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

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

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

ED subdissociative ketamine instead of opioids:^{10, 11}

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 years
• 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 effects^13-15

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

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 both
• 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 patients^19,20
  • 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

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