In this episode, I’ll discuss a pre-planned analysis of long term outcomes of haloperidol use in the Agents Intervening against Delirium in the ICU Trial.
Back in episode 762 I discussed the AID-ICU trial which was a placebo-controlled randomized blinded trial of 1000 patients with ICU delirium published in NEJM. Patients were split between treatment with haloperidol or placebo. The IV haloperidol group received 2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg. There was no limit set on the duration of treatment. At 90 days there was no difference between groups in the primary outcome of days alive and out of the hospital. However, the mortality rate at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group, and this difference was statistically significant.
Part of the original trial protocol was a planned analysis of mortality in the study participants at 1 year, and this analysis was recently published in the journal Intensive Care Medicine. In addition to looking at mortality, the authors compared health-related quality of life (HRQoL) which was assessed by the Euroqol (EQ) 5-dimension 5-level questionnaire (EQ-5D-5L) index values and EQ visual analogue scale (EQ VAS).
One-year mortality was 44.7% in the haloperidol group vs. 51.6% in the placebo group. The absolute risk difference was 6.4% lower mortality in favor of haloperidol and this was statistically significant. For health-related quality of life there were no statistically significant differences between groups.
The authors noted a separation between the survival curves early in the intervention period (5 to 10 days after being randomized) and this separation remained through one year. This could mean that haloperidol does have an impact on the treatment of delirium that positively impacts survival.
This data is the first from a randomized controlled trial to show a mortality benefit from haloperidol in ICU delirium. Although the trial was a high quality, multi-center trial, over 96% of the patients were in Danish ICUs which may limit the external validity of the trial. However, the trial inclusion criteria were very broad, requiring only a patient to be 18 years or older, admitted to the ICU for an acute condition, and have a positive delirium assessment.
At the very least, this data seems to shift the evidence supporting haloperidol to treat delirium from “no benefit or harm compared to placebo” to “possible mortality benefit compared to placebo” and therefore many clinicians will be more likely to want to use haloperidol for treatment of ICU delirium.
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