL-1.5 Even in sedative-
hypnotic and alcohol withdrawal delirium, where
GABA-receptor agonists are first-line agents, anti-
psychotics have been shown to be useful adjuncts.
To date, there are few large-scale studies of anti-
psychotics for delirium exclusively in the ICU
population. Per Society of Critical Care Medicine
guidelines, haloperidol remains the first-line phar-
macotherapeutic agent for the management of de-
lirium in the intensive care setting.6 Its use in
managing delirium in the ICU is supported by
a long track record with multiple observational
studies and case series that have shown both efficacy
and safety even at high doses administered via in-
travenous (IV) infusion.7,8 The use of haloperidol
for delirium remains off-label, however, and rela-
tively few placebo-controlled trials exist in the ICU
population. Furthermore, though IV haloperidol is
thought to carry less of a risk for extrapyramidal
symptoms (EPS), its use warrants caution, given an
focus.psychiatryonline.org
BELDOWSKI AND TRUTIA
increased risk for QTc prolongation and poly-
morphic ventricular tachyarrhythmias, such as tor-
sades de pointes.9,10
With the advent of second generation antipsy-
chotics, we now have more options in patients who
are sensitive to dopamine antagonism (specifically
D2 receptor antagonism). Studies thus far have not
shown atypical antipsychotics to be superior in ef-
ficacy to haloperidol for the management of delirium
in the ICU setting; however, there are multiple studies
attesting to the equal efficacy of atypical anti-
psychotics and haloperidol.11―13 With the added
benefit of multiple dosage forms and routes of
administration, however, haloperidol will likely
remain a first-line agent in managing delirium in
the ICU.
While studies comparing atypical antipsychotics
and haloperidol have mostly been done in non-ICU
populations, a recent study by Skrobik and col-
leagues looked at a cohort of 73 ICU patients who
developed delirium.14 The study sample was sub-
sequently randomized to receive either haloperidol
or olanzapine. Comparable to non-ICU studies,
findings showed that there were no significant dif-
ferences in delirium index, benzodiazepine dose
administered over time, or clinical improvement
between the two study groups. As expected, the
olanzapine group had a lower incidence of EPS.
Limitations of this study included a lack of blinding,
no placebo arm, as well as a relatively small sample
PUBLICATIONS
INFLUENTIAL
size. In addition, both groups utilized additional
PRN haloperidol, which may have confounded
results.
To date, there are only two major randomized,
placebo-controlled trials of antipsychotics for de-
lirium exclusively in the ICU population. The
MIND (Modifying the Incidence of Delirium) trial
looked at 101 adult mechanically-ventilated medical
and surgical ICU patients who were randomly
assigned to receive haloperidol, ziprasidone, or pla-
cebo every 6 hours for up to 14 days.15 Delirium was
then assessed for up to 21 days. Findings showed
that there were no differences between groups in the
duration of delirium or days alive without delirium.
Interestingly, this study also showed that neither
haloperidol nor ziprasidone was significantly better
than placebo in treating delirium in this population.
In addition, mortality, length of hospitalization, and
ventilator-free days were all similar between groups.
One must take these results with caution, however.
There were major study limitations in the MIND
trial including: small sample size, inclusion of non-
delirious patients in the study group, exposure to
open-label PRN haloperidol for breakthrough agi-
tation in each study arm, and multiple rigid exclu-
sion criteria.15,16
FOCUS Fall 2013, Vol. XI, No. 4 569
 BELDOWSKI AND TRUTIA
The second study, by Devlin and colleagues,
looked at 36 ICU patients with delirium who were
assigned to receive either quetiapine or placebo in
addition to PRN haloperidol.17 Study findings
showed that quetiapine was associated with a shorter
“time to first resolution” of delirium (1 day vs. 4.5
days in the placebo arm) and reduced duration of
delirium (36 hours vs. 120 hours, respectively). In
addition, the quetiapine group required less PRN
haloperidol than the placebo group. Mortality and
length of ICU stay were similar between study
groups. Again, major limitations included small
sample size and multiple exclusion criteria. In ad-
dition, when measuring “time to first resolution” of
delirium, the investigators may have inadvertently
included patients that were in a lucid interval yet still
delirious.
Generalizations cannot be made based on the
findings of the study by Devlin and colleagues or on
those of the MIND trial. Both studies were un-
derpowered and excluded patients with multiple
co-morbidities including: patients with primary
neurologic conditions and those exposed to anti-
psychotics prior to the studies, in addition to patients
on QTc-interval prolonging medications and those
with various cardiac anomalies. Extrapolation of
these findings to most ICU populations would be
premature at this point. Furthermore, there remains
an abundance of anecdotal data that supports the
routine usage of antipsychotics for the management
of delirium. Additional large-scale prospective stud-
ies are still needed to solidify practice guidelines in
the ICU population. Both of the above studies did,
however, show that prospective, placebo-controlled
trials of antipsychotics for delirium in the ICU
population are both possible and safe.
CHOLINESTERASE INHIBITORS
Cholinesterase inhibitors have garnered recent
attention as possible pharmacotherapeutic options
in treating delirium. The reasoning behind their
use relates to the central cholinergic deficiency
hypothesis of delirium.3 Cholinesterase inhibitors
function primarily by inhibiting enzymatic break-
down of acetylcholine. Observational studies and
anecdotal reports using physostigmine, a proto-
typical cholinesterase inhibitor, in the reversal of
anticholinergicinduced delirium were promising
and prompted further investigation into the po-
tential utility of using newer agents (such as done-
pezil, galantamine, and rivastigmine). As with other
agents, there is a relative lack of data in the ICU
population. The results are currently mixed, with
successful reports of cholinesterase inhibitors treat-
ing delirium in case studies and smaller prospective
570 Fall 2013, Vol. XI, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY
studies offset by relatively poor outcomes in larger
prospective trials.
For the most part, recent studies of cholinesterase
inhibitors in ICU patients who have been diagnosed
with delirium have focused on rivastigmine. The
single largest prospective study to date was a multi-
center, randomized, placebo-controlled trial by van
Eijk and colleagues in the Netherlands.18 This study
initially planned to look at 440 ICU patients di-
agnosed with delirium who were randomized to
receive an increasing dose of either rivastigmine or
placebo as an adjunct to haloperidol for the man-
agement of delirium. The study was prematurely
stopped, after the inclusion of 104 patients, due to
an increase in mortality in the rivastigmine group
(n 5 12, 22%) compared with placebo (n 5 4, 8%).
Furthermore, the median duration of delirium was
longer in the rivastigmine group (5 days) compared
with placebo (3 days). In addition, the patients in
the rivastigmine group had a higher severity of de-
lirium, stayed longer in the ICU, and received
higher cumulative doses of haloperidol, lorazepam,
and propofol. Overall, the van Eijk study did
not support the widespread use of cholinesterase
inhibitors in treating delirium in the ICU. If any-
thing, this study suggested that these agents should
be used with the utmost caution in the critically ill,
though further studies are still needed to make any
definitive conclusions.
a-2 AGONISTS
Though most often used in sedation and analgesia
protocols in the ICU, a-2 agonists have recently
been shown to reduce the incidence of, and treat,
delirium in the critically ill. These agents have the
added benefit of minimizing respiratory suppression
and facilitating the maintenance of a low heart rate,
thereby minimizing hemodynamic fluctuations and
reducing energy/demand expenditure that may
contribute to global cerebral insult.19 These agents
are also thought to be neuroprotective by inhibiting
the release and production of neurotoxic gluta-
mate.20
Recent studies investigating the efficacy in treating
delirium with a-2 agonists have focused on the
novel agent, dexmedetomidine. This is a centrally-
acting a-2 agonist that is eight times more selective
for a-2 adrenoreceptors than clonidine.21 Dexme-
detomidine works both pre- and post-synaptically
to decrease norepinephrine release and reduce
sympathetic activity in the CNS.21 While initially
approved for use in ICU patients for a duration of
less than 24 hours, at least four recent clinical trials
have shown that dexmedetomidine can be used
safely for up to 30 days.22–27 Though shown to have
 Table 1. Major Randomized Trials of Pharmacotherapeutic Interventions for Delirium in the ICU Population
Study
I. Antipsychotics
Olanzapine vs. haloperidol
(Skrobik et al14)
focus.psychiatryonline.org
MIND Trial (Girard et al15)
Quetiapine (Devlin et al17)
Risperidone (Prakanrattana
et al36)
II. Cholinesterase Inhibitors
Rivastigmine (van Eijk et al18)
Rivastigmine (Gamberini
et al38)
III. NMDA Antagonists
Ketamine (Hudetz et al37)
IV. a-2 Agonists
Clonidine (Rubino et al40)
Dexmedetomidine vs.
Haloperidol (Reade et al27)
Dexmedetomidine
(Maldonado et al31)
FOCUS
DEXCOM Study (Shehabi
et al39)
MENDS Trial
(Pandharipande et al24)
Fall 2013, Vol. XI, No. 4
571
Characteristics
73 Medical/surgical ICU patients diagnosed with delirium
randomized to olanzapine (n 5 28) or haloperidol (n 5 45)
101 Medical/surgical ICU patients randomized to
haloperidol (n 5 35), ziprasidone (n 5 30), or
placebo (n 5 36) for up to 14 days
36 Medical/surgical ICU patients diagnosed with delirium
randomized to quetiapine (N 5 18) or placebo (n 5 18)
until first resolution of delirium, for up to 10 days, or
until ICU discharge, whichever came first
126 Cardiac surgery patients (ICU) randomized to a single
postoperative dose of risperidone (n 5 63) or placebo (n 5 63)
104 ICU patients diagnosed with delirium randomized to
rivastigmine (n 5 54) or placebo (n 5 50) as an adjunct
to haloperidol
120 Cardiac surgery patients (ICU) randomized to rivastigmine
(n 5 59) or placebo (n 5 61) for 6 postoperative days
58 Cardiac surgery patients (ICU) randomized to ketamine
(n 5 29) or placebo (n 5 29) during anesthetic induction
30 Surgical ICU patients who underwent acute repair of
thoracic aortic dissection randomized to clonidine
(n 5 15) or placebo (n 5 15) infusion during weaning
from mechanical ventilation
20 Medical/surgical ICU patients who were difficult to
extubate secondary to superimposed delirium
randomized to a continuous infusion of
dexmedetomidine (n 5 10) or haloperidol (n 5 10)
118 Cardiac surgery patients (ICU) randomized to
dexmedetomidine (n 5 40), propofol (n 5 38), or
midazolam (n 5 40) for postoperative sedation
306 Cardiac surgery patients (ICU) randomized to
dexmedetomidine (n 5 154) or morphine (n 5 152)
for postoperative sedation/analgesia
106 Medical/surgical ICU patients randomized to
dexmedetomidine (n 5 54) or lorazepam (n 5 52) for
sedation
PUBLICATIONS
INFLUENTIAL
Primary Outcome Measure
Severity of delirium and benzodiazepine
use over 5 days
Days alive without delirium or coma
Time to first resolution of delirium
Incidence of post-operative delirium
Duration of delirium
Incidence of postoperative delirium
Incidence of postoperative delirium
Incidence and severity of postoperative
delirium
Time to extubation
Incidence of postoperative
delirium
Incidence of postoperative
delirium
Days alive without delirium or
coma
Results
No significant difference in delirium index or
benzodiazepine use
No significant differences between groups
Neither haloperidol nor ziprasidone were better
than placebo in treating delirium
Quetiapine associated with a shorter time to
first resolution of delirium
Incidence of postop delirium lower in the
risperidone group
Study prematurely stopped due to increased
mortality in the rivastigmine group
Median duration of delirium was longer
in the rivastigmine group
Incidence of postop delirium higher in the
rivastigmine group
Incidence of postop delirium lower in the
ketamine group
No statistically significant difference in incidence
of delirium between groups. severity of delirium
lower in the clonidine group
Dexmedetomidine group had a significantly
shorter time to extubation
Dexmedetomidine group had an increased
proportion of time spent with minimal
or no delirium symptoms
Incidence of delirium was significantly lower in
the dexmedetomidine group
Incidence of delirium was markedly higher in the
propofol and midazolam groups
Incidence of postop delirium was statistically
similar between groups
Duration of delirium was shorter in the
dexmedetomidine group
Dexmedetomidine group had significantly more
days alive without delirium or coma
Dexmedetomidine group had significantly more
coma-free days but not delirium-free days
BELDOWSKI AND TRUTIA
 BELDOWSKI AND TRUTIA
a lower incidence of rebound hypertension and
tachycardia on abrupt discontinuation compared
with clonidine, dexmedetomidine carries an in-
creased risk for hypotension and bradycardia, es-
pecially with high-rate infusions.21
The proposed benefit of dexmedetomidine over
standard agents for sedation/analgesia has centered
on its lack of significant anticholinergic effects,
promotion of sleep/wake cycle regulation, and re-
duced need for opioid analgesics (by as much as 40%
in some studies) and GABA agonists.28–33 These pro-
perties impart a unique profile to dexmedetomidine,
thereby reducing the potential precipitating risk
factors that play a role in delirium pathophysiology.
Case in point, a recent study by Pandharipande and
colleagues underscored the potential risks of ben-
zodiazepine use in a cohort of 198 mechanically-
ventilated ICU patients, showing that lorazepam
use was an independent risk factor for progression
to delirium in this at risk population.34 Findings
showed that in addition to a substantial increase in
the risk for developing delirium at low doses, the
probability of progressing to delirium reached 100%
after total daily lorazepam doses of $ 20 mg.34
Studies such as these underscore the importance of
seeking out alternative agents for sedation and an-
algesia protocols.
There are numerous case studies examining the
efficacy of using dexmedetomidine as both a primary
and adjunctive therapy in sedation/analgesia pro-
tocols. Many of these studies examine the effec-
tiveness of dexmedetomidine in treating symptoms
attributable to delirium (such as agitation) as well as
the incidence of delirium. Most prospective studies
have evaluated the efficacy of using dexmedetomidine
for sedation/analgesia protocols in mechanically-
ventilated patients and looked at delirium inci-
dence only as a secondary endpoint. There are few
studies using dexmedetomidine as a primary agent in
patients who were diagnosed with delirium at the
onset on the study and even fewer have actually
looked at the reduction in severity or resolution of
delirium as primary endpoints.
The pivotal prospective study was performed by
Reade and colleagues on 20 ICU patients exhibiting
severe agitation presumed to be secondary to de-
lirium at onset, then subsequently randomized to
receive either dexmedetomidine or haloperidol
infusions.27 Time to extubation was the primary
outcome measure and delirium incidence and se-
verity was a secondary measure. A total of 10
patients (five in each study arm) met criteria for
delirium by the end of the study; however, the
dexmedetomidine group had an increased pro-
portion of time spent with minimal or no delirium
symptoms as measured by the Intensive Care De-
572 Fall 2013, Vol. XI, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY
lirium Screening Checklist (ICDSC), with the
dexmedetomidine group spending 95.5% of the
time with a ICDSC score of ,4 and 61% of the time
with a score ,1 compared with the haloperidol group
who spent 31.5% and 0% of the time with the same
respective scores. In addition, the dexmedetomidine
group had a shorter time to extubation (median
length of 19.9 hours vs. 42.5 hours in the haloper-
idol group), shorter length of ICU hospitalization
(4.5 days vs. 8 days in the haloperidol group), as well
as an overall shorter time in mechanical restraints and
a reduced necessity for supplemental propofol when
compared to the haloperidol group. Though prom-
ising, this study had multiple limitations including:
small sample size, lack of blinding, possible under-
dosing in the haloperidol arm, and the assumption
that agitation was due to delirium when, in fact,
agitation is a nonspecific symptom with multiple
potential causes.27
Large-scale, randomized, placebo-controlled trials
are still needed to establish the efficacy of using
dexmedetomidine as a primary agent in treating
delirium in the ICU population. Furthermore, the
high cost of dexmedetomidine (on average $300–
$400 per day) seems to be a limiting factor at first
glance; however, a recent cost minimization analysis
comparing dexmedetomidine and midazolam for
sedation in a cohort of 366 mechanically-ventilated
ICU patients showed that usage of dexmedetomidine
resulted in a median total ICU cost savings of $9679
compared with midazolam.25,35 Findings such as
these are promising and suggest that usage of dex-
medetomide may in fact lower overall healthcare
costs; however, further replication of such studies is
necessary to make any definitive conclusions on this
basis. Nonetheless, dexmedetomidine remains a vi-
able alternative in managing treatment-refractory
delirium in the critical care population.
PHARMACOLOGIC PROPHYLAXIS
The increasingly apparent morbidity and mor-
tality associated with delirium in the ICU promotes
the search for possible pharmacologic prevention
strategies. While such prophylactic measures are still
experimental, some promising studies have shown
a possible role for premedicating certain at-risk pa-
tient populations in the interest of reducing delirium
incidence and resultant sequelae. Most of these
studies have been done in non-ICU populations, are
relatively underpowered, and remain mixed at best.
Those studies limited to the ICU population are far
fewer.
A large proportion of studies looking at pharma-
cologic prophylaxis measures for delirium have been
limited to patients undergoing elective surgical

procedures. Of these, only the studies examining
prophylaxis in elective cardiac surgery have involved
patients in the ICU setting.31,36–39 While a-2
agonists are discussed below, the studies to date have
also looked at antipsychotics, ketamine, and cho-
linesterase inhibitors. One such study, by Pra-
kanrattana and colleagues, looked at 126 patients
undergoing cardiac surgery who were randomized
to receive a single dose of either risperidone or pla-
cebo post-surgically.36 The risperidone group was
found to have a lower incidence of postoperative
delirium (11.1% vs. 31.7% in the placebo arm).
Similarly, a smaller study by Hudetz and colleagues
examined the incidence of postoperative delirium in
58 cardiac surgery patients randomized to receive
either ketamine or placebo during anesthetic in-
duction with fentanyl and etomidate.37 Findings
showed that patients who received ketamine had
a lower incidence of postoperative delirium (3% vs.
31% in the placebo arm). Finally, Gamberini and
colleagues looked at 120 patients undergoing car-
diac surgery who were randomized to receive either
rivastigmine (three doses daily starting the evening
before surgery and continued until the sixth post-
operative day) or placebo.38 Akin to the findings of
most large-scale studies using cholinesterase inhib-
itors for delirium, there was no significant difference
in the incidence of postoperative delirium between
the rivastigmine and placebo groups (32% vs. 30%,
respectively).
When looking exclusively at the ICU population,
studies examining the efficacy of pharmacologic
delirium prophylaxis have focused mainly on a-2
agonists. Despite one small-scale placebo-controlled
study looking at the incidence of delirium with IV
clonidine during ventilator weaning, most large-
scale studies have focused on dexmedetomidine.40
A pivotal trial was performed by Pandharipande and
colleagues and is known as the maximizing effi-
cacy of targeted sedation and reducing neurologic
dysfunction (MENDS) trial.24 In this double-blind
trial, 106 mechanically-ventilated patients from two
tertiary care centers were randomized to receive ei-
ther dexmedetomidine or lorazepam for sedation.
The primary outcome measure was days alive with-
out delirium or coma. The dexmedetomidine group
was found to have significantly more days alive
without coma or delirium compared with the lor-
azepam group (7 days vs. 3 days). Furthermore,
though not statistically significant, mortality mea-
sured after 28 days was found to be lower in the
dexmedetomidine group compared with the lor-
azepam group (17% vs. 27%) as were ventilator-free
days (22 days vs. 18 days, respectively). Subsequent
subgroup analysis looking at septic vs. non-septic
patients in the MENDS trial showed even greater dif-
focus.psychiatryonline.org
BELDOWSKI AND TRUTIA
ferences, with septic patients in the dexmedetomidine
group having significantly more days alive without
delirium or coma, 70% less risk of mortality at 28
days, and more ventilator-free days compared with
the septic patients in the lorazepam group.41
Limitations of the MENDS trial included the lack
of a placebo arm and exclusion of patients with
neurologic diseases (such as stroke or active seizures),
severe liver disease, alcohol abuse, active myocardial
infarction, second- or third-degree heart block, de-
mentia, benzodiazepine dependence, severe hearing
impairment, or being non-English speaking. Fur-
thermore, per study design guidelines imple-
mented by the FDA, dexmedetomidine could not
be administered for more than 120 hours.24 This
may have potentially introduced confounders
given the necessity to switch to standard sedation
(lorazepam or midazolam) in patients who were in
the dexmedetomidine study arm and necessitated
continued sedation beyond 120 hours.24
A similar study by Maldonado and colleagues
looked at 118 mechanically ventilated cardiac surgery
patients randomized to receive dexmedetomidine,
propofol, or midazolam for postoperative sedation.31
The incidence of delirium was found to be signifi-
cantly lower in the dexmedetomidine group (3%)
compared with the propofol (50%) and midazolam
groups (50%). The study lacked a placebo arm, was
limited to patients undergoing valve replacement
surgery, and excluded patients with the following
PUBLICATIONS
INFLUENTIAL
conditions: dementia, on psychotropic medications,
those with a history of substance abuse, advanced
heart block, pregnancy, stroke within the past 6 months,
and those age ,18 years or .90 years. Further-
more, despite the lower incidence of delirium in the
dexmedetomidine group, there were no significant
differences in mean ICU or hospital stay.
Similarly, Shehabi and colleagues looked at 306
mechanically ventilated patients who underwent
cardiac surgery and were randomized to receive
either dexmedetomidine or morphine at equivalent
levels of sedation/analgesia with delirium incidence
as the primary endpoint.39 Findings showed that
there was no statistically significant difference in
delirium incidence between groups (8.6% in the
dexmedetomidine vs. 15% in the morphine group);
however, dexmedetomidine patients spent 3 fewer
days in delirium compared with the morphine group
and were extubated sooner. Upon subgroup analysis,
those patients who required an intra-aortic balloon
pump and were in the dexmedetomidine group had
a significantly lower incidence of delirium compared
with the same subgroup of patients in the morphine
arm (15% vs. 36%, respectively). This particular
study was limited by its homogeneous population
(cardiac surgery patients aged 60 yrs and older),
FOCUS Fall 2013, Vol. XI, No. 4 573
 BELDOWSKI AND TRUTIA
a lack of delirium surveillance beyond 5 days, and
the fact that the use of open-label morphine in the
dexmedetomidine study group may have con-
founded results.
Other studies with dexmedetomidine in various
sedation/analgesia protocols have looked at delirium
incidence and duration only as secondary endpoints
and have yielded mixed results. Compared with
standard sedation protocols, dexmedetomidine has
been shown to be as effective for moderate sedation
with the added benefit of a significantly lower in-
cidence of delirium in one study.25 On the other
hand, a similar study did not show a significant re-
duction in the incidence of delirium.26 Results remain
mixed and further studies looking at delirium in-
cidence as a primary endpoint are still needed to
make any definitive conclusions. Dexmedetomidine
remains a viable alternative to standard sedating
medications in mechanically-ventilated ICU patients
who are already at an increased risk for developing
or exacerbating delirium; however, use in delirium
prophylaxis alone should still be exercised with
caution as efficacy is yet to be solidified.
CONCLUSIONS
This article summarizes the spectrum of phar-
macologic intervention studies for delirium in the
critical care population. It remains of paramount
importance for the practicing psychiatrist to be fa-
miliar with the breadth of pharmacotherapeutic
options for the management and potential pre-
vention of delirium. Studies to date remain mixed
at best and warrant further investigation in this
population.
REFERENCES
Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, Harrell FE Jr., et al: Delirium
as a predictor of mortality in mechanically ventilated patients in the intensive care
unit. JAMA 2004; 291(14):1753–1762
Heymann A, Radtke F, Schiemann A, Lütz A, MacGuill M, Wernecke KD, et al:
Delayed treatment of delirium increases mortality rate in intensive care unit
patients. J Int Med Res 2010; 38(5):1584–1595
Hshieh TT, Fong TG, Marcantonio ER, Inouye SK: Cholinergic deficiency hypoth-
esis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci
2008; 63(7):764–772
Schetz JA, Perez E, Liu R, Chen S, Lee I, Simpkins JW: A prototypical s-l receptor
antagonist protects against brain ischemia. Brain Res 2007; 1181:1–9
Song C, Lin A, Kenis G, Bosmans E, Maes M: Immunosuppressive effects of
clozapine and haloperidol: enhanced production of the interleukin-1 receptor
antagonist. Schizophr Res 2000; 42(2):157–164
Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, et al: Task
Force of the American College of Critical Care Medicine (ACCM) of the Society
of Critical Care Medicine (SCCM), American Society of Health-System Phar-
macists (ASHP), American College of Chest Physicians. Clinical practice guide-
lines for the sustained use of sedatives and analgesics in the critically ill adult.
Crit Care Med 2002; 30(1):l19–141; Erratum in: Crit Care Med 2002; 30(3):
726
Riker RR, Fraser GL, Cox PM: Continuous infusion of haloperidol controls agitation
in critically ill patients. Crit Care Med 1994; 22(3):433–440
574 Fall 2013, Vol. XI, No. 4 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY
Seneff MG, Mathews RA: Use of haloperidol infusions to control delirium in
critically ill adults. Ann Pharmacother 1995; 29(7/8):690–693
Menza MA, Murray GB, Holmes VF, Rafuls WA: Decreased extrapyramidal symp-
toms with intravenous haloperidol. J Clin Psychiatry 1987; 48(7):278–280
Glassman AH, Bigger JT Jr.: Antipsychotic drugs: Prolonged QTc interval, tor-
sades de pointes, and sudden death. Am J Psychiatry 2001; 158(11):1774–
1782
Lonergan E, Britton AM, Luxenberg J, Wyller T: Antipsychotics for delirium.
Cochrane Database Syst Rev 2007; 2:CD005594. Review
Rea RS, Battistone S, Fong JJ, Devlin JW: Atypical antipsychotics vs. haloperidol
for treatment of delirium in acutely ill patients. Pharmacotherapy 2007; 27(4):
588–594
Han C, Kim Y: A double-blind trial of risperidone and haloperidol for the treatment
of delirium. Psychosomatics 2004; 45(4):297–301
Skrobik YK, Bergeron N, Dumont M, Gottfried SB: Olanzapine vs. haloperidol:
treating delirium in a critical care setting. Intensive Care Med 2004; 30(3):444–
449
Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE,
et al: MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for
intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit
Care Med 2010; 38(2):428–437
Balas MC. Free your MIND and the rest will follow: decoding delirium in the
intensive care unit. Crit Care Med 2010; 38(2):697–698
Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, et al: Efficacy and
safety of quetiapine in critically ill patients with delirium: a prospective, multicen-
ter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med
2010; 38(2):419–427
van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, et al:
Effect of rivastigmine as an adjunct to usual care with haloperidol on duration
of delirium and mortality in critically ill patients: a multicenter, double-blind,
placebo-controlled randomised trial. Lancet 2010; 376(9755):1829–1837
Aantaa R, Jalonen J: Perioperative use of a-2 adrenoceptor agonists and the
cardiac patient. Eur J Anaesthesiol 2006; 23(5):361–372
Huang R, Chen Y, Yu AC, Hertz L: Dexmedetomidine-induced stimulation of
glutamine oxidation in astrocytes: a possible mechanism for its neuroprotective
activity. J Cereb Blood Flow Metab 2000; 20(6):895–898
Gertler R, Brown HC, Mitchell DH, Silvius EN: Dexmedetomidine: a novel sedative-
analgesic agent. Proc (Bayl Univ Med Cent) 2001; 14(1):13–21
Guinter JR, Kristeller JL. Prolonged infusions of dexmedetomidine in critically ill
patients. Am J Health-Syst Pharm 2010; 67:1246–1253
Gerlach AT, Murphy CV, Dasta JF: An updated focused review of dexmedetomidine
in adults. Ann Pharmacother 2009; 43(12):2064–2074
Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al: Effect of
sedation with dexmedetomidine vs. lorazepam on acute brain dysfunction in
mechanically ventilated patients: the MENDS randomized controlled trial. JAMA
2007; 298(22):2644–2653
Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al:
SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam)
Study Group. Dexmedetomidine vs. midazolam for sedation of critically ill
patients: a randomized trial. JAMA 2009; 301(5):489–499
Ruokonen E, Parviainen I, Jakob SM, Nunes S, Kaukonen M, Shepherd ST, et al:
“Dexmedetomidine for Continuous Sedation” Investigators. Dexmedetomidine vs.
propofol/midazolam for long-term sedation during mechanical ventilation. Inten-
sive Care Med 2009; 35(2):282–290
Reade MC, O’Sullivan K, Bates S, Goldsmith D, Ainslie WR, Bellomo R: Dexme-
detomidine vs. haloperidol in delirious, agitated, intubated patients: a randomized
open-label trial. Crit Care 2009; 13(3):R75
Aho M, Lehtinen AM, Erkola O, Kallio A, Korttila K: The effect of intravenously
administered dexmedetomidine on perioperative hemodynamics and isoflurane
requirements in patients undergoing abdominal hysterectomy. Anesthesiology
1991; 74(6):997–1002
Buttermann AE, Reid K, Maze M. Are cholinergic pathways involved in the anes-
thetic response to a-2 agonists. Toxicol Lett 1998; 100/101:17–22
Hsu YW, Cortinez LI, Robertson KM, Keifer JC, Sum-Ping ST, Moretti EW, et al:
Dexmedetomidine pharmacodynamics: part I: crossover comparison of the re-
spiratory effects of dexmedetomidine and remifentanil in healthy volunteers.
Anesthesiology 2004; 101(5):1066–1076
Maldonado JR, Wysong A, van der Starre PJ, Block T, Miller C, Reitz BA: Dexme-
detomidine and the reduction of postoperative delirium after cardiac surgery.
Psychosomatics 2009; 50(3):206–217
Nelson LE, Lu J, Guo T, Saper CB, Franks NP, Maze M. The a-2 adrenoceptor
agonist dexmedetomidine converges on an endogenous sleep-promoting path-
way to exert its sedative effects. Anesthesiology 2003; 98(2):428–436
Weinbroum AA, Ben-Abraham R: Dextromethorphan and dexmedetomidine:
new agents for the control of perioperative pain. Eur J Surg 2001; 167(8):563–
569
Pandharipande P, Shintani A, Peterson J, Pun BT, Wilkinson GR, Dittus RS, et al:
Lorazepam is an independent risk factor for transitioning to delirium in intensive
care unit patients. Anesthesiology 2006; 104(1):21–26

Dasta JF, Kane-Gill SL, Pencina M, Shehabi Y, Bokesch P, Wisemandle W, et al:
A cost minimization analysis of dexmedetomidine compared with midazolam for
long-term sedation in the intensive care unit. Crit Care Med 2010; 38(2):497–503
Prakanrattana U, Prapaitrakool S. Efficacy of risperidone for prevention of post-
operative delirium in cardiac surgery. Anaesth Intensive Care 2007; 35(5):714–
719
Hudetz JA, Patterson KM, Iqbal Z, Ganhi SD, Byrne AJ, Hudetz AG, et al: Ketamine
attenuates delirium after cardiac surgery with cardiopulmonary bypass. J Car-
diothorac Vase Anesth 2009; 23(5):651–657
Gamberini M, Bolliger D, Lurati Buse GA, Burkhart CS, Grapow M, Gagneux A,
et al: Rivastigmine for the prevention of postoperative delirium in elderly patients
undergoing elective cardiac surgery—a randomized controlled trial. Crit Care
Med 2009; 37(5):1762–1768
NOTES
focus.psychiatryonline.org
BELDOWSKI AND TRUTIA
Shehabi Y, Grant P, Wolfenden H, Hammond N, Bass F, Camp bell M, et al:
Prevalence of delirium with dexmedetomidine compared with morphine based
therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine
COmpared to Morphine-DEXCOM Study). Anesthesiology 2009; 111(5):1075–
1084
Rubino AS, Onorati F, Caroleo S, Galato E, Nucera S, Amantea B, et al: Impact of
clonidine administration on delirium and related respiratory weaning after surgi-
cal correction of acute type-A aortic dissection: results of a pilot study. Interact
Cardiovasc Thorac Surg 2010; 10(l):58–62
Pandharipande P, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK,
et al, MENDS investigators: Effect of dexmedetomidine vs. lorazepam on outcome
in patients with sepsis: an a priori-designed analysis of the MENDS randomized
controlled trial. Crit Care 2010; 14(2):R38
PUBLICATIONS
INFLUENTIAL
FOCUS Fall 2013, Vol. XI, No. 4 575