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Ketamine for Excited Delirium Syndrome

Delirium canstockphoto11866731Excited 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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

1.
Vilke G, DeBard M, Chan T, et al. Excited Delirium Syndrome (ExDS): defining based on a review of the literature. J Emerg Med. 2012;43(5):897-905. [PubMed]
2.
Hick J, Ho J. Ketamine chemical restraint to facilitate rescue of a combative “jumper”. Prehosp Emerg Care. 2005;9(1):85-89. [PubMed]
3.
Melamed E, Oron Y, Ben-Avraham R, Blumenfeld A, Lin G. The combative multitrauma patient: a protocol for prehospital management. Eur J Emerg Med. 2007;14(5):265-268. [PubMed]
4.
Le C, Gynther B, Hunter E, Schuller P. Ketamine sedation for patients with acute agitation and psychiatric illness requiring aeromedical retrieval. Emerg Med J. 2012;29(4):335-337. [PubMed]
5.
Burnett A, Salzman J, Griffith K, Kroeger B, Frascone R. The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehosp Emerg Care. 2012;16(4):553-559. [PubMed]
6.
Ho J, Smith S, Nystrom P, et al. Successful management of excited delirium syndrome with prehospital ketamine: two case examples. Prehosp Emerg Care. 2013;17(2):274-279. [PubMed]
7.
Scheppke K, Braghiroli J, Shalaby M, Chait R. Prehospital use of i.m. ketamine for sedation of violent and agitated patients. West J Emerg Med. 2014;15(7):736-741. [PubMed]
8.
Burnett A, Peterson B, Stellpflug S, et al. The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. Am J Emerg Med. 2015;33(1):76-79. [PubMed]
9.
Iwanicki JL, et al. Prehospital ketamine for excited delirium in the setting of acute drug intoxication. Clin Toxicol 2014;52:685-6. Abstract #9.
10.
Keseg D, Cortez E, Rund D, Caterino J. The Use of Prehospital Ketamine for Control of Agitation in a Metropolitan Firefighter-based EMS System. Prehosp Emerg Care. 2015;19(1):110-115. [PubMed]
11.
Hayes B. Ketamine for agitation: a key cog in the prehospital treatment armamentarium wheelhouse. Clin Toxicol (Phila). 2016;54(7):545-546. [PubMed]
12.
Olives T, Nystrom P, Cole J, Dodd K, Ho J. Intubation of Profoundly Agitated Patients Treated with Prehospital Ketamine. Prehosp Disaster Med. 2016;31(6):593-602. [PubMed]
13.
Isbister G, Calver L, Downes M, Page C. Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department. Ann Emerg Med. 2016;67(5):581-587.e1. [PubMed]
14.
Cole J, Klein L, Nystrom P, et al. A prospective study of ketamine as primary therapy for prehospital profound agitation. Am J Emerg Med. October 2017. [PubMed]
15.
Parsch C, Boonstra A, Teubner D, Emmerton W, McKenny B, Ellis D. Ketamine reduces the need for intubation in patients with acute severe mental illness and agitation requiring transport to definitive care: An observational study. Emerg Med Australas. 2017;29(3):291-296. [PubMed]

Expert Peer Review

Thanks to Bryan for a concise review of the topic of ketamine and its use to manage excited delirium syndrome and more broadly, acute behavioural emergencies in the prehospital setting.

For completeness of the literature review, please consider the earlier articles from Melamed et al, on prehospital military use of ketamine sedation for agitated wounded soldiers AND the original article that sparked my own research interest in prehospital ketamine for agitation, the Hick case report from Hennepin here.

One thing I wish readers to bear in mind, is to exercise caution in the notion that a single IM ketamine dose will be sufficient to manage the excited delirium patient in prehospital care. As a rapid sedation option in event no intravenous access is available, it is an effective choice and in my opinion, one of the safer choices but clearly as this literature review has shown, it is not without complications. An intubation rate between 20-50% following IM ketamine indicates caution is needed in its use. Why? Ketamine is an anaesthetic agent, unlike the other commonly used sedatives like midazolam, haloperidol, olanzapine, droperidol etc. Clearly then the higher dose you administer of an anaesthetic agent, the more likely you will induce deeper states of sedation. IM dosing for ketamine has always been with higher doses than intravenous, as we would expect with any anaesthetic or sedative. This clearly carries more complications with higher doses and this is well recognised in the vast experience of ketamine therapeutic use.

It is why in my own practice and research, IV ketamine is utilised and we have demonstrated a dramatic reduction in the need to intubate patients with acute agitation requiring aeromedical retrieval. IV route allows lower dosing, targeted titration to a safe sedation level and moreover the initiation of infusion based ketamine sedation. In a personal communication to this group, I can convey some details of study I have undergoing peer review as a journal submission. In a before and after study of intubation rates and use of a standardised IV ketamine sedation protocol, we found a drop in intubations from 3-5% before the protocol, to less than 1% after the protocol.

In my own recently published Surviving Sedation guidelines 2015, IM ketamine is advocated still as a second line option but at the lower dosing of 4mg/kg. It is true we dont know the optimal IM dosing for prehospital use. The 5mg/kg is based on ED procedural sedation studies and practice. In my opinion, IM ketamine should be used to facilitate rapid IV access , application of minimum sedation monitoring and patient assessment.

Minh Le Cong, MBBS, FRACGP, FACRRM, FARGP, GEM, GDRGP , DipAeroRT (Otago)
Senior Medical Officer, Royal Flying Doctor Service, Queensland, Australia Editor/Author of the PHARM Podcast & Blogsite, prehospitalmed.com

Minh, thanks for your comments.

I added the two references you suggested to provide additional background on the topic. Your insight into the IV vs. IM ketamine dosing is excellent. I updated the post to reflect that the optimal IM dose is unknown and that administering it really may be a way just to facilitate IV access where lower (and safer) doses can be used. I also included a link to the Surviving Sedation Guidelines as they add some great information germane to this post. I appreciate you spending the time reviewing the post for us.

Bryan Hayes, PharmD, DABAT, FAACT
ALiEM Associate Editor; Clinical Assistant Professor, University of Maryland (UM); Clinical Pharmacy Specialist, EM and Toxicology

Expert Peer Review

This is an easy to read and follow piece, consistent with the author\'s style and previous works. It simply and effectively outlines an increasingly common problem within the target audience.

The article has broad applicability to the EM and prehospital communities of practice and would be applicable to institutions or organisations no matter their size and shape.

The reference to \'B-52\' is the only part of the article which narrows the scope from a broader application - this is effectively a US only reference. The \'B-52\' approach is not commonly used within the European or Australian context, however it is well reported within the US and as such the comment - popular choice - is probably correct.

The article does not mention of Droperidol amongst the various agents that might be used in this situation, despite the link to the Surviving Sedation Guidelines 2015 later in the article. This may be due to US availability and the residual black box warning. Despite the black box warning there has been increasing moves towards Droperidol within the Australian context and the latest literature around its use in the ED is the DORM II paper with the SOOTHE study also underway to further add to the literature base.

The drawing together of the selected papers is tidy and deliberately kept in a format that is easy to read. The nomination of 4mg/kg IM is sensible and it is becoming more common within those providers who are using Ketamine frequently. Whilst Ketamine is effective via the IM route in a relatively short timeframe, and this makes it a useful agent for rapid intervention in this patient group, there remains a strong feeling to see it used as a second line agent following either an anti-psychotic or a benzodiazepine in sympathomimetic syndromes. If using Ketamine for sedation in this patient group, the availability of either an anti-psychotic or benzodiazepine to supplement the sedation, or to manage any emergence response makes clinical sense.

The link to the Surviving Sedation Guidelines 2015 is appropriate as it provides excellent recommendations that go beyond the selection of the appropriate agent to use in these situations and covers the essential items of: patient safety, equipment and staff preparation, physical and mechanical restraint, and ongoing monitoring needs.

Alan K Eade ASM
Intensive Care Paramedic, Ambulance Victoria (Australia)

Thank you so much for your review. You raise several great points that I have incorporated into the post.

I have added a clarifying remark that the B-52 is probably more common in the U.S. I also added droperidol as an option and mentioned the limited availability in the U.S.

I added some further clarifying verbiage about ketamine\'s use as a second line agent and having benzodiazepines or antipsychotics available to provide synergistic sedation/manage emergence reactions. Additionally, I added this as an additional take home point.

Bryan Hayes, PharmD, DABAT, FAACT
ALiEM Associate Editor; Clinical Assistant Professor, University of Maryland (UM); Clinical Pharmacy Specialist, EM and Toxicology
Bryan D. Hayes, PharmD, FAACT, FASHP

Bryan D. Hayes, PharmD, FAACT, FASHP

Chief Science Officer, ALiEM
Creator and Lead Editor, Capsules series, ALiEMU
Attending Pharmacist, EM and Toxicology, MGH
Assistant Professor of EM, Harvard Medical School
  • Mike Abernethy

    Great review. One important note. Unfortunately ketamine is usually stocked in 2-3 different concentrations ( 10mg/ml, 20 mg/ml 100mg/ml). This is a ripe situation for a med error. I suggest stocking only the 5 ml vials of the 100mg/ml. Due to volume issues, this is the ONLY form/concentration that can be given via IM route. If it is desired to administer ketamine IV, you can simply dilute it.

    • Bryan D. Hayes

      Great point Mike, I considered adding a note on that at the end of the post and will do so now.

  • jeff riddell

    Thanks for this discussion Bryan and review Minh and Alan.

    I want to speak to Minh’s point that Ketamine use has a 20-50% inutbation rate (even though his new data may show a drop). In the ED setting, ketamine does not seem to have the same increase in intubations seen in the pre-hospital setting. The case series from Denver (Iwanicki JL, et al. Clin Toxicol 2014;52:685-6. Abstract #9) with a 50% intubation rate does not jive with our experience. We just presented an abstract at #SAEM15 in which we prosepctively observed our ED sedation practice. 21 acutely agitated ED patients received ketamine for sedation and one got intubated. Our study wasn’t powered for adverse effects, but 11 patients (13.4%) had adverse events: 4 had hypotension (2 benzodiazepine, 1 ketamine, 1 haloperidol) and 4 required intubation (2 haloperidol, 1 benzodiazepine, 1 ketamine). Adverse events occurred in 4 (17%) patients receiving haloperidol, 3 (14%) receiving ketamine, and 4 (10%) receiving benzodiazepines.

    This data is not from pre-hospital EMS use. It includes both IV and IM ketamine. I fear that the Colorado paramedics infamiliarity with dissociative anesthetics led to a high intubation rate, whereas ED providers who are familiar with ketamine have an intubation rate after ketamine that is simlar to benzos and antipsychotics. I don’t want ED proivders to fear ketamine use in the ED based on pre-hospital case series.

    An excellent review Bryan, thank you.

    • Bryan D. Hayes

      Thanks for the comment Jeff, and your willingness to share your data. You raise great points. Interestingly, none of the patients who were intubated had it performed in the field. In all of the studies (case series) where intubation was reported, it was all done in the ED. I do think if the ketamine were given in the ED, the outcomes may be more favorable in terms of less intubations. Perhaps it is a comfort level dependent on familiarity with ketamine. Since not all ED providers have extensive experience with ketamine, maybe they would be more likely to intubate a patient after receiving it in the field.

      • jeff riddell

        I see. Interesting.

        Agree, Maybe if I received a dissociated patient from EMS and had not seen a lot of ketamine, I might also jump to intubation.

        We really do need better studies on this. We are working on an IRB for an RCT, but there are so many difficulties inherent in this. A group in Minnesota is already working on a pre-hospital randomization: https://clinicaltrials.gov/ct2/show/NCT02103881 – their data will be very helpful.

        • Mitchell Li

          I can easily see an ED provider who is not familiar with ketamine and sees a patient with a GCS <9 who came in from the field just reflexively jump to intubation if the history isn't clear.

          Really interesting that a condition often attributed to PCP can be controlled with another PCP-like drug!

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  • asif rahman

    Any issues with hypertensive emergency in patients given ketamine? Most patients with adrenergic release usually have associated hypertension and I would be hesitant to use in those settings.

    • Bryan D. Hayes

      Yes, this is a great question. Ketamine weakly inhibits catecholamine reuptake; an increase in blood pressure and heart rate is induced. Rapid IV infusion produces a more pronounced effect than by IM injection. It’s interesting that a drug that can increase catecholamine levels produces a calming, sedative effect in excited delirium syndrome. Retrospective EMS data is not ideal for documentation of adverse effects, but exacerbated hypertension was not reported. There are cases of patients not having an increased catecholamine response, thought to be due to catecholamine depletion (http://www.ncbi.nlm.nih.gov/pubmed/22644454). Perhaps this is a similar scenario in excited delirium syndrome where there are no excess catecholamines to release, thereby only causing sedation.