Valproic Acid in the Management of Delirium.

Context: Antipsychotics and benzodiazepines do not improve delirium. Valproic acid (VPA) has been used recently to treat agitation in delirium.

Objectives: To review the evidence for VPA in the management of Delirium.

Methods: Systematic review. English language, age 19 and above, from 1946 to January 12, 2021.

Mesh Terms: "Valproic acid", "valproate", "sodium valproate", "delirium", "acute mania with delirium" in PubMed and Ovid.

Exclusion: Studies of VPA used for diagnoses other than delirium.

Results: 21 abstracts were identified and 10 studies were included in the review (252 patients): One prospective open label study (n: 7), 2 case series (n: 22), 4 retrospective studies (n: 219) and 3 case reports (n: 4). No randomized controlled trial (RCT) evaluates the effect of VPA in delirium. 237/250 (94.8%) patients were in the ICU. Mean age was 59.7 (27-87). 153/204 (74%) were male. The mean starting dose was 733 mg/day in 148 patients and the mean dose at follow up was 1061 mg/day in 205 patients. CAM ICU was used to diagnose delirium in 6 reviews. Delirium improved in case series in 19/22 patients. Delirium improved in retrospective studies at day 3 compared to day 1. VPA levels were not consistently reported. Hyperammonemia (12-19%) and thrombocytopenia (9-13%) were the most common side effects. No deaths were attributed to VPA.

Conclusion: VPA is being used more frequently for delirium. The evidence is limited to retrospective studies and case series. There is a need for RCT to evaluate the effect of VPA in delirium compared to other alternatives and placebo.