Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

doi:10.1056/nejmc1901272

Cited by 7 publications

(4 citation statements)

References 40 publications

(41 reference statements)

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“…[23][24][25][26][27][28] The incidence of delirium in critically ill patients is high, and the delirium prevalence was reported to be 48% in a large, 21-centre, prospective study that included only mechanically ventilated and shock patients, a population that for >15 years had consistently shown delirium rates of approximately 75% using the same methodology. 29 However, the incidence of ICU delirium reported in the previous literature varies greatly because of the population studied. According to epidemiological studies, the incidence of postoperative delirium is approximately 45-50%.…”

Section: Discussionmentioning

confidence: 99%

Association between body mass index and delirium incidence in critically ill patients: a retrospective cohort study based on the MIMIC-IV Database

Fu,

Zhang,

Zhang

et al. 2024

BMJ Open

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ObjectivesDelirium is a form of brain dysfunction with high incidence and is associated with many negative outcomes in the intensive care unit. However, few studies have been large enough to reliably examine the associations between body mass index (BMI) and delirium, especially in critically ill patients. The objective of this study was to investigate the association between BMI and delirium incidence in critically ill patients.DesignA retrospective cohort study.SettingData were collected from the Medical Information Mart for Intensive Care-IV V2.0 Database consisting of critically ill participants between 2008 and 2019 at the Beth Israel Deaconess Medical Center in Boston.ParticipantsA total of 20 193 patients with BMI and delirium records were enrolled in this study and were divided into six groups.Primary outcome measureDelirium incidence.ResultsGeneralised linear models and restricted cubic spline analysis were used to estimate the associations between BMI and delirium incidence. A total of 30.81% of the patients (6222 of 20 193) developed delirium in the total cohort. Compared with those in the healthy weight group, the patients in the different groups (underweight, overweight, obesity grade 1, obesity grade 2, obesity grade 3) had different relative risks (RRs): RR=1.10, 95% CI=1.02 to 1.19, p=0.011; RR=0.93, 95% CI=0.88 to 0.97, p=0.003; RR=0.88, 95% CI=0.83 to 0.94, p<0.001; RR=0.94, 95% CI=0.86 to 1.03, p=0.193; RR=1.14, 95% CI=1.03 to 1.25, p=0.010, respectively. For patients with or without adjustment variables, there was an obvious U-shaped relationship between BMI as a continuous variable and delirium incidence.ConclusionBMI was associated with the incidence of delirium. Our results suggested that a BMI higher or lower than obesity grade 1 rather than the healthy weight in critically ill patients increases the risk of delirium incidence.

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Section: Discussionmentioning

confidence: 99%

Association between body mass index and delirium incidence in critically ill patients: a retrospective cohort study based on the MIMIC-IV Database

Fu,

Zhang,

Zhang

et al. 2024

BMJ Open

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“…The Hope-ICU trial, a trial assessing prophylactic effect of haloperidol, found that haloperidol reduced agitation [ 18 ], which is in line with our findings. An explanation could be that the EuRIDICE trial had a higher rate of agitated patients as compared to other trials (mixed delirium 73% in EuRIDICE versus 45% in AID-ICU [defined as RASS > 0] and 37% in MIND-USA with only 11% with agitated delirium upon inclusion) and included patients with lower disease severity (SOFA 5/6 vs. 11 in MIND-USA and mortality 16–21% as opposed to around 40% in the other two trials) [ 7 , 8 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

Smit,

Slooter,

Devlin

et al. 2023

Crit Care

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Background The role of haloperidol as treatment for ICU delirium and related symptoms remains controversial despite two recent large controlled trials evaluating its efficacy and safety. We sought to determine whether haloperidol when compared to placebo in critically ill adults with delirium reduces days with delirium and coma and improves delirium-related sequelae. Methods This multi-center double-blind, placebo-controlled randomized trial at eight mixed medical-surgical Dutch ICUs included critically ill adults with delirium (Intensive Care Delirium Screening Checklist ≥ 4 or a positive Confusion Assessment Method for the ICU) admitted between February 2018 and January 2020. Patients were randomized to intravenous haloperidol 2.5 mg or placebo every 8 h, titrated up to 5 mg every 8 h if delirium persisted until ICU discharge or up to 14 days. The primary outcome was ICU delirium- and coma-free days (DCFDs) within 14 days after randomization. Predefined secondary outcomes included the protocolized use of sedatives for agitation and related behaviors, patient-initiated extubation and invasive device removal, adverse drug associated events, mechanical ventilation, ICU length of stay, 28-day mortality, and long-term outcomes up to 1-year after randomization. Results The trial was terminated prematurely for primary endpoint futility on DSMB advice after enrolment of 132 (65 haloperidol; 67 placebo) patients [mean age 64 (15) years, APACHE IV score 73.1 (33.9), male 68%]. Haloperidol did not increase DCFDs (adjusted RR 0.98 [95% CI 0.73–1.31], p = 0.87). Patients treated with haloperidol (vs. placebo) were less likely to receive benzodiazepines (adjusted OR 0.41 [95% CI 0.18–0.89], p = 0.02). Effect measures of other secondary outcomes related to agitation (use of open label haloperidol [OR 0.43 (95% CI 0.12–1.56)] and other antipsychotics [OR 0.63 (95% CI 0.29–1.32)], self-extubation or invasive device removal [OR 0.70 (95% CI 0.22–2.18)]) appeared consistently more favorable with haloperidol, but the confidence interval also included harm. Adverse drug events were not different. Long-term secondary outcomes (e.g., ICU recall and quality of life) warrant further study. Conclusions Haloperidol does not reduce delirium in critically ill delirious adults. However, it may reduce rescue medication requirements and agitation-related events in delirious ICU patients warranting further evaluation. Trial registration: ClinicalTrials.gov (#NCT03628391), October 9, 2017.

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“…The median number of days alive without delirium or coma was 8.5 (95% confidence interval 5.6 to 9.9) in the placebo group, 7.9 (4.4 to 9.6) in the haloperidol group, and 8.7 (5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups) 89. Furthermore, no significant between group differences were seen in the secondary endpoints (30 day and 90 day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge) 89. These findings are consistent with a systematic review of 16 RCTs and 10 observational studies, which found no difference in delirium outcomes (for example, incidence, duration, or severity of delirium, sedation status, length of stay, cognitive function, or death) in patients treated with haloperidol, second generation antipsychotic drugs, or placebo 90.…”

Section: Management Of Deliriummentioning

confidence: 97%

“…The largest trial of antipsychotic treatment to date, the Modifying the Impact of Neuropsychological Dysfunction-USA (MIND-USA) study, was a multisite RCT comparing haloperidol, ziprasidone, and placebo in 566 patients with delirium, which found no significant difference in number of days alive without delirium or coma during the 14 day intervention period 89. The median number of days alive without delirium or coma was 8.5 (95% confidence interval 5.6 to 9.9) in the placebo group, 7.9 (4.4 to 9.6) in the haloperidol group, and 8.7 (5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups) 89. Furthermore, no significant between group differences were seen in the secondary endpoints (30 day and 90 day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge) 89.…”

Section: Management Of Deliriummentioning

confidence: 99%

Delirium and long term cognition in critically ill patients

Wilcox

Girard

Hough

2021

BMJ

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Delirium, a form of acute brain dysfunction, is very common in the critically ill adult patient population. Although its pathophysiology is poorly understood, multiple factors associated with delirium have been identified, many of which are coincident with critical illness. To date, no drug or non-drug treatments have been shown to improve outcomes in patients with delirium. Clinical trials have provided a limited understanding of the contributions of multiple triggers and processes of intensive care unit (ICU) acquired delirium, making identification of therapies difficult. Delirium is independently associated with poor long term outcomes, including persistent cognitive impairment. A longer duration of delirium is associated with worse long term cognition after adjustment for age, education, pre-existing cognitive function, severity of illness, and exposure to sedatives. Interestingly, differences in prevalence are seen between ICU survivor populations, with survivors of acute respiratory distress syndrome experiencing higher rates of cognitive impairment at early follow-up compared with mixed ICU survivor populations. Although cognitive performance improves over time for some ICU survivors, impairment is persistent in others. Studies have so far been unable to identify patients at higher risk of long term cognitive impairment; this is an active area of scientific investigation.

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Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

Cited by 7 publications

References 40 publications

Association between body mass index and delirium incidence in critically ill patients: a retrospective cohort study based on the MIMIC-IV Database

Association between body mass index and delirium incidence in critically ill patients: a retrospective cohort study based on the MIMIC-IV Database

Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: the EuRIDICE randomized clinical trial

Delirium and long term cognition in critically ill patients

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