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Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

ABSTRACT: 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.

SUBMITTER: Schrijver EJ

PROVIDER: S-EPMC4161272 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

Schrijver Edmée J M EJ de Vries Oscar J OJ Verburg Astrid A de Graaf Karola K Bet Pierre M PM van de Ven Peter M PM Kamper Ad M AM Diepeveen Sabine Ha SH Anten Sander S Siegel Andrea A Kuipéri Esther E Lagaay Anne M AM van Marum Rob J RJ van Strien Astrid M AM Boelaarts Leo L Pons Douwe D Kramer Mark H H MH Nanayakkara Prabath W B PW

BMC geriatrics 20140828

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

PMID: 25168927

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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:Delirium is associated with increased morbidity and mortality. We implemented a delirium prevention policy in intensive care unit (ICU) patients with a high risk of developing delirium, and evaluated if our policy resulted in quality improvement of relevant delirium outcome measures.This study was a before/after evaluation of a delirium prevention project using prophylactic treatment with haloperidol. Patients with a predicted risk for delirium of ? 50%, or with a history of alcohol abuse or dementia, were identified. According to the prevention protocol these patients received haloperidol 1 mg/8 h. Evaluation was primarily focused on delirium incidence, delirium free days without coma and 28-day mortality. Results of prophylactic treatment were compared with a historical control group and a contemporary group that did not receive haloperidol prophylaxis mainly due to non-compliance to the protocol mostly during the implementation phase.In 12 months, 177 patients received haloperidol prophylaxis. Except for sepsis, patient characteristics were comparable between the prevention and the historical (n = 299) groups. Predicted chance to develop delirium was 75 ± 19% and 73 ± 22%, respectively. Haloperidol prophylaxis resulted in a lower delirium incidence (65% vs. 75%, P = 0.01), and more delirium-free-days (median 20 days (IQR 8 to 27) vs. median 13 days (3 to 27), P = 0.003) in the intervention group compared to the control group. Cox-regression analysis adjusted for sepsis showed a hazard rate of 0.80 (95% confidence interval 0.66 to 0.98) for 28-day mortality. Beneficial effects of haloperidol appeared most pronounced in the patients with the highest risk for delirium. Furthermore, haloperidol prophylaxis resulted in less ICU re-admissions (11% vs. 18%, P = 0.03) and unplanned removal of tubes/lines (12% vs. 19%, P = 0.02). Haloperidol was stopped in 12 patients because of QTc-time prolongation (n = 9), renal failure (n = 1) or suspected neurological side-effects (n = 2). No other side-effects were reported. Patients who were not treated during the intervention period (n = 59) showed similar results compared to the untreated historical control group.Our evaluation study suggests that prophylactic treatment with low dose haloperidol in critically ill patients with a high risk for delirium probably has beneficial effects. These results warrant confirmation in a randomized controlled trial.clinicaltrial.gov Identifier: NCT01187667.

Project description:Introduction:Resistant Gram-positive organisms, such as methicillin-resistant staphylococci, account for a significant proportion of infections following joint replacement surgery. Current surgical antimicrobial prophylaxis guidelines recommend the use of first-generation or second-generation cephalosporin antibiotics, such as cefazolin. Cefazolin, however, does not prevent infections due to these resistant organisms; therefore, new prevention strategies need to be examined. One proposed strategy is to combine a glycopeptide antibiotic with cefazolin for prophylaxis. The clinical benefit and cost-effectiveness of this combination therapy compared with usual therapy, however, have not been established.Methods and analysis:This randomised, double-blind, parallel, superiority, placebo-controlled, phase 4 trial will compare the incidence of all surgical site infections (SSIs) including superficial, deep and organ/space (prosthetic joint) infections, safety and cost-effectiveness of surgical prophylaxis with cefazolin plus vancomycin to that with cefazolin plus placebo. The study will be performed in patients undergoing joint replacement surgery. In the microbiological sub-studies, we will examine the incidence of SSIs in participants with preoperative staphylococci colonisation (Sub-Study 1) and incidence of VRE acquisition (Sub-Study 2). The trial will recruit 4450 participants over a 4-year period across 13 orthopaedic centres in Australia. The primary outcome is the incidence of SSI at 90 days post index surgery. Secondary outcomes include the incidence of SSI according to joint and microorganism and other healthcare associated infections. Safety endpoints include the incidence of acute kidney injury, hypersensitivity reactions and all-cause mortality. The primary and secondary analysis will be a modified intention-to-treat analysis consisting of all randomised participants who undergo eligible surgery. We will also perform a per-protocol analysis.Ethics and dissemination:The study protocol was reviewed and approved by The Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/102) on 9 July 2018. Study findings will be disseminated in the printed media, and learnt forums.Trial registration number:ACTRN12618000642280.

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.

Dataset Information

Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

Publications

Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

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