Update from the K-Hole: Ketamine in the ED

ketamine

In this post, we discuss the pharmacology, myths, and a myriad of roles for Ketamine in the ED; including analgesia, sedation, agitation, alcohol withdrawal, and suicidal ideation.

Part I: Pharmacokinetics and pharmacodynamics of ketamine

  • Produced in 1970s, structurally related to PCP
  • Use declined with: advent of propofol, increasing documented cases of abuse, concerns regarding side effects and ICP effects1
  • Relegated to “Horse Tranquilizer”
  • Resurgence in its use in past 20 years2

Mechanism of action:

  • NMDA receptor antagonist3
  • Sympathomimetic reuptake inhibitor
  • Dissociative anesthetic

Pharmacokinetics:

  • Rapidly distributes across the blood brain barrier4
  • Metabolized by the liver and eliminated by the kidneys
  • Dosing based on ideal not actual body weight
    • Onset IV: <1 min
    • Duration (of dissociation) IV: 5-10 min

Pharmacodynamics: dosing ranges4

ketamine

ketamine

Take home points:

  • Ketamine has different dosing ranges that are crucial to it’s use in the ED
  • Ketamine should be used either in the:
    • Analgesic dosing range (0.1-0.3 mg/kg), or
    • Dissociative range (>1 mg/kg)
  • Avoid in cases of psychotic disorders
  • There are many uses for ketamine in the ED other than RSI

Part II: Ketamine for Analgesia

  • There is interest in the ED for a non-opioid analgesic alternative such as subdissociative ketamine for the following reasons:
    • Patients’ pain in the ED is often poorly controlled
    • The rising opioid crisis
    • The rising rate of chronic pain

Mechanism of action:

  • Glutamate is released by afferent nociceptive neurons in the dorsal horn of the spinal cord5
  • This pathway appears to be not only involved in acute pain but also involved in the development of chronic pain
    • Central sensitization
    • Opioid tolerance
    • Opioid hyperalgesia
  • Ketamine’s action of blocking these NMDA receptors should treat acute pain and also may help prevent chronic pain and opioid tolerance6

ED subdissociative ketamine combined with opioids:7-9

ketamine

For a full review of Beaudoin et al. 2014 see here

ED subdissociative ketamine instead of opioids:10, 11

ketamine

For a full review of Motov et al. 2015 see here

IV push vs short infusion:

  • A study by Motov et al. 2017 compared giving ketamine 0.3 mg/kg IV over 5 min (IVP) OR mixed in 100 cc NS given over 15 min (short infusion)12
  • Same analgesic effect in reducing pain scores
  • They found feeling of unreality 91.7% IVP vs 54.2% infusion (p=0.008) and that the IVP group showed more sedation at 5 min (median RASS -2 vs 0)

Take home points:

  • Subdissociative ketamine is a viable choice for treatment of both acute and chronic pain in the ED
  • It can be given alone or combined with multimodal agents (ex: opioids)
  • Dosing:
    • 0.3 mg/kg IV over 15 min (mixed in 100 cc NS) – best evidence, or
    • 0.1 mg/kg IVP over 3 min
  • No monitoring is required at this dosing range

Part III: Ketamine for Procedural Sedation

Ketamine Single Agent Sedation

  • Ketamine has been the single most popular agent for procedural sedation in children for over 20 yearsketamine
  • Has been underutilized as an agent in the adult population
  • If single agent sedation – use a fully dissociative dose31-2 mg/kg IV
    • 5 mg/kg IM
  • Benefits:
    • Potent analgesia, sedation, and amnesia
    • Preserved respiratory drive and airway reflexes
    • HD neutral/indirect sympathomimetic

Ketamine single agent sedation: Adverse effects13-15

ketamine

Ketamine single agent sedation: Contraindications

Absolute:3

  • Age < 3 months
  • Schizophrenia

Relative:

  • Procedures with laryngeal stimulation
    • Okay for ED procedures (oral laceration, dental, foreign body removal)
    • High rate of laryngospasm in EGD (8%)
  • URTI (peds)
  • Cardiac disease (increased myocardial oxygen demand)

Ketamine single agent sedation: Mitigating Common Adverse Effects

Nausea:

  • Prophylactic Zofran may reduce vomiting

Emergence reactions:

  • Routine prophylactic benzos may benefit adults but not children
  • Midazolam 0.03 mg/kg IV effective to prevent and terminate emergence in adults

ketamine

Multi Agent Sedation with Ketamine

  • A study done by Messenger et al. in 2008 compared using ketamine 0.3 mg/kg IV vs Fentanyl 1.5 mcg/kg in addition to titrated Propofol16
  • They found severe adverse events occurred in 0% of the ketamine group and 16% of the fentanyl group
  • The ketamine group also had:
    • Smaller propofol requirement
    • Shorter recovery time
    • No difference in patient or team satisfaction
    • Zero cases of emergence phenomenon

See here for Andolfatto et al.‘s 2012 study on the effectiveness of “Ketofol” in procedural sedation

Take home points:

Ketamine single agent

    • Give full dissociative dose (1-2 mg/kg)
    • Consider prophylactic ondansetron and midazolam
    • Benzos to treat emer gence (consider routinely writing a PRN)

0.3 mg/kg and titrated Propofol

    • Less adverse reactions compared to fentanyl and Propofol
    • Less emergence reactions

Part IV: Ketamine for Agitation

  • Classically options have included benzodiazepines, antipsychotics, or combinations of bothketamine
  • Emerging evidence to use Ketamine IM as an alternative for undifferentiated agitation
    • Listed on ACEP white paper for agents to be used for agitated delirium17
    • Being rolled out to EMS in Ontario in the next few months

Evidence: Ketamine as Rescue

  • Isbister et al. 2016 performed an observational prospective study looking at ketamine as rescue for difficult to sedate pts in ED18
    • Most pts received 2 doses of 10mg droperidol prior (some 3 doses)
    • Received Ketamine 4-6 mg/kg IM
    • 6% had adverse effects
      • Vomiting (n=2); oxygen desat to 90% (n=1)

Evidence: Ketamine single agent for agitation

Con studies:

  • Two studies by Cole et al. published in 2016 and 2017 looked at prehospital use of Ketamine 5 mg IM for sedation of agitated patients19,20
    • Ketamine worked very quickly (time to sedation): 4-5 min
    • Extremely high rate of adverse events, most notably ED intubation rates of 39% and 57%; not entirely clear why rate so high

Pro studies:

  • Riddell et al. published a prospective ED study in 2017 comparing different agents for sedation of agitated patients21
    • Time to sedation fastest in ketamine group (6.6 min vs 15 min for midazolam and 13.4 min for Haldol)
    • Changes in vital signs similar between groups
    • 2 intubations in ketamine group, single intubation in other groups
    • Limitations: too small to detect serious adverse events, small doses of sedatives used

Take home points:

  • Ketamine 5 mg/kg IM is a viable option for sedating agitated patients
  • More studies are needed to determine rates of rare but serious adverse events
  • Current suggestions for use:
    • Initial dose(s) of benzos fail (second line agent), or
    • Extremely rapid take down (required for safety)

Part V: Ketamine for Alcohol Withdrawal

Mechanism of ketamine in alcohol withdrawal:

  • Repeated EtOH use causes:22
    • Downregulation of GABA receptors
    • Upregulation of excitatory NMDA receptors
  • Most treatments simulate GABA receptors (benzos, Propofol, phenobarbital)
  • Ketamine as an NMDA receptor antagonist works on other side of pathophysiology

Evidence:23-25

ketamine

Take home points:

  • Limited evidence for Ketamine use in EtOH withdrawal, none are ED studies
  • Consider in ED if large doses of benzos and considering intubation
    • Most studies used infusion at 0.1-0.3 mg/kg/hr +/- bolus of 0.3 mg/kg
  • Benzos remain by far first line for EtOH withdrawal

Part VI: Ketamine for Suicidal Ideation

Ketamine for depression:

  • Berman et al. 1990 published a small study with 7 patients showing that ketamine 0.5 mg/kg possessed antidepressant qualities26
  • Many subsequent trials support this effect but antidepressant effects seems to be transient (effect abating at about 1 week post infusion)

Ketamine for suicidal ideation:

  • Grunebaum et al. in 2018 performed a double blind RCT with 80 inpatients (voluntary admission) and compared Ketamine 0.5 mg/kg over 40 mins vs. Midazolam 0.02 mg/kg (active control)27
    • They found that ketamine had greater reduction in suicidality (SSI score) 55% vs 30% on day 1 (NNT=4)
  • A meta-analysis published in 2018 by Wilkinson et al. included 10 studies done in a variety of settings (none the ED) and found that Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation28

Ketamine for suicidal ideation in the ED:

A study done by Kashni et al. in 2014 looked at EPs administering ketamine to decrease suicidality in the ED29

  • Patients received Ketamine 0.2 mg/kg IV over 1 min
  • Suicidal ideation measured with standardized scales before injection, 40 min, 80 min, 120 min, 10 days via telephone
  • 10 day follow-up 85.7% did not have any suicidal thoughts
  • Numerous limitations:
    • No control group, small study
    • Different setting compared to Canadian EDs
    • Ethical implications
    • Abuse potential

Take home points:

  • No role at present for ketamine use in the ED for suicidality
  • More studies needed, logistical, and ethical roadblocks remain
  • Possible future role (after much more study) for single dose ketamine in the ED and expedited follow up for selected patients with suicidal ideation

 

References:

  1. Mion G. History of anaesthesia: The ketamine story – past, present and future. Eur J Anaesthesiol. 2017;34(9):571-575.
  2. Sheikh S, Hendry P. The Expanding Role of Ketamine in the Emergency Department. Drugs. 2018;
  3. Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011;57(5):449-61.
  4. Strayer. SMACC Presentation 2015 https://www.smacc.net.au/2015/12/ketamine-how-to-use-it-fearlessly-for-all-its-indications-by-reuben-strayer/
  5. Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous sub-anesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32(2):160-7.
  6. Kurdi MS, Theerth KA, Deva RS. Ketamine: Current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014;8(3):283-90.
  7. Bowers KJ, Mcallister KB, Ray M, Heitz C. Ketamine as an Adjunct to Opioids for Acute Pain in the Emergency Department: A Randomized Controlled Trial. Acad Emerg Med. 2017;24(6):676-685.
  8. Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014;21(11):1193-202.
  9. Sin B, Tatunchak T, Paryavi M, et al. The Use of Ketamine for Acute Treatment of Pain: A Randomized, Double-Blind, Placebo-Controlled Trial. J Emerg Med. 2017;52(5):601-608.
  10. Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015;33(3):402-8.
  11. Motov S, Rockoff B, Cohen V, et al. Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2015;66(3):222-229.e1.
  12. Motov S, Mai M, Pushkar I, 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 in the ED. Am J Emerg Med. 2017;35(8):1095-1100.
  13. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med. 2008;26(9):985-1028.
  14. Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54(2):158-68.e1-4.
  15. Bhatt M, Johnson DW, Chan J, et al. Risk Factors for Adverse Events in Emergency Department Procedural Sedation for Children. JAMA Pediatr. 2017;171(10):957-964.
  16. Messenger DW, Murray HE, Dungey PE, Van vlymen J, Sivilotti ML. Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial. Acad Emerg Med. 2008;15(10):877-86.
  17. ACEP White Paper Report on Excited Delirium Syndrome 2009
  18. Isbister GK, Calver LA, Downes MA, Page CB. 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.
  19. Cole JB, Klein LR, Nystrom PC, et al. A prospective study of ketamine as primary therapy for prehospital profound agitation. Am J Emerg Med. 2017;
  20. Cole JB, Moore JC, Nystrom PC, et al. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clin Toxicol (Phila). 2016;:1-7.
  21. Riddell J, Tran A, Bengiamin R, Hendey GW, Armenian P. Ketamine as a first-line treatment for severely agitated emergency department patients. Am J Emerg Med. 2017;35(7):1000-1004.
  22. Nelson LS, Lewin NA, Howland MA et al. Goldfrank’s Toxicologic Emergencies, Ninth Edition. McGraw Hill Professional; 2010.
  23. Wong A, Benedict NJ, Armahizer MJ, Kane-gill SL. Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome. Ann Pharmacother. 2015;49(1):14-9.
  24. Pizon AF, Lynch MJ, Benedict NJ, et al. Adjunct Ketamine Use in the Management of Severe Ethanol Withdrawal. Crit Care Med. 2018;
  25. Shah P, Mcdowell M, Ebisu R, Hanif T, Toerne T. Adjunctive Use of Ketamine for Benzodiazepine-Resistant Severe Alcohol Withdrawal: a Retrospective Evaluation. J Med Toxicol. 2018;
  26. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4.
  27. Grunebaum MF, Galfalvy HC, Choo TH, et al. Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial. Am J Psychiatry. 2018;175(4):327-335.
  28. Wilkinson ST, Ballard ED, Bloch MH, et al. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2018;175(2):150-158.
  29. Kashani P, Yousefian S, Amini A, Heidari K, Younesian S, Hatamabadi HR. The Effect of Intravenous Ketamine in Suicidal Ideation of Emergency Department Patients. Emerg (Tehran). 2014;2(1):36-9.
Simeon Mitchell

Simeon Mitchell

Dr. Mitchell is a 5th year Emergency Medicine resident at the University of Ottawa, with a special interest in Emergency Medicine Services and Pre-hospital care.
Richard Hoang

Richard Hoang

Dr. Richard Hoang is a 3rd year Emergency Medicine Resident at the University of Ottawa with a variety of academic interests including military medicine, simulation, FOAMed, and social media.

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