2026 Southeastern Residency Conference

Agitation and Delirium in the ICU: Management with Valproic Acid
Maddie Treadway; Sarah Wyatt; Robert Steed; Steve Lindley
Background: Agitation and delirium are common complications in critically ill patients, with delirium occurring in up to 80% of mechanically ventilated patients in the intensive care unit (ICU) setting. These conditions are associated with an increased cost to healthcare systems due to prolonged hospital and ICU length of stay, long-term cognitive impairment, and increased morbidity and mortality. Pharmacological management of delirium and agitation in the ICU often involves antipsychotics or sedatives, which are limited by their arrhythmogenic and deliriogenic side effects. Due to the lack of improvement in clinically meaningful patient-centered outcomes, the Society of Critical Care Medicine’s focused guideline update could not make a recommendation for or against the use of antipsychotics over usual care. More recently, valproic acid (VPA), has emerged as a potential alternative for the management of delirium and agitation in the ICU. Despite promising preliminary data for VPA, evidence remains limited, and institutional practices vary widely. The purpose of this study was to evaluate the efficacy and safety of VPA for the management of agitation and delirium in ICU patients.

Methods: This single-center, retrospective descriptive analysis evaluated 60 adult patients admitted to a medical, surgical-trauma, or cardiovascular ICU from 1/1/2022-7/1/2025. Patients were included if they were ≥ 18 years old, admitted to an ICU for ≥ 24 hours, and received scheduled VPA for the management of delirium or agitation for ≥ 3 days. Patients were excluded if they received VPA for any other indication (i.e., seizures), were pregnant, had a critical care pain observation tool score ≥ 3 immediately before VPA initiation, or were prescribed VPA prior to admission. The primary outcome was the overall change in the Intensive Care Delirium Screening Checklist (ICDSC) and Riker Sedation-Agitation Scale (SAS) scores. The secondary outcomes were the incidence of agitation (SAS > 4) and delirium (ICDSC ≥ 4) for up to 7 days and the change in concurrent psychoactive medications over 7 days. The safety outcome was the incidence of adverse events.

Results: A total of 988 VPA orders were identified, corresponding to 182 patients after removal of duplicate orders. Ninety patients met initial screening criteria, with 60 patients included in the outcomes analysis based on availability of ICDSC and SAS scores. Following initiation of VPA, the incidence of agitation decreased from 80% on days 0–1 to 18.3% on days 3–7 (z = - 5.8, P < 0.001). The incidence of delirium decreased from 46.7% on days 0–1 to 25% during days 3–7 (z = - 2.9, P = 0.003). The median concurrent psychoactive medication use was 3 (IQR 1-5) vs. 3 (IQR 1.75-4.25) on day 1 vs. day 7, respectively. Thrombocytopenia (platelets < 100 10*3/µL) occurred in 4 (6.7%) patients, elevated AST (> 80 IU/L) in 12 (20%) patients, elevated ALT (> 80 IU/L) in 8 (13.3%) patients, and hyperammonemia (> 60 µmol/L) in 7 (11.7%) patients.

Conclusion: In this retrospective analysis, initiation of VPA was associated with statistically significant reductions in agitation and delirium scores among critically ill patients. However, interpretation of these results should be made cautiously given the retrospective design, documentation variability, and the complex nature of critically ill patient populations. Further prospective studies are needed to compare VPA to the standard of care for agitation and delirium treatment in the ICU and establish optimal dosing strategies.