Valproic Acid…for Delirium?

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Nishika Patel
Nishika Patel
Critical care pharmacist with a fondness for cats, wine, and all things vintage. Also an insta-nerd who likes to teach ICU tidbits on her IG page @dr.scriptsndrips.

The Pre-brief

Delirium affects 10-60% of medical inpatients and up to 82% of mechanically-ventilated patients in the ICU. 

It is associated with increases in hospital LOS, patient morbidity and mortality, long-term cognitive impairment, and increased likelihood of requiring a SNF level of care post-discharge. 

Valproic acid (VPA) can be used to treat delirium and may be preferred over antipsychotics or dexmedetomidine in select patients. Read on to find out more. 

What do the guidelines tell us about delirium? 

The 2018 SCCM PADIS guidelines suggest against the routine use of haloperidol to treat delirium (conditional recommendation; low quality of evidence), however the short-term use of haloperidol or an atypical antipsychotic may be warranted, despite a lack of evidence, for patients who experience distressing symptoms (ex: hallucinations, delusion-associated fearfulness) or for patients who may be a danger to themselves or others.  

They also suggest using dexmedetomidine for delirium in mechanically ventilated patients where agitation is precluding weaning/extubation (conditional recommendation; low quality of evidence). 

Why VPA? 

VPA is an antiepileptic agent commonly used for seizures, migraine prophylaxis, and bipolar disorder. However, it can also be used for delirium.  

The pathophysiology of delirium involves: 

1) Cholinergic hypofunction 

2) Excess dopaminergic activity 

3) Excess glutamate 

4) Altered levels of GABA 

5) Disturbances in serotonin, histamine, and melatonin 

VPA addresses these issues by decreasing glutamate, increasing GABA, increasing serotonin,  increasing melatonin, and increasing acetylcholine. 

Several retrospective studies and case reports have been published demonstrating a reduction in agitation, delirium, and adjunctive psychoactive medication use within 48 hours of initiating valproic acid. 

VPA’s place in delirium therapy: 

VPA is a good option for patients who meet the following criteria: 

1) Require rapid control of agitation due to delirium 

2) Require the IV route for delirium treatment 

3) Cannot receive treatment with antipsychotics due to any of the following:

  • If antipsychotics are not effective
  • In the setting of elevated QTc or severe arrhythmias
  • If the patient has Parkinson’s disease or severe antipsychotic-induced EPS 

4) Cannot receive treatment with dexmedetomidine due to any of the following:

  • If adverse cardiovascular side effects
  • If cost is an issue 

VPA should be avoided in pregnancy, hypoactive delirium, current active bleeding or platelets <80,  significant hepatic dysfunction, or pancreatitis. 

Patients who are on carbapenems should avoid treatment with VPA as VPA is unlikely to be effective in these patients. Carbapenems can decrease the serum concentration of valproate products and simply increasing the dose of valproic acid may not adequately compensate for this interaction. 

Valproic acid can cause thrombocytopenia and LFT elevations so these labs should be monitored. Consider checking an ammonia level if mental status worsens during treatment as hyperammonemia can occur.

Recommended dosing of VPA for delirium: 

A range of dosing strategies has been attempted based on published literature.  A review article written by Sher and colleagues recommends the following: 

  • For adult patients: 250 mg PO/IV daily in the morning, 250 mg PO/IV daily in the  afternoon, and 500 mg PO/IV daily before bedtime
  • May increase by up to 2000-2500 mg per 24 hours in DIVIDED doses with a max dose of 60 mg/kg/day
  • For elderly adult patients: 125 mg PO/IV daily in the morning and 250 mg PO/IV daily  before bedtime
  • May titrate up to 1500 mg per 24 hours in DIVIDED doses 

After the patient has improved, taper the dose by 250-500 mg daily (starting with the daytime doses) until it can be discontinued.

The Debrief

  • Delirium is associated with significant patient morbidity and mortality as well as increased hospital LOS and long-term cognitive impairment. 
  • VPA is an effective alternative for patients who cannot receive antipsychotics or dexmedetomidine for delirium treatment. 
  • VPA dosing for delirium varies from study to study; however, a review article written by  Sher and colleagues recommends that adult patients receive 250 mg PO/IV daily in the morning, 250 mg PO/IV daily in the afternoon, and 500 mg PO/IV daily before bedtime and that elderly patients receive 125 mg PO/IV daily in the morning and 250 mg PO/IV  daily before bedtime. 

References

  1. References:

    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. 

  2. Valproic Acid and Derivatives. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc.  Riverwoods, IL. Available at: http://online.lexi.com. 
  3. Sher Y, Cramer A, Ament A, et al. Valproic Acid for Treatment of Hyperactive or Mixed  Delirium: Rationale and Literature Review. Psychosomatics. 2015; 56: 615-25. Bourgeois J, Koike A, Simmons J, et al. J Neuropsychiatry Clin Neurosci. 2005; 17:232-38. Gagnon D, Fontaine G, Smith K, et al. Valproate for Agitation in Critically Ill Patients: A  Retrospective Study. J Crit Care. 2017; 37: 119-25. 
  4. 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. 
  5. Quinn N, Hohlfelder B, Wanek M, et al. Prescribing Practices of Valproic Acid for  Agitation and Delirium in the Intensive Care Unit. Ann Pharmacother. 2021; 55(3): 311- 17. 
  6. Crowley K, Urben L, Hacobian G, et al. Valproic Acid for the Management of Agitation and Delirium in the Intensive Care Setting. Critical Care Medicine. 2018; 46(1): 430.  

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