Ketamine for Excited Delirium Syndrome

Excited delirium syndrome is defined as “a syndrome of uncertain etiology characterized by delirium, agitation, and hyperadrenergic autonomic dysfunction”.¹ You may have encountered a patient like this in the ED or prehospital setting. Although the etiology is impossible to determine in many cases, stimulant abuse and other drugs are involved in a majority of cases. An 8% mortality has been ascribed to Excited Delirium Syndrome, resulting from hyperthermia, severe metabolic acidosis, and cardiovascular collapse.

Pharmacologic Options

In addition to other measures such as intensive cooling, how do you control these wildly agitated patients while keeping ED staff, prehospital providers, and the patient safe? Benzodiazepines and antipsychotics are probably the most often used medications. The ‘B-52’ is a popular choice in the U.S.; an intramuscular (IM) shot of Diphenhydramine (Benadryl) 50 mg + Haloperidol 5 mg + Lorazepam 2 mg. Midazolam, olanzapine, ziprasidone, and droperidol are other options (though droperidol’s availability has been limited in the U.S. for the past few years).

However, these options are not ideal. The benzodiazepines have a slower onset when given via the IM route. The antipsychotics have anticholinergic properties which can impair heat dissipation. In addition, animal models have linked haloperidol to lowering the seizure threshold which can be problematic in stimulant overdose/abuse situations. If only there were a medication that could be given as a single agent, in one dose, with a quick onset of action, and have minimal effects on respiratory drive… what about ketamine?

Ketamine for Excited Delirium Syndrome

There are several reports in the past few years that have evaluated ketamine for excited delirium syndrome. One of the earliest cases dates back to 2005 where Hennepin County EMS utilized IM ketamine to subdue a patient threatening to jump off a bridge.² The purpose of this post is to review the literature for IM ketamine, though a quick overview of the IV literature will provide some background and context.

Route: Intravenous Ketamine

1. Melamed E, et al. Eur J Emerg Med 2007;14(5):265-8.³
   
   A retrospective case series described prehospital ketamine for sedation of agitated wounded soldiers. Five patients received intravenous (IV) ketamine, in three of which it was coadministered with midazolam. Sedation with ketamine given alone, or combined with other drugs, was effective in all five cases. In no case did a patient become more agitated after administration. No adverse effects were recorded by the prehospital caregivers.

2. Le Cong M, et al. Emerg Med J 2012;29(4):335-7.⁴
   
   Dr. Minh Le Cong’s (@ketaminh) group published a case series using ketamine for sedation in patients with acute agitation and psychiatric illness requiring aeromedical retrieval. They used IV ketamine bolus 0.5-1 mg/kg +/- infusion. Many patients also received midazolam. 18 patients over a 3-year period were sedated during retrieval with intravenous ketamine. Effective sedation was achieved in all cases with no significant adverse events noted during retrieval or 72 hours afterwards.

Route: Intramuscular Ketamine

1. Burnett AM, et al. Prehosp Emerg Care 2012;16(4):553-9.⁵
   
   In a quality improvement study, 13 patients were administered IM ketamine for chemical restraint in the prehospital setting. The objective was to better understand the risk-benefit ratio. Patients received IM ketamine 5 mg/kg. Ketamine had a very quick onset (~2 minutes) and produced moderate-to-deep sedation. 3 patients developed hypoxia (2 required intubation upon ED arrival). 5 of the 11 nonintubated patients required additional sedation and 3 patients experienced emergence reactions (which were successfully treated with midazolam and reassurance). It is unclear how much ketamine contributed to the hypoxia cases.

2. Ho JD, et al. Prehosp Emerg Care 2013;17(2):274-9.⁶
   
   Two cases are reported in which IM ketamine was successfully used in the prehospital setting with good outcomes and no complications. The ketamine dose was ~5 mg/kg IM in each case.

3. Scheppke KA, et al. West J Emerg Med 2014;15(7):736-41.⁷
   
   In a retrospective review of paramedic run sheets, this case series included 52 patients who were administered ketamine for sedation and control. The ketamine dose was ~4 mg/kg +/- midazolam. 50 of the 52 patients achieved peak sedation < 5 minutes after ketamine administration (average 2 minutes). Average time to ED arrival was 19 minutes and sedation was still present in all 50 cases. About half the patients received midazolam in addition to ketamine. 3 cases of respiratory depression occurred (2 required intubation). In all 3 cases, patients had also received midazolam. No other negative side effects were noted.

4. Burnett AM, et al. Am J Emerg Med 2015;33(1):76-9.⁸
   
   A retrospective review of a convenience sample of consecutive prehospital care reports and associated ED records was conducted. 49 excited delirium syndrome patients were included. The dose of IM ketamine was 5 mg/kg. Intubation occurred in 29% of patients upon arrival to the ED. When back-calculating patient weights, the patients who were intubated received 6.1 mg/kg vs. 4.9 mg/kg in the nonintubated group (p = 0.02). The authors’s speculate that part of the high-intubation rate was related to ED provider comfort level in treating patients who had received ketamine, as only one patient had hypoxia prior to intubation. The intubation rate is also consistent with other prehospital studies of excited delirium patients, so it may not be related to the drug itself. More research is needed to determine optimal ketamine dose.

5. Iwanicki JL, et al. Clin Toxicol 2014;52:685-6. Abstract #9.⁹
   
   An abstract presented at the 2014 North American Congress of Clinical Toxicology meeting reported 35 patients who received IM ketamine 5 mg/kg for excited delirium. Less than 1/3 required additional sedation. Half were intubated, but the authors noted that the intubation rate decreased over time as ED providers gained comfort in managing patients post ketamine administration. No cases of laryngospasm, emergency phenomena, or death were reported.

What does it all mean?

Though IM ketamine may be a good choice in excited delirium patients without IV access, it is not without complications. A single IM dose may not be sufficient in some prehospital cases with prolonged transport times. We also don’t know the optimal IM dose. Those who use it frequently err on the side of caution and use 4 mg/kg (see Surviving Sedation Guidelines 2015). In fact, they recommend using ketamine as a second line option with the intent of facilitating IV access where a lower dose can be used safely. The existing literature consists only of retrospective case series without comparison to other agents. Adverse effects (other than intubation) were rarely reported, though retrospective studies typically underreport adverse effects.

Take Home Points

• IM ketamine works rapidly to produce sedation in excited delirium.
• An IM ketamine dose of 4 mg/kg seems to be the most appropriate based on existing data, though less may still work and the optimal dose is unknown.
• ED providers are not always comfortable managing patients after receiving ketamine.
• For now, ketamine should probably remain a second line agent following either an antipsychotic or a benzodiazepine in sympathomimetic syndromes.

Ketamine offers a potential option for treating these difficult to manage excited delirium syndrome cases. While more data is needed, it seems to work quickly and may be an appropriate alternative in the prehospital setting or emergency department. Adding a benzodiazepine or antipsychotic may provide supplemental sedation and help manage emergence reactions.

A note on concentrations : Ketamine is available in 10 mg/mL (20 mL), 50 mg/mL (10 mL), and 100 mg/mL (5 mL) concentrations. Having more than one concentration available could lead to medication errors; the 100 mg/mL concentration is most appropriate for IM administration.

Update: June 2015

A new retrospective study from the Columbus Division of Fire (Ohio) was published utilizing ketamine in the prehospital setting.¹⁰ Demographic and clinical information on 35 patients was available in the EMS medical record and analyzed in the study. ED data were only available in 31 patients. Four patients received IV ketamine alone, 29 patients received IM ketamine alone, and 2 patients received IM followed by IV ketamine. Of the 29 patients receiving IM ketamine, the dose was documented as 4 mg/kg for 2 patients. In the remaining patients, the total dose of ketamine was recorded. The mean IV dose of ketamine was 138 mg. The mean IM dose of ketamine was 324 mg. Prehospital records noted an improvement in patient condition after ketamine administration in 32 cases (91%). In 3 cases, ketamine did not improve patient condition. Additional sedation methods (benzodiazepines or significant force) were used in 14 cases. Eight patients received sedation before ketamine administration. Six patients required sedation post-ketamine administration either by EMS (n = 2) or in the ED (n = 4). Eight (23%, 95% CI 10–40%) patients were endotracheally intubated in the prehospital setting or in the ED post-ketamine administration.

Articles published since June 2015

• Cole JB, et al. Clin Toxicol 2016.¹¹
• Hayes BD. Clin Toxicol 2016.¹¹
• Olives TD, et al. Prehosp Disaster Med 2016.¹²
• Isbister GK, et al. Ann Emerg Med 2016.¹³
• Riddell J, et al. Am J Emerg Med 2017.¹⁴
• Parsch CS, et al. Emerg Med Australas 2017.¹⁵
• Cole JB, et al. Am J Emerg Med 2017.¹⁴

Original: May 18, 2015
Updated: June 14, 2015

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