Brought in By Ambulance #5: Chemical Takedown - IM Ketamine for Prehospital Restraint

Clinical scenario: You are working the overnight shift in the Emergency Department (ED) when a pre-arrival for "agitation" pops up on the board.  You see EMS roll by with several police officers and decide that you should follow.  On the stretcher lies a partially clothed, basically unresponsive patient who is maintaining a respiratory rate of 10 and oxygen saturation of 88% on room air.  As you quickly slap on the oxygen, check the patient's response to pain with a sternal rub, see an end-tidal CO2 reading of 35, and contemplate intubation, EMS starts to provide their signout.  The paramedics responded to a call for "altered behavior" and were confronted with a psychotic, agitated, diaphoretic patient who would likely fit the description of Excited Delirium Syndrome (ExDS).  The patient quickly ran at and jumped on a paramedic.  The paramedics, fire department, and police restrained the patient who required multiple doses of Haldol and Ativan to facilitate transport.  As you further assess the patient, you wonder, "is there a better way to chemically restrain a patient that maximizes the safety of EMS providers and patients?".  As the patient's sats improve to 98%, you realize that you have some time to think. You have recently heard about prehospital use of IM ketamine for just this purpose and decide to review the evidence.

Practical exercise:  Calculate the IM Ketamine dose to takedown the Incredible Hulk.

Literature Review:
In 2011, the term "Excited Delirium Syndrome (ExDS)" was coined to describe the clinical syndrome referred to in different venues as "agitated delirium", "excited delirium", or "Sudden Death in Custody Syndrome".   The American College of Emergency Physicians (ACEP) convened a task force to define the spectrum of the syndrome which has the following clinical features [1,2]:

                   - hyper-aggressive or bizarre behavior, including lack of clothing
                   - lack of sensitivity to pain
                   - hyperthermia
                   - diaphoresis
                   - attraction to light or shiny objects

The exact etiology of ExDS is unknown, but there is a strong association with pre-existing psychiatric disease (in particular, schizophrenia) and drugs of abuse (cocaine, methamphetamine, and PCP) [2].

Most importantly,  ExDS conveys a high risk of mortality, in the realm of 10% [1,2].  The exact cause of death is not completely clear, but is thought to arise from severe acidosis or hyperkalemia, and is usually the end result of physical struggle or restraint.  Agitated, combative patients also pose a risk to prehospital providers.  Follow this link to watch a video of ExDS from presentation to death. 

Multiple pharmacologic therapies for chemical restraint of patients with ExDS have been suggested, from anti-psychotics, to benzodiazepines to the dissociative drug, ketamine:
Table 2 from Vilke et. al (Ref 3).

Anti-psychotics and benzodiazepines have long delays to peak effect when given via the IM route, in the realm of 15-30 minutes.  Because of its relatively rapid onset,  there has more widespread  prehospital of IM ketamine for chemical restraint of ExDS.

Several studies have attempted to examine the efficacy of ketamine for prehospital management of ExDS.  Anecdotal evidence for the effectiveness of prehospital ketamine came from initial case series and has been adopted into EMS protocols for extreme agitation [4,5].  These initial case series also highlighted the potential adverse effects of the drug, including hypersalivation, laryngospasm, and hypoxia (at least in the doses used ~ 5 mg/kg IM).

After the initial case series were reported, a pilot, retrospective study of prehospital ketamine for ExDS was published in the Western Journal of Emergency Medicine [6].  In this study, the authors reviewed the paramedic run sheets for 52 violent and agitated patients who were given a single 4 mg/kg dose of IM ketamine  The average time to sedation and medical control was approximately 2 minutes. At the 4 mg/kg IM dosage,  3/52 patients developed respiratory depression, two of whom were intubated.  In each of these cases, the patients had received IV midazolam in conjunction ketamine to prevent emergence reaction.  The authors concluded that "ketamine may be safely and effectively used by trained paramedics following a specific protocol."  A major caveat to this study is that the authors did not examine what happened later in the emergency department.  Interestingly, a previously published case series of 13 patients found that of the three patients who developed respiratory distress, two did so only after arrival to the ED while one patient arrived with ventilation being assisted by EMS [5].  In none of these cases was the impending respiratory distress documented in the prearrival note, suggesting that 6% may be a gross underestimation of the true incidence of respiratory complications. 

Another outcome measure for respiratory complication is by examining incidence of intubation after the patients arrive in the emergency department.  A recent retrospective study published in the American Journal of Emergency Medicine examined the correlation between ketamine dosage and need for intubation [7].  They reviewed the prehospital and emergency department records for 51 consecutive patients who were administered ketamine for prehospital chemical restraint.  Fourteen (29%) of patients required intubation.  Of note, none of these patients were intubated in the field.  Patients who were intubated were administered a significantly higher ketamine dose (6.16 +/- 1.62 mg/kg) than those who were not (4.90 +/- 1.54 mg/kg).  It is not clear what proportion of patients were intubated as a side-effect of the ketamine as opposed to facilitation of  medical care in the emergency department.  It was specifically noted that two of the patients were intubated because of "recurrent agitation and need for additional sedation" and one patient was intubated to facilitate medical workup (a lumbar puncture).  The mortality rate for these patients was not documented, but 71% of the patients were admitted to the hospital, primarily on medical (55%) rather than psychiatric (14%) services.

A final consideration is whether ketamine interacts at all with the psychiatric disorders that underlie some cases of ExDS.  Ketamine acts as an NMDA-receptor antagonist, thereby causing a deficiency in glutamate-mediated
Ketamine chemical structure (wiki)

neurotransmission [8] .   Because PCP and ketamine-abuse can model some aspects of schizophrenia, some have postulated that some aspects of schizophrenia are due to defects in glutamate-mediated neurotransmission.  Indeed, in one study they found that CSF from schizophrenic patients had lower glutamate content when compared with controls [9].  While the "glutamate hypothesis of schizophrenia" remains controversial, because a subset of ExDS syndrome patients have psychotic disorders, one might be concerned that ketamine could have an adverse effect on the underlying psychiatric disease, although this does not appear to have been directly studied anywhere and there are no reports in the limited literature regarding ketamine administration for chemical restraint.

Take Home Points:  ExDS is a syndrome with a high rate of mortality. IM Ketamine is a promising treatment for the prehospital realm because of its rapid time of onset (~2-5 min).  Providers administering ketamine need to have heightened awareness and ability to handle potential respiratory complications, including respiratory depression and laryngospasm.  The long-term effects of single dose ketamine administration in patients with underlying psychiatric diagnoses is unclear.

Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by H. Phil Moy

1. Vilke, G. M., DeBard, M. L., Chan, T. C., Ho, J. D., Dawes, D. M., Hall, C., ... & Bozeman, W. P. (2012). Excited delirium syndrome (ExDS): defining based on a review of the literature. The Journal of emergency medicine, 43(5), 897-905.
2. Vilke, G. M., Payne-James, J., & Karch, S. B. (2012). Excited delirium syndrome (ExDS): redefining an old diagnosis. Journal of forensic and legal medicine, 19(1), 7-11.
3. Vilke, G. M., Bozeman, W. P., Dawes, D. M., DeMers, G., & Wilson, M. P. (2012). Excited delirium syndrome (ExDS): treatment options and considerations. Journal of forensic and legal medicine, 19(3), 117-121.
4. Ho, J. D., Smith, S. W., Nystrom, P. C., Dawes, D. M., Orozco, B. S., Cole, J. B., & Heegaard, W. G. (2013). Successful management of excited delirium syndrome with prehospital ketamine: two case examples. Prehospital Emergency Care, 17(2), 274-279.
5.Burnett, A. M., Salzman, J. G., Griffith, K. R., Kroeger, B., & Frascone, R. J. (2012). The emergency department experience with prehospital ketamine: a case series of 13 patients. Prehospital Emergency Care, 16(4), 553-559.
6. Scheppke, K. A., Braghiroli, J., Shalaby, M., & Chait, R. (2014). Prehospital use of IM ketamine for sedation of violent and agitated patients. Western Journal of Emergency Medicine, 15(7), 736.
7. Burnett, A. M., Peterson, B. K., Stellpflug, S. J., Engebretsen, K. M., Glasrud, K. J., Marks, J., & Frascone, R. J. (2014). The association between ketamine given for prehospital chemical restraint with intubation and hospital admission. The American journal of emergency medicine.
8. Murray, R. M., Paparelli, A., Morrison, P. D., Marconi, A., & Di Forti, M. (2013). What can we learn about schizophrenia from studying the human model, drug‐induced psychosis?. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 162(7), 661-670.
9.  Kim, J. S., Kornhuber, H. H., Schmid-Burgk, W., & Holzmüller, B. (1980). Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia. Neuroscience letters, 20(3), 379-382.