Background Intensive care unit (ICU) delirium affects approximately one-third to one-half of critically ill adults and is associated with prolonged mechanical ventilation, increased ICU and hospital length of stay, higher mortality, and long-term cognitive impairment [1]. Contemporary Society of Critical Care Medicine Guidelines for Prevention and Management of Pain, Anxiety, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (SCCM PADIS) emphasize structured delirium assessment, non-pharmacologic prevention, and cautious sedation, while discouraging routine antipsychotic use based on neutral findings from major randomized trials such as MIND-USA and AID-ICU [2]. Despite these recommendations, antipsychotics remain frequently used, with variability in agent selection and route, including off-label intravenous ziprasidone, raising safety and monitoring concerns. This study aims to compare duration of first-episode ICU delirium in patients receiving scheduled quetiapine versus as needed (PRN) ziprasidone, and to evaluate safety and utilization outcomes, including baseline corrected QT interval (QTc) prolongation, ventilator days, and ICU and hospital length of stay.
Methods A retrospective analysis was performed in critically ill adults admitted to the ICU who received newly initiated antipsychotic therapy for delirium at AdventHealth Winter Park from December 2023 to November 2025. Eligible patients were ≥18 years old, had an ICU admission, received scheduled quetiapine for >24 hours or PRN ziprasidone, and screened positive on Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Patients were excluded if pregnant, had QTc >500 msec, received antipsychotics prior to ICU admission, or had neurologic or psychiatric conditions confounding delirium assessment, including schizophrenia, bipolar disorder, Parkinson’s disease, traumatic brain injury, stroke, psychosis, dementia, neurosurgical conditions, alcohol withdrawal, or coma. Patients were stratified by regimen (scheduled quetiapine vs PRN ziprasidone). The primary endpoint was duration of first episode of delirium in hours. Secondary outcomes included adverse drug events, QTc prolongation, ventilator days, ICU/hospital length of stay, and an exploratory subgroup comparing intramuscular versus intravenous ziprasidone. Categorical variables were analyzed using chi-square testing, and continuous variables were assessed for normality with the Shapiro-Wilk test and compared using the Mann-Whitney U test when non-normally distributed.
Results After screening 251 patients, 93 met inclusion criteria; 10 who received both agents were excluded, leaving 83 patients (scheduled quetiapine n=38; PRN ziprasidone n=45). There was no significant difference in duration of first-episode ICU delirium (median 35.0 hours [IQR 24.0-57.5] with quetiapine vs 28.4 hours [IQR 12.9-52.5] with ziprasidone; p=0.29). QTc prolongation >500 ms occurred in 11% of quetiapine and 27% of ziprasidone patients, without statistical significance (p=0.12). Median RASS at positive CAM-ICU was -1.5 (IQR -3.0 to 0.0) vs -1.0 (IQR -2.0 to 1.0), respectively (p=0.34). Subgroup analyses showed no differences in delirium duration or QTc prolongation between intravenous and intramuscular ziprasidone.
Conclusion In this retrospective study, scheduled quetiapine and PRN ziprasidone were associated with similar durations of first-episode ICU delirium and comparable safety outcomes, including QTc prolongation. Subgroup analyses showed no differences between intravenous and intramuscular ziprasidone. However, this study was limited by an insufficient sample size to achieve adequate statistical power, which may have impacted the ability to detect differences. Overall, antipsychotic selection and route of administration showed no statistically significant difference between delirium duration or safety outcomes.
References: - Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753-1762.
- Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU (PADIS). Crit Care Med. 2018.
