© 2003-17 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D. Published by
Elephant Care International
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Chemistry – A congener of phencyclidine, ketamine HCl occurs as white, crystalline powder. It has a melting point of 258-261°C., a characteristic odor, and will precipitate as the free base at high pH. One gram is soluble in 5 ml of water, and 14 ml of alcohol. The pH of the commercially available injections are between 3.5-5.5.
Storage/Stability/Compatibility – Ketamine may be mixed with sterile water for injection, D5W, and normal saline for diluent purposes. Ketamine is compatible with xylazine in the same syringe. Do not mix ketamine with barbiturates or diazepam in the same syringe or IV bag as precipitation may occur.
Pharmacology – Ketamine is a rapid acting general anesthetic that also has significant analgesic activity and a lack of cardiopulmonary depressant effects. It is thought to induce both anesthesia and amnesia by functionally disrupting the CNS through over stimulating the CNS or inducing a cataleptic state. Ketamine inhibits GABA, and also may block serotonin, norepinephrine, and dopamine in the CNS. The thalamoneocortical system is depressed while the limbic system is activated. It induces anesthetic stages I & II, but not stage III. In cats, it causes a slight hypothermic effect as body temperatures decrease on average by 1.6°C after therapeutic doses.
Effects on muscle tone are described as being variable, but ketamine generally either causes no changes in muscle tone or increased tone. Ketamine does not abrogate the pinnal and pedal reflexes, nor the photic, corneal, laryngeal or pharyngeal reflexes.
Ketamine’s effects on the cardiovascular system include increased cardiac output, heart rate, mean aortic pressure, pulmonary artery pressure, and central venous pressure. Its effects on total peripheral resistance are described as being variable. Cardiovascular effects are secondary to increased sympathetic tone; ketamine has negative inotropic effects if the sympathetic system is blocked,
Ketamine does not cause significant respiratory depression at usual doses, but at higher doses it can cause respiratory rates to decrease. In humans with asthma, ketamine causes decreased airway resistance.
Uses/Indications – Ketamine has been approved for use in humans, sub-human primates and cats, although it has been used in many other species (see dosage section). The approved indications for cats include, “for restraint, or as the sole anesthetic agent for diagnostic, or minor, brief, surgical procedures that do not require skeletal muscle relaxation…. and in subhuman primates for restraint.” (Package Insert; Ketaset® – Bristol).
Pharmacokinetics – After IM injection in the cat, peak levels occur in approximately 10 minutes. Ketamine is distributed into all body tissues rapidly, with highest levels found in the brain, liver, lung, and fat. Plasma protein binding is approximately 50% in the horse, 53% in the dogs, and 37-53% in the cat.
The drug is metabolized in the liver principally by demethylation and hydroxylation and these metabolites along with unchanged ketamine are eliminated in the urine. Ketamine will induce hepatic microsomal enzymes, but there appears to be little clinical significance associated with this effect. The elimination half-life in the cat, calf, and horse is approximately 1 hour, in humans it is 2-3 hours. Like the thiobarbiturates, the redistribution of ketamine out of the CNS is more of a factor in determining duration of anesthesia than is the elimination half-life.
By increasing the dose, the duration of anesthesia will increase, but not the intensity.
Contraindications/Precautions – Ketamine is contraindicated in patients who have exhibited prior hypersensitivity reactions to it and in animals to be used for human consumption. Its use in patients with significant hypertension, heart failure, and arterial aneurysms could be hazardous. The manufacturer warns against its use in hepatic or renal insufficiency, but in humans with renal insufficiency the duration of action has been demonstrated not to be prolonged. Because ketamine does not give good muscle relaxation, it is contraindicated when used alone for major surgery.
Ketamine can cause increases in CSF pressure and it should not be used in cases with elevated pressures or when head trauma has occurred. Because of its supposed epileptogenic potential, it should generally not be used (unless very cautiously) in animals with preexisting seizure disorders. As myelography can induce seizures, ketamine should be used cautiously in animals undergoing this procedure.
Ketamine is considered to be relatively contraindicated when increased intra-ocular pressure or open globe injuries exist, and for procedures involving the pharynx, larynx, or trachea. Animals who have lost significant amounts of blood, may require significantly reduced ketamine dosages.
While ketamine has been used safely in humans with malignant hyperthermia, its use in animals susceptible to this is controversial. Hyperthyroid human patients (and those receiving exogenous thyroid replacement) may be susceptible to developing severe hypertension and tachycardia when given ketamine. The veterinary significance of this potential problem is unknown.
Cat’s eyes remain open after receiving ketamine, and should be protected from injury plus an ophthalmic lubricant (e.g., Lacrilube®) should be applied to prevent excessive drying of the cornea.
To minimize the incidences of emergence reactions, it is recommended to minimize exposure to handling or loud noises during the recovery period. The monitoring of vital signs should still be performed during the recovery phase, however.
Because ketamine can increase blood pressure, careful control of hemorrhaging post-surgery (e.g., declawing) should be accomplished. It is not essential to withhold food or water prior to surgery, but in elective procedures it is recommended to withhold food for 6 hours prior to surgery.
Adverse Effects/Warnings – In approved species the following adverse reactions are listed by the manufacturer: “respiratory depression….following high doses, emesis, vocalization, erratic and prolonged recovery, dyspnea, spastic jerking movements, convulsions, muscular tremors, hypertonicity, opisthotonos and cardiac arrest. In the cat, myoclonic jerking and/or tonic/clonic convulsions can be controlled by ultrashortacting barbiturates or acepromazine. These latter drugs must be given intravenously, cautiously, and slowly, to effect (approximately 1/6 to 1/4 the normal dose may be required).” (Package Insert; Ketaset® – Bristol)
Seizures have been reported to occur in up to 20% of cats that receive ketamine at therapeutic dosages. Diazepam is suggested to be been used for treatment if necessary. Pain after IM injection may occur.
To reduce the incidence of hypersalivation and other autonomic signs, atropine or glycopyrrolate is often administered.
Overdosage – Ketamine is considered to have a wide therapeutic index (approximately 5 times greater when compared to pentobarbital). When given in excessive doses or too rapidly, significant respiratory depression may occur. Treatment using mechanically assisted respiratory support is recommended versus the use of analeptic agents. In cats, yohimbine with 4-aminopyridine has been suggested to be used as a partial antagonist.
Drug Interactions – Narcotics, barbiturates, or diazepam may prolong the recovery time after ketamine anesthesia. When used with halothane, ketamine recovery rates may be prolonged and the cardiac stimulatory effects of ketamine may be inhibited. Close monitoring of cardiac status is recommended when using ketamine with halothane. Chloramphenicol (parenteral) may prolong the anesthetic actions of ketamine. Thyroid hormoneswhen given concomitantly with ketamine have induced hypertension and tachycardia in humans. Beta-blockers (e.g., propranolol) may be of benefit in treating these effects. Neuromuscular blockers (e.g., succinylcholine and tubocurarine) may cause enhanced or prolonged respiratory depression.
Horses: Note: Always used after heavy premedication with a sedative.
a) Initially give xylazine 1.1 mg/kg IV and wait for full sedative effect (4-8 minutes); then give ketamine 2.2 – 2.75 mg/kg IV only (the higher dose may be necessary for ponies, young “high-strung” Arabians, Hackneys, and Thoroughbreds) as a bolus. Do not administer to an “excited” horse. If surgery time requires additional anesthesia, 1/3-1/2 of the original xylazine/ketamine doses may be given IV. For procedures where better muscle relaxation is required, use guaifenesin-thiobarbiturate. Do not disturb horse until fully recovered. (Thurmon and Benson 1987)
b) For foals and ponies: Add 500 mg ketamine and 250 mg xylazine to 500 ml of 5% guaifenesin solution. For induction, give 1.1 ml/kg IV rapidly. Anesthesia may be maintained by constant IV infusion of 2-3 ml/kg/hr. Lower doses for foals, higher doses for ponies. (Thurmon and Benson 1987)
c) For induction of surgical colic patients: Use guaifenesin to effect, than 1.6 – 2.2 mg/kg ketamine (Mandsager 1988)
d) 200 mg bolus (in a 454 kg horse) intra-operatively to reduce movement with light general anesthesia (Mandsager 1988)
CAUTION! Sedative and anesthetic drug dosages for African elephants often vary from those for Asian elephants. Do not assume that the recommendations for one species can be applied to the other. Significant variation may also occur between individual elephants. Higher doses may be needed in wild or excited animals. Unless otherwise specified, doses refer to captive elephants. The information provided here should be used as a guideline only. Consultation with experienced colleagues is advised.
a,b) Adverse effect: A single case of photosensitization (similar to that noted with the use of acepromazine) was seen in an Asian elephant sedated with ketamine-xylazine. The author also reports that “the synergy of ketamine-xylazine combination seen in other animals like carnivores is not noticed in elephants.” (Cheeran, 2002).
c) 5-10 mg/kg ketamine IM; can be combined with xylazine; the dose of individual drugs can be reduced up to 50% when combinations are used (Nayer et.al. 2002).
d) ketamine:xylazine in a 1.25:1 ratio with xylazine (Sarma et.al. 2001).
e) 0.33 mg/kg ketamine combined with 0.12 mg/kg xylazine for immobilization of baby or juvenile Asian elephants; 1.14 mg/kg ketamine combined with 0.14 mg/kg xylazine for immobilization of baby or juvenile African elephants (Fowler, 1995).
f) A 3000 kg Asian cow was immobilized with 350 mg ketamine and 350 mg xylazine IM to repair a ventral hernia. Induction took 10 minutes, the cow became recumbent, and the duration of anesthesia was 120 minutes. Sedation was adequate for surgical manipulation (Nayar et.al. 1992).
g) A mixture containing 100-150 mg xylazine and 50-100 mg ketamine injected IV in laterally recumbent Asianelephants produces quick, safe and dependable analgesia, anesthesia, and muscular relaxation (Pathak, 1991).
h) A 650 kg African elephant was premedicated with 0.27 mg/kg ketamine (175 mg) and 0.23 mg/kg xylazine (150 mg) IM followed 20 minutes later by an IV injection of 0.9 µg/kg etorphine (0.6 mg) then maintained on 1.0-1.5% halothane to perform a tusk extraction. Following a 3- hour surgery, the elephant was reversed with 1.8 µg/kg diprenorphine (1.2 mg) IV and 46 µg yohimbine IV and was standing in 5 minutes (Welsch et.al. 1989).
i) Xylazine (0.1 ± 0.04 mg/kg of body weight, mean ± SD) and ketamine (0.6 ± 0.13 mg/kg) administered IM induced good chemical restraint in standing juvenile African elephants during a 45-minute transport period before administration of general anesthesia (Heard et.al. 1988).
j) For standing sedation of adult Asian elephants: 0.3 to 0.7 mg/kg ketamine and 0.1 mg/kg xylazine IM. For immobilization of Asian elephants: 1.0 to 1.5 mg/kg ketamine and 0.14 mg/kg xylazine IM. In 13 of 14 immobilized elephants, respiratory and heart rates remained stable throughout the duration of immobilization. The mean induction time was 11.6 minutes and the mean duration of immobilization was 27 minutes. Mean respiratory and heart rates were 17 and 45 /minute respectively (Jacobson, 1988).
k) A 4000 kg African elephant immobilized with 2.3 µg/kg carfentanil was given 100 mg ketamine IV during a 50 minute duration period (Jacobson et.al 1988).
l) A group of 15 African elephants were immobilized with a combination of xylazine (0.2 mg/kg of body weight, IM) and ketamine (1 to 1.5 mg/kg of body weight, IM). See details in abstract below (Allen, 1986).
m) A 1125 kg African elephant was sedated with 100 mg ketamine, 100 mg xylazine and 8 mg butorphanol given IM for a tusk examination. A 423 kg African elephant as given 160 mg ketamine and 35 mg xylazine IM for radiography of tusks (Heard et.al 1986).
n) Twenty-two juvenile African elephants were given a combination of xylazine (mean +/- SD = 0.14 +/- 0.03 mg/kg of body weight) and ketamine (1.14 +/- 0.21 mg/kg) as a single IM injection. See details in abstract below (Jacobson et.al 1985).
a) Cheeran,J. 2002. Adverse drug experiences in elephants. Journal of Indian Veterinary Association Kerala 7:(3):61
b) Cheeran,J.V., Chandrasekharan,K., and Radhakrishnan,K. 2002. Tranquilization and translocation of elephants. Journal of Indian Veterinary Association Kerala 7:(3):42-46
c) Nayar,K.N.M., Chandrasekharan,K., and Radhakrishnan,K. 2002. Management of surgical affections in captive elephants. Journal of Indian Veterinary Association Kerala 7:(3):55-59
d) Sarma,K.K. and Pathak,S.C. 2001. Cardio vascular response to xylazine and Hellabrunn mixture with Yohimbine as reversal agent in Asian elephants. Indian Veterinary Journal 78:(5):400-492 Abstract: Xylazine (0.1 mg/kg body weight) produced highly significant bradycardia and hypotension in recumbent Asian elephants, with a peak depression observed at the 30th minute for heart rate and 30th minute in the mean arterial pressure (MAP). Ketamine (1.25 : 1 ratio with xylazine) mildly marginalised the bradycardia, but remarkably improved the MAP. Yohimbine, used to reverse the sedation produced by xylazine did not appear to influence these parameters to any appreciable levels.
e) Fowler,M.E., 1995. Elephants. In: Restraint and handling of wild and domestic animals. Iowa State University Press, Ames, Iowa, USA pp. 265-269
f) Nayar,K.N.M., Radhakrishnan,K., Chandrasekharan,K., Cheeran,J.V., Ravindran,S., and George,P.O., 1992. Anaesthesia for surgical manipulations in the elephant. In: Silas,E.G., Nair,M.K., and Nirmalan,G. (Editors), The Asian Elephant: Ecology, Biology, Diseases, Conservation and Management (Proceedings of the National Symposium on the Asian Elephant held at the Kerala Agricultural University, Trichur, India, January 1989). Kerala Agricultural University, Trichur, India pp. 156-158 Abstract: Anaesthesia using chloral hydrate, thiopentone sodium, xylazine and ketamine was induced in ten elephants. The effects, duration of induction and anaesthesia were recorded. Post anaesthesia complications were not encountered in any of the animals. Surgical manipulations could be carried out under anaesthesia induced with these drugs.
g) Pathak,S.C. 1991. Xylazine-ketamine anesthesia in Indian elephant (Elephas maximus indicus) – trial on 53 clinical cases. International Seminar on Veterinary Medicine in Wild and Captive Animals, Nov. 8-10, Bangalore, India. Pages: 21 Abstract: Veterinarians are often required to attend and undertake surgery on elephants. Unless the animal is deeply sedated or anesthetized certain works become impractical. Xylazine has proved to be a good sedative and analgesic in elephants. This drug is not freely available in India and is costly. The drug is usually used by intramuscular route but to reduce the dose it has been used intravenously. Intravenous use may be risky for its bradycardia effect and fall in cardiac output. Ketamine, on the other hand, has no depressant effect on the cardiovascular and respiratory system but produces muscular tremor and stiffness of the skeletal muscle. Combination of Xylazine and Ketamine minimizes the undesirable aspects of both the drugs. A mixture containing 100-150 mg xylazine and 50-100 mg ketamine injected intravascularly to the laterally recumbent elephant produced quick, safe and dependable analgesia, anesthesia, and muscular relaxation. Surgical operations like tusk extraction, bullet extraction, umbilical and pleural herniorraphy, trunk injury, extensive wound repair, etc. were performed in 53 elephants. Recovery followed without excitement and untoward effect based on the observations of this trial on clinical cases, combination of Xylazine and Ketamine is recommended in elephant.
h) Welsch,B., Jacobson,E.R., Kollias,G.V., Kramer,L., Gardner,H., and Page,C.D. 1989. Tusk extraction in the African elephant (Loxodonta africana). Journal of Zoo and Wildlife Medicine 20:(4):446-453 Abstract:Unilateral dentoalveolar abscesses and/or tusk fractures were identified and tusk extractions performed in seven 3.5-21-yr-old African elephants (Loxodonta africana) of both sexes weighing 650-3,000 kg. Following immobilization with etorphine hydrochloride or carfentanil citrate, six of seven elephants were intubated and maintained on a 1-1.5% halothane in oxygen mixture; one elephant was maintained in lateral recumbency by multiple i.v. injections of etorphine. All elephants were positioned with the affected tusk up. For one elephant, two surgical procedures were required to remove the tusk. In six of seven elephants, the tusks were sectioned transversely and the tusk wall thinned by enlarging the pulp cavity with carbide burs. In those tusks with remaining pulp, the pulp was removed with stainless steel rods and hooks. Next, the tusk was sectioned longitudinally into three or four segments using a wood saw within the pulp chamber. bone gouges, osteotomes, and a mallet were used to free the outer epithelial and alveolar attachments from the tusk. Starting with the smallest segment, the sections were removed using long screwdriver-shaped stainless steel rods. The alveolar chamber was then periodically flushed postsurgically with a dilute organic iodine solution. For six of seven elephants, complete granulation of the alveolar chamber was evident by 4 mo postsurgery; the seventh elephant showed partial healing with granulation tissue at 2 mo following surgery.
i) Heard,D.J., Kollias,G.V., Webb,A.I., Jacobson,E.R., and Brock,K.A. 1988. Use of halothane to maintain anesthesia induced with etorphine in juvenile African elephants. Journal of the American Veterinary Medical Association 193:254-256 Excerpts: Sixteen 3- to 5-year-old African elephants were anesthetized one or more times for a total of 27 diagnostic and surgical procedures. Xylazine (0.1 ± 0.04 mg/kg of body weight, mean ± SD) and ketamine (0.6 ± 0.13 mg/kg) administered IM induced good chemical restraint in standing juvenile elephants during a 45-minute transport period before administration of general anesthesia. After IM or IV administration of etorphine (1.9 ± 0.56 micrograms/kg), the mean time to lateral recumbency was 20 ± 6.6 and 3 ± 0.0 minutes, respectively. The mean heart rate, systolic blood pressure, and respiration rate during all procedures was 50 ± 12 beats/min, 106 ± 19 mm of Hg, and 10 ± 3 breaths/min, respectively.
Cardiac arrhythmias were detected during 2 procedures. In one elephant paroxysmal ventricular tachycardia was detected and the procedure terminated when the arrhythmia failed to stabilize after multiple doses of lidocaine (1 mg/kg, IV). In another elephant, second degree atrioventricular block returned to normal sinus rhythm after IV administration of atropine (0.04 mg/kg).
In one elephant, low mean blood pressure (54 mm of Hg) responded to reduction in halothane (vaporizer setting 1 to 0.75%) and slow infusion of dobutamine HCl ((250 mg/1,000 ml) given to effect. The systolic blood pressure increased to 90 mm of Hg and remained high with a continuous infusion of dobutamine (5 µg/kg/min).
Immediately after induction in another elephant, profound respiratory depression (< 1 breath / minute) and palpably weak arterial pulse were identified. Intravenous administration of diprenorphine at half the recommended reversal dose resulted in improvement of respiration and palpable arterial pulse, without the elephant developing signs of complete anesthetic reversal.
Alterations in systolic blood pressure, ear flapping, and trunk muscle tone were useful for monitoring depth of anesthesia. Results indicated that halothane in oxygen was effective for maintenance of surgical anesthesia in juvenile African elephants after induction with etorphine. Note: A correction appeared in a later volume 193(6): p.721.
j) Jacobson,E.R. 1988. Chemical restraint and anesthesia of elephants. Proc.Ann.Elephant Workshop 9. Pages: 112-119
k) Jacobson,E.R., Kollias,G.V., Heard,D.J., and Caligiuri,R. 1988. Immobilization of African elephants with carfentanil and antagonism with nalmefene and diprenorphine. Journal of Zoo Animal Medicine 19:1-7
l) Allen,J.L. 1986. Use of tolazoline as an antagonist to xylazine-ketamine-induced immobilization in African elephants. American Journal of Veterinary Research 47:(4):781-783 Abstract: A group of 15 African elephants (Loxodonta africana) were immobilized with a combination of xylazine (0.2 mg/kg of body weight, IM) and ketamine (1 to 1.5 mg/kg of body weight, IM). Ten of the African elephants were allowed to remain recumbent for 30 minutes and the remaining 5 elephants, for 45 minutes before they were given tolazoline (0.5 mg/kg of body weight, IV). For the group of 15, the mean induction time (the time required from injection of the xylazine-ketamine combination until onset of recumbency) was 14.2 ± 4.35 minutes (mean ± SD), and standing time (the time required from the tolazoline injection until the elephant stood without stimulation or assistance) was 2.8 ± 0.68 minutes. All of the elephants were physically stimulated (by pushing, slapping, shouting) before they were given tolazoline, and none could be aroused. After tolazoline was given and the elephant was aroused, relapses to recumbency did not occur. Recovery was characterized by mild somnolence in an otherwise alert and responsive animal. Failure (no arousal) rates were 0% (95% confidence interval, 0 to 0.3085) for elephants given tolazoline after 30 minutes of recumbency and 100% for elephants that were not given tolazoline. There was no significant (P less than 0.05) difference in standing time 30 or 45 minutes after tolazoline injection.
m) Heard,D.J., Jacobson,E.R., and Brock,K.A. 1986. Effects of oxygen supplementation on blood gas values in chemically restrained juvenile African elephants. Journal of the American Veterinary Medical Association 189:(9):1071-1074
Abstract: Arterial oxygen and carbon dioxide tensions were determined in sedated immature African elephants and in elephants immobilized with etorphine hydrochloride or with an etorphine-ketamine combination. For manipulative and surgical procedures, the Hudson demand value was used for oxygen supplementation during 6 procedures, and insufflation was used during 2 procedures. The Hudson demand value was more effective than insufflation in sustaining adequate arterial oxygenation.
n) Jacobson,E.R., Allen,J., Martin,H., and Kollias,G.V. 1985. Effects of yohimbine on combined xylazine-ketamine-induced sedation and immobilization in juvenile African elephants. Journal of the American Veterinary Medical Association 187:(11):1195-1198 Abstract: Twenty-two juvenile African elephants were given a combination of xylazine (mean +/- SD = 0.14 +/- 0.03 mg/kg of body weight) and ketamine (1.14 +/- 0.21 mg/kg) as a single IM injection; one elephant was immobilized twice, 77 days apart. After injection, 14 elephants were immobilized, 4 were sedated deeply, 2 were sedated moderately, and 2 were sedated minimally. Immobilized elephants had a mean immobilization time of 11.6 +/- 6.9 minutes. At the conclusion of a variety of clinical procedures, 12 of the 14 elephants immobilized with a single dose combination of xylazine and ketamine were given yohimbine (0.13 +/- 0.03 mg/kg) IV, and the remaining 2 elephants were allowed to recover spontaneously; the elephants given yohimbine had a mean standing time of 2.4 +/- 1.1 minutes. Of the 8 sedated elephants, 5 were given an additional dose of combined xylazine (0.08 +/- 0.03 mg/kg), and ketamine (0.61 +/- 0.19 mg/kg) IM, and 1 elephant was given ketamine (0.47 mg/kg) IV. After injection, 4 of the 8 elephants were recumbent laterally within 17 minutes and 2 remained standing, under deep sedation. Seven of the 8 elephants were given yohimbine (0.13 +/- 0.03 mg/kg) IV; all were ambulatory in 2 minutes. Results indicated that yohimbine may be useful in controlling duration of xylazine-ketamine sedation and immobilization in juvenile African elephants.
Raath,J.P., 1999. Relocation of African elephants. In: Fowler,M.E. and Miller,R.E. (Editors), Zoo and Wild Animal Medicine: Current Therapy 4. W.B. Saunders, Philadelphia, PA, USA pp. 525-533
Altmann,D. and Krebs,W. 1981. Combined Vetalar-Combelen anesthesia of elephant for surgical removal of foreign body from eye. Erkrankungen der Zootiere 261-265
Monitoring Parameters –
1) Level of anesthesia/analgesia
2) Respiratory function; cardiovascular status (rate, rhythm, BP if possible)
3) Monitor eyes to prevent drying or injury
4) Body temperature
Client Information – Should only be administered by individuals familiar with its use.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times –
Ketamine HCl for Injection 100 mg/ml in 10 ml vials; Ketaset® (Fort Dodge); Vetalar® (Fort Dodge);VetaKet® (Lloyd) (Rx) Approved for use in cats and sub-human primates.
Ketamine HCl for Injection 10 mg/ml in 20, 25, and 50 ml vials; 50 mg/ml in 10 ml vials; 100 mg/ml in 5 ml vials; Ketalar® (Parke-Davis); (Rx)