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

OBJECTIVE: 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. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Six tertiary care medical centers in the US. PATIENTS: One hundred one mechanically ventilated medical and surgical intensive care unit patients. INTERVENTION: 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. MEASUREMENTS AND MAIN OUTCOMES: The primary end point was the number of days patients were alive without delirium or coma. During the 21-day study period, patients in the haloperidol group spent a similar number days alive without delirium or coma (median [interquartile 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 extrapyramidal symptoms was similar between treatment groups (p = .46). CONCLUSIONS: 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.

A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults.

INTRODUCTION: Hospitalized patients are often unable to ingest or tolerate oral antipyretics and recently an aqueous formulation of intravenous (IV) ibuprofen was approved by the US-FDA for the reduction of fever in adults. METHODS: We evaluated IV ibuprofen to reduce fever exceeding 101.0 degrees F, measured as the percentage of subjects achieving a temperature <101.0 degrees F at four hours after a single dose of IV ibuprofen vs. placebo. Secondary evaluations included the effect on temperature at 24 hours. Nine sites randomized patients to receive either a placebo or IV ibuprofen (100, 200, or 400 mg), and patients were given four hours for six doses. Subjects were excluded for platelet count <30 k and/or creatinine >3.0 mg/dL. RESULTS: At entry, there were no significant baseline differences between the IV ibuprofen group and placebo, n = 120. At four hours, the number (percentage) with T<101.0 degrees F was: Placebo n = 9/28 (32%); 100 mg IV ibuprofen n = 19/31 (61%), P = 0.0264; 200 mg IV ibuprofen n = 21/30 (70%) P = 0.0043; 400 mg IV ibuprofen n = 24/31 (77%) P = 0.0005. A total of 53/120 patients (44%) were prospectively defined as critically ill at baseline and similar temperature reductions were observed in this subgroup. There were no statistically significant differences between treatment groups or when compared to placebo in transfusion, bleeding, renal failure or mortality. CONCLUSIONS: All doses of IV ibuprofen tested reduced fever at four hours and throughout the first 24 hours of dosing. The 400 mg dose was effective in lowering temperature to normal and maintaining this over the first 24 hours of dosing. IV ibuprofen was effective in reducing fevers in critically ill and non-critically ill groups. Following 24 hours of administration of IV ibuprofen, no clinically significant differences in any safety parameter including renal function or bleeding occurred through the 28-day follow-up period. TRIAL REGISTRATIONS: Clinicaltrials.gov registration number: NCT01131000.