Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. Objective: To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. Design, Setting, and Participants: An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Interventions: Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Main Outcomes and Measures: Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. Results: A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. Conclusions and Relevance: The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. Trial Registration: ClinicalTrials.gov Identifier: NCT01211522.

In-Hospital Depressed Level of Consciousness and Long-Term Functional Outcomes in ICU Survivors.

OBJECTIVES: Among critically ill patients, acutely depressed level of consciousness is associated with mortality, but its relationship to long-term outcomes such as disability and physical function is unknown. We investigated the relationship of level of consciousness during hospitalization with long-term disability and physical function in ICU survivors. DESIGN: Multi-center observational cohort study. SETTING: Medical or surgical ICUs at five U.S. centers. PATIENTS: Adult survivors of respiratory failure or shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Depressed level of consciousness during hospitalization was defined using the Richmond Agitation Sedation Scale (RASS) score (including all negative scores) by calculating the area under the curve using linear interpolation. Sedative-associated level of consciousness was similarly defined for all hospital days that sedation was received. We measured disability in basic activities of daily living (BADLs), instrumental activities of daily living (IADLs), discharge destination, and self-reported physical function. In separate models, we evaluated associations between these measures of level of consciousness and outcomes using multivariable regression, adjusted for age, sex, race, body mass index, education level, comorbidities, baseline frailty, baseline IADLs and BADLs, hospital type (civilian vs veteran), modified mean daily Sequential Organ Failure Assessment score, duration of severe sepsis, duration of mechanical ventilation, and hospital length of stay. Of the 1,040 patients enrolled in the ICU, 781 survived to hospital discharge. We assessed outcomes in 624 patients at 3 months and 527 patients at 12 months. After adjusting for covariates, there was no association between depressed level of consciousness (total or sedation-associated) with BADLs or IADLs at either 3- or 12-month follow-up. There was also no association with self-reported physical function at 3 or 12 months or with discharge destination. CONCLUSIONS: Depressed level of consciousness, as defined by the RASS, was not associated with disability or self-reported physical function. Future studies should investigate additional modifiable in-hospital risk factors for disability and poor physical function following critical illness.