Ketamine

See Also

Indications

Indicated for ASA Physical Status Score 2 and 3
Drug of choice for Conscious Sedation in children
1. Not FDA approved
2. Ear Foreign Body
3. Entrapment of penis in zipper
4. Abscess Incision and Drainage
5. Imaging studies
6. Laceration Repair or Wound Debridement
7. Fracture or dislocation reduction
Conscious Sedation in adults
1. Excellent Procedural Sedation in single provider procedures or resource poor environments
2. No Hypotension and low apnea risk compared with Propofol (typically used for adult Procedural Sedation)
Sedation in Excited Delirium
1. Excellent first-line Sedative to allow for controlled evaluation and management (Ketamine 4-5 mg/kg IM)
Sedation in Rapid Sequence Intubation (or Delayed Sequence Intubation)
1. Useful in Status Asthmaticus (Bronchodilator) to avoid suppressing respirations
2. Ketamine is the only Sedative induction agent with Analgesic properties
Analgesia
1. Excellent choice before Fracture or joint reduction, for Opioid tolerant patient
2. Low dose Ketamine (0.1 to 0.3 mg/kg, study used up to 0.6 mg/kg) as adjunct for analgesia in ED
  1. Lester (2010) Am J Emerg Med 28(7): 820-7 [PubMed]
Refractory Depression Management
1. Esketamine (Spravato) is an active isomer of Ketamine used intranasally
2. C-III medication with abuse potential and requiring provider REMS enrollment

Contraindications
General

Absolute contraindications
1. Ketamine Hypersensitivity
2. Schizophrenia or other Psychosis
3. Pregnancy
4. Age <3 months
  1. Contraindication is related Neuronal injury observed when large doses were given to neonatal rats
  2. May be considered in severe injury (including neurologic injury)
  3. May be considered for RSI and hemodynamic instability
  4. Bhutta and Claudius (2024, Feb) EM:Rap, accessed 2/2/2024
Relative Contraindications
1. Posterior oropharynx procedures
2. Tracheal surgery or tracheal stenosis
3. Significant upper respiratory tract infection
4. Uncontrolled Hypertension

Contraindications
Disproven Relative Contraindications

See Adverse Effects as below
Schizophrenia or other Psychosis
Age <3 months of age
Coronary Artery Disease
1. Theoretical risk of worsening severe coronary ischemia
2. However improves cardiac contractility as well as improving stunned Myocardium
3. Not contraindicated in Coronary Artery Disease, Congestive Heart Failure or Hypertension
Increased Intracranial Pressure
1. Older data recommends avoiding in Closed Head Injury (risk of Increased Intracranial Pressure)
  1. Newer data suggests safe in Head Injury
    1. In fact neuroprotective with increased Cerebral Perfusion Pressure
  2. No adverse effects on Intracranial Pressure in critically ill adults
    1. No adverse effect on Cerebral Perfusion Pressure, neurologic outcomes
    2. Cohen (2014) Ann Emerg Med [PubMed]
Eye Injury or Increased Intraocular Pressure
1. ACEP 2011 guidelines lists Glaucoma and acute globe injury as contraindications for Ketamine use in children
2. Ketamine does increase Intraocular Pressure in children
  1. However these changes appear to mild (typically <3-5 mmHg) at standard Procedural Sedation doses
  2. Halstead (2012) Acad Emerg Med 19(10):1145-50 [PubMed]

Mechanism

Synthetic derivative of Phencyclidine (PCP) first developed in 1962
1. N-Methyl-D-Aspartate Antagonist (NMDA Antagonist)
2. Blocks Glutamate binding in the Central Nervous System
Dissociative Anesthetic
1. Prevents CNS from perceiving visual, auditory, and painful stimuli
2. Produces a trance-like state
3. May be less well tolerated in elderly patients
Additional effects (beyond Anesthetic effect)
1. Analgesic effect
2. Amnestic effect
3. Bronchodilation and minimal respiratory depression
4. Increases Blood Pressure and Heart Rate
Effects are dose dependent
1. Pure Analgesic effects
  1. Dose: 0.1 to 0.2 mg/kg IV
  2. Strong Analgesic without significant Intoxication or altered Perception or emotion
2. Intoxicant effects
  1. Dose: 0.2 to 0.5 mg/kg IV
  2. See Ketamine Abuse
  3. Very strong Analgesic effects
  4. Intoxicated with altered Perception and Hallucinations
  5. May require redirection to calm patient
3. Partial dissociative effects
  1. Dose: 0.4 to 0.8 mg/kg IV
  2. Partially aware of outside stimuli and able to follow some commands and direction
  3. Potentially distressing
    1. Give additional Ketamine if patient distressed soon after Ketamine initiation
    2. Emergence reactions may be treated with Benzodiazepines (e.g. Midazolam)
4. Complete dissociative effects
  1. Dose: 0.8 mg/kg IV and higher
  2. Dosing used in Procedural Sedation and Rapid Sequence Intubation
  3. Patient is completely unaware of external stimuli
  4. Cardiopulmonary function is minimally affected
5. Higher doses
  1. Doses above complete dissociation extend duration but do not have additional adverse effects

Precautions

Procedural Sedation risks respiratory and cardiovascular depression
1. Ketamine does not appear to cause significant apnea at typical doses (when used as only Sedative)
2. However, apnea may still occur, especially when combined with Opioids, Benzodiazepines or other Sedatives
3. IV doses may impair respiratory drive if >5 mg/kg IV or infused faster than over 30-45 seconds
  1. Best practice is to bolus over 1-2 minutes
Agitated Delirium patients in the pre-hospital setting
1. Ketamine is often used as a very effective and safe pre-hospital Chemical Restraint
2. Ketamine at high dose (4-5 mg/kg) results in GCS 3, but typically maintained respiratory drive (GCS-3K)
3. Inconsistent ED response on Ambulance arrival after Ketamine induced sedation
  1. Many providers prematurely intubate based on arrival GCS 3 (despite Ketamine induced)
  2. However, with close monitoring, Ketamine sedated patients may be safely observed without intubation
4. References
  1. Swaminathan and Perlmutter in Herbert (2018) EM:Rap 18(7): 15-6
Monitoring is critical
1. See Procedural Sedation and Analgesia
2. Monitoring includes Blood Pressure, Pulse Oximetry, Capnography and cardiac monitoring
Recheck Ketamine concentration
1. Multiple Ketamine concentrations may cause confusion and over-dosage
2. Ketamine IV concentration is typically 10 mg/ml, whereas IM concentration is 50-100 mg/ml
Do not use with Atropine (to dry secretions)
1. Previously used to decrease Ketamine-induced Hypersalivation
2. Worsens increased airway secretions by thickening them

Dosing
Analgesia

Single subdissociative dose protocol
1. Ketamine IV
  1. Dose: 0.1 to 0.3 mg/kg IV push over 1-2 min (or IV infused over 10 minutes)
  2. Doses of 0.1 to 0.2 mg are subdissociative and unlikely to cause emergence reaction
  3. Consider single 10 mg Ketamine dose for weights 50-150 kg
    1. May repeat 10 mg IV dosing as needed
2. Ketamine IM
  1. Dose: Up to 1 mg/kg
  2. Typical Adult Dose: 50 mg IM
3. Ketamine Intranasal
  1. Use 100 mg/ml if available (maximal nasal dose volume 0.5 ml)
  2. Child: 1 to 1.5 mg/kg intranasally
  3. Typical Adult Dose: 50 mg Intranasal
  4. Onset of action: 10 min
  5. Duration: 15-20 min
  6. Graudins (2015) Ann Emerg Med 65(3): 248-54 +PMID:25447557 [PubMed]
4. Consider in combination with Fentanyl (see below)
5. Lester (2010) Am J Emerg Med 28(7): 820-7 [PubMed]
6. Ahern (2015) Am J Emerg Med 33(2): 197-201 [PubMed]
Continuous subdissociative analgesia
1. Initial: 0.2 to 0.3 mg/kg IV
2. Maintenance: 0.2 to 0.3 mg/kg/hour IV infusion
3. Drake (2015) Acad Emerg Med 22(7): 887-9 [PubMed]
4. Motov (2015) Ann Emerg Med 66(3): 222-9 [PubMed]

Dosing
Sedation

Intravenous
1. Initial
  1. Adult: 1.0 mg/kg slow IV over 1-2 min (some start at 1.5 mg/kg)
  2. Child: 1.5 mg/kg slow IV over 1-2 min
2. Next
  1. Administer 1/2 of intial dose every 10 min as needed
Intramuscular (esp. for Excited Delirium as Chemical Restraint)
1. Initial: 4-5 mg/kg IM (adult and child)
2. Repeat 4-5 mg/kg IM after 10 min for one dose if needed
Intranasal
1. Not recommended intranasally for Anesthesia
2. Amount delivered intranasally is too low for Anesthesia dosing and onset varies widely
3. Protocol
  1. Use 100 mg/ml if available (maximal nasal dose volume 0.5 ml)
  2. Child: 2 to 4 mg/kg intranasally
  3. Onset of action: 10 min
  4. Duration: 15-20 min
  5. Observe for 60 min after procedure
Consider concurrent Midazolam (especially in adults)
1. Blunts Sympathomimetic effect
2. Reduces Agitation (emergence reaction) on recovery from Ketamine
3. Midazolam (Versed) dosing: 0.03 mg/kg IV (Max dose: 4.0 mg)

Dosing
Induction for Rapid Sequence Intubation (RSI)

Ketamine 1.5 mg/kg (120 mg for an 80 kg adult)

Preparations
Combinations

Ketaphol (Ketamine with Propofol)
1. Postulated to reduce risk of Hypotension and apnea of Propofol by cutting dose with Ketamine
  1. Initial studies recommended ratio of 4:1 Propofol to Ketamine for adequate effect
  2. Some protocols start 1:1 ratio Propofol to Ketamine 0.5 then add Propofol to effect
2. Typical protocol
  1. Start: Administer mix of Propofol 0.5 mg/kg AND Ketamine 0.5 mg/kg
  2. Next: Administer additional Propofol 0.5 mg/kg every 90 seconds as needed to adequate effect
3. Most studies show no significant benefit over Propofol alone (similar efficacy and safety)
Ketamine with Fentanyl
1. May offer excellent Analgesic effect without Ketamine intoxicant effects
2. Dosing
  1. Ketamine 0.1 mg/kg IV
  2. Fentanyl 1.5 mg/kg IV
Ketamine with Dexmedetomidine (KetaDex) Intranasal
1. Being studied for Procedural Sedation (combines Ketamine analgesia with Dexmedetomidine sedation)
2. Intranasal Dosing via atomizer
  1. Ketamine 2-4 mg/kg in one nostril
  2. Dexmedetomidine 2-4 mcg/kg in other nostril

Pharmacokinetics

Intravenous dosing
1. Onset: 1 minute
2. Dissociation Duration: 15 minutes
3. Recovery: 60 minutes
Intramuscular dosing
1. Onset: 5 minutes
2. Dissociation Duration: 15-30 minutes
3. Recovery: 90-150 minutes

Efficacy

Sedation
1. Results in >90% of children with adequate sedation
Analgesia
1. Ketamine 0.3 mg/kg as effective as 0.1 mg/kg IV Morphine in acute moderate to severe pain
  1. More Dizziness and Disorientation occurred with Ketamine
  2. Motov (2015) Ann Emerg Med 66(3):222-9 +PMID:25817884 [PubMed]
Induction agent for Rapid Sequence Intubation (RSI)
1. Asthma or Angioedema
  1. Variable efficacy in studies, but theoretically this should be a Ketamine strong suit
  2. Bronchodilatory effects are unique to Ketamine (among the RSI induction agents)
  3. Ketamine is not associated with apnea, regardless of dose
2. Safe and effective alternative to Etomidate for adults with Sepsis
  1. Jabre (2009) Lancet 374(9686): 293-300 [PubMed]
3. Appears safe in Head Trauma even with increased ICP
  1. Appears to be neuroprotective by increasing Cerebral Perfusion Pressure
  2. Does not lower Seizure threshold
  3. Himmelseher (2005) Anesth Analg 101(2): 524-34 [PubMed]

Safety

Background
1. Minimal to no data for either pregnancy or Lactation
2. Not typically recommended in pregnancy or Lactation
Pregnancy Category C
Unknown safety in Lactation

Adverse Effects
General

Blood Pressure elevation
Confusion or Delirium
Anterograde Amnesia
Visual Hallucinations
1. Floating outside the body
2. Vivid, dream-like state
Flashbacks may occur weeks after use
Emergence Reaction (Agitation on recovery from agent)
1. Acheive adequate analgesia before procedure
2. Frequently reorient and calm patient with mild distress
3. Consider concurrent or prn Midazolam in adults (0.03 mg/kg) to counter emergence reaction
  1. However, risk of respiratory depression, especially in children
  2. PRN dosing is preferred instead (have Benzodiazepine ready in case of moderate to severe emergence)
  3. Sener (2011) Ann Emerg Med 57(2):109-114 [PubMed]
Transient laryngospasm
1. Occurs in 0.3 to 0.4% of cases, especially children
2. Manage with airway repositioning, Jaw Thrust, or two person bag-valve mask
3. Laryngospasm Notch Maneuver may also be used with relief within 1-2 breaths
4. In severe, persistent cases, paralyze (Rocuronium or Succinylcholine) and intubate
Skeletal Muscle hypertonicity and rigidity
Vomiting
1. Typically occurs during recovery
2. Peak Incidence in teen years
3. Occurs in up to 20% of cases when used IM and 10% with IV use
4. Consider prophylaxis with Ondansetron (Zofran)
Ptyalism (Hypersalivation)
1. Drooling and increased oral secretions
2. Manage with suction or wiping away secretions with gauze
3. Avoid Anticholinergics such as Atropine or Diphenhydramine
  1. Simply thickens the increased secretions
Respiratory depression
1. Respiratory drive is typically preserved, however, transient apnea (10-20 s) may occur with rapid infusion
  1. Administer Ketamine slowly (over 1-2 minutes)
2. Brief Positive Pressure Ventilation may be needed
3. Start by repositioning head and neck, and Jaw Thrust maneuver
4. Mild Oxygen desaturation (most common side effect)
  1. Significant oxygen desaturation <85% occurred in <1%
  2. Most cases: Return to baseline within 2 minutes

Adverse Effects
Disproven or not thought to be Clinically Significant

Increased Intracranial Pressure (ICP)
1. Consider alternatives in Intracranial Mass or Hydrocephalus (although not an absolute contraindication)
2. ICP not found to be increased with Ketamine
  1. Cohen (2015) Ann Emerg Med 65(1):43-51 [PubMed]
Increased Intraocular Pressure (IOP)
1. Consider alternatives in Glaucoma and globe injury (although not an absolute contraindication)
2. IOP not increased in adults and only minimally increased in children
  1. Drayna (2012) Am J Emerg Med 30(7): 1215-8 [PubMed]
  2. Halstead (2012) Acad Emerg Med 19(10): 1145-50 [PubMed]

Resources

Ketamine (DailyMed)
1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e8f864-8b8a-4e7e-8439-e510d3107063

References

Acker, Koval and Leeper (2017) Crit Dec Emerg Med 31(4): 3-13
Hipskind and Kamboj (2016) Crit Dec Emerg Med 30(10): 15-23
Kay (2015) Crit Dec Emerg Med 29(8): 11-17
Mell in Herbert (2015) EM:Rap 15(5): 4-5
Nordt, Poonai and Ramiakhan in Swadron (2022) EM:Rap 22(3): 5-6
Brown (2005) Am Fam Physician 71:85-90 [PubMed]
Gahlinger (2004) Am Fam Physician 69:2619-27 [PubMed]
Green (1998) Ann Emerg Med 31:688-97 [PubMed]
Jansen (1993) BMJ 306:601-2 [PubMed]
Parker (1997) Pediatrics 99:427-31 [PubMed]