ketamine

Ketamine

Overview

Derived from Phencyclidine
Ketamine consists of two stereoisomers, S(+) and R(-). S(+) is more potent and has fewer side effects
Only partially water-soluble, and is 5-10X more lipid soluble than thiopental, thus it undergoes RAPID distribution
Differs from other anesthetic drugs in that it produces significant analgesia, in addition to unconsciousness and some amnesia
Usually does not depress the cardiovascular and respiratory systems
Ketamine is used for
o Induction of general anesthesia
o Maintenance of general anesthesia
o Sedation
o Analgesia
Major side effects
o adverse psychological effects (similar to phencyclidine) ® especially emergence reactions
o increases intra-ocular pressure
o causes HTN and tachycardia, which increases myocardial O₂ consumption

Pharmacokinetics

The pharmacokinetic profile of ketamine is best described by a two-compartment model
Important Pharmacokinetic Variables
o Vd_ss = 2.5-3.5 L/kg
o Clearance = 12-17 mL/kg/min
o Alpha Elimination Half-life = 11-16 min
o Beta Elimination Half-life = 2-4 hours
o 12% protein bound
Metabolism
o metabolized by hepatic microsomal enzymes
o major pathway = Ketamine ®_{N-demethylation} to Norketamine (metabolite I) ®_{hydroxylation}tohydroxynorketamine ® products are then conjugated to glucuronide and excreted in urine
o Norketamine is active, has 20-30% of activity of ketamine, and helps to prolong analgesic properties of ketamine
Onset of action of ketamine is within 30-60 sec of infusion, with maximal effect at about 1 minute. The following properties allow ketamine to rapidly cross the blood-brain barrier:
o low molecular weight
o pK_a near physiologic pH (high proportion is non-ionized in plasma)
o high lipid solubility
Duration of ketamine anesthesia after single bolus of 2 mg/kg (induction dose) is 10-15 min., with A/O x 3 by 15-30 min.
o relatively short duration of action is due to redistribution from brain and blood to lean body mass
Even after a prolonged, maintenance infusion, the CNS effects of ketamine are terminated relatively quickly due to its high clearance

Pharmacodynamics

CNS
o Ketamine antagonizes NMDA receptors, which may mediate its general anesthetic and analgesic properties
o Some evidence that ketamine interacts with opiate receptors in the brain and spinal cord, which may account for some of its analgesic properties
o Produces dose-related unconsciousness and analgesia
§ often referred to as "dissociative anesthesia" = patients appear to be in a cataleptic state rather than sleeping. Patients tend to keep their eyes open and retain many reflexes, such as corneal, cough, and swallow reflexes (but do NOT assume they are protective)
o Ketamine produces some amnesia (no recall of surgery or anesthesia), but not as much as BDZs
o After administration, pupils dilate moderately, nystagmus occurs, lacrimation and salivation are common, and patients often have increased skeletal muscle tone accompanied by coordinated, but purposeless movements of extremities, trunk and head
o Analgesia occurs at considerably lower blood levels than LOC ® meaning that ketamine can provide effective postoperative analgesia after its general anesthetic effect has terminated
o Ketamine increases cerebral metabolism (CMRO₂), CBF, and ICP (due to increase in CBF and sympathetic activation)
o Cerebrovascular responsiveness to CO₂ is preserved with ketamine - so hyperventilation can attenuate the increase in ICP after ketamine administration
o MAJOR DISADVANTAGE - ketamine (like PCP) has emergence reactions (undesirable psychological reactions upon emergence from general anesthesia)
§ Common reactions include: vivid dreaming, extracorporeal experiences (out of body experience), and illusions.
§ These common reactions are accompanied by excitement, confusion, euphoria, or fear
§ Usually they appear within the first hour of emergence and cease within 1 to several hours.
§ Incidence appears to be 10-30% of adult patients, with severity widely ranging
§ Factors that affect the incidence of emergence reactions:
Age - less reactions in pediatric patients
Dose - larger doses with rapid administration predispose to emergence reactions
Gender - men have lower incidence
Pyschological susceptibility - individuals who commonly dream at home more likely to have postoperative dreams with ketamine
Concurrent drugs - BDZs are the most effective drugs in attenuating or treating emergence reactions
Respiratory System
o Ketamine has minimal effects on central respiratory drive
o Can have a transient decrease in minute ventilation with an induction dose (2 mg/kg IV)
o However, ketamine may affect ventilatory control in children, so consider it a respiratory depressant in children when given as a bolus
o Another potential problem in children may be increased salivation after ketamine administration
§ can cause upper airway obstruction complicated by laryngospasm
o Ketamine is a bronchial smooth muscle relaxant ® pulmonary compliance is improved in patients with reactive airway disease and bronchospasm
Cardiovascular System
o Ketamine stimulates the cardiovascular system ® increases BP, HR, and CO, and leads to increased myocardial oxygen consumption
§ Healthy patients are able to compensate for the increased myocardial O₂ consumption
o Interestingly, the hemodynamic changes are NOT dose-related
§ A second dose of ketamine produces hemodynamic changes less than or opposite to the first dose
o Centrally mediated sympathetic responses to ketamine likely contribute to the hemodynamic stimulation
o Hemodynamic effects of ketamine can be blocked by adrenergic antagonists, various vasodilators, and clonidine.
§ Most useful approach to blunt the hemodynamic stimulation caused by ketamine may be prior administration of BDZs, using a continuous infusion of ketamine (rather than a bolus), or administering inhalational anesthetics or propofol.

Uses

Induction of general anesthesia
o Dose = 0.5-2 mg/kg IV and 4-6 mg/kg IM
o Particularly useful when its sympathomimetic activity and bronchodilating capabilities are needed during induction
o Most patients who are candidates for ketamine induction are high-risk with respiratory and cardiovascular disorders (excluding ischemic heart disease/CAD). Patients with reactive airway disease or hemodynamic compromise due to hypovolemia or cardiomyopathy are particularly good candidates
§ Reactive airway disease ® ketamine bronchodilation and analgesia allow the use of high O₂ concentrations
§ Patients with cardiac tamponade or restrictive pericarditis may benefit from ketamine, since it preserves HR and right atrial pressure
§ Otherwise healthy trauma victims with extensive hemorrhage tolerate ketamine well
§ BEWARE ® if intrinsic catecholamine stores have been depleted in septic or trauma patients before arrival in the OR, the myocardial depressant effects of ketamine may manifest during induction.
Maintenance of general anesthesia
o Dose = 30-90 µg/kg/min IV
o Ketamine plus BDZ or BDZ and sufentanil reduces tachycardia, hypertension, and postoperative emergence reactions, thus producing anesthesia with minimal hemodynamic perturbations, profound analgesia, dependable amnesia, and clean emergence
o Ketamine plus propofol - emerging as a technique of total IV anesthesia for noncardiac cases ® results in stable hemodynamics, minimal ventilatory depression, good pain control
Sedation (also premedication)
o Dose = 0.2-0.8 mg/kg IV over 2-3 min. and 2-4 mg/kg IM
o Ketamine is very useful for pediatric patients undergoing outpatient surgery. Pediatric patients have fewer emergence reactions than adults
o Ketamine can be used as an adjunct during regional anesthesia
§ Ketamine can be used before the placing a painful block, or for sedation during long and uncomfortable procedures
o For outpatient surgery, a combination of midazolam (1-2 mg premedication), low dose propofol infusion, and intermittent ketamine (analgesia) provides excellent sedation, analgesia, and recovery
o Ketamine can be used in the ICU setting due to its favorable hemodynamic effects, sedative, and analgesic properties
Analgesia
o Dose = 0.15-0.25 mg/kg IV
o Ketamine decreases postoperative analgesic consumption
§ Low dose ketamine (20-60 mg) perioperatively ® decrease in opiate use, improved analgesia and reduced opiate-associated side effects (esp. PONV)
o Ketamine has also been used for chronic pain ® seems to attenuate opiate tolerance and hyperalgesia

Side Effects/Contraindications

Emergence reactions are common (10-30%)
Cardiovascular stimulation
Contraindications:
o Patients with increased ICP and intracranial mass lesions who are administered ketamine experience an increase in ICP and possibly apnea
o Patients with open eye injury or opthamalogic disorder since ketamine can increase intra-ocular pressure
o Patients with ischemic heart disease
§ ketamine causes hypertension and tachycardia, resulting in an increase in myocardial oxygen consumption
o Patients with vascular aneurysms (ketamine causes increase in BP)
o Patients with a history of psychiatric disease, or adverse reaction to ketamine, and patients with the possibility of having postoperative delirium secondary to other causes (delirium tremens)

Intrathecal or epidural infusions of ketamine are contraindicated since the preservative of ketamine, chlorobutanol, is neurotoxic

Anesthesiology Rotation & Elective