# Ketamine: Renaissance of a Classic Agent

## Pharmacology

### Chemical Properties

Ketamine is a phencyclidine (PCP) derivative classified as an arylcyclohexylamine. It is available as a racemic mixture or as the S(+)-enantiomer (esketamine). It is water-soluble and available in concentrations of 10, 50, and 100 mg/mL. With a pKa of 7.5, approximately 50% is unionized at physiologic pH.

### Mechanism of Action

Ketamine's primary mechanism is non-competitive antagonism at the NMDA receptor, where it blocks the ion channel in its open state (use-dependent block). It has several secondary mechanisms that contribute to its broad clinical profile: opioid receptor agonism (mu, kappa, delta) contributing to analgesia, monoamine reuptake inhibition (norepinephrine, serotonin, dopamine) producing sympathomimetic effects, sodium channel blockade conferring local anesthetic-like properties, and interactions with cholinergic, GABAergic, and purinergic systems. HCN1 channel blockade contributes to its hypnotic effect.

### Pharmacokinetics

Ketamine's IV onset is 30-60 seconds, producing a dissociative state within 1-2 minutes. IM onset is 3-5 minutes. Duration is 10-20 minutes IV and 20-30 minutes IM after a single dose. Hepatic metabolism occurs via CYP3A4 and CYP2B6 to norketamine, an active metabolite with 1/3 to 1/5 the potency of the parent compound. The elimination half-life is 2-3 hours. Bioavailability varies by route: 100% IV, 93% IM, 20-25% oral (significant first-pass effect), and 45-50% intranasal.

| Route | Bioavailability | Onset | Duration (single dose) |
|---|---|---|---|
| IV | 100% | 30–60 sec | 10–20 min |
| IM | 93% | 3–5 min | 20–30 min |
| Oral | 20–25% | 15–30 min | Variable |
| Intranasal | 45–50% | 5–10 min | Variable |

### S-Ketamine (Esketamine)

The S(+)-enantiomer has 3-4 times greater affinity for the NMDA receptor than the R(-)-enantiomer and is approximately twice as potent as racemic ketamine as an anesthetic. Recovery may be faster and psychotomimetic effects possibly fewer, though this is debated. Esketamine nasal spray (Spravato) is FDA-approved for treatment-resistant depression.

## Clinical Effects

### Cardiovascular

Ketamine is sympathomimetic, increasing heart rate, blood pressure, cardiac output, and myocardial oxygen demand through central sympathetic stimulation and inhibition of norepinephrine reuptake. However, it is a direct myocardial depressant — an effect that is unmasked in catecholamine-depleted states such as critical illness, chronic heart failure, and septic shock. It increases pulmonary artery pressure (warranting caution in pulmonary hypertension). Its preserved or augmented hemodynamics make it valuable for induction in hypovolemic or shocked patients, with the important caveat about catecholamine depletion.

### Respiratory

At sub-anesthetic and standard dissociative doses, ketamine causes minimal respiratory depression. It preserves functional residual capacity and is a potent bronchodilator through smooth muscle relaxation and catecholamine release. Airway reflexes are relatively preserved, though aspiration can still occur — ketamine is not a substitute for airway protection. It increases salivation (glycopyrrolate pretreatment should be considered), and laryngospasm can occur, particularly in pediatric patients.

### Central Nervous System

Ketamine produces dissociative anesthesia — a cataleptic state with eyes open, nystagmus, and preserved reflexes. It increases cerebral blood flow and CMRO2, which historically led to it being considered contraindicated in raised ICP. This position has been largely revised: recent evidence in mechanically ventilated patients shows ketamine does not worsen ICP and may actually improve cerebral perfusion pressure through hemodynamic support. Ketamine is anticonvulsant at anesthetic doses and has been used for refractory status epilepticus. Psychotomimetic effects — vivid dreams, hallucinations, emergence delirium — occur in 10-30% of patients.

### Analgesia

Ketamine is a potent analgesic at sub-anesthetic doses (0.1-0.5 mg/kg). By blocking NMDA receptors, it prevents central sensitization, reduces opioid consumption by 20-40% when used as an adjunct, and is anti-hyperalgesic (preventing and treating opioid-induced hyperalgesia). It is effective for neuropathic pain components.

## Sub-Anesthetic Ketamine for Perioperative Analgesia

### Dosing Protocols

Typical protocols include a bolus of 0.1-0.5 mg/kg IV at induction, followed by an intraoperative infusion of 0.1-0.25 mg/kg/hr, and a postoperative infusion of 0.05-0.15 mg/kg/hr for up to 24-72 hours. Some protocols use a 0.5 mg/kg bolus followed by 10 mg/hr. There is no consensus on the optimal regimen, and significant institutional variation exists.

| Context | Bolus Dose | Infusion Rate | Duration |
|---|---|---|---|
| Intraoperative analgesia | 0.1–0.5 mg/kg IV | 0.1–0.25 mg/kg/hr | Duration of surgery |
| Postoperative analgesia | — | 0.05–0.15 mg/kg/hr | Up to 24–72 hr |
| Procedural sedation (ED) | 1–2 mg/kg IV or 4–5 mg/kg IM | — | Single dose |
| Depression (off-label) | 0.5 mg/kg IV over 40 min | — | Series of infusions |

### Evidence Base

Multiple meta-analyses demonstrate reduced postoperative opioid consumption and pain scores, with the greatest benefit in opioid-tolerant patients and after major surgery. The 2018 Consensus Guidelines on IV ketamine for acute pain (Schwenk et al.) recommend use as an adjunct in opioid-tolerant patients, opioid-dependent patients, patients at risk for opioid-related adverse effects, and patients undergoing major surgery expected to produce significant postoperative pain.

### Contraindications and Cautions

Relative contraindications include poorly controlled hypertension or cardiovascular disease with high oxygen demand, severe hepatic dysfunction, psychiatric history with psychosis (risk-benefit analysis required), raised ICP without mechanical ventilation (traditional teaching that is evolving), and pregnancy (teratogenic in animals at high doses).

## Ketamine in Specific Clinical Contexts

### Opioid-Sparing Protocols

Ketamine plays a central role in ERAS and multimodal analgesia. It is synergistic with regional anesthesia, NSAIDs, and acetaminophen. It may reduce chronic postsurgical pain by preventing NMDA-mediated central sensitization. It is a component of opioid-free anesthesia (OFA) regimens.

### Emergency Medicine and Trauma

A dissociative dose (1-2 mg/kg IV, 4-5 mg/kg IM) provides procedural sedation. Ketamine is the induction agent of choice in hemodynamically unstable trauma, with the caveat about catecholamine depletion. It facilitates ketamine-assisted intubation in agitated patients (delayed sequence intubation).

### Depression and Suicidality

Ketamine produces a rapid-onset antidepressant effect within hours, lasting days to weeks. The mechanism involves AMPA receptor activation, BDNF release, and synaptogenesis. Esketamine (Spravato) nasal spray is approved for treatment-resistant depression under a REMS program. IV ketamine clinics for off-label depression treatment are proliferating, and anesthesiologists are increasingly involved in ketamine infusion services.

### Pediatric Use

Ketamine is widely used for pediatric procedural sedation, with the IM route being particularly useful. IM dosing is 4-5 mg/kg and IV dosing is 1-2 mg/kg for dissociation. The incidence of emergence delirium is actually higher in adults than in children. Recovery agitation in children can be managed with midazolam co-administration (0.05 mg/kg), though routine benzodiazepine co-administration is debated.

### Status Epilepticus

Ketamine serves as a third-line agent for refractory status epilepticus. Its rationale is that NMDA blockade targets glutamate-mediated excitotoxicity. During prolonged seizures, GABA receptors become internalized, making GABAergic agents less effective, while NMDA receptors are upregulated — this creates a pharmacologic window for ketamine.

<image>A receptor-level diagram showing ketamine's multiple mechanisms of action: (1) NMDA receptor channel block with glutamate and glycine binding sites labeled, (2) opioid receptor (mu, kappa) agonism, (3) monoamine transporter inhibition at a noradrenergic synapse, and (4) sodium channel blockade. Each mechanism is connected to its clinical effect: analgesia, dissociation, sympathomimetic action, and local anesthetic properties.</image>

<image>A clinical dosing infographic for sub-anesthetic ketamine showing three panels: (1) Intraoperative use with bolus 0.25-0.5 mg/kg and infusion 0.1-0.25 mg/kg/hr, (2) Postoperative use with infusion 0.05-0.15 mg/kg/hr for 24-72 hours, and (3) Emergency department procedural sedation with 1-2 mg/kg IV or 4-5 mg/kg IM. Side effects and monitoring requirements are listed for each context.</image>

<image>A timeline diagram of ketamine's antidepressant mechanism showing: acute phase (0-2 hours) with NMDA blockade and glutamate surge activating AMPA receptors, subacute phase (2-24 hours) with mTOR pathway activation and BDNF release, and sustained phase (days to weeks) with synaptogenesis and dendritic spine formation in the prefrontal cortex. Clinical response curve overlaid showing rapid mood improvement within hours.</image>

## Clinical Pearls

Ketamine is the only IV induction agent that provides analgesia, amnesia, and hemodynamic stimulation, making it ideal for hemodynamically unstable patients — but clinicians must beware of direct myocardial depression in catecholamine-depleted states. The "ICP myth" has been largely debunked: in intubated, ventilated patients with controlled ventilation, ketamine does not cause dangerous ICP elevation and may actually improve CPP. Emergence phenomena can be reduced with concurrent benzodiazepines, propofol, or dexmedetomidine, though routine prophylaxis with benzodiazepines is debated. Sub-anesthetic ketamine (0.1-0.5 mg/kg/hr) is one of the most evidence-supported adjuncts for opioid-sparing analgesia, particularly in opioid-tolerant patients. Ketamine should always be considered in patients with severe bronchospasm refractory to standard treatment. Increased salivation is a real problem — glycopyrrolate 0.2 mg IV is a useful pretreatment.

## References

- Schwenk ES, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management. *Reg Anesth Pain Med*. 2018;43(5):456-466.
- Cohen SP, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain. *Reg Anesth Pain Med*. 2018;43(5):521-546.
- Zeiler FA, et al. The ketamine effect on ICP in traumatic brain injury. *Neurocrit Care*. 2014;21(1):163-173.
- Abdallah CG, et al. Ketamine and rapid-acting antidepressants: a window into a new neurobiology for mood disorder therapeutics. *Annu Rev Med*. 2015;66:509-523.
- Miller RD, et al. *Miller's Anesthesia*, 9th edition. Chapter on Intravenous Anesthetics.