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

ABSTRACT: 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.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.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.Clinicaltrials.gov: NCT01785290.EudraCT number: 2012-004012-66.

SUBMITTER: van den Boogaard M

PROVIDER: S-EPMC4222562 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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

van den Boogaard Mark M Slooter Arjen J AJ Brüggemann Roger J M RJ Schoonhoven Lisette L Kuiper Michael A MA van der Voort Peter H J PH Hoogendoorn Marga E ME Beishuizen Albert A Schouten Jeroen A JA Spronk Peter E PE Houterman Saskia S van der Hoeven Johannes G JG Pickkers Peter P

Trials 20131121

<h4>Background</h4>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 effectiven ...[more]

PMID: 24261644

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Project description:Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10 to 80% (Schonauer et al., J Pept Sci. 2017). Delirium was first described more than half a century ago in the cardiac surgery population (Blachy and Starr, Am J Psychiatry 121:371-5, 1964), where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population (Sessler et al., Am J Respir Crit Care Med 166:1338-44, 2002). This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies (Nishio et al., Crit Care Med 5:953-7, 1997; Ehlenbach et al., JAMA 303:763-70, 2010; Jahangir et al., World J Cardiol 3:383-7, 2011; Abegunde et al., Lancet 370:1929-1938, 2007; Darmon et al., Intensive Care Med 43:829-840, 2017; Marino et al., J Nephrol 28:717-24, 2015; Ng LL et al., J Am Coll Cardiol 69:56-69, 2017; Sezen et al., J Pharmacol Exp Ther 287:238-45, 1998; Kim et al., Ann Lab Med 37:388-97, 2017). Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100? will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery.The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo.There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium.ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.

Project description:To compare the efficacy and safety of scheduled low-dose haloperidol versus placebo for the prevention of delirium (Intensive Care Delirium Screening Checklist ? 4) administered to critically ill adults with subsyndromal delirium (Intensive Care Delirium Screening Checklist = 1-3).Randomized, double-blind, placebo-controlled trial.Three 10-bed ICUs (two medical and one surgical) at an academic medical center in the United States.Sixty-eight mechanically ventilated patients with subsyndromal delirium without complicating neurologic conditions, cardiac surgery, or requiring deep sedation.Patients were randomly assigned to receive IV haloperidol 1 mg or placebo every 6 hours until delirium occurred (Intensive Care Delirium Screening Checklist ? 4 with psychiatric confirmation), 10 days of therapy had elapsed, or ICU discharge.Baseline characteristics were similar between the haloperidol (n = 34) and placebo (n = 34) groups. A similar number of patients given haloperidol (12/34 [35%]) and placebo (8/34 [23%]) developed delirium (p = 0.29). Haloperidol use reduced the hours per study day spent agitated (Sedation Agitation Scale ? 5) (p = 0.008), but it did not influence the proportion of 12-hour ICU shifts patients spent alive without coma (Sedation Agitation Scale ? 2) or delirium (p = 0.36), the time to first delirium occurrence (p = 0.22), nor delirium duration (p = 0.26). Days of mechanical ventilation (p = 0.80), ICU mortality (p = 0.55), and ICU patient disposition (p = 0.22) were similar in the two groups. The proportion of patients who developed corrected QT-interval prolongation (p = 0.16), extrapyramidal symptoms (p = 0.31), excessive sedation (p = 0.31), or new-onset hypotension (p = 1.0) that resulted in study drug discontinuation was comparable between the two groups.Low-dose scheduled haloperidol, initiated early in the ICU stay, does not prevent delirium and has little therapeutic advantage in mechanically ventilated, critically ill adults with subsyndromal delirium.

Project description:BackgroundDelirium is a significant cause of morbidity and mortality among older people admitted to both acute and long-term care facilities (LTCFs). Multicomponent interventions have been shown to reduce delirium incidence in the acute care setting (30-73%) by acting on modifiable risk factors. Little work, however, has focused on using this approach to reduce delirium incidence in LTCFs.MethodsThe objective is to assess the effectiveness of the multicomponent PREPARED Trial intervention in reducing the following primary outcomes: incidence, severity, duration, and frequency of delirium episodes in cognitively impaired residents. This 4-year, parallel-design, cluster randomized study will involve nursing staff and residents in 45-50 LTCFs in Montreal, Canada. Participating public and private LTCFs (clusters) that provide 24-h nursing care will be assigned to either the PREPARED Trial intervention or the control (usual care) arm of the study using a covariate constrained randomization procedure. Approximately 400-600 LTC residents aged 65 and older with dementia and/or cognitive impairment will be enrolled in the study and followed for 18 weeks. Residents must be at risk of delirium, delirium-free at baseline and have resided at the facility for at least 2 weeks. Residents who are unable to communicate verbally, have a history of specific psychiatric conditions, or are receiving end-of-life care will be excluded. The PREPARED Trial intervention consists of four main components: a decision tree, an instruction manual, a training package, and a toolkit. Primary study outcomes will be assessed weekly. Functional autonomy and cognitive levels will be assessed at the beginning and end of follow-up, while information pertaining to modifiable delirium risk factors, medical consultations, and facility transfers will be collected retrospectively for the duration of the follow-up period. Primary outcomes will be reported at the level of intervention assignment. All researchers analyzing the data will be blinded to group allocation.DiscussionThis large-scale intervention study will contribute significantly to the development of evidence-based clinical guidelines for delirium prevention in this frail elderly population, as it will be the first to evaluate the efficacy of a multicomponent delirium prevention program translated into LTC clinical practice on a large scale.Trial registrationNCT03718156 , ClinicalTrials.gov .

Project description:Delirium is associated with substantial morbidity and mortality rates in elderly hospitalised patients, and a growing problem due to increase in life expectancy. Implementation of standardised non-pharmacological delirium prevention strategies is challenging and adherence remains low. Pharmacological delirium prevention with haloperidol, currently the drug of choice for delirium, seems promising. However, the generalisability of randomised controlled trial results is questionable since studies have only been performed in selected postoperative hip-surgery and intensive care unit patient populations. We therefore present the design of the multicenter, randomised, double-blind, placebo-controlled clinical trial on early pharmacological intervention to prevent delirium: haloperidol prophylaxis in older emergency department patients (The HARPOON study).In six Dutch hospitals, at-risk patients aged 70 years or older acutely admitted through the emergency department for general medicine and surgical specialties are randomised (n?=?390) for treatment with prophylactic haloperidol 1 mg or placebo twice daily for a maximum of seven consecutive days. Primary outcome measure is the incidence of in-hospital delirium within seven days of start of the study intervention, diagnosed with the Confusion Assessment Method, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for delirium. Secondary outcome measures include delirium severity and duration assessed with the Delirium Rating Scale Revised 98; number of delirium-free days; adverse events; hospital length-of-stay; all-cause mortality; new institutionalisation; (Instrumental) Activities of Daily Living assessed with the Katz Index of ADL, and Lawton IADL scale; cognitive function assessed with the Six-item Cognitive Impairment Test, and the Dutch short form Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be contacted by telephone three and six months post-discharge to collect data on cognitive- and physical function, home residency, all-cause hospital admissions, and all-cause mortality.The HARPOON study will provide relevant information on the efficacy and safety of prophylactic haloperidol treatment for in-hospital delirium and its effects on relevant clinical outcomes in elderly at-risk medical and surgical patients.EudraCT Number: 201100476215; ClinicalTrials.gov Identifier: NCT01530308; Dutch Clinical Trial Registry: NTR3207.

Project description:BackgroundDelirium is a common complication among intensive care unit (ICU) patients that is linked to negative clinical outcomes. However, adherence to the Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU (PADIS guidelines), which recommend the use of the ABCDEF bundle, is sub-optimal in routine clinical care. To address this issue, AI-AntiDelirium, a nurse-led artificial intelligence-assisted prevention and management tool for delirium, was developed by our research team. Our pilot study yielded positive findings regarding the use of AI-AntiDelirium in preventing patient ICU delirium and improving activities of daily living and increasing intervention adherence by health care staff.MethodsThe proposed large-scale pragmatic, open-label, parallel-group, cluster randomized controlled study will assess the impact of AI-AntiDelirium on the incidence of ICU delirium and delirium-related outcomes. Six ICUs in two tertiary hospitals in China will be randomized in a 1:1 ratio to an AI-AntiDelirium or a PADIS guidelines group. A target sample size of 1,452 ICU patients aged 50 years and older treated in the ICU for at least 24 hours will be included. The primary outcome evaluated will be the incidence of ICU delirium and the secondary outcomes will be the duration of ICU delirium, length of ICU and hospital stay, ICU and in-hospital mortality rates, patient cognitive function, patient activities of daily living, and ICU nurse adherence to the ABCDEF bundle.DiscussionIf this large-scale trial provides evidence of the effectiveness of AI-AntiDelirium, an artificial intelligence-assisted system tool, in decreasing the incidence of ICU delirium, length of ICU and hospital stay, ICU and in-hospital mortality rates, patient cognitive function, and patient activities of daily living while increasing ICU nurse adherence to the ABCDEF bundle, it will have a profound impact on the management of ICU delirium in both research and clinical practice.Clinical trial registrationChiCTR1900023711 (Chinese Clinical Trial Registry).

Dataset Information

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

Publications

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

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