Valproic Acid in the Management of Delirious, Agitated, Critically Ill Toxicology Patients

Background/Significance: Delirium is a frequent complication of both severe intoxication itself, and of methods involved in critical care management. Valproic acid (VPA) is an anticonvulsant with distinct mechanisms of action that may be considered adjunctive to standard sedatives in cases of “refractory hyperactive delirium” (Sher, 2015). We report on the use of VPA in the management of 9 toxic patients with delirium and agitation in the intensive care unit (ICU).

Case Series: Patients came to the attention of the Consultation-Liaison Psychiatry service after being admitted to the ICU for severe agitation deemed secondary to intoxication and/or withdrawal. Patients were chosen to receive VPA if they had been treated with dexmedetomidine, propofol, midazolam, and haloperidol and/or olanzapine without achieving adequate sedation and then progressing toward extubation by the fifth day of admission. 8 patients were given parenteral ketamine (2-5 mg/kg) during initial management prior to ICU admission. 7 of the 9 patients were men between the ages of 20 and 42. By toxicologic testing, 7 patients had confirmed exposure to methamphetamines; 2 had exposure to cocaine. 4 were reported to have consumed a synthetic cannabinoid; 2 were suspected of using a synthetic stimulant – toxicologic testing was not available for confirmation of novel substances. 5 of the patients had detectable ethanol on serum assays. There were documented histories of PTSD and antisocial personality disorder in 6 and 4 patients, respectively.

Doses of VPA were employed well above what would be given based on standard pharmacokinetics (range 3500-7000 mg IV/day, divided 4 times daily). Serum concentrations of VPA guided dosing, with a target range of 70-120 mg/L. Levocarnitine was given empirically (500-1000 mg IV 3 times daily) to support safe VPA metabolism. The other active sedative treatments above were continued initially, with preference typically given to discontinue olanzapine first, then propofol, then benzodiazepines once effects of VPA were realized.

Results: Patients displayed less agitation as measured by the RASS an average of 42 hours after initiation of VPA (range 16-108 hours). Average RASS on the day of initiation of VPA was 3.1, decreasing to 1.2 two days later. Prior to this treatment series, several patients with these toxicologic and psychiatric characteristics could not be safely extubated; tracheostomies were performed with protracted mechanical ventilation and discharge to long-term acute care hospitals. All 9 VPA-treated patients successfully liberated from mechanical ventilation (28-170 hours after VPA) without tracheostomy.

Conclusion: High-dose VPA is a potentially effective adjunct in the management of agitation in acute toxicology patients. Concerns about hyperammonemia may be alleviated with co-administration of levocarnitine.

Reference:

1 Sher Y, Miller AC, Lolak S, et al. Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale. J Neuropsychiatry Clin Neurosci. 2015;27:365-70.