Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU
Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU
Delirium is the most often encountered psychiatric diagnosis in the general hospital, with
 incidence up to 85% in the intensive care unit (ICU) setting and with significant
 consequences on patients' morbidity and mortality. Currently, although not FDA approved,
 antipsychotics are often considered the first-line pharmacological treatment. However, there
 can be limitations to their use, including side effects or lack of efficacy. Valproic acid
 (VPA) is one of the alternatives at times used in such patients which from limited case
 series data appears to be helpful and tolerated. VPA can provide relief from agitation that
 poses a threat to the safety and recovery of the patient. Moreover, mechanistically it
 addresses the neurochemical and cellular abnormalities inherent in delirium (it has
 NMDA-antagonist, anti-dopaminergic, GABAergic,anti-inflammatory, anti-apoptotic, and histone
 deacetylase inhibitor properties, among others). The purpose of this study is to evaluate the
 efficacy and tolerability of the VPA in the first known to us randomized controlled trial.
The investigators plan to investigate the efficacy and tolerability of scheduled VPA as
 compared to placebo with as needed basis (PRN) haloperidol (as a back-up in both arms) for
 treatment of hyperactive or mixed delirium. Patients will be randomized to scheduled VPA or
 placebo (normal saline) and both arms will have flexible PRN dosing of haloperidol. Thus, the
 investigators plan to learn the time to delirium resolution in patients treated with VPA
 versus placebo; percentage of patients responding to VPA versus placebo; tolerability of VPA
 versus placebo. If addition of scheduled VPA proves to shorten time to delirium resolution as
 compared to placebo, lead to less use of haloperidol, and/or have fewer side effects, it
 would provide a very important addition to our limited evidence-based repertoire of delirium
 treatment. Moreover, this pilot study would then pave the way for the bigger randomized
 control trial powered to detect its effect size.
Inclusion Criteria:

 -  patients 18 years of age and older

 -  admitted to surgical ICU

 -  diagnosed with hyperactive or mixed delirium

 Exclusion Criteria:

 -  hypoactive delirium

 -  primary team does not think patient is appropriate to participate

 -  no oral access (PO or NGT)

 -  non-English speaking

 -  contraindication to study medications

 -  pregnant women or woman of child-bearing age not on documented contraception

 -  QTc = or greater than 480

 -  hepatic dysfunction

 -  decreased platelets or platelet dysfunction

 -  bleeding disorder, current major bleeding

 -  history of NMS, epilepsy, or PD

 -  diagnosis of schizophrenia, bipolar disorder or schizoaffective disorder

 -  on warfarin or carbapenems

 -  delirium due to alcohol withdrawal

 -  treated with antipsychotics for more than 48 hours prior to study enrollment.