• Home
  • Featured Clinical Topic: A Review of Ketamine in the Emergency Department

Featured Clinical Topic: A Review of Ketamine in the Emergency Department

23 May 2018 1:36 PM | MSHP Office (Administrator)

Authors: Brandon Reynolds, PharmD: UMKC School of Pharmacy Class of 2018 and  Kerra Cissne, PharmD: PGY-2 Pharmacy Resident at Truman Medical Center

Introduction:

Ketamine was first described as an anesthetic and “chemical derivative” of phencyclidine (PCP) in 1965 by the American Society for Clinical Pharmacology and Therapeutics.1 Ketamine, like PCP, has the capability of inducing a state of dissociative anesthesia as well as producing a strong analgesic and amnestic effect.2,3 Unlike PCP, ketamine demonstrates a shorter duration of action and less pronounced psychotomimetic effects than its parent drug, vastly improving its clinical properties as an anesthetic.4 In contrast to other medications employed for analgesia and procedural sedation, ketamine preserves respiratory function and hemodynamic stability.5 In the emergency department, ketamine has several uses, including acute pain management, procedural sedation, limb reduction, and anesthesia in patients with diminished or worsening respiratory drive.6

Pharmacology:        

Ketamine has multiple mechanisms of action. The most studied mechanism is the drug’s ability to block glutamate receptors, such as the N-methyl-D-aspartate (NMDA) receptor and the non-NMDA glutamate receptors.4 Although there are several other proposed mechanisms related to analgesia such as µ-opioid receptor agonism,7 NMDA receptor antagonism is expected to induce the characteristic properties of ketamine use such as amnesia, analgesia, and psychosensory effects.4 Interestingly, the dissociative anesthesia induced by ketamine is proposed to be caused by a disconnect between the thalamo-neocortical and limbic systems, which may also be associated with the emergence phenomenon8 afflicting an estimated 23% of patients that do not receive adjunctive benzodiazepines.8,9 This phenomenon, however, is still relatively poorly understood and is described in a heterogeneous manner throughout the literature.

Literature Analysis:

Subanesthetic analgesia: A prospective, randomized, double-dummy trial of IV ketamine use for subdissociative analgesia in the emergency department (ED) was published in the American Journal of Emergency Medicine in August 2017 by Motov et al12

  • Power: set and met at 80%, requiring 24 patients per group. Alpha set at 0.05.
  • Comparison: ketamine 0.3 mg/kg via IV push (over 5 minutes) or by IV infusion over 15 minutes compounded in a 100 mL 0.9% sodium chloride bag.
  • Primary outcome measure: overall rates of adverse effects as measured on the SERSDA scale (Side Effects Rating Scale for Dissociative Anesthetics).
  • Exclusion criteria was significant for excluding patients weighing <46 kg or >115 kg.
  • Result: among the SERDSA list of possible adverse effects, 91.7% of patients in the IV push group experienced feelings of unreality, while 54.2% of patients in the slow IV infusion group experienced this effect (p=0.008).

Procedural sedation and analgesia: Ferguson I et al 14 published the POKER study in the Annals of Emergency Medicine in 2016. POKER is the largest randomized, double-blind, prospective clinical trial to date comparing propofol to ketofol, a 1:1 mixture of ketamine and propofol, for procedural sedation in adults

  • This trial set and met power at 90%, requiring 263 patients per group. Alpha was set at 0.05.
  • The primary outcome was the occurrence of an adverse respiratory event that required physician intervention.
  • The only statistically significant differences between groups was hypotension as determined by a systolic blood pressure less than 90 mmHg being recorded in 7% of patients in the propofol group compared with 1% in the ketofol group (p=0.0001).
  • The researchers deemed this result to not be clinically significant as patients that experienced hypotension did not require further intervention after administration of a fluid bolus.

Dissociative sedation for excited delirium: A prospective, single-center, observational study evaluated different treatment modalities for emergency department patients with excited delirium, a condition is characterized by violent outbursts oftentimes due to acute psychosis or intoxication15

  • Patients were placed in one of five groups: ketamine, midazolam, lorazepam, haloperidol, or a combination of a benzodiazepine and haloperidol.
  • Power was set but not met at 80%, requiring 17 patients per group. Alpha was set at 0.05.
  • The primary outcome was the time required to reach adequate sedation (defined as an agitation score of ≤2: a patient that at most is “mildly” aroused).
  • Patients receiving ketamine were significantly younger than those receiving other medications (p=0.033).
  • Due to the observational nature of the study, groups did not receive a standard dose of any medication used. The average ketamine dose was 0.87 mg/kg IV or 2.97 mg/kg IM, and the midazolam dosage was on average 3.08 mg IV and 2.25 mg IM. These dosages are lower than the published dosage ranges for these medications.15
  • There were statistically significantly more patients that were no longer aroused in the ketamine group than in the other medication groups at 5, 10, and 15 mins (p=0.001, <0.001, and 0.032 respectively).


Conclusions:

Ketamine has a multitude of uses and beneficial effects due to its unique pharmacology, and it harbors significant advantages over current mainstream therapies. It is an opioid-sparing pain-relieving agent6, it preserves respiratory drive while facilitating painful procedures13,14, and can very rapidly dissociate a patient experiencing excited delirium.15,16 Of note, ketamine does have drawbacks, including an increase in nausea and vomiting as well as the risk of emergence phenomenon in higher dosages.17 Research continues to be published on the use of ketamine in several situations, as evidenced by the recent surge of literature for esketamine, the active S-enantiomer of ketamine, for treatment of major depressive disorder with an imminent suicide risk.18 With new research and the overarching threat of opioid addiction in the United States, ketamine may present itself as an old drug with new tricks. 

References:

  1. Domino E, Chodoff P, and Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965; 6:279-91
  2. Priestley S, Taylor J, McAdam C, and Francis P. Ketamine sedation for children in the emergency department. Emergency Med. 2001; 13:82-90
  3. World Health Organization. Ketamine update review report. Switzerland 2014
  4. Mion G and Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci & Therapeutics. 2013; 370-380
  5. Ahern T, Herring A, Miller S, and Frazee B. Low-dose ketamine infusion for emergency department patients with severe pain. Pain Med. 2015; 16(7):1402-1409
  6. Ketalar® [package insert]. Par Pharmaceutical, Inc., Chestnut Ridge, NY; Updated May 5, 2017
  7. Sleigh J, Harvey M, Voss L, and Denny B. Ketamine – more mechanisms of action than just NMDA blockade. Trends in Anesth and Crit Care. 2014; 4(2-3):76-81
  8. Corssen G. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966; 45(1):29-40
  9. White P, Way W and Trevor A. Ketamine-its pharmacology and therapeutic uses. Anesth. 1982; 56(2):119-136
  10. American College of Emergency Physicians. PREP sub-dissociative ketamine for analgesia. 2017. Available from: https://www.acep.org/Clinical---Practice-Management/Sub-dissociative-Dose-Ketamine-for-Analgesia/#sm.00000ywtftjttyd4py5ihwzksxnh9
  11. Kurdi M, Theerth K, and Deva R. Ketamine: current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014; 8(3):283-290
  12. Motov S, Mai M, Pushkar I, Likourezos A, Drapkin J, et al. A prospective randomized, double-dummy trial comparing IV push low dose ketamine to short infusion of low dose ketamine for treatment of pain the ED. Am J Emerg. Med. 2017; 35(8):1095-1100
  13. Godwin S, Burton J, Gerardo C, Hatten B, Mace S, Silvers S, et al. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg. Med. 2014;63(2):247-258
  14. Ferguson I, Bell A, Treston G, New L, Ding M, and Holdgate A. Propofol or ketofol for procedural sedation and analgesia in emergency medicine – the POKER study: a randomized double-blind clinical trial. Ann Emerg. Med. 2016; 68(5):574-582
  15. Green S, Roback M, Kennedy R, and Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011; 57(5):449-461
  16. Riddell J, Tran A, Bengiamin R, Hendey G, and Armenian P. Ketamine as a first-line treatment for severely agitated emergency department patients. Am J Emerg. Med. 2017; 35:1000-1004
  17. Gao M, Rejaei D, and Liu H. Ketamine use in current practice. Acta Pharmacol Sin. 2016; 37(7):865-872
  18. Johnson & Johnson. Esketamine receives breakthrough therapy designation from U.S. Food and Drug Administration for major depressive disorder with imminent risk for suicide. N.J., 2016

Upcoming events


Copyright 2019, Missouri Society of Health-System Pharmacists
501(c)6 non-profit organization. 2650 S. Hanley Rd., Suite 100, St. Louis, MO 63144
p: 314-416-2246, f: 314-845-1891, www.moshp.org
Powered by Wild Apricot Membership Software