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Free your MIND and the rest will follow: decoding delirium in the intensive care unit.

Delirium is a major burden in the intensive care unit (ICU). Delirium is a seemingly ubiquitous syndrome affecting 22% to 87% of all ICU patients (1, 2). The syndrome is associated with multiple untoward patient outcomes, including longer ICU and hospital length of stay (1, 3–6), higher ICU and hospital costs (7), higher inpatient and 6-month mortality (1, 4), abnormalities on mental status examination at hospital discharge (2, 5, 8, 9), self-extubation (10), decreased functional ability at hospital discharge (11), increased likelihood of new institutionalization (11), and less ventilator-free days (12). The signs and symptoms of delirium fluctuate and are extraordinarily distressing for the individual and their family. Behaviors exhibited by delirious patients, particularly those displaying the hyperactive form, put themselves and healthcare providers at risk for injury. Typical and atypical antipsychotic medications are often used in the ICU in an attempt to manage these symptoms. Until recently, few ICU studies have evaluated the efficacy and safety of these medications in the treatment of delirium. In this issue of Critical Care Medicine, Dr. Girard et al (13) report the results of a multicentered, prospective, randomized, double-blind, placebo-controlled trial designed to demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the ICU. They hypothesized that both haloperidol and ziprasidone would be efficacious and safe for the treatment of ICU delirium. Importantly, this is one of the first studies of its kind conducted in the ICU setting. The investigators report neither haloperidol nor ziprasidone significantly increased the number of days patients were alive without delirium or coma, compared with placebo, and the duration of both delirium and coma were similar among treatment groups. The daily delirium risk was also not significantly different between those patients treated with haloperidol or ziprasidone when compared with placebo. Duration of ICU and hospital stay, time spent alive and breathing without assistance, and mortality during study period were similarly unaffected by antipsychotic treatment. Although no subjects experienced a serious adverse event during the trial, 29% of haloperidol group, 20% of ziprasidone group, and 19% of placebo group experienced symptoms consistent with akathisia, and 10 subjects had prolongation of the QT corrected interval 500 msec. The authors of this study, leaders in the field of ICU delirium research, should be commended for their ground-breaking work. This well-written article presents useful data for critical care investigators and clinicians and addresses an important and timely topic. The investigation incorporates exquisite attention to appropriately defining efficacy end points, screens for pre-existing cognitive impairment with two separate tools, utilizes appropriate and advanced statistical modeling, and reflects the persistence, energy, and creativity that are needed in conducting delirium research. Several study limitations warrant comment. First, it is important to note that it took this experienced research team 2 yrs to enroll 103 subjects from six different sites. The study had 10 exclusion criteria, many of which were presumably developed to project subjects who may be at particular risk if treated with antipsychotics (dementia, at high risk for ventricular dysrhythmias, etc). The decision to permit open-label antipsychotic use, particularly in the placebo arm, may have served to “dilute out” any potential benefit of the antipsychotics. As the investigators acknowledge, the study’s small sample size, lack of standardized sedation protocol, multiple analyses performed, and restrictive inclusion/exclusion criteria may hinder the ability to reliably detect differences in efficacy and safety outcomes and limits the generalizability of their findings. The finding of the absence of any clear benefit from antipsychotic medication administration in the treatment of ICU delirium is sure to cause controversy. It affords us, however, the opportunity to re-conceptualize the way we deliver care to our most vulnerable patients. Crucial to this discussion is reiteration of the Diagnostic and Statistical Manual of Mental Disorders, Fouth Edition (14) definition of delirium. The Diagnostic and Statistical Manual of Mental Disorders, Fouth Edition describes delirium not as a disease but rather as a clinical syndrome (set of symptoms) that results from an underlying medical condition, is substance-induced, and is caused by multiple etiologies or by conditions not otherwise specified. The cornerstone of treatment of delirium is recognition, and removal or reversal, of the underlying cause of the disorder. A common and potentially dangerous error some ICU clinicians and investigators make is accepting the belief that if we treat some of the behaviors manifested by delirious patients with typical or atypical antipsychotics, we are actually treating their delirium. This is not the case. Again, the gold standard of delirium treatment is recognition and removal of the underlying cause of the disorder. As this study illustrates, it is possible that treating ICU delirium with antipsychotic medications will have little to no effect on the actual course of delirium. This finding is also consistent with those from the Clinical Antipsychotic Trials in Intervention Effectiveness—Alzheimer’s disease (CATIE-AD) trial (15), which suggests that there is no clinical benefit of treatment with atypical antipsychotic drugs in patients with Alzheimer’s disease. *See also p. 428.