Prophylactic Haloperidol Effects on Long-Term Quality of Life In
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CRITICAL CARE MEDICINE ABSTRACT Background: Delirium incidence in intensive care unit patients is high and associated with impaired long-term outcomes. The use of prophylactic halo- peridol did not improve short-term outcome among critically ill adults at high Prophylactic Haloperidol risk of delirium. This study evaluated the effects of prophylactic haloperidol use on long-term quality of life in this group of patients and explored which Effects on Long-term factors are associated with change in quality of life. Methods: A preplanned secondary analysis of long-term outcomes of the Quality of Life in Critically pRophylactic haloperidol usE for DeliriUm in iCu patients at high risk for dElirium (REDUCE) study was conducted. In this multicenter randomized Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/131/2/328/377461/20190800_0-00022.pdf by guest on 29 September 2021 Ill Patients at High Risk clinical trial, nondelirious intensive care unit patients were assigned to pro- phylactic haloperidol (1 or 2 mg) or placebo (0.9% sodium chloride). In all for Delirium groups, patients finally received study medication for median duration of 3 days [interquartile range, 2 to 6] until onset of delirium or until intensive care Results of the REDUCE Study unit discharge. Long-term outcomes were assessed using the Short Form-12 questionnaire at intensive care unit admission (baseline) and after 1 and 6 Paul J. T. Rood, R.N., M.Sc., Marieke Zegers, Ph.D., months. Quality of life was summarized in the physical component summary Arjen J. C. Slooter, M.D., Ph.D., Albert Beishuizen, M.D., Ph.D., and mental component summary scores. Differences between the haloperidol Koen S. Simons, M.D., Ph.D., Peter H. J. van der Voort, M.D., Ph.D., and placebo group and factors associated with changes in quality of life were Meta C. E. van der Woude, M.D., Peter E. Spronk, M.D., Ph.D., analyzed. Johannes G. van der Hoeven, M.D., Ph.D., Results: Of 1,789 study patients, 1,245 intensive care unit patients were Peter Pickkers, M.D., Ph.D., Mark van den Boogaard, R.N., Ph.D. approached, of which 887 (71%) responded. Long-term quality of life did not differ between the haloperidol and placebo group (physical component ANESTHESIOLOGY 2019; 131:328–35 summary mean score of 39 ± 11 and 39 ± 11, respectively, and P = 0.350; and mental component summary score of 50 ± 10 and 51 ± 10, respec- tively, and P = 0.678). Age, medical and trauma admission, quality of life EDITOR’S PERSPECTIVE score at baseline, risk for delirium (PRE-DELIRIC) score, and the number of sedation-induced coma days were significantly associated with a decline in What We Already Know about This Topic long-term quality of life. • Delirium is a frequently occurring disorder in intensive care unit Conclusions: Prophylactic haloperidol use does not affect long-term quality patients associated with impaired short-term and long-term of life in critically ill patients at high risk for delirium. Several factors, including outcomes the modifiable factor number of sedation-induced coma days, are associated • Prophylactic haloperidol neither reduces delirium incidence nor its short-term clinical consequences with decline in long-term outcomes. • Many intensive care unit survivors suffer from long-term impair- (ANESTHESIOLOGY 2019; 131:328–35) ment of physical, cognitive, or mental health status, but there is a gap in knowledge regarding which factors are associated with such a change in quality of life in the post–intensive care unit period unit (ICU). Delirium is characterized by acute confusion, What This Article Tells Us That Is New inattention, and altered consciousness, and symptoms tend 3 • Prophylactic haloperidol does not affect long-term outcome of crit- to fluctuate during the day. Delirium is a complex syn- ically ill patients at high risk for delirium drome that can be triggered by a plethora of factors (e.g., • Every additional day of sedation-induced coma is associated with use of sedatives and opioids, metabolic disturbances, pain, further decline of long-term physical and mental function mechanical ventilation, and latency of sleep; so-called pre- cipitating risk factors). These precipitating factors are of ith an incidence rate of approximately 30%1 and specific relevance in patients with predisposing risk factors Wprevalence rates up to 87%,2 it is clear that delirium such as advanced age, a history of cognitive dysfunction, is a major burden for patients admitted to the intensive care and comorbidities.4 Reducing delirium in ICU patients is This article is featured in “This Month in Anesthesiology,” page 1A. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org). This article has an audio podcast. This article has a visual abstract available in the online version. The results described in this article have not been presented elsewhere. The short-term results have been presented in a Hot Topic session of the European Society of Intensive Care Medicine Congress in Vienna, Austria, September 27, 2017, and the European Delirium Association Congress in Oslo, Norway, November 16, 2017. P.J.T.R. and M.Z. contributed equally to this article. Copyright © 2019, the American Society of Anesthesiologists, Inc. All Rights Reserved. Anesthesiology 2019; 131:328–35. DOI: 10.1097/ALN.0000000000002812 328 AUGUST 2019 ANESTHESIOLOGY, V 131 • NO 2 Copyright © 2019, the American Society of Anesthesiologists, Inc. Unauthorized reproduction of this article is prohibited. Prophylactic Haloperidol and Quality of Life paramount because it is associated with impaired short-term clinically relevant ventricular arrhythmia, and inability to outcome (e.g., prolonged mechanical ventilation, ICU, and provide written informed consent.10,11 Patients or next of hospital stay5) but also with worse long-term outcome.6,7 kin were asked for written informed consent, and if this Because increasing numbers of patients survive the ICU,8 was not possible, a deferred consent procedure was used. the long-term effects of ICU stay and interventions have Patients were randomly assigned to the intervention group become more relevant. (intravenous administration 3 × 1 mg or 3 × 2 mg of halo- It is well known that many ICU survivors suffer from peridol or the control group (0.9% sodium chloride). The impaired physical, cognitive, or mental health status, a first dose of study medication was administered within 24 h phenomenon known as “post–intensive care syndrome.”9 after ICU admission. The administration of study medica- However, there is a paucity of knowledge on factors associ- tion was terminated at day 28 or earlier in case of either ated with these changes in quality of life. ICU discharge or occurrence of delirium. In the latter case, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/131/2/328/377461/20190800_0-00022.pdf by guest on 29 September 2021 In the present study, we primarily evaluated the effects of patients were treated with open-label haloperidol accord- prophylactic haloperidol use on long-term quality of life.10 ing to the study protocol.10 Because no dose–effect relation The secondary aim was to explore which factors are asso- was established,11 the data of the two haloperidol dosage ciated with changes in long-term quality of life of ICU groups were combined for the analyses described in this survivors. article. Quality of life was measured using the Short Form- Materials and Methods 1212 questionnaire. This is a validated instrument, consist- ing of eight domains: physical functioning, role–physical, The pRophylactic haloperidol usE for DeliriUm in iCu bodily pain and general health, vitality, social functioning, patients at high risk for dElirium (REDUCE) study was a role–emotional, and mental health, which are summarized randomized, double-blind, placebo-controlled study con- into two components: physical component summary and ducted in 21 Dutch hospitals, involving ICU patients at mental component summary.12 The Short Form-12 was high risk of developing delirium. The short-term results of completed at ICU admission (baseline) and at 1 and 6 this study were recently published elsewhere.11 The effect months after ICU admission by patients or their next of of haloperidol on long-term quality of life was a secondary kin in case patients were not able to fill in the questionnaire outcome of the REDUCE study10 and is the primary focus themselves.13 The 1- and 6-month questionnaires were sent of this article. In addition, exploratory secondary analyses to patients’ home addresses once, irrespective of whether were carried out to determine which factors are associated the patient was still admitted to the hospital. with changes in long-term quality of life. This predefined Demographic and in-hospital characteristics, including substudy was conducted in 9 of the 21 ICUs participating age, sex, Acute Physiology and Chronic Health Evaluation in the REDUCE study. II score, (early) prediction of ICU delirium ([E-]PRE- The medical ethics committee approved this study DELIRIC) score,14,15 admission type, mechanical ventila- (study number 2012/424). The study is registered in the tion, and length of stay (ICU and hospital), were collected ClinicalTrials.gov database (NCT01785290). The published from the electronic patient record. Patients were diagnosed study protocol10 provides detailed information regarding with delirium when they had at least one positive delir- the inclusion and exclusion criteria of patients, randomiza- ium assessment using the confusion assessment method for tion, and study medication procedures. ICU2 during the first 28 days of their ICU-stay. A delirium Briefly, patients aged 18 yr or older who were deliri- day was defined by at least one positive delirium assessment um-free at ICU admission and had an anticipated ICU stay on a given day.