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.

Study Overview

• Status: Terminated
• Conditions: Hyperactive Delirium; Mixed Delirium
• Intervention / Treatment: Drug: Valproic Acid; Drug: Haloperidol; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Valproic Acid; 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; 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; Other Names: Depakote; Valproate; VPA; Drug: Haloperidol; Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN; Other Names: Haldol
Placebo Comparator: Placebo; Placebo: PO/NGT BID Rescue: HAL IV 2-5 mg Q4hr PRN	Drug: Haloperidol; Both arms (intervention VPA and placebo) will receive flexible as needed haloperidol: Rescue: HAL IV 2-5 mg Q4hr PRN; Other Names: Haldol; Drug: Placebo; Placebo 500 mg matched to VPA BID PO/NGT

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Yelizaveta Sher, M.D., Stanford University; Study Director: Jose R Maldonado, M.D., Stanford University

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: January 8, 2015
• First Submitted That Met QC Criteria: January 21, 2015
• First Posted (Estimate): January 22, 2015

Study Record Updates

• Last Update Posted (Actual): June 26, 2019
• Last Update Submitted That Met QC Criteria: May 31, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Valproic Acid; Hyperactive delirium; Mixed delirium; Anti-psychotic; Haldol
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Dyskinesias; Psychomotor Disorders; Delirium; Psychomotor Agitation; Hyperkinesis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; GABA Agents; Anticonvulsants; Antimanic Agents; Anti-Dyskinesia Agents; Valproic Acid; Haloperidol; Haloperidol decanoate
• Other Study ID Numbers: 28330

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No