Treating Agitation of Delirium with Valproic Acid and Climbing Mt. Everest Alike?

I saw the a summary of Dr. Yelizaveta Sher’s study evaluating the use of valproic acid for treating hyperactive delirium.  I think it’s an interesting approach. It was presented at a recent Academy of Psychosomatic Medicine meeting. This led to my clicking around the internet in search of further literature about it. I’m always looking for ways to improve my skill and knowledge base as a psychiatric consultant.

Remember to think about delirium
Remember to think about delirium, image credit to Higgins, I., The detection & prevention of delirium in acute care: an evaluation of the uptake & utility of guidelines by health professionals 2005: Newcastle. What’s the primary intervention for delirium? That’s right; finding and treating the underlying medical causes.
“…And we must build a culture of humanistic clinical excellence.”—Jamos the Elder
“…And we must build a culture of humanistic clinical excellence.”—Jamos the Elder














I also found the TedTalk by Mt. Everest climber Alison Levine.

We’ll come back to that.

After I read Dr. Sher’s summary, I found the most recent case report in PubMed about using valproic acid for agitation from delirium in patients with Bickerstaff Brainstem Encephalitis [1]. One of the references listed at the end of this paper is the case series by Bourgeois and colleagues about using valproic acid as adjuntive therapy in delirious patients in the intensive care unit [2]. Many of the patients had pulmonary disease (and no mention of alcohol or sedative-hypnotic withdrawal) that might have been at least a relative contraindication to the benzodiazepines that were being used as sedating agents in those patients at that time and to which valproic acid was added.

Interestingly, about a year after that paper was published, Pandharipane’s study was published, in which benzodiazepines were discovered to be an independent risk factor for the development of delirium in ICU patients [3]. I wonder if stopping the benzodiazepines might have been one of the first steps in managing the delirium, possibly obviating the necessity to even consider using valproic acid.

While antipsychotics have their drawbacks in the setting of delirium, so does valproic acid, which authors describe fully and which psychiatric consultants would do well to remember to include in the risk/benefit discussion with patients and family. This should cover the risk for valproic acid itself causing delirium from hyperammonemia, and drug-drug interactions which could increase the risk for reduction in blood level of valproic acid (e.g., meropenem interaction) as well as others.

I was glad to read that, according to Dr. Sher in the May 13, 2014 online Clinical Psychiatry New article (which for some reason I could access early in the day yesterday and simply could not access in the afternoon), that a “…randomized controlled trial of valproic acid for the treatment of hyperactive delirium in the ICU is underway.” However, I couldn’t find it listed at Maybe someone out there knows where I could find out more. And here’s a stab at tweeting Dr. Sher’s article:

Research into delirium pathophysiology and clinical care methods is an unbelievably complicated task and it’s a lot like climbing a mountain. There are many parallels to climbing Mt. Everest.

  • Change is a constant feature. We learn one tiny bit about delirium one year–and the next year we find out something that changes everything we assume and everything we do.
  • There’s no room for complacency in this field, either as a researcher or as a geezer psychiatric consultant.
  • Most of the time, delirium presents differently each time I see it. I have developed boilerplate recommendations for dealing with the most common behaviors challenging clinicians who struggle to keep patients safe and to help them recover from delirium. But I frequently find I have to meet new situations not so much with a premixed plan, but a willingness to evolve, exercise flexibility–and sometimes to act with implacability when necessary, regardless of what my boilerplate says.
  • Being a psychiatric consultant and dealing with delirium every day, I’ve gotten acclimatized to some degree to the stress of my job. Often I have to remind myself that trying to teach others how to “think delirium” feels much of the time like I’m going backward more than forward.
  • It’s hard to have as few tools as we have to prevent and manage delirium and yet suck it up and do the job anyway.
  • In fact, it can be helpful to take on the labor of working on delirium quality improvement programs in small steps–and to appreciate the sometimes meager rewards. Showing the bizarre results of a delirious patient’s Clock Drawing Task results to a colleague who thinks the patient has “anxiety” sometimes works like a switch, making the light come on–dimly, but it comes on.
  • Often enough, I feel like I’ve failed because I still get called to evaluate delirium, even when it’s clear that the clinician requesting the consultation recognizes that the problem is delirium. I’ve failed to reach the summit. But we both learn something each and every time. The journey’s the thing, after all.
  • And there will always be other mountains. That’s how it is in managing delirium, running a psychiatry consultation service, and living my life.

Delirium is a complicated field of study and a scourge for our patients. We need to carefully consider all reasonable options for supporting efforts to conduct more research and develop methods of improved clinical care. It’s a lot like climbing Mt. Everest.


Maldonado's Delirium Treatment Algorithm






1. Alam, A. and N. V. Puri (2014). “Inefficacy of antipsychotics in treatment of delirium and agitation in two cases of bickerstaff brainstem encephalitis.” J Neuropsychiatry Clin Neurosci 26(2): 176-178.
The authors report two unusual cases of Bickerstaff encephalitis that presented with encephalopathy and severe agitation. Management with neuroleptics typically used for management of delirium was not effective and worsened agitation. Valproic acid was effective in treatment of agitation and well tolerated.

2. Bourgeois, J. A., et al. (2005). “Adjunctive valproic acid for delirium and/or agitation on a consultation-liaison service: a report of six cases.” J Neuropsychiatry Clin Neurosci 17(2): 232-238.
The authors present six cases in which valproate was used in patients seen by a consultation-liaison service (CLS) to manage delirium and/or psychotic agitation. The intravenous (IV) preparation (Depacon, Abbott Laboratories) was used in two nothing by mouth (NPO) patients, while the liquid oral preparation (Depakene, Abbott Laboratories) was used via nasogastric tube (NGT) in the other patients. All of these cases had suboptimal responses and/or concerning side effects from conventional therapy with benzodiazepines and/or antipsychotics. In all six cases, the CLS use of valproic acid combined with conventional antidelirium medications resulted in improved control of behavioral symptoms without significant side effects from valproic acid. Consultation-liaison psychiatrists should consider the addition of valproic acid to control behavioral symptoms of delirium when conventional therapy is inadequate. This may be especially advisable when problematic side effects result from more conventional psychopharmacological management. Specifically, intravenous valproate sodium may be a viable option for NPO patients.

3. Pandharipande, P., et al. (2006). “Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients.” Anesthesiology 104(1): 21-26.
BACKGROUND: Delirium has recently been shown as a predictor of death, increased cost, and longer duration of stay in ventilated patients. Sedative and analgesic medications relieve anxiety and pain but may contribute to patients’ transitioning into delirium. METHODS: In this cohort study, the authors designed a priori an investigation to determine whether sedative and analgesic medications independently increased the probability of daily transition to delirium. Markov regression modeling (adjusting for 11 covariates) was used in the evaluation of 198 mechanically ventilated patients to determine the probability of daily transition to delirium as a function of sedative and analgesic dose administration during the previous 24 h. RESULTS: Lorazepam was an independent risk factor for daily transition to delirium (odds ratio, 1.2 [95% confidence interval, 1.1-1.4]; P = 0.003), whereas fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios. Increasing age and Acute Physiology and Chronic Health Evaluation II scores were also independent predictors of transitioning to delirium (multivariable P values < 0.05). CONCLUSIONS: Lorazepam administration is an important and potentially modifiable risk factor for transitioning into delirium even after adjusting for relevant covariates.