With interest, we read Valerie J Page and colleagues’ report1 of the HopeICU trial in which they conclude that haloperidol does not shorten the duration of delirium in critically ill patients. The investigators state that haloperidol should be reserved only for management of acute agitation. These findings are in contrast with other recent studies,2,3 which might be a result of several limitations to Page and colleagues’ study. First, the study was powered to ﬁnd a treatment diﬀerence of 2 days, which we assume that the investigators deemed relevant. However, each day that a patient is delirious results in a 10% higher mortality.4 Therefore the observed diﬀerence of 1 day could be clinically relevant, but would need a sample size that was about four times larger than the one used here. Second, although the investigators did not establish the actual delirium risk of patients with the recent developed prediction model,5 they chose to use a surrogate measure—ie, need for mechanical ventilation within 72 h of admission. Therefore, plausibly, patients with a low risk of delirium might have been included, resulting in a diluted efficacy of haloperidol. We previously reported the results of a non-randomised controlled trial, showing that patients with the highest risk of developing delirium seem to benefit the most from prophylactic treatment with haloperidol.3 Third, and most importantly, Page and colleagues enrolled both nondelirious and delirious patients at time of inclusion. This implies that they studied both the prophylactic and therapeutic efficacy of haloperidol, which we think should be reported separately. Based on these three issues, we believe that the absence of a prophylactic and treatment effect of haloperidol has not yet been established, and warrants further study. www.thelancet.com/respiratory Vol 1 October 2013
We declare that we have no conﬂicts of interest.
*Mark van den Boogaard, Peter Pickkers [email protected]
Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, Netherlands 1
Page VJ, Ely EW, Gates S, et al. Eﬀect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1: 515–23. Wang W, Li HL, Wang DX, et al. Haloperidol prophylaxis decreases delirium incidence in elderly patients after noncardiac surgery: a randomized controlled trial. Crit Care Med 2012; 40: 1–9. van den Boogaard M, Schoonhoven L, Van Achterberg T, Van der Hoeven JG, Pickkers P. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Critical Care 2013; 17: R9. Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med 2009; 180: 1092–97. van den Boogaard M, Pickkers P, Slooter AJ, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 2012; 344: e420.
Prophylactic haloperidol: too early to lose hope Delirium is a very prevalent syndrome and an important independent predictor of negative outcome in patients in the intensive-care unit (ICU), but there is no proven pharmacological intervention to prevent or treat this disorder.1 Therefore, the study by Valerie J Page and colleagues,2 which provided an assessment of the use of haloperidol in the ICU setting, was needed. However, the results of this trial should not be classed as deﬁnitive because the study has some limitations. First, haloperidol was used as both a prophylaxis and treatment, and the number of patients with delirium at enrolment was not stated. We would expect that the dose needed to treat a patient with delirium would be higher
than the prophylactic dose. Also, the criteria for stopping the drug should be reconsidered, since although patients might be 2 days free of delirium, they still could be at risk of developing delirium. Second, regarding the statistical analysis, the primary outcome was the number of delirium-free and comafree days in the first 14 days after randomisation, but patients who died before day 14 were recorded as having zero days free of delirium and coma, restricting the analysis to survivors, and correcting the incidence of the main outcome (delirium) according to the competing event (death). When analysing time-to-event data and competing outcomes, a technique known as cumulative incidence analysis can be used to assess the actual incidence of delirium. 3 This type of analysis would have provided more accurate results in Page and colleagues’ study, and should be used in future trials that intend to address delirium incidence. Last, the study authors conclude that their results do not support the use of haloperidol in patients needing mechanical ventilation, irrespective of whether patients screen positive for delirium or are in a coma. They believe that haloperidol should be reserved for short-term management of acute agitation; however, we think it is too soon to come to this conclusion.
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Hope for haloperidol in delirium
We declare that we have no conﬂicts of interest.
*Marina Verçoza Viana, Rafael B Moraes, Tiago A Tonietto, Marcio M Boniatti [email protected]
Hospital de Clinicas de Porto Alegre, Serviço de Medicina Intensiva, Ramiro Barcelos 2350, Porto Alegre, Rio Grande do Sul, Brazil 1
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263–306. Page VJ, Ely EW, Gates S, et al. Eﬀect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013; 1: 515–23.