Ketamine

Overview

Ketamine is a dissociative anesthetic agent used in dogs and cats for chemical restraint, dissociative anesthesia, and perioperative analgesia. It is commonly administered in combination with other sedative or anesthetic agents to improve muscle relaxation and anesthetic quality.

Ketamine may provide visceral and somatic analgesia and inhibit central sensitization by blocking N-methyl-D-aspartate (NMDA) receptors; however, its analgesic effect may be variable. It is also used as an adjunctive analgesic during the perioperative period, although optimal analgesic dosing has not been fully established.

Dissociative anesthesia produced by ketamine is characterized by mild stimulation of cardiac output and blood pressure, modest respiratory depression, and preservation of cranial nerve reflexes. When used alone at anesthetic doses, skeletal muscle hypertonicity and spontaneous movement may occur.

Mechanism of Action (MOA): Ketamine antagonizes glutamate at NMDA receptors within the central nervous system. It also interacts with opioid receptors by antagonizing mu receptors and exhibiting agonist activity at delta and kappa receptors.

Indications

• Chemical restraint: Used as part of sedation and restraint protocols.
• Dissociative anesthesia: Used to provide dissociative anesthesia, typically in combination with other agents.
• Perioperative analgesia: Used as an adjunctive analgesic during the perioperative period.
• Licensed indication in cats: In cats this is the licensed indication: restraint, or use as the sole anesthetic agent for diagnostic or minor, brief surgical procedures that do not require skeletal muscle relaxation.
• Seizure emergencies: Refractory status epilepticus, as a last-resort adjunct when conventional anticonvulsants have failed.

Dosage (Reference)

Dog

Cat

Warnings & Precautions

• Ocular disease: Not recommended for animals whose eyes are at risk of perforation or that have increased intraocular pressure.
• Increased intracranial pressure: Traditionally avoided in animals with raised intracranial pressure, although the evidence for a rise is now considered weak, and more recent work in people and in animals with head injury reports no increase.
• Alpha-2 agonist combinations: Alpha-2 reversal timing is protocol-specific: one feline ketamine, dexmedetomidine and opioid protocol allows immediate reversal with an equal volume of atipamezole, other sources advise waiting 30 minutes or 45 to 60 minutes after ketamine, and one medetomidine protocol advises against atipamezole reversal altogether.
• Eye protection: The eyes remain open during anesthesia and should be protected with a bland ophthalmic ointment.
• Use alone: When used alone at doses adequate to provide general anesthesia, ketamine may cause skeletal muscle hypertonicity and movement unrelated to surgical stimulation.
• Prolonged infusion: Prolonged administration by infusion may result in drug accumulation and prolonged recovery.
• Controlled drug: Ketamine is a controlled drug – Schedule III in the United States and Schedule 2 in the United Kingdom.
• Renal or hepatic insufficiency: Contraindicated in cats with renal or hepatic insufficiency, and use lower doses in cats with renal disease or urinary tract obstruction.
• Cardiomyopathy and cardiovascular disease: Avoid in cats with hypertrophic or restrictive cardiomyopathy, and use with caution where a rise in heart rate, blood pressure or myocardial oxygen consumption would be harmful, including shock and congestive heart failure.
• Seizure disorders: Use with caution, or not at all, in animals with a pre-existing seizure disorder, and during myelography with contrast agents that can induce seizures.
• Sole agent for major surgery: Not suitable as the sole agent for major surgery, because ketamine does not provide good muscle relaxation.
• Monitoring and airway support: Use only where monitoring and airway support – intubation and ventilation – are immediately available.
• Blood loss, hyperthermia and airway procedures: Relative contraindications include significant blood loss, malignant hyperthermia, and procedures involving the pharynx, larynx or trachea; animals that have lost significant blood may need markedly reduced doses.
• Hypersensitivity and other cautions: Ketamine is contraindicated in animals with prior hypersensitivity to it. Use with caution in animals with significant hypertension, heart failure, arterial aneurysm or hyperthyroidism.
• Pulmonary disease and high sympathetic tone: Use with caution in animals with pulmonary disease or unstable cardiopulmonary function, and where sympathetic tone is already high, such as pheochromocytoma or hyperthyroidism.
• Postoperative hemorrhage: Because ketamine can increase blood pressure, control postoperative hemorrhage carefully.
• Pregnancy: Ketamine crosses the placenta and may stimulate uterine contractions, and developmental delays and increased fetal resorption have been noted in laboratory animals; it should only be used when the maternal benefits outweigh the potential risks to the offspring.
• Cesarean section: At cesarean section ketamine may cause dose-dependent respiratory and neurologic depression in the neonates; the rapidly acting induction agents listed for this procedure are propofol and alfaxalone.
• Feline urethral obstruction: In cats with urethral obstruction, correct dehydration and hyperkalemia before giving ketamine, which can induce cardiac dysrhythmia in that setting.
• High-alert medication: Ketamine is classed as a high-alert medication in human medicine: check the dose and the volume independently before administration.
• Recovery management: Keep handling and noise to a minimum during recovery to reduce emergence reactions, while continuing to monitor vital signs.

Drug Interactions

• General management: Unless otherwise noted, concomitant use is not necessarily contraindicated; weigh the potential risks and perform additional monitoring when appropriate.
• Alpha-2 agonists: In dogs, medetomidine may reduce ketamine metabolism in vitro; dexmedetomidine may considerably reduce this interaction risk. Xylazine reduced norketamine formation in canine liver microsomal preparations.
• Barbiturates: May prolong recovery following ketamine anesthesia. Lower doses of each drug may be required.
• Benzodiazepines: May prolong recovery following ketamine anesthesia. Lower doses of each drug may be required.
• Halothane: May prolong recovery and inhibit the cardiac stimulatory effects of ketamine.
• Neuromuscular blockers: May enhance or prolong respiratory depression.
• Opioids: May prolong recovery following ketamine anesthesia. Lower doses of each drug may be required.
• Theophylline and aminophylline: Ketamine may lower the seizure threshold; this is reported in humans and its significance in dogs and cats is unknown.
• Thyroid hormones: Given with thyroid hormones, ketamine has induced hypertension and tachycardia in humans; a beta-blocker such as propranolol may be used to treat this.
• Physical incompatibility: Mixing ketamine with barbiturates or diazepam in the same syringe or fluid bag is not recommended, as precipitation may occur; alkalinizing solutions may also cause instability or precipitation.
• Physical compatibility: Ketamine is physically compatible in the same syringe with xylazine, cefazolin, diphenhydramine, fentanyl, hydromorphone, lidocaine, midazolam and morphine.

Side Effects & Overdose

Side Effects

• Cardiovascular effects: Cardiovascular depression and arrhythmias may occur in animals with high sympathetic nervous system tone, such as those in shock or with severe cardiovascular disease.
• Tachycardia: May occur following administration of high intravenous doses.
• Respiratory depression: May be marked in some animals.
• Recovery abnormalities: Spacey or abnormal behavior may occur for 1–2 hours during recovery.
• Common effects at lower doses: At lower doses adverse effects are generally minimal, but emesis, salivation, vocalization, mydriasis and regurgitation may occur.
• Musculoskeletal effects: Muscle tremors, myoclonus, hypertonicity, opisthotonos and convulsions may occur.
• Seizures in cats: Seizures have been reported in up to 20% of cats given ketamine alone at therapeutic doses; diazepam is suggested if treatment is needed.
• Hyperthermia in cats: Mild, self-limiting hyperthermia has been documented in cats given 5 to 10 mg/kg; acepromazine 0.01 to 0.02 mg/kg IV may alleviate it.
• Pain on injection: Intramuscular injection is painful (the solution has a pH of 3.5).
• Apnea and cardiac arrest: Apnea, respiratory arrest, cardiac arrest and death have occasionally been reported with ketamine used alone, and more frequently when it is combined with sedatives or other anesthetics; dyspnea and nystagmus are also reported.
• Managing hypersalivation: Atropine or glycopyrrolate may be given to reduce hypersalivation and other autonomic signs.
• Hepatic effects: Increased liver enzymes and hepatotoxicity have been reported in people receiving repeated doses or prolonged infusions.
• Rare reported outcomes: Blindness and death have rarely been reported.
• Apneustic breathing: Ketamine can cause apneustic breathing – rapid breaths followed by breath holding.

Overdose

• Ketamine is considered to have a wide therapeutic index (ie, ≈5 times greater as compared with pentobarbital). When ketamine is given too rapidly or in excessive doses, significant respiratory depression may occur.
• It is recommended that ketamine overdoses be treated using mechanically assisted respiratory support versus analeptic agents (eg, doxapram).
• Although there is no specific reversal agent for ketamine, in cats, yohimbine with 4-aminopyridine has been suggested for use as a partial antagonist.
• In cats, do not exceed 50 mg/kg during any single procedure.
• For a known or suspected overdose, contact a 24-hour veterinary poison control service.

Key Notes

• Dissociative anesthetic: Ketamine is a centrally acting dissociative anesthetic agent: it depresses the thalamoneocortical system while the limbic system is activated.
• Analgesic properties: May provide visceral and somatic analgesia and may be used as an adjunctive perioperative analgesic, although references describe the analgesic effect as anything from profound to mild.
• NMDA receptor blockade: Inhibits central sensitization through antagonism of NMDA receptors.
• Preservation of reflexes: Cranial nerve reflexes are generally maintained during anesthesia.
• Combination protocols: Commonly administered with alpha-2 agonists and/or benzodiazepines rather than as a sole anesthetic agent.
• Cardiovascular effects: Dissociative anesthesia is typically associated with mild stimulation of cardiac output and blood pressure.
• Regulatory status: Ketamine is licensed in cats only; every use in dogs, and every infusion protocol in either species, is extra-label.
• Route of administration: Ketamine undergoes significant first-pass metabolism, limiting absorption after swallowed oral administration, and it is normally injected intravenously, intramuscularly or subcutaneously; oromucosal administration in cats has been described, with ketamine sprayed into the mouth at 10 mg/kg.
• Duration of action: The half-life is short – 60 to 90 minutes in most animals – and the duration of action is generally 30 minutes or less; intravenous infusions have been used for longer procedures.
• Elimination in cats: Cats excrete ketamine almost entirely unchanged in the urine, so a full recovery still occurs in renal disease but more slowly, and lower doses should be used.
• Onset after intramuscular injection: After intramuscular injection in cats, peak concentrations occur at about 10 minutes.
• Monitoring: Monitor depth of anesthesia and analgesia, ventilation using end-tidal CO2, heart rate and rhythm, blood pressure, pulse oximetry, body temperature, and the eyes for drying or injury.
• Available formulations: The only veterinary presentation is an injection of 100 mg/mL in 10 mL vials; human-labeled ketamine is also supplied at 10 mg/mL and 50 mg/mL, and all of them are prescription controlled products.
• Storage: Store at room temperature protected from light, and follow the specific product label for discard timing after first vial puncture, which varies by manufacturer; the solution may darken with prolonged light exposure without losing potency, but do not use it if a precipitate appears.
• Laboratory interference: Ketamine raises plasma cortisol, so cortisol is not a reliable marker of pain in an animal that has received it.
• Hemodynamic effects: In healthy animals ketamine increases cardiac output, heart rate, mean aortic pressure, pulmonary artery pressure and central venous pressure, while its effect on total peripheral resistance is variable.
• Pain scoring in cats: Ketamine can confound the psychomotor subscale of the feline pain scale.