Drugs Ther Perspect (2013) 29:4044

DOI 10.1007/s40267-012-0004-x

DISEASE MANAGEMENT

Manage delirium in critically ill patients through prevention,

early diagnosis and treatment
Adis Medical Writers

Published online: 20 December 2012

 Springer International Publishing Switzerland 2012

Abstract Delirium is common in critically ill patients in Many potential causes

the intensive care unit (ICU). Management of ICU delirium
involves prevention and treatment with nonpharmacological The cause of delirium is multifactorial and may include
and pharmacological interventions. Intravenous haloperidol one or more of the following [1]:
is the recommended treatment for delirium and may also be
imbalances in neurotransmitter systems in the brain
considered for prophylaxis. The use of sedative and anal-
(e.g. reduced acetylcholine activity);
gesic agents that may cause delirium should be avoided.
brain lesions (e.g. in the basal ganglia, prefrontal
cortex, thalamus and hippocampus);
sepsis-induced inflammation leading to neuroinflam-
Delirium is common in the intensive care setting
mation;
aberrant stress response (e.g. stress-induced stimulation
Delirium develops over a short period of time and is char-
of brain adrenocortical function resulting in corticoste-
acterized by fluctuating disturbances of consciousness and
roids crossing the bloodbrain barrier);
changes in cognition, especially attention [1]. It is com-
changes in GABA and NMDA receptor activity
monly seen in critically ill patients in the intensive care unit
following alcohol withdrawal;
(ICU) setting, but estimates of the incidence of delirium in
patient-related predisposing factors and precipitating
these patients varies widely (1689 %), presumably because
factors (see Table 1).
of differences in study methodology [1]. The occurrence of
delirium in the ICU is expected to rise in coming years
Associated with a worse prognosis?
because of the aging population. In ICU patients, the median
duration of delirium is 3 days (range 144 days) [13].
Although several studies have found that ICU delirium is
Currently, delirium is considered a disease that varies in
associated with longer ICU and hospital stays, higher ICU/
severity [1]. The following clinical subtypes based on psycho-
hospital costs, worse cognitive outcomes, and higher hos-
motor features have been proposed, but are not yet validated:
pital and 6-month mortality rates, study design may have
hyperactive delirium (restlessness/agitation), hypoactive
resulted in confounding of results [1]. Therefore, it is
delirium (apathy, slow/lack of movement), and mixed delir-
uncertain whether there is a true association between
ium (alternates between hyper- and hypoactive delirium) [1].
delirium in the ICU and poor prognosis. Nevertheless, early
This article provides a summary of the management of
detection and treatment of delirium is recommended, with
delirium in critically ill patients, as reviewed by Zaal and
the aim being to improve prognosis [1].
Slooter [1].

Screening for delirium recommended

Adis Medical Writers (&)
41 Centorian Drive, Private Bag 65901, Mairangi Bay,
North Shore 0754, Auckland, New Zealand Tools for routine screening of delirium in the ICU have
e-mail: DTP@adis.com been developed because, without the use of such tools,
(2013) 29:4044 41

Table 1 Patient-related risk factors for delirium [1]

patients, interventions that prevented immobility (via
exercise and mobilization protocols), minimized ambient
Predisposing factors Precipitating factors
noise (e.g. single-room rather than multi-ward ICUs, or
Advanced agea Acute illness, infection or sepsis
providing patients with ear plugs for sleeping) and/or
Pre-existing cognitive Medications (e.g. dopaminergic
increased daylight exposure were associated with reduc-
impairment/dementiaa drugs, anticholinergic drugs,
benzodiazepines) tions in the incidence of and/or duration of delirium [1].
Impaired vision/hearing Sleep deprivation
Alcohol abuse Metabolic disturbances
Prophylactic antipsychotics effective
Immobilization
Prophylactic pharmacotherapy with antipsychotics may be
Environmental factors
a
given to all ICU patients or only those at higher risk of
One of the most important factors in the intensive care setting
delirium [1]. Antipsychotic prophylaxis with risperidone
[8] or low-dose haloperidol [9] effectively reduced the
delirium diagnosis is often missed (up to 75 % of cases are
incidence of postoperative delirium in double-blind, pla-
not diagnosed) [4]. Delirium is challenging to diagnose in
cebo-controlled studies in ICU patients who had undergone
this patient population, as patients may have difficulty
elective surgical procedures (Table 2). It is not yet clear
communicating because of endotracheal intubation or the
whether these results are generalizable to nonsurgical ICU
effects of sedatives. The following are the two most
patients [1].
commonly used and best-validated ICU screening tools [1]:
Although intravenous ketamine (an NMDA-receptor
Intensive Care Delirium Screening Checklist (ICDSC) antagonist) also lowered the incidence of postoperative
[5]. Provides a graded outcome (no delirium, subsyn- delirium in ICU patients (Table 2) [10], it may cause hal-
dromal delirium or delirium). lucinations and other psychological manifestations [11].
Confusion Assessment Methods adapted for use in the Rivastigmine, an acetylcholinesterase inhibitor, was not
ICU (CAM-ICU) [6]. Provides a binary outcome effective in reducing the incidence or duration of delirium
(delirium or no delirium). in elderly patients undergoing elective cardiac surgery
(Table 2) [12].
It is important to identify patients at high risk of delir-
ium within the first 24 h of ICU admission, in order that
preventative treatment may be considered [1].
Sedate sensibly and treat pain

Anticholinergic drugs and GABA agonists (such as ben-

Prevention possibly successful
Prevention of delirium in ICU patients can be achieved
through both nonpharmacological and pharmacological
means [1]. A broad integrated patient management protocol
that provides systematic management of pain, sedation,
delirium, physical therapy and breathing therapy could
improve clinical outcomes (e.g. the duration of mechanical
ventilation and length of ICU stay) in ICU patients [1].
Although the implementation of such an approach in an
ICU did not reduce the incidence of delirium in a pro-
spective cohort study in a total of 1214 patients, it did
lower the subsyndromal delirium rate and mortality rate,
and shortened the ICU stay relative to prior to implemen-
tation of the protocol [7].
Reduce precipitating factors
ICU patients are exposed to many factors that can precip-
itate delirium, such as the presence of health personnel
throughout the day and night, and continuous exposure to
noise and light [1]. In the few available studies in ICU
zodiazepines) increase the risk of delirium (Table 1).
More than 600 medications have anticholinergic effects
[11]. The use of these drugs in ICU patients should be
avoided [1].
Dexmedetomidine, a potent a2-adrenergic receptor
agonist, is a suitable alternative sedative [11]. Although it
is more expensive than commonly used sedatives, use of
dexmedetomidine achieves sedation and reduces the
delirium burden. In randomized, controlled trials, the
duration of delirium with dexmedetomidine was shorter
than that with lorazepam in mechanically ventilated ICU
patients [13], midazolam in critically ill patients [14] and
morphine in patients in the ICU after cardiac surgery [15].
The presence of pain is associated with delirium, so pain
treatment may reduce the risk of delirium [1]. Whether
opioid pain treatment should or should not be used in ICU
patients is not clear, because there is conflicting evidence
regarding the potential for opioids themselves to cause
delirium. Dexmedetomidine can be considered instead of
opioids; dexmedetomidine and morphine provided equiv-
alent analgesia and sedation in a randomized, double-blind
trial [15].
42
Table 2 Summary of the results of randomized, controlled trials of antipsychotics and other agents for prevention of postoperative delirium in
patients in the intensive care setting
Regimen (no. of patients)
Single dose of oral risperidone 1 mg vs. placebo (126) [8]
Intravenous low-dose haloperidol (0.5 mg bolus then 0.1 mg/h
infusion for 12 h) vs. placebo (457) [9]
Intravenous ketamine 0.5 mg/kg bolus vs. placebo (58) [10]
Oral rivastigmine 1.5 mg every 8 h vs. placebo (113) [12]
Variety of options to treat delirium
Once the underlying condition is diagnosed and treated,
delirium can be managed through nonpharmacological
means (e.g. mobilization, minimization of noise, and
exposure to daylight) and/or pharmacological means [1].
Clinical evidence for the use of pharmacotherapy in the
treatment of delirium in ICU patients from four random-
ized, controlled trials [1619] is summarized in Table 3.
Pharmacological treatment is usually administered to
patients with hyperactive delirium episodes [1]. When
extreme agitation is present during such an episode, seda-
tives may be required to avoid patient harm from com-
monly used ICU devices (e.g., central venous lines,
endotracheal tubes and catheters). However, use of a sed-
ative or an agent with sedative effects is to be avoided in
those who have hypoactive delirium [20].
Haloperidol remains the first choice
Haloperidol is commonly used for the treatment of delir-
ium in ICU patients [1]. It can be administered via several
routes (i.e. orally, intramuscularly or intravenously), with
the intravenous route often being preferred in ICU patients,
since their enteral absorption may be impaired [1]. For this
reason, haloperidol remains the first choice of antipsy-
chotic, because although there is some evidence of efficacy
with second-generation antipsychotics, they are not avail-
able in an intravenous formulation. At the low recom-
mended dose of haloperidol (Table 4), the risk of adverse
(2013) 29:4044
Key results and comments
Incidence of delirium was lower with risperidone than with placebo (11
% vs. 32 %; p = 0.009)
Incidence of delirium was lower with haloperidol than with placebo (15
% vs. 23 %; p = 0.031)
Time to onset of delirium was longer with haloperidol than with placebo
(6.2 vs. 5.7 days; p = 0.021)
Mean number of delirium-free days was greater with haloperidol than
with placebo (6.8 vs. 6.7 days; p = 0.027)
Administered during anaesthetic induction in the presence of fentanyl
and etomidate
Incidence of postoperative delirium was lower with ketamine than with
placebo (3.4 % vs. 31 %; p = 0.01)
Treatment was administered from the evening before surgery to the sixth
postoperative day
Incidence and duration of postoperative delirium were similar in both
treatment groups
effects, such as neuroleptic malignant syndrome, tardive
dyskinesia and torsade de pointes, is probably low. Halo-
peridol should not be used in patients with Parkinsons
disease or Lewy body disease, because of the drugs
extrapyramidal adverse effects [1].
Newer antipsychotics are also useful
There is generally positive, albeit limited, evidence for use
of second-generation antipsychotics in ICU patients with
delirium (Table 3) [17, 18]. Table 4 shows suggested
dosages of second-generation antipsychotics for treatment
of ICU delirium. Second-generation antipsychotics are
expected to be better tolerated than first-generation anti-
psychotics, because of differences in their pharmacological
action. However, newer agents may still cause extrapyra-
midal and cardiac adverse effects, albeit less frequently
than haloperidol [1]. There is, therefore, no clinical evi-
dence to recommend one class of antipsychotic over
another, but haloperidol has the advantage of being able to
be administered intravenously.
Other agents of no or unproven benefit
The conclusions from several studies in ICU and non-ICU
patients with delirium suggest that cholinesterase inhibi-
tors, such as rivastigmine, are not effective in the treatment
of delirium [1]. In a study comparing rivastigmine with
placebo as adjunctive treatment to haloperidol, treatment
(2013) 29:4044
Table 3 Summary of the results of randomized, controlled trials of antipsychotics and other agents in the treatment of delirium in patients in
the intensive care setting
Regimen (no. of patients)
Oral haloperidol 2.55 mg every 8 h vs. oral olanzapine
5 mg once daily (73) [16]
Oral haloperidol 5 mg every 6 h vs. oral ziprasidone 40 mg
every 6 h vs. placebo for up to 14 days (101) [17]
Oral quetiapine 50200 mg every 12 h vs. placebo (36) [18]
Oral rivastigmine 1.56 mg every 12 h vs. placebo (104) [19]
Table 4 Recommended dosages of antipsychotics in the treatment
of delirium in the intensive care setting [1]
Drug (route) Recommended dosage
Haloperidol Usual: 12.5 mg every 812 h
(intravenous)
In the elderly: 0.51 mg every 812 h
Olanzapine (oral) Usual: 5 mg titrated
In the elderly: 2.5 mg titrated
Quetiapine (oral) 2550 mg at night, titrated to a maximum of
200 mg every 12 h
Ziprasidone (oral) 40 mg every 6 h
was stopped early because of increased mortality in the
rivastigmine treatment arm (Table 3) [19].
Evidence for treating patients with delirium with dex-
medetomidine, methylphenidate or exogenous melatonin is
limited to very small studies or case reports (B20 patients),
and not all studies were specifically in ICU patients [1].
Further research is required on the role of these agents in
the treatment of delirium in the ICU.
43
Key results and comments
Reductions in the severity of delirium symptoms were similar in both
treatment groups
Olanzapine was better tolerated than haloperidol
Extrapyramidal symptoms were not reported with olanzapine, but were
reported in 13% of haloperidol recipients
All patients were mechanically ventilated
Median no. of days alive without delirium or coma did not differ between
haloperidol, ziprasidone and placebo (14.0 vs. 15.0 vs. 12.5 days)
The lack of a significant treatment effect was attributed to the small sample
size and lack of a standardized sedation protocol
No significant between-group differences in the frequency of extrapyramidal
symptoms were shown
Time to first resolution of delirium was shorter with quetiapine than with
placebo (1.0 vs. 4.5 days; p = 0.001)
Delirium duration was shorter with quetiapine than with placebo (36 vs.
120 h; p = 0.006)
Agitation duration was shorter with quetiapine than with placebo (6 vs. 36 h;
p = 0.02)
Number of days that patients used as-needed haloperidol was shorter with
quetiapine than with placebo (3 vs. 4 days; p = 0.05)
No significant between-group differences in the incidence of corrected QT
interval prolongation and extrapyramidal symptoms
Treatment was given as an adjunct to usual care with haloperidol
The trial was stopped early as the addition of rivastigmine was associated with
higher mortality rates than the addition of placebo (22 % vs. 8 %; p = 0.07)
The median duration of delirium did not differ significantly between the
rivastigmine and placebo groups (5.0 vs. 3.0 days)
Lorazepam for alcohol withdrawal
Benzodiazepines are the first choice of treatment for
alcohol withdrawal delirium [1]. Lorazepam is an attractive
agent as it may be administered intravenously (e.g. 24 mg
as needed every 14 h) [20]. Propofol may be used instead
of benzodiazepines, but patients should be monitored for
adverse effects, such as hypotension [8].
Patients treated for alcohol withdrawal delirium may
require additional therapy in the following clinical cir-
cumstances [1]:
b-adrenoceptor agonists or a-agonists for autonomic
hyperactivity;
haloperidol for psychosis;
thiamine for patients who have Wernickes encepha-
lopathy or who are malnourished.
Disclosure This article was adapted from Drugs 2012;72(11):
145771 [1] by Adis editors and medical writers. The preparation of
these articles was not supported by any external funding.
44
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