Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial

Trials, Nov 2013

Background Delirium 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. Methods This 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. Discussion This 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 registration Clinicaltrials.gov: NCT01785290. EudraCT number: 2012-004012-66.

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Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial

Boogaard et al. Trials Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial Mark van den Boogaard 0 1 Arjen J Slooter 1 Roger JM Brggemann 1 Lisette Schoonhoven 1 Michael A Kuiper 1 Peter HJ van der Voort 1 Marga E Hoogendoorn 1 Albert Beishuizen 1 Jeroen A Schouten 1 Peter E Spronk 1 Saskia Houterman 1 2 Johannes G van der Hoeven 1 3 Peter Pickkers 0 1 0 Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre , P.O. box 9101, internal post 710, 6500HB Nijmegen , Netherlands 1 Medicine, Gelre Hospitals , Location Lukas, Albert Schweitzerlaan 31, 7334DZ Apeldoorn , Netherlands 2 Catharina Hospital , Michelangelolaan 2, 5623EJ Eindhoven , Netherlands 3 Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre , PO box 9101, 6500HB Nijmegen , Netherlands Background: Delirium 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. Methods: This 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. Discussion: This 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. Critically ill; Delirium; Haloperidol; Intensive care; Mortality; Prevention; Prophylaxis; Randomized trial - Background Delirium is a neuropsychiatric disorder characterized by an acute onset of confusion, inattention, and a change in level of consciousness that tends to fluctuate during the day [1,2]. The incidence of delirium in intensive care unit (ICU) patients is high [3-6], approximately 3050%. Further, its occurrence is associated with detrimental outcome, including prolonged duration of mechanical ventilation, increased ICU and hospital length of stay (LOS) [4-6], unplanned removal of tubes and catheters [6], increased mortality [6-8], and long-term cognitive disturbances [9,10]. Therefore, a strategy that can prevent delirium in high-risk patients may also decrease short-term (i.e., 28-day) mortality. The first step in the management of delirium is to treat the underlying disease. If delirium does not subside, haloperidol is the most frequently used pharmacologic treatment of delirium. However, this drug may also be used to prevent delirium. In non-ICU patients, beneficial effects have been reported of prophylactic haloperidol in older and surgical patients [11,12]. For critically ill patients, data concerning prevention with anti-psychotic drugs are scarce and inconsistent [13-15]. 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]. Only 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]. However, only a very low dose, for 12 h infusion of haloperidol was administered and many of the patients were in the ICU for less than 24 h [17]. Thus, there are no large, definitive trials that have studied the effect of haloperidol prophylaxis in ICU patients. Recently, a model was developed and validated to pr (...truncated)


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Mark van den Boogaard, Arjen J Slooter, Roger JM Brüggemann, Lisette Schoonhoven, Michael A Kuiper, Peter HJ van der Voort, Marga E Hoogendoorn, Albert Beishuizen, Jeroen A Schouten, Peter E Spronk, Saskia Houterman, Johannes G van der Hoeven, Peter Pickkers. Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial, Trials, 2013, pp. 400, 14, DOI: 10.1186/1745-6215-14-400