What is the mechanism of action, clinical indications, dosing regimens, adverse effects, contraindications, and alternative agents for ketamine?

Ketamine: Comprehensive Clinical Overview

Mechanism of Action

Ketamine functions primarily as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, producing a dissociative anesthetic state that blocks sensory recognition of painful stimuli and memory. 1

• The drug creates a functional dissociation between limbic and cortical systems, selectively depressing the cortex and thalamus while stimulating parts of the limbic system 1
• Ketamine also blocks opioid receptors in the brain and spinal cord, contributing significantly to its analgesic properties 2, 1
• At subanesthetic doses, it modulates central sensitization, prevents hyperalgesia, and blocks the development of opioid tolerance through NMDA antagonism 1
• Additional mechanisms include interactions with GABA, dopamine, serotonin, sigma, and cholinergic receptors, as well as voltage-gated ion channels 3

Clinical Indications

Ketamine is indicated for procedural sedation, anesthesia induction and maintenance, acute and chronic pain management, and as an adjunct in difficult-to-sedate patients. 2, 1

Primary Uses:

• Procedural sedation and analgesia in both pediatric and adult populations 2, 1, 4
• Anesthesia induction for surgical procedures requiring rapid onset and recovery 1, 5
• Orthopedic procedures including fracture reductions, particularly in children 1, 6
• Emergency medicine applications including wound repair, burn care, and lumbar puncture 1, 4
• Perioperative pain management as an adjunct to opioid therapy 1
• Bronchospasm management due to bronchodilatory and anti-inflammatory properties 5

Special Clinical Scenarios:

• Hemodynamically unstable patients, as ketamine maintains blood pressure through preserved sympathetic tone 4
• Patients with difficult venous access, given multiple administration routes 5
• Critically ill adults requiring opioid-sparing analgesia 4

Dosing Regimens

Intravenous Administration:

For procedural sedation, administer 1.5-2 mg/kg IV, which is significantly more effective than lower doses, with only 5.5% of patients requiring additional doses compared to 54% at 1 mg/kg. 1, 4

• Anesthesia induction: 1-2 mg/kg IV 1
• Brief procedures: 1-1.5 mg/kg IV 1
• Perioperative pain management: Bolus <0.35 mg/kg, followed by continuous infusion at 0.125-0.25 mg/kg/h (maximum 0.5 mg/kg/h) 1
• Critically ill adults: 0.5 mg/kg IV push followed by 1-2 μg/kg/min infusion as adjunct to opioids 4
• Onset of action: 30-96 seconds (average 1 minute) 1, 4
• Duration: 15-30 minutes 2, 1

Intramuscular Administration:

For pediatric procedural sedation when IV access is unavailable, administer 4 mg/kg IM, with onset within 3-5 minutes. 1, 4

• Wound repair, burn care, or lumbar puncture: 4 mg/kg IM 1
• Laceration repair: 2.5 mg/kg IM 1
• With atropine for lumbar puncture: 4 mg/kg IM ketamine + 0.01 mg/kg IM atropine (minimum 0.1 mg, maximum 0.5 mg) 4
• Repeat dosing: 2-4 mg/kg after 5-10 minutes if needed 4
• Onset of action: 3-5 minutes (average 4 minutes 42 seconds) 1

Combination Therapy:

Consider adding midazolam 0.05-0.1 mg/kg to reduce emergence reactions, particularly in patients over 10 years old, reducing recovery agitation from 35.7% to 5.7%. 4

• Pediatric endoscopy: Ketamine 0.75-2.0 mg/kg + midazolam 0.05-0.2 mg/kg 2
• Dental procedures/lacerations: Ketamine 3 mg/kg + midazolam 0.05 mg/kg 1
• Adult procedural sedation: Midazolam 0.07 mg/kg followed by ketamine 2 mg/kg 4
• Pediatric orthopedic procedures: Ketamine/midazolam provides superior respiratory safety compared to fentanyl/midazolam, reducing hypoxia from 20% to 6% 4, 6

Antisialagogue Premedication:

Administer atropine 0.02-0.05 mg/kg IV or 0.01 mg/kg IM before ketamine to reduce excessive salivation and facilitate airway management. 4

Pharmacokinetics

• Highly lipid soluble with rapid onset (1 minute IV, 3-5 minutes IM) 2, 1
• Volume of distribution: High, with brain levels 10-40 times higher than blood levels 1
• Protein binding: 90-99% 1
• Metabolism: Extensively metabolized by CYP2B6 and CYP3A4 with high first-pass metabolism 1
• Elimination half-life: Approximately 2-3 hours 1
• Excretion: Metabolites excreted mainly through kidneys 1
• Recovery time: Average 84 minutes IV (range 22-215 minutes); median 103 minutes in pediatrics (IQR 76-146 minutes) 4

Cardiovascular and Respiratory Effects

Unlike most sedatives, ketamine stimulates rather than depresses cardiovascular and respiratory systems, making it uniquely suitable for hemodynamically unstable patients. 2, 1

• Produces dose-dependent increases in heart rate, blood pressure, and cardiac output through sympathetic nervous system stimulation 2, 1, 4
• Does not depress airway or cardiovascular reflexes even at doses 5-100 times greater than intended 2, 1
• Maintains protective airway reflexes during sedation 2
• Bronchodilatory properties make it the anesthetic of choice for patients with bronchospasm 5

Adverse Effects

Common (Non-Serious):

Emergence reactions occur in 10-30% of adults, manifesting as floating sensations, vivid dreams, hallucinations, and delirium. 2, 1

• Recovery agitation: 17.6% mild, 1.6% moderate-to-severe 4; associated with higher ASA status and younger age 4
• Emesis without aspiration: 6.7% of cases, associated with increasing age 2, 4
• Nausea: 4-5% of patients 6
• Ataxia: 7-8% of patients 6
• Dysphoria: 1% of patients 6
• Excessive salivation and bronchial secretions 1

Serious (Rare):

Respiratory depression requiring intervention is rare but possible, with hypoxemia occurring in 1.6-7.3% of patients, typically transient and responsive to supplemental oxygen. 4

• Bag-valve-mask ventilation required in approximately 2% of cases 4
• Laryngospasm: Very low incidence (0.9-1.4%) 6
• Combination with midazolam increases risk of respiratory depression, requiring particular vigilance 1

Pitfall to Avoid:

The combination of ketamine with midazolam, while reducing emergence reactions, increases respiratory depression risk and demands more intensive monitoring than ketamine alone 1

Contraindications

Ketamine should be avoided in patients with uncontrolled cardiovascular disease, active psychosis, severe hepatic dysfunction, or elevated intracranial/ocular pressure. 1, 4

Absolute Contraindications:

• Active psychosis 1, 4
• Severe hepatic dysfunction 1
• Elevated intracranial pressure 1, 4
• Elevated intraocular pressure 1, 4

Relative Contraindications:

• Ischemic heart disease 1, 4
• Cerebrovascular disease 1, 4
• Uncontrolled hypertension 1, 4
• Pregnancy 4

Special Consideration for Trauma:

In hemodynamically unstable trauma patients, use the lower end of the dosing range (1 mg/kg) despite cardiovascular stimulation, as multiply injured patients may have depleted catecholamine reserves 4

Monitoring Requirements

Continuous monitoring of oxygen saturation, heart rate, blood pressure, and capnography (when available) is required throughout sedation, with vital signs documented at least every 5 minutes during deep sedation. 1, 4

• Maintain oxygen saturation >93% on room air during procedures 4
• Patients should not be discharged until they return to baseline mental status, have stable vital signs, and have adequate airway reflexes restored 4
• Approximately 80% of pediatric patients exhibit quiet recovery, 17% mild agitation, and only 3% moderate agitation 4

Alternative Agents

For Procedural Sedation:

• Propofol: Faster recovery but requires deeper sedation with higher risk of respiratory depression and hypotension 2
• Midazolam/fentanyl combination: More respiratory depression than ketamine/midazolam, particularly in pediatric orthopedic procedures (20% vs 6% hypoxia) 4, 6
• Nitrous oxide: Comparable analgesia with faster recovery (32 vs 60 minutes) but less effective for deeply painful procedures 2

For Anesthesia Induction:

• Etomidate: Better hemodynamic stability but no analgesic properties 5
• Thiopental: Faster onset but significant cardiovascular depression 5

Key Advantage Over Alternatives:

Ketamine uniquely combines potent analgesia, sedation, and amnesia while preserving cardiovascular stability and airway reflexes, making it superior for hemodynamically unstable patients and emergency settings. 2, 1, 5

Patient and Provider Satisfaction

• Parental satisfaction consistently high: 92-99% rating experience as "excellent" or "good" 6
• Physician satisfaction: 88% rating ketamine sedation as "excellent" or "good" 6
• Studies demonstrate significantly lower observed distress scores during orthopedic manipulations with ketamine/midazolam versus alternatives (1.12 vs 2.70, P<0.0001) 6