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762 PART 6: Neurologic Disorders

generalizable to the ICU setting; further investigation of strategies for the symptoms of delirium (eg, hallucinations, unstructured thought patterns,
prevention and management of ICU delirium is needed. Nevertheless, in etc). Haloperidol can also have a sedative effect, though this is variable and,
the ICU, where risk factors for delirium are nearly ubiquitous, manage- unlike most sedative agents, does not result in respiratory suppression. In
ment and minimization of known risk factors should take precedent. the non-ICU setting, the recommended starting dose of haloperidol
Risk-factor management strategies may be easily implemented in the is 0.5 to 1.0 mg orally or parenterally, with doses repeated every 20 to
ICU by frequently reorienting patients, removing restraints and catheters 30 minutes until the desired effect, which is usually resolution of agita-
as quickly as possible, minimizing sleep interruptions and noise during tion rather than complete resolution of delirium. In the ICU, alternatively,
nighttime hours, implementing early mobilization protocols, and ensur- higher doses are often recommended, eg, 2 to 5 mg intravenously with
ing vision and hearing assist devices (eg, eyeglasses and hearing aides) doses repeated every 20 to 30 minutes until the desired effect. Some prac-
are present. 44,93,95 titioners use scheduled haloperidol every 6 to 12 hours (intravenously or
Whereas most prevention strategies have focused on the use of orally). No strong data exist indicating the ideal dose, but maximal effec-
nonpharmacologic methods in non-ICU populations, a notable excep- tive doses are believed to be approximately 20 mg/d based upon data that
tion has been studies of the α -agonist dexmedetomidine as a sedative this dose is usually adequate to achieve the “theoretically optimal” 60% to
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for mechanically ventilated ICU patients. Two randomized trials have 80% D receptor blockade while avoiding the complete D receptor satu-
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compared the use of this novel sedative with benzodiazepine sedatives, ration associated with the adverse effects described belo 101,102 Because
https://kat.cr/user/tahir99/w.
finding lower rates of delirium among patients sedated with dexme- extreme agitation in the ICU is an urgent problem, due to the potential for
detomidine. The MENDS (maximizing the efficacy of targeted sedation inadvertent removal of catheters, endotracheal tubes, and other devices,
and reducing neurologic dysfunction) trial randomized 106 patients to much larger doses of haloperidol are sometimes used, but this approach
sedation with either dexmedetomidine or lorazepam. Patients who were is based upon anecdotal experience and expert opinion and should be
sedated with dexmedetomidine had a median of 4 more days alive with- considered unproven until more data are available.
out delirium or coma than those sedated with lorazepam (7 vs 3 days). Neither haloperidol nor similar agents (eg, droperidol and chlor-
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A second trial, the SEDCOM (safety and efficacy of dexmedetomidine promazine) have been extensively studied in the ICU. In fact, the only
compared with midazolam) study randomized 375 patients in a 2 : 1 placebo-controlled trial examining the effect of haloperidol on ICU
fashion to sedation with dexmedetomidine or midazolam. Patients delirium found no significant improvement with this agent. This pilot
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receiving dexmedetomidine demonstrated a 23% absolute reduction study was small, however, and cannot be taken to rule out a beneficial
in delirium prevalence compared with the midazolam group (delirium effect of haloperidol in delirium.
prevalence 54% in dexmedetomidine group vs 76.6% in midazolam Some observational studies of the use of antipsychotics in non-ICU
group). Taken together, these studies provide evidence that choice of patients with delirium have reported improvements in delirium in
sedation agent may be associated with a reduction in ICU delirium. patients treated with antipsychotics. Nevertheless, these conclusions are
Nevertheless, it remains unclear whether the reduction in ICU delirium not supported by randomized controlled trials, therefore it is unknown
is due to treatment with dexmedetomidine or simply due to the avoid- if this association is due to the natural history of the disease, treatment
ance of benzodiazepines. of underlying medical conditions or antipsychotics themselves. 103,104
In addition to using antipsychotics to treat delirium once present, one
DELIRIUM TREATMENT study explored the use of antipsychotic prophylaxis in elderly hip frac-
ture patients at risk of developing postoperative delirium. Low-dose
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When delirium is diagnosed, potential underlying causes should be haloperidol did not reduce the incidence of delirium compared with
sought immediately, and treatment of suspected causes should be under- placebo, but the duration of delirium was shorter in the haloperidol
taken. Then, if the patient remains delirious and to prevent the harmful group. These data suggest a potential role for antipsychotics in the treat-
sequelae of persistent delirium, current guidelines recommend treat- ment of delirium, but further studies are needed.
ment with pharmacologic agents. To date, there have been only small, In addition to haloperidol, “atypical” antipsychotic agents (eg, ris-
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preliminary trials examining pharmacologic treatments for delirium in peridone, ziprasidone, quetiapine, and olanzapine) are also used to treat
the ICU. 96-98 Without large, well-designed, adequately powered, placebo- delirium in the ICU. 96-98 The rationale behind the use of atypical anti-
controlled, randomized trials to guide drug use for the prevention or psychotics over haloperidol (especially in hypoactive/mixed subtypes of
treatment of delirium in critically ill patients, evidence must be extrapo- delirium) is theoretical and arises from the atypical antipsychotics’ effect
lated from studies of non-ICU populations. not only on dopamine but also on other potentially key neurotransmit-
Benzodiazepines are used commonly in the ICU for both sedation ters, such as serotonin, acetylcholine, and norepinephrine. Results
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and the treatment of delirium, but this class of drugs is not recom- of prospective studies comparing atypical antipsychotics with placebo
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mended for the management of delirium because of the likelihood of and/or typical antipsychotics in the treatment of delirium have been
oversedation, exacerbation of delirium, and other adverse effects (eg, mixed. 96-98 Though one very small randomized trial found quetiapine
respiratory suppression). As mentioned in the section on risk factors, was effective in treating delirium compared with placebo, another
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benzodiazepines actually increase the likelihood of developing delirium small randomized trial found no differences in neurologic outcomes
for most patients. 13,17,39 Benzodiazepines, however, remain the drugs of among patients treated with ziprasidone, haloperidol, or placebo. In
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choice for the treatment of delirium tremens (and other withdrawal aggregate, these trials do not provide strong evidence for use of atypical
syndromes) and seizures. antipsychotics over typical antipsychotics.
Though a number of medications are frequently used to treat delirium Adverse effects of both typical and atypical antipsychotics include
in the ICU, there are currently no drugs approved by the U.S. Food hypotension, acute dystonia, extrapyramidal effects, thrombotic compli-
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and Drug Administration for this indication. Expert guidelines from cations, oversedation, laryngeal spasm, neuroleptic malignant syndrome,
the Society of Critical Care Medicine, the American Psychiatric glucose and lipid dysregulation, and anticholinergic effects, such as dry
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Association, and other authoritative bodies recommend haloperidol as mouth, constipation, and urinary retention. One of the most imme-
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the drug of choice for the treatment of delirium, but it is acknowledged diately life-threatening adverse effects of antipsychotics is torsades de
that these recommendations are based on sparse data from nonrandom- pointes, 107-109 so these agents should be given to patients with prolonged
ized case series and anecdotal reports. QTc intervals only with extreme caution. Outpatients treated with either
Haloperidol, a butyrophenone, “typical” antipsychotic, is the most widely typical or atypical antipsychotics for schizophrenia are at an increased
used neuroleptic agent for delirium. 66,100 It works primarily as a dopamine risk of sudden cardiac death, 107,109 with this risk increasing as either dose
receptor antagonist by blocking the D receptor, which is believed to or duration of antipsychotic therapy increases. 107,109 It remains unclear
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treat—borrowing terminology from the schizophrenia literature—positive whether similar risk affects critically ill patients, who typically receive

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