Abstract
BackgroundDelirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis.MethodsThis will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged ≥18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates.DiscussionThis will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival.Trial registrationClinicaltrials.gov: NCT01785290.EudraCT number: 2012-004012-66.
Highlights
Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences
Its occurrence is associated with detrimental outcome, including prolonged duration of mechanical ventilation, increased ICU and hospital length of stay (LOS) [4,5,6], unplanned removal of tubes and catheters [6], increased mortality [6,7,8], and long-term cognitive disturbances [9,10]
In one retrospective cohort study, ICU patients who received haloperidol were found to have a lower mortality rate compared to ICU patients that did not receive haloperidol [16]
Summary
Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis. The incidence of delirium in intensive care unit (ICU) patients is high [3,4,5,6], approximately 30–50%. One prospective, randomized trial in critically ill patients is available, showing that haloperidol prophylaxis in non-cardiac surgical ICU patients had beneficial effects on delirium incidence and the number of delirium freedays [17]. There are no large, definitive trials that have studied the effect of haloperidol prophylaxis in ICU patients
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