No reason for haloperidol for delirium in ICU patients

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Prophylactic use of the drug haloperidol does not help to prevent delirium in intensive care patients or improve their chances of survival, found a large three-year Dutch study. Therefore, there is no reason anymore to administer the drug as a preventive measure to reduce the burden of delirium.

This was revealed following a three-year, large-scale study among 1,800 patients in 20 Dutch ICUs, headed by Radboud University Medical Centre. The results of this world’s largest research project into delirium prevention in the ICU show acute confusion, or delirium, occurs in approximately one third to half of all patients in the intensive care unit (ICU), and hasserious short-term and long-term consequences.

Patients who develop delirium need mechanical ventilation for a longer time and their stay in the ICU and in the hospital is also longer. Also, patients with delirium are more likely to die compared to patients without delirium. If a patient develops delirium, the drug haloperidol is often used to treat it.

There were indications that haloperidol could be effective not only to treat, but also to prevent delirium. A large-scale trial, headed by Dr Mark van den Boogaard from the Radboud University Medical Centre, was conducted in 20 Dutch ICUs to investigate if prophylactic use of haloperidol could reduce delirium and its consequences. A total of 1,800 ICU patients with a high risk of delirium were included in this trial and received a low dose of haloperidol, or a placebo. This trial, funded by ZonMw (the Netherlands Organisation for Health Research and Development), is worldwide the largest trial in this field.

As mortality rates among patients with delirium are higher, the researchers tried to find out whether using prophylactic haloperidol would reduce the mortality and delirium and its sequelae.

The conclusions of this trial were crystal clear: prophylactic therapy with haloperidol did not affect any of the endpoints being studied. Van den Boogaard said: “This large-scale study shows indisputably that use of prophylactic haloperidol in ICU patients has no beneficial effects whatsoever. These findings will lead to fewer unnecessary drugs being prescribed to ICU patients.”

Head of the research, Professor Peter Pickkers said: “The scope of the study and the fact that the results are so unambiguous make the message from our research abundantly clear: there is absolutely no point in administering haloperidol to ICU patients as a preventive measure.”

Importance: Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium.
Objective: To determine whether prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days.
Design, Setting, and Participants: Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017.
Interventions: Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride.
Main Outcome and Measures: The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay.
Results: All 1789 randomized patients (mean, age 66.6 years [SD, 12.6]; 1099 men [61.4%]) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group).
Conclusions and Relevance: Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults.

Mark van den Boogaard, Arjen JC Slooter, Roger JM Brüggemann, Lisette Schoonhoven, Albertus Beishuizen, J Wytze Vermeijden, Danie Pretorius, Jan de Koning, Koen S Simons, Paul JW Dennesen, Peter HJ Van der Voort, Saskia Houterman, JG van der Hoeven, Peter Pickkers

Radboud University Medical Centre material
JAMA abstract

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