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Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial.

ABSTRACT: Importance:Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. Objective:To determine whether prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. Interventions:Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. Main Outcome and Measures:The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. Results:All 1789 randomized patients (mean, age 66.6 years [SD, 12.6]; 1099 men [61.4%]) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, -3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 [0.3%] for the 2-mg haloperidol group vs 1 [0.1%] for the placebo group). Conclusions and Relevance:Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. Trial Registration:clinicaltrials.gov Identifier: NCT01785290.

SUBMITTER: van den Boogaard M

PROVIDER: S-EPMC5839284 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:BackgroundDelirium has been long considered as a major contributor to cognitive impairments and increased mortality following a critical illness. Pharmacologic and non-pharmacologic strategies are used against delirium in the intensive care unit (ICU), despite these strategies remaining controversial. Previous studies have shown the feasibility of using virtual reality within the ICU setting, and we propose to use this technology to investigate the effect of immersive virtual reality stimulation on the incidence of delirium in the ICU. Moreover, we propose to use motion sensors to determine if patient movement patterns can lead to early prediction of delirium onset.MethodsThis study is conducted as a randomized clinical trial. A total of 920 critically ill patients in the ICU will participate. The control group will receive standard ICU care, whereas the intervention group will, in addition to the standard ICU care, receive relaxing 360-degree immersive virtual reality content played inside a head-mounted display with noise-cancelling headphones, three times a day. The first 100 patients, regardless of their group, will additionally have their movement patterns recorded using wearable and ambient sensors. Follow-up measurements will take place 6 months after discharge from the ICU.DiscussionDelirium is widely present within the ICU setting but lacks validated prevention and treatment strategies. By providing patients with virtual reality stimulation presented inside a head-mounted display and noise-cancelling headphones, participants may be isolated from disturbances on an ICU. It is believed that by doing so, the incidence of delirium will be decrease among these patients. Moreover, identifying movement patterns associated with delirium would allow for early detection and intervention, which may further improve long-term negative outcomes associated with delirium during critical care.Trial registrationClinicalTrials.gov NCT04498585 . Registered on August 3, 2020.

Project description:Ketamine is increasingly being used for analgosedation, but its effect on delirium remains unclear. We compared delirium risk variables and ketamine analgosedation use between adults who developed incident delirium and those who did not, evaluated whether ketamine analgosedation increases delirium risk, and compared ICU delirium characteristics, treatments, and outcomes between ketamine and nonketamine patients with delirium.DesignSecondary, subgroup analysis of a cohort study.SettingSingle, 36-bed mixed medical-surgical ICU in the Netherlands from July 2016 to February 2020.PatientsConsecutive adults were included. Patients admitted after elective surgery, not expected to survive greater than or equal to 48 hours, admitted with delirium, or where delirium occurred prior to ketamine use were excluded.InterventionNone.Measurements and main resultsTrained ICU nurses evaluated patients without coma (Richmond Agitation Sedation Scale. -4/-5) every 8 hours with the Confusion Assessment Method ICU; a delirium day was defined by greater than or equal to1 + Confusion Assessment Method ICU and/or scheduled antipsychotic use. Among 11 variables compared between the delirium and nondelirium groups (Baseline: age, Charlson Comorbidity score, cognitive impairment, admission type, and Acute Physiology and Chronic Health Evaluation-IV score, daily ICU [until delirium occurrence or discharge]: Sequential Organ Failure Assessment score, coma, benzodiazepine, opioid, and ketamine use) and total ICU days, 7 (age, Charlson score, Sequential Organ Failure Assessment score, coma, benzodiazepine, opioid, and ketamine use) were significantly different and were entered, along with delirium occurrence, in a logistic regression model. A total of 332 of 925 of patients (36%) developed delirium. Ketamine use was greater in patients with delirium (54 [16%] vs 4 [0.7%]; p < 0.01). Ketamine use (adjusted odds ratio, 5.60; 95% CI, 1.09-29.15), age (adjusted odds ratio, 1.03; 95% CI, 1.01-1.06), coma (adjusted odds ratio, 2.10; 95% CI, 1.15-3.78), opioid use (adjusted odds ratio, 171.17; 95% CI, 66.45-553.68), and benzodiazepine use (adjusted odds ratio, 34.07; 95% CI, 8.12-235.34) were each independently and significantly associated with increased delirium. Delirium duration, motoric subtype, delirium treatments, and outcomes were not different between the ketamine and nonketamine groups.ConclusionsKetamine analgosedation may contribute to increased ICU delirium. The characteristics of ketamine and nonketamine delirium are similar. Further prospective research is required to evaluate the magnitude of risk for delirium with ketamine use.

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Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial.

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