Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: The MIND randomized, placebo-controlled trial

Delirium is an acute disorder of consciousness and cognition that occurs in 60% to 80% of mechanically ventilated intensive care unit (ICU) patients (1–3). Among these patients, this manifestation of acute brain dysfunction conveys profound risk for morbidity and mortality, as it is associated with self-extubation (4), prolonged hospital stays (5, 6), and increased mortality (1, 6, 7). It is estimated, in addition, that ICU delirium is associated with health care costs ranging between $6 to $20 billion annually in the United States alone (8). Despite its numerous deleterious effects, no placebo-controlled clinical trials exist to support the use of pharmacologic agents solely intended to treat delirium in the ICU. In fact, the majority of delirious patients receive no specific treatment for this neuropsychiatric syndrome, in large part because it frequently remains unrecognized in clinical practice (9, 10). When diagnosed, delirium should first prompt the identification and management of potential underlying causes. Then, to prevent harmful sequelae, the Society of Critical Care Medicine (SCCM) has recommended the use of haloperidol for the treatment of delirium in critically ill patients (11), despite its unproven efficacy and the absence of Food and Drug Administration (FDA) approval for this indication. In keeping with this recommendation, haloperidol is currently the medication most widely used to treat ICU delirium (12). In recent years, however, newer “atypical” antipsychotics (e.g., risperidone, olanzapine, quetiapine, and ziprasidone) have also gained popularity (13), though only olanzapine has been studied in the ICU (14). Given the lack of compelling evidence supporting the use of antipsychotics for delirium in critically ill patients and the potential adverse effects associated with these medications, including torsades de pointes and sudden cardiac death (15, 16), hypotension (17), neuroleptic malignant syndrome (18), and extrapyramidal symptoms (19), placebo-controlled clinical trials are greatly needed to evaluate the efficacy of antipsychotic medications in reducing the burden of delirium in the ICU. Thus, to demonstrate the feasibility of a randomized, placebo-controlled trial of antipsychotics in mechanically ventilated ICU patients, we conducted the Modifying the INcidence of Delirium (MIND) Trial, a multicenter, randomized, double-blind, placebo-controlled trial. We hypothesized that both haloperidol and ziprasidone would be efficacious and safe for the treatment of ICU delirium. This work has been presented in abstract form (20).