THE USE OF VALPROIC ACID FOR

DELIRIUM AND AGITATION IN

THE INTENSIVE
,
CARE UNIT
SETTING

VICTORIA LIU, PHARMACY STUDENT

NICOLE TOKIKO ANDREWS, PHARMD, BCCCP
 OBJECTIVES
1. Explain pertinent background information regarding
the use of sedatives and antipsychotics for intensive
care unit (ICU) delirium and agitation
2. Describe a patient case emphasizing the course of
their ICU stay, and the progression of delirium and
agitation
3. Identify and critique primary literature describing
the efficacy and safety of using valproic acid (VPA)
for ICU delirium and agitation
4. Apply literature and guidelines to answer the clinical
question
BACKGROUND

Delirium and agitation are

associated with poor
About 32% of patients outcomes including
hospitalized in the ICU worsening cognition post-
experience delirium, an discharge, increased
acute change in
mortality, and increased
cognition and attention
length of hospital stay​
PADIS GUIDELINES

• Emphasizes management of ICU delirium and agitation

through pain control optimization and adequate sedation
• Recommends non-pharmacologic interventions that improve
cognition such as optimizing sleep, mobility, hearing and
vision
• Does not recommend haloperidol, atypical
antipsychotics, dexmedetomidine, statins, or ketamine for
preventing or treating delirium in the ICU
 19 y.o. male presents from OSH
PATIENT following anticholinergic overdose c/b
cardiac electrical instability, status
CASE epilepticus, and AHHRF, now with
cardiogenic/distributive shock.

On day 5 of hospital stay, pt presented

with agitation and delirium likely due to
withdrawal, ICU delirium and overall lack
of sleep.

Psych recommended initiating IV

VPA 250 mg BID with PRN Depakote
Sprinkles.
PATIENT CASE
• RN notified providers that patient growing increasingly agitated, being
inappropriate with staff and has not slept for over 36 hours
• Psych consulted regarding which sleep medications can be safely given
o Patient was subsequently started on scheduled melatonin
o Valproic acid order:

• Subjective/Objective:
o HR 78, BP 130/70, RR 32
o Sedation gtts weaned, RASS +3
o LFTs trending up: AST 154, ALT 211, Alk phos 68
o CBC and BMP WNL
VALPROIC ACID (VPA) AND DIVALPROEX (DVP)
• Divalproex sodium is the stable coordinated compound of VPA and sodium
valproate
o Pharmacokinetically, they are similar but not the same
• Mood stabilizer and anti-convulsant with indications for seizures, migraine
prophylaxis, bipolar disorder
Pathophysiology of delirium:
1. Cholinergic hypofunction VPA works on delirium by
2. Excess dopaminergic activity decreasing glutamate,
3. Excess glutamate
4. Altered levels of GABA
increasing GABA, increasing
5. Disturbances in serotonin, histamine serotonin, and increasing
and melatonin acetylcholine.
 Black Box warnings:
VALPROIC
• Fetal risk
ACID ADVERSE • Hepatotoxicity
EFFECTS AND •
•
Mitochondrial disease
Pancreatitis
MONITORING
Other adverse events:

• Thrombocytopenia
• Hyperammonemia and encephalopathy
• CNS effects
• Interactions

Monitoring:

• Valproic acid total and free levels (for seizures)

• LFTs
• Ammonia
CLINICAL EVIDENCE
• Two retrospective studies and one systematic review:
o 2020 - Crowley et al. Valproic Acid for the Management of
Agitation and Delirium in the Intensive Care Setting: A Retrospective
Analysis
• 2022 - Cuartas et al. Valproic Acid in the Management of Delirium
o 2024 - Swayngm et al. Use of Valproic Acid for the Management of
Delirium and Agitation in the Intensive Care Unit
VALPROIC ACID FOR
THE MANAGEMENT Background: VPA has been proposed as an
OF AGITATION AND alternative agent for treatment of delirium and
DELIRIUM IN THE agitation in the ICU
INTENSIVE CARE
SETTING: A Question: What is the clinical safety and efficacy
RETROSPECTIVE AN of using VPA for delirium and agitation in the
ALYSIS ICU setting?
CROWLEY ET AL.
Methods: Retrospective, descriptive analysis at a
tertiary academic medical center
• Inclusion criteria:
• Received any formulation of VPA during stay for delirium
or agitation for minimum of 3 days
• Exclusion criteria:
• Received VPA for indication other than delirium or
agitation
 • End Points
o Efficacy end point: Prevalence of delirium and agitation while
patients were receiving VPA therapy for min of 3 days to up to 7
days
• Agitation: RASS ≥ 2
• Delirium: at least 1 positive CAM-ICU

o Safetyend point: Prevalence of leukopenia,

thrombocytopenia, hyperammonemia, LFT abnormalities, and
pancreatitis
• Hematologic: WBC < 4200, Plt < 140, or decrease in plt > 50%
• Liver function: >3 times the ULN
RASS = Richmond Agitation Sedation Scale
• Hyperammonemia:
CAM-ICU = Confusion >60ICU
Assessment Method for the micromol/L
RESULTS
• N = 46
• Mean VPA dose: 500 mg or 6.2 mg/kg, titrated to 1000 mg/day or 11.1 mg/kg/day on day 7 of therapy,
mean VPA level, n = 33: 34.9 microg/mL
• Median duration of therapy: 8 days
• No major adverse events observed
AUTHOR'S CONCLUSIONS

o Prevalence of delirium and agitation had a downward

trend throughout VPA therapy
o Decrease in number of sedative agents during VPA therapy
including benzodiazepines, propofol, dexmedetomidine, and
antipsychotic agents
o Can be used as an alternative to assist in the management of ICU
delirium and agitation for those unable to receive antipsychotic
agents
o Additional prospective data are needed to validate these findings
 Strengths: Included patients who are unable to tolerate or use antipsychotics or
STRENGTHS sedatives for delirium and agitation
AND
LIMITATIONS Patient population included trauma, surgical and oncology patients.
Most common reasons for admission included trauma/burns,
transplant, pneumonia, coronary artery disease and heart failure

Defined delirium and agitation using the RASS and CAM-ICU

scoring system (Gold Standard in the ICU setting)

Limitation Did not record non-pharmacologic therapies used (i.e. mobility,

hearing, sleep cycle management) though
s:
No placebo group – unable to establish degree of reduction in
agitation and delirium

No assessment of change in degree of delirium/agitation (difference

in RASS scores/CAM-ICU scores) throughout therapy
PERSONAL
VPA may be an appropriate alternative for patients
CONCLUSIONS refractory or intolerant to other antipsychotics

Since our patient exhibited more symptoms of

hyperactive delirium, perhaps could have benefited
from a more sedating agent

Study population consisted of trauma, transplant and

oncology patients

Larger randomized trials need to be conducted to

evaluate the use of VPA as an alternative to
antipsychotics
PATIENT CASE

• After 3 days of IV VPA 250 mg BID with

divalproex sprinkles 250 mg TID PRN, LFTs
began trending up
o Discontinued on day 10 per psych for rising LFTs
and improvement in behavior
 Improvement due to mobility?
o RASS from +4 to 0
• Transferred to 5WA for psychiatric evaluation
o Patient exhibited continued improvement in
behavior, was allowed friends and family to visit
• Discharged on day 16 with no new medications
REFERENCES
Crowley K, Urben L, Hacobian G, et al. Valproic Acid for the Management of Agitation and Delirium in the
Intensive Care Setting: A Retrospective Analysis. Clin Ther. 2020; 42(4): 65-73.
Cuartas CF, Davis M. Valproic Acid in the Management of Delirium. Am J Hosp Palliat Care. 2022;39(5):562-
569. doi:10.1177/10499091211038371
Devlin J, Skrobik Y, Gelinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain,
Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care
Medicine. 2018; 46(9): 825-873.
Farzane Abaseynejad, Rahim Akrami, Reza Mohebbati, Sajad Sehab Negah, Mohammad Mohammad-Zadeh, et
al., The Effect of Sodium Valproate on Cardiovascular Responses in Pentylenetetrazol Kindling Model of
Epilepsy. Biomed J Sci & Tech Res 42(3)-2022. BJSTR. MS.ID.006746.
Swayngim R, Preslaski C, Dawson J. Use of Valproic Acid for the Management of Delirium and Agitation in
the Intensive Care Unit. J Pharm Pract. 2024;37(1):118-122. doi:10.1177/08971900221128636
Valproic Acid and Derivatives. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available
at: http://online.lexi.com.
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