Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Valproic Acid for Treatment of Hyperactive or Mixed Delirium in ICU

Conditions
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Hyperactive Delirium, Mixed Delirium

Intervention / Treatment
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* Drug: Valproic Acid
* Drug: Placebo
* Drug: Haloperidol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valproic Acid<br>Start: VPA PO/NGT 500 mg BID If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1000 mg PO/NGT QHS If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1500 mg PO/NGT QHS If need to increase in 24 or more hours: VPA 500 mg PO/NGT Q am, 2000 mg PO/NGT QHS Rescue at all stages: HAL IV 2-5 mg Q4hr PRN | Drug: Valproic Acid<br>* 1. Start: VPA PO/NGT 500 mg BID 2. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1000 mg PO/NGT QHS 3. If need to increase in 24 or more hours: VPA 500 mg PO/NGT q am, 1500 mg PO/NGT QHS 4.If need to increase in 24 or more hours: VPA 500 mg PO/NGT Q am, 2000 mg PO/NGT QHS<br>* Other names: Depakote;Drug: Haloperidol<br>* Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN<br>* Other names: Haldol;|
| Placebo Comparator: Placebo<br>Placebo: PO/NGT BID Rescue: HAL IV 2-5 mg Q4hr PRN | Drug: Placebo<br>* Placebo 500 mg matched to VPA BID PO/NGT<br>Drug: Haloperidol<br>* Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN<br>* Other names: Haldol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Delirium Resolution | Delirium resolution was defined as three negative Confusion Assessment Method (CAM) assessments, performed by nurses every 12 hours. | Up to 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Use of as Needed Anti-psychotic Agent | Amount of Haldol administered. | Up to 5 days | 
| Side Effects From Medications | Side effects may have included liver function test (LFT) increase, platelet decrease, bleeding, or QTc prolongation. | Up to 5 days | 
| Intensity of Delirium as Measured by the Intensive Care Delirium Screening Checklist (ICDSC) Delirium Severity Scale | The items include the assessment of: (1) consciousness ( deep sedation/coma, agitation, normal wakefulness, or light sedation); (2) inattention; (3) disorientation; (4) hallucination, delusion, or psychosis; (5) psychomotor agitation or retardation; (6) inappropriate speech or mood; (7) sleep-wake cycle disturbances; and (8) fluctuation of symptomatology. The maximum score is eight; scores of ≥4 indicate the presence of delirium and score zero is indicate not in delirium. Each item is scored 0-8. | Up to 5 days | 
| Length of ICU Stay |  | During expected average hospitalization (of 1 month) | 
| Length of Hospital Stay | Participation in the study ended once delirium was resolved and the patient was off study drug. This outcome presents the total length of hospital stay, which may have been longer than participation in the study. | During expected average hospitalization (of 1 month) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperactive delirium, Mixed delirium, Anti-psychotic, Haldol, Valproic Acid