Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial.
BACKGROUND
Delirium is frequently diagnosed in critically ill patients and is associated with poor clinical outcomes. Haloperidol is the most commonly used drug for delirium despite little evidence of its effectiveness. The aim of this study was to establish whether early treatment with haloperidol would decrease the time that survivors of critical illness spent in delirium or coma.


METHODS
We did this double-blind, placebo-controlled randomised trial in a general adult intensive care unit (ICU). Critically ill patients (≥18 years) needing mechanical ventilation within 72 h of admission were enrolled. Patients were randomised (by an independent nurse, in 1:1 ratio, with permuted block size of four and six, using a centralised, secure web-based randomisation service) to receive haloperidol 2.5 mg or 0.9% saline placebo intravenously every 8 h, irrespective of coma or delirium status. Study drug was discontinued on ICU discharge, once delirium-free and coma-free for 2 consecutive days, or after a maximum of 14 days of treatment, whichever came first. Delirium was assessed using the confusion assessment method for the ICU (CAM-ICU). The primary outcome was delirium-free and coma-free days, defined as the number of days in the first 14 days after randomisation during which the patient was alive without delirium and not in coma from any cause. Patients who died within the 14 day study period were recorded as having 0 days free of delirium and coma. ICU clinical and research staff and patients were masked to treatment throughout the study. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Registry, number ISRCTN83567338.


RESULTS
142 patients were randomised, 141 were included in the final analysis (71 haloperidol, 70 placebo). Patients in the haloperidol group spent about the same number of days alive, without delirium, and without coma as did patients in the placebo group (median 5 days [IQR 0-10] vs 6 days [0-11] days; p=0.53). The most common adverse events were oversedation (11 patients in the haloperidol group vs six in the placebo group) and QTc prolongation (seven patients in the haloperidol group vs six in the placebo group). No patient had a serious adverse event related to the study drug.


CONCLUSIONS
These results do not support the hypothesis that haloperidol modifies duration of delirium in critically ill patients. Although haloperidol can be used safely in this population of patients, pending the results of trials in progress, the use of intravenous haloperidol should be reserved for short-term management of acute agitation.


BACKGROUND
National Institute for Health Research.
Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, UK; Faculty of Medicine, Imperial College, London, UK. Electronic address: valerie.page@whht.nhs.uk.
Valerie J
VJ
Page
Vanderbilt University Medical Center, Pulmonary and Critical Care, Nashville, TN, USA; Tennessee Valley VA Geriatric Research Education Clinical Center, Nashville, TN, USA.
E Wesley
EW
Ely
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
Simon
S
Gates
Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, UK.
Xiao Bei
XB
Zhao
Intensive Care Unit, Watford General Hospital, West Hertfordshire Hospitals NHS Trust, Watford, UK.
Timothy
T
Alce
Vanderbilt University Medical Center, Pulmonary and Critical Care, Nashville, TN, USA.
Ayumi
A
Shintani
Vanderbilt University Medical Center, Pulmonary and Critical Care, Nashville, TN, USA.
Jim
J
Jackson
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK; Heart of England NHS Foundation Trust, Birmingham, UK.
Gavin D
GD
Perkins
Centre for Infection and Immunity, Queen's University of Belfast, Belfast, UK; Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK.
Daniel F
DF
McAuley
D000368:Aged; D003128:Coma / Q000188:drug therapy*; D003422:Critical Care / Q000379:methods; D016638:Critical Illness; D003693:Delirium / Q000188:drug therapy*; D018492:Dopamine Antagonists / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage*; D006801:Humans; D007262:Infusions, Intravenous; D007902:Length of Stay; D008297:Male; D012121:Respiration, Artificial; D016896:Treatment Outcome
D018492:Dopamine Antagonists; D006220:Haloperidol