- Journal club critique
- Open Access
Clearing up the confusion: The results of two pilot studies of antipsychotics for ICU delirium
© BioMed Central Ltd 2010
- Published: 11 August 2010
Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, Pun BT, Thompson JL, ShintaniAK, Meltzer HY, Bernard GR, Ditt us RS, Ely EW: Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med 2010, 38:428-437 .
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, placebo-controlled clinical trials are greatly needed.
To demonstrate the feasibility of a placebo-controlled trial of antipsychotics for delirium in the intensive care unit and to test the hypothesis that antipsychotics would improve days alive without delirium or coma.
Randomized, double-blind, placebo-controlled trial.
Six tertiary care medical centers in the US.
One hundred one mechanically ventilated medical and surgical intensive care unit patients.
Patients were randomly assigned to receive haloperidol or ziprasidone or placebo every 6 hrs for up to 14 days. Twice each day, frequency of study drug administration was adjusted according to delirium status, level of sedation, and side effects.
The primary end point was the number of days patients were alive without delirium or coma. Secondary efficacy end points included daily delirium risk, duration of delirium, duration of coma, the number of days patients were alive and breathing without assistance during the 21-day study period (ventilator-free days), time to ICU and hospital discharge, and all-cause 21-day survival.
During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [inter quartile range], 14.0 [6.0-18.0] days) as did patients in the ziprasidone (15.0 [9.1-18.0] days) and placebo groups (12.5 [1.2-17.2] days; p = 0.66). No differences were found in secondary clinical outcomes, including ventilator-free days (p = .25), hospital length of stay (p = .68), and mortality (p = .81). Ten (29%) patients in the haloperidol group reported symptoms consistent with akathisia, compared with six (20%) patients in the ziprasidone group and seven (19%) patients in the placebo group (p = .60), and a global measure of extra pyramidal symptoms was similar between treatment groups (p = .46).
A randomized, placebo-controlled trial of antipsychotics for delirium in mechanically ventilated intensive care unit patients is feasible. Treatment with antipsychotics in this limited pilot trial did not improve the number of days alive without delirium or coma, nor did it increase adverse outcomes. Thus, a large trial is needed to determine whether use of antipsychotics for intensive care unit delirium is appropriate.
Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, Robbins T, Garpestad E: Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multi center, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 2010, 38:419-427 .
To date, there are no published double-blind, randomized, placebo-controlled trials to establish the efficacy or safety of any antipsychotic medication in the management of delirium in the ICU.
To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol.
Prospective, randomized, double-blind, placebo-controlled study.
Three academic medical centers in the US and Canada.
Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score > = 4), tolerating enteral nutrition, and without a complicating neurologic condition.
Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 m gevery 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy > = 10 days, or intensive care unit discharge.
The primary end point was time to first resolution of delirium. Secondary outcomes included duration of mechanical ventilation, ICU and hospital length of stay, hospital mortality, and discharge disposition. Measures of safety included total number of adverse and serious adverse events related to study drug, incidence of extra pyramidal symptoms, and episodes of QTc interval prolongation.
Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (inter quartile range [IQR], 0.5-3.0) vs. 4.5 days (IQR, 2.0-7.0; p = .001)], a reduced duration of delirium [36 (IQR, 12-87) vs. 120 hrs (IQR, 60-195; p = .006)], and less agitation (Sedation-Agitation Scale score > = 5) [6 (IQR, 0-38) vs. 36 hrs (IQR, 11-66; p = .02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p = .06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2-4)] vs. 4 days (IQR, 3-8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66).
Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.
Taken together, the result of these pilot studies highlight the need for much larger, multicenter, placebo-controlled trials to determine whether continued use of antipsychotics in the ICU is warranted. Though screening for delirium using a validated instrument and treating with haloperidol remain recommended by national guidelines, clinicians should routinely monitor for adverse events, especially QTc prolongation.
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