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

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.

Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. METHODS: This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. RESULTS: We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. CONCLUSIONS: Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. TRIAL REGISTRATION: CRD42017081133, date of registration 28 November 2017.

Prognostic significance of delirium subtypes in critically ill medical and surgical patients: a secondary analysis of a prospective multicenter study.

BACKGROUND: The prognostic implication of delirium subtypes in critically ill medical and surgical patients is scarcely investigated. The objective was to determine how delirium subtypes are associated with hospital mortality and other clinical outcomes. METHODS: We performed a secondary analysis on data from a prospective multicenter study aimed at implementation of delirium-oriented measures, conducted between 2012 and 2015 in The Netherlands. We included adults (≥ 18 years) admitted to the medical or surgical intensive care unit (ICU). Exclusion criteria were neurological admission diagnosis, persistent coma or ICU readmissions. Delirium was assessed using the Confusion Assessment Method-ICU or Intensive Care Delirium Screening Checklist, and delirium subtypes (hypoactive, hyperactive, or mixed) were classified using the Richmond Agitation-Sedation Scale. The main outcome was hospital mortality. Secondary outcomes were ICU mortality, ICU length of stay, coma, mechanical ventilation, and use of antipsychotics, sedatives, benzodiazepines and opioids. RESULTS: Delirium occurred in 381 (24.4%) of 1564 patients (52.5% hypoactive, 39.1% mixed, 7.3% hyperactive). After case-mix adjustment, patients with mixed delirium had higher hospital mortality than non-delirious patients (OR 3.09, 95%CI 1.79-5.33, p = 0.001), whereas hypoactive patients did not (OR 1.34, 95%CI 0.71-2.55, p = 0.37). Similar results were found for ICU mortality. Compared to non-delirious patients, both subtypes had longer ICU stay, more coma, increased mechanical ventilation frequency and duration, and received more antipsychotics, sedatives, benzodiazepines and opioids. Except for coma and benzodiazepine use, the most unfavourable outcomes were observed in patients with mixed delirium. CONCLUSIONS: Patients with mixed delirium had the most unfavourable outcomes, including higher mortality, compared with no delirium. These differences argue for distinguishing delirium subtypes in clinical practice and future research. Trial registration ClinicalTrials.gov NCT01952899.

Delirium in older COVID-19 patients: Evaluating risk factors and outcomes.

OBJECTIVES: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. METHODS: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. RESULTS: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3-33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1-22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40-1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71-4.72] p < 0.001), but not in multivariable analyses. CONCLUSIONS: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty.

Haloperidol, clonidine and resolution of delirium in critically ill patients: a prospective cohort study.

PURPOSE: Haloperidol and clonidine are commonly used to treat agitation in delirious intensive care unit (ICU) patients, but it is unclear whether these agents may shorten the duration of delirium. The objective of this study was to determine whether haloperidol, clonidine, or their combined administration to delirious ICU patients results in delirium resolution. METHODS: This was a cohort study on a mixed ICU, excluding patients with a primary neurological disorder. The main outcome was the probability of delirium resolution, using propensity score matching and Markov multinomial logistic regression models for daily transitions. Secondary outcomes were delirium duration, number of delirium days, ventilation days, length of stay in the ICU and hospital, and ICU mortality. RESULTS: A total of 3614 patients were included (1165 delirious [32%]; 2449 non-delirious [68%]). Delirium occurred on 4708 (18.9%) of 24,906 days. The probability of delirium resolution was lower in delirious patients who received haloperidol (OR 0.47, 95% CI 0.39-0.57), clonidine (OR 0.78, 95% CI 0.63-0.97), or both (OR 0.45, 95% CI 0.36-0.56) compared to untreated delirious patients. Delirious patients who received haloperidol, clonidine, or both had generally longer delirium duration, more delirium and ventilation days, and spent more time in the ICU and in hospital than untreated delirious patients. These agents had no effect on ICU mortality. CONCLUSION: Haloperidol and clonidine use in delirious ICU patients may be associated with reduced probability of delirium resolution. This finding, however, merits further investigation given inherent limitations of this observational analysis.

Efficacy of halopeRIdol to decrease the burden of Delirium In adult Critically ill patiEnts (EuRIDICE): study protocol for a prospective randomised multi-centre double-blind placebo-controlled clinical trial in the Netherlands.

INTRODUCTION: Delirium in critically ill adults is associated with prolonged hospital stay, increased mortality and greater cognitive and functional decline. Current practice guideline recommendations advocate the use of non-pharmacological strategies to reduce delirium. The routine use of scheduled haloperidol to treat delirium is not recommended given a lack of evidence regarding its ability to resolve delirium nor improve relevant short-term and longer-term outcomes. This study aims to evaluate the efficacy and safety of haloperidol for the treatment of delirium in adult critically ill patients to reduce days spent with coma or delirium. METHODS AND ANALYSIS: EuRIDICE is a prospective, multi-centre, randomised, double-blind, placebo-controlled trial. Study population consists of adult intensive care unit (ICU) patients without acute neurological injury who have delirium based on a positive Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU) assessment. Intervention is intravenous haloperidol 2.5 mg (or matching placebo) every 8 hours, titrated daily based on ICDSC or CAM-ICU positivity to a maximum of 5 mg every 8 hours, until delirium resolution or ICU discharge. Main study endpoint is delirium and coma-free days (DCFD) up to 14 days after randomisation. Secondary endpoints include (1) 28-day and 1-year mortality, (2) cognitive and functional performance at 3 and 12 months, (3) patient and family delirium and ICU experience, (4) psychological sequelae during and after ICU stay, (4) safety concerns associated with haloperidol use and (5) cost-effectiveness. Differences in DCFDs between haloperidol and placebo group will be analysed using Poisson regression analysis. Study recruitment started in February 2018 and continues. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus University Medical Centre Rotterdam (MEC2017-511) and by the Institutional Review Boards of the participating sites. Its results will be disseminated via peer-reviewed publication and conference presentations. TRIAL REGISTRATION: NCT03628391.

Sudden unresponsive patient with normal vital signs: what is going on?

PURPOSE OF REVIEW: To summarize the differential diagnosis and diagnostic approach of sudden unresponsiveness with normal vital signs in various settings, including the ICU. RECENT FINDINGS: Sudden unresponsiveness may be either transient or persistent, and may result from primary brain diseases or nonstructural systemic conditions. Life-threatening causes should always be discriminated from those more benign. Regional epidemiology, for example regarding intoxications, and evolving therapeutic management, for example for ischemic stroke, should always be taken into account for optimal opportunity for rapid diagnosis and best management. SUMMARY: Sudden unresponsiveness with normal vital signs should trigger immediate and focused diagnostic evaluation to find or exclude those conditions requiring urgent, and possibly life-saving, management.

Abnormal asymmetry in frontostriatal white matter in children with attention deficit hyperactivity disorder.

A growing body of work utilizing structural and functional brain imaging and neurocognitive measures of executive and attentional function indicates anomalous asymmetry in ADHD. This study examined the white-matter volume and diffusion properties of frontostriatal tracts, as a function of hemisphere, in ADHD and healthy controls. Forty-three young males (21 ADHD-Combined Type and 22 controls) aged 10-18 years underwent structural and diffusion weighted MRI. Tractography applying constrained spherical deconvolution (CSD) was used to construct frontostriatal tracts between each of caudate and putamen and each of dorsolateral prefrontal, ventrolateral prefrontal and orbitofrontal cortices (DLPFC, VLPFC and OFC) in each hemisphere, to examine both volumetric and diffusion microstructure properties. Young people with ADHD did not show the right hemisphere lateralization of volume in the Caudate-VLPFC and Caudate-DLPFC tracts that was evident in controls, however the ADHD group displayed a pronounced lateralization to the left for fractional anisotropy in the Putamen-VLPFC tracts. The degree of volume asymmetry did not correlate with symptom severity; however fractional anisotropy (FA) values that were more strongly lateralized to the left in the Putamen-VLPFC white matter were associated with greater symptom severity. ADHD was associated with anomalous hemispheric asymmetries in both tract volume and underlying white-matter microstructure in major fibre tracts of the frontostriatal system. Our observations of both weaker lateralization to the right in terms of tract volume and stronger lateralization to the left in terms of FA values for the ADHD group, suggests that previous inconsistencies in the literature may reflect the influence of such asymmetries.