Haloperidol for ICU delirium: No effect on duration or incidence versus placebo

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1. For ICU patients requiring mechanical ventilation, no decrease in duration or incidence of delirium or coma was found with prophylactic haloperidol versus placebo.

2. Antipsychotic medications may reduce analgesic and hypnotic total dosage and days of treatment.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Delirium is an acute dysfunction in neurological functioning that is especially prevalent in mechanically ventilated ICU patients. Haloperidol and other antipsychotics are standard adjuncts of ICU protocols to support sedation. However, no studies to date show any statistically significant effect of antipsychotics in decreasing the incidence and duration of delirium in this population.

This study was a double-blind randomized controlled trial conducted with 142 mechanically ventilated adult patients randomized to receive either haloperidol or a saline placebo. Results demonstrated no statistically significant difference between the intervention and control groups in terms of delirium or coma duration and incidence.

This study is a new look at antipsychotics’ effect on delirium in the ICU setting; prior studies were limited by different patient acuities or by statistical power. This study was specifically powered to assess for a true difference (in number of delirium-free and coma-free days) of two days within the 14-day primary outcome time frame. However, this is not particularly rigorous statistically. Given the meticulous monitoring of ICU patients, a follow-up study powered to detect more minute differences using a larger study population could provide more representative results.

Click to read the study, published today in Lancet

Click to read the associated comment in Lancet

Relevant Reading: Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: A randomized controlled trial

Lead author Professor Dr. Valerie Page talks to 2 Minute Medicine: Imperial College, United Kingdom

“Despite a limited evidence base, increasing numbers of patients are being exposed to haloperidol for the management of delirium,” says Dr Page. “Our results suggest a commonly used haloperidol dose regimen does not decrease delirium in critically ill patients requiring mechanical ventilation, when commenced early during ICU stay.”

“Although haloperidol can be used safely in this population of patients, our results do not support the idea that haloperidol modifies duration of delirium in critically ill patients.  Identification of a drug to prevent or reduce delirium and improve adverse outcomes, including in the intensive care setting, needs to be a high priority within delirium research.”

In-Depth [randomized controlled trial]: This study was a double blind randomized controlled trial conducted at one clinical site. 142 patients mechanically ventilated patients 18 years or older were randomized either to receive haloperidol or a saline placebo. Haloperidol or saline placebo was prepared and administered every 8 hours by a staff member not associated with the study. Sedation was maintained with analgesics and hypnotics to achieve a Richmond agitation sedation scale (RASS) of 0 to -1, and reassessed every 4 hours. Acute agitation was defined as a RASS +2 or greater, delirium as RASS -2 to +4, and coma as RASS of -3 to -5. If acute agitation was observed in either experimental or control group, antipsychotics including haloperidol were administered; 18 control group patients and 8 experimental group patients required open-label antipsychotics for agitation. If coma was diagnosed by RASS, study drug dosage was halved.

The primary outcome measured was delirium-free and coma-free days within14 days of randomization. Secondary outcomes included: delirium-free and coma-free days within 28 days, ventilator-free days, mortality at 28 days, adverse outcomes related to haloperidol, and required dosages of analgesics and hypnotics. No statistically significant difference were observed. Patients in the experimental group had a borderline statistically significant difference in number of days additional haloperidol was needed for acute agitation (p = 0.08). A borderline statistically significant decrease in total dose and number of days of one analgesic (fentanyl, p=0.06, p=.25, respectively) and one hypnotic (propofol, p = 0.06 and 0.08, respectively) suggested that haloperidol may reduce requirements for other medications, though the study was not powered to assess this effect.

As a single site study, there is ample bias including a wide variety of indications for mechanical ventilation and residual confounding. Other potential sources of bias include: selection bias in accounting for all variations in acuity, variations in staff responses to acute agitation, confounding via antipsychotic dosing to placebo group for acute agitation, and wide variability in subject primary and secondary outcomes.

By Philip Hewes and Mimmie Kwong

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