In this episode the methods I am going to discuss in this episode are not first line or even second line therapies for controlling acute agitation. I use them rarely – as in a few times per year or less. But in some difficult situations they are like having an Ace up your sleeve!

Almost all acutely agitated patients can be treated with benzodiazepines and/or antipsychotics. If doses escalate to the point of respiratory failure, the patient is sedated further, intubated and is then awakened later after the period of acute agitation is over.

But occasionally patients do not respond to benzodiazepines or antipsychotics. Other times, patients may have conditions that make benzodiazepines or antipsychotics relatively contraindicated, may have advanced heart or lung disease and might never wean from the ventilator, or have an advanced directive that prohibits intubation.

Here are three strategies that can be used in these circumstances:

-Valproic acid

-High dose dexmedetomidine infusion

-Ketamine

Valproic acid

About two years ago an intensivist I work with (also named Joe by the way) suggested using a loading dose of 15mg/kg valproic acid to control acute agitated delirium in an ICU patient. I could not find much evidence, but other therapies had not been very effective for the patient and we gave it a try. The patient in question had a history of various mental health diagnoses, and the addition of valproic acid seemed to control the agitation over the next few days.

Ever since then I’ve been keeping an eye out for the use of valproic acid in acute agitation. I was very happy when in May 2015 a randomized, double blind trial directly comparing valproic acid to haloperidol for acute agitation was published. The trial was published in the journal of International Clinical Psychopharmacology and compared valproic acid 20mg/kg IV vs haloperidol 5mg IM in 80 patients in an emergency department with acute agitation. Agitation was measured at baseline and 30 min after the first injection using 3 different scales: the Agitation–Calmness Evaluation Scale (ACES), the Positive and Negative Syndrome Scale-Excited Component subscale, and the Agitated Behavior Scale.

No significant differences were observed between groups after 30 min for the agitation scales. More patients in the haloperidol group experienced intense sedation (36%) and extrapyramidal symptoms (8%) compared with the valproate group (2.5% for intense sedation, no patient for extrapyramidal symptoms). The findings suggest that in an emergency setting, IV valproic acid is as effective as haloperidol in reducing agitation, with a better safety profile.

Since the publication of this article I have had the opportunity to use valproic acid twice in acutely agitated patients. Both times the patients were young adult males experiencing withdrawal from multiple substance abuse including K-2 (synthetic marijuana), opioids, alcohol, and benzodiazepines. Both patients were requiring physical restraint and multiple security guards to help keep them and the healthcare providers safe. The dose given in each of these cases was closer to 15mg/kg than 20 mg/kg. Each time, the patient’s agitation was much less after the addition of valproic acid. One of the patients did experience intense sedation, but he had also received very high doses of clonidine, benzodiazepines and atypical antipsychotics in an attempt to control his agitation. He was eventually able to transfer to an appropriate level of psychiatric care at another hospital.

High dose dexmedetomidine infusion

High dose dexmedetomidine infusion is another strategy I have used occasionally to spare intubation in agitated patients. Even though it is now generic, dexmedetomine is an expensive sedative. I usually do not count on it to provide anything more than moderate sedation, and I like to use it primarily to help anxious patients wean from the ventilator. The pharmacy drug budget will never get credit for avoiding an intubation, but every once in a while it seems like pushing the dose of dexmedetomidine above the usual maximum has a chance to spare a patient mechanical ventilation.

Literature support for this technique is scant, but there was a pharmacokinetic study in 13 ICU patients that looked at dexmedetomidine doses up to 2.5mcg/kg/hr. Only 8 of the patients in the study ever reached that maximum dose. In this small sample, safety outcomes were as expected with dexmedetomidine. Four of the 53 adverse events recorded were assessed as being related to the study treatment: three episodes of bradycardia and one episode of first-degree AV block. All of these events resolved, with either dose reduction (1 bradycardia and the AV block) or administration of atropine and glycopyrrolate (2 bradycardias).

The mean age of the study was 57 years, and all but 1 patient who reached 2.5mcg/kg/hr was below age 60 (an 82 year old).

To even consider this strategy, the patient should have good cardiovascular reserve and not already be hypotensive or bradycardiac. It should also be very convincing that this strategy has a good chance of avoiding intubation due to the high cost.

The two most recent patients I have used this in were 1. A patient who needed control of agitation but could not be intubated due to an advanced directive and 2. An obese patient who was 1 day post stent placement for MI and went into withdrawal from alcohol, benzodiazepine, and high dose zolpidem abuse.

In the 2nd patient the physicians felt if they could catch up with treatment for alcohol withdrawal they might avoid intubation, and we were already using 8 mg of lorazepam every hour IV push to control the patient. We used dexmedetomidine up to 2.1mcg/kg/hr, at a cost of about $1400/day. When I last saw the patient he was not intubated but still requiring high doses of benzodiazepines and dexmedetomidine.

Ketamine

Ketamine has been used to successfully manage acutely agitated and violent patients. The dose for this indication is 2mg/kg IV or 5mg/kg IM. In addition to not requiring intubation, ketamine does have the advantage of possible IM injection, which may be the only choice in some agitated patients.

I’ve never used ketamine for this purpose. Due to it’s duration of about 10 to 20 minutes, I’m not sure what role it has other than to sedate the patient enough to allow definitive treatment of the agitation such as intubation. If you are interested in hearing more about ketamine and its use in critical care settings, check out episode 16.

If you’ve ever used any of the above techniques, or if you have a technique for sedation without intubation of agitated patients that I have not discussed, I’d love to hear from you!

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

<– Previous Post Next Post –>