Reversal of ketamine/xylazine anesthesia in the rabbit with yohimbine

Ketamine and xylazine used in combination have been shown to be effective, easily administered, cost efficient agents for surgical anesthesia in the rabbit. The effect of xylazine on the central nervous system has been shown to be mediated through alpha-2 adrenergic receptors. Yohimbine, an alpha-2 adrenergic antagonist has been shown to reverse xylazine induced depression and partially antagonize ketamine in other species. We evaluated the antagonistic effect of yohimbine on ketamine/xylazine anesthesia in the rabbit. Six New Zealand White rabbits were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (10 mg/kg) to establish baseline parameters including respiratory rate, heart rate, and palpebral, pedal and postural reflex activity. Fourteen days later each rabbit was subjected to the same anesthetic regimen followed 30 minutes later by the intravenous administration of yohimbine (0.2 mg/kg). The duration of anesthesia estimated by the time elapsed between the loss and return of the palpebral reflex was reduced in the yohimbine treated trial (means = 29.7 +/- 1.9 minutes) compared to the control trial (means = 67.0 +/- 13.5 minutes). The palpebral reflex returned within 5 minutes following yohimbine treatment. Our results indicated that yohimbine is an effective antagonist of ketamine/xylazine anesthesia in the rabbit. Yohimbine decreases anesthetic duration after intravenous administration and also may aid in the control of undesirable anesthetic effects and overdosage.     

Effects of combined ketamine/xylazine anesthesia on light induced retinal degeneration in rats

Objectives

To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats.

Methods

Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively) for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG) and morphological assessment by in vivo imaging (optical coherence tomography), histology (hematoxylin/eosin staining, TUNEL assay) and immunohistochemistry (GFAP and rhodopsin staining) were performed at baseline (ERG), 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls.

Results

Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL) thickness in the non-anesthetized group at 36 h (p<0.01) and significant reduction one week (p<0.01) after light damage. In contrast, ketamine-xylazine pre-treated animals showed no significant alteration of total retinal or ONL thickness at either time point (p>0.05), indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d), thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01) and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03) were observed in non-treated vs. ketamine-xylazine treated animals.

Conclusions

Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage.     

Cardiovascular pathology possibly associated with ketamine/xylazine anesthesia in Dutch belted rabbits.

BACKGROUND AND PURPOSE: After myocardial necrosis and fibrosis was observed in five rabbits which had been anesthetized a variable number of times, the potential relationship of these lesions and anesthesia was evaluated in 35 other rabbits. METHODS: Anesthesia was induced by intramuscular administration of ketamine and xylazine followed by infusion of lactated Ringer's solution also containing ketamine and xylazine. Group A rabbits (n = 9) were subjected to multiple anesthesias and were evaluated by echocardiography, thoracic radiography, electrocardiography, determination of serum coronavirus titer, vitamin E concentration, and complete necropsy. Prior to a single acute procedure followed by necropsy, group B rabbits (n = 11) were evaluated by echocardiography only. Group C rabbits (n = 10) had never been anesthetized and were necropsied after euthanasia. Group D rabbits (n = 5) had intermediate anesthesia exposure history and were evaluated by echocardiography only. Myocardial fibrosis was scored semi-quantitatively on a scale of 0 to 4. RESULTS: Canine coronavirus test results were negative; hypovitaminosis E was evident, and fibrosis scores were significantly increased in group A, compared with group B or group C, rabbits. CONCLUSION: Etiologic differentials included alpha2-agonist-mediated coronary vasoconstriction with associated myocardial hypoperfusion, hypovitaminosis E and free radical injury, and other anesthetic-induced physiologic trespass.     

Acute hyperglycemia induced by ketamine/xylazine anesthesia in rats: mechanisms and implications for preclinical models

The effects of anesthetic agents, commonly used in animal models, on blood glucose levels in fed and fasted rats were investigated. In fed Sprague-Dawley rats, ketamine (100 mg/kg)/xylazine (10 mg/kg) (KX) produced acute hyperglycemia (blood glucose 178.4 +/- 8.0 mg/dl) within 20 min. The baseline blood glucose levels (104.8 +/- 5.7 mg/dl) reached maximum levels (291.7 +/- 23.8 mg/dl) at 120 min. Ketamine alone did not elevate glucose levels in fed rats. Isoflurane also produced acute hyperglycemia similar to KX. Administration of pentobarbital sodium did not produce hyperglycemia in fed rats. In contrast, none of these anesthetic agents produced hyperglycemia in fasted rats. The acute hyperglycemic effect of KX in fed rats was associated with decreased plasma levels of insulin, adrenocorticotropic hormone (ACTH), and corticosterone and increased levels of glucagon and growth hormone (GH). The acute hyperglycemic response to KX was dose-dependently inhibited by the specific alpha2-adrenergic receptor antagonist yohimbine (1-4 mg/kg). KX-induced changes of glucoregulatory hormone levels such as insulin, GH, ACTH, and corticosterone were significantly altered by yohimbine, whereas the glucagon levels remained unaffected. In conclusion, the present study indicates that both KX and isoflurane produce acute hyperglycemia in fed rats. The effect of KX is mediated by modulation of the glucoregulatory hormones through stimulation of alpha2-adrenergic receptors. Pentobarbital sodium did not produce hyperglycemia in either fed or fasted rats. Based on these findings, it is suggested that caution needs to be taken when selecting anesthetic agents, and fed or fasted state of animals in studies of diabetic disease or other models where glucose and/or glucoregulatory hormone levels may influence outcome and thus interpretation. However, fed animals are of value when exploring the hyperglycemic response to anesthetic agents.     

Nitric oxide induced by ketamine/xylazine anesthesia maintains hepatic blood flow during hypothermia.

Among the anesthetics influencing the nitric oxide (NO) pathway, ketamine is widely reported in the literature. We researched the variations in blood physiological parameters following ketamine/xylazine- or pentobarbital-induced anesthesia, with particular emphasis on plasmatic NO levels and oxidative stress-related factors. The effects of ketamine on hepatic blood flow during deep hypothermia were also examined. Adult male Sprague-Dawley rats were anesthetized intraperitoneally with ketamine/xylazine or with sodium pentobarbital. Animals underwent serial blood extraction to analyze acid-base balance and lactate levels in blood, as well as NO, MDA, SH groups, and AST levels in plasma samples. We demonstrated that ketamine leads to increased plasmatic NO levels, induces metabolic acidosis, and causes oxidative damage, though without reaching hepatic toxicity. When experimental hypothermia was induced, ketamine affected hepatic blood flow. Based on these results, we suggest that studies on physiological processes involving NO should exercise caution if anesthesia is induced by ketamine.     

Lack of efficacy of injectable ketamine with xylazine or diazepam for anesthesia in chickens

Compared to other laboratory animals, little is known about the use of anesthetics in birds, potentially resulting in the use of improper dosing regimens. The authors compared two commonly used ketamine combinations with isoflurane and concluded that the injectable doses were ineffective for induction of surgical anesthesia in chickens.     

A comparison of carfentanil/xylazine and Telazol/xylazine for immobilization of white-tailed deer

October 2001 to January 2002, captive free-ranging white-tailed deer (Odocoileus virginianus) were immobilized with a combination of carfentanil citrate and xylazine hydrochloride. From this study, we selected a dose of carfentanil/xylazine for the purpose of comparing immobilization parameters and physiologic effects with those of a combination of tiletamine and zolazepam (Telazol) and xylazine. Animals were initially given intramuscular injections of 10 mg xylazine and one of four doses of carfentanil (i.e., 0.5, 1.0, 1.5, and 2.0 mg). A carfentanil dose of 1.2 mg (x +/- SD = 23.5 +/- 3.2 microg/kg) and 10 mg xylazine (0.2 +/- 0.03 mg/kg) were selected, based on induction times and previously published reports, to compare with a combination of 230 mg of Telazol (4.5 +/- 0.6 mg/kg) and 120 mg xylazine (2.3 +/- 0.3 mg/kg). Time to first observable drug effects and to induction were significantly longer for deer treated with carfentanil/xylazine than with Telazol/xylazine (P < 0.01). Hyperthermia was common in deer immobilized with carfentanil/xylazine, but heart rate, respiration rate, and hemoglobin saturation were within acceptable levels. Degree of anesthesia of deer immobilized with Telazol/xylazine was superior to deer immobilized with carfentanil/xylazine. The combination of 120 mg of naltrexone hydrochloride and 6.5 mg of yohimbine hydrochloride provided rapid and complete reversal (1.9 +/- 1.1 min) of carfentanil/xylazine immobilization. Animals immobilized with Telazol/xylazine had long recovery times with occasional resedation after antagonism with 6.5 mg of yohimbine. The combination of carfentanil and xylazine at the doses tested did not provide reliable induction or immobilization of white-tailel (leer even though drug reversal was rapid and safe using naltrexone and yohimbine.     

Long term anesthesia using a continuous infusion of guaifenesin, ketamine and xylazine in cats.

Cats (Felis catus) were anesthetized with a solution containing guaifenesin, ketamine and xylazine (GKX) in 0.9% saline. Anesthesia was induced by intravenous (IV) injection and was maintained for 6 hours by IV infusion. Heart rate, respiratory rate and PvO2 did not change significantly during the 6 hour monitoring period and remained consistently within the published normal ranges for cats. Although the PvCO2 did not change significantly, many values were abnormal. Venous pH decreased to slightly below normal values. Lead II ECG tracings showed no abnormalities. Loss of response to pedal pinch and jaw tone indicates maintenance of a surgical plane of anesthesia and adequate muscle relaxation throughout the 6 hour anesthetic period. Cats exhibited voluntary motor movement and were in sternal recumbency in just over 2 hours and were showing no residual clinical effects of the anesthesia 16 hours later. Although a transient mild acidosis was observed, we conclude that GKX provides a safe, effective and easily administered anesthetic regime for cats for periods up to 6 hours.     

Butorphanol/xylazine/ketamine immobilization of free-ranging Baird's tapirs in Costa Rica

Cardiopulmonary effects and the utility of a butorphanol/xylazine/ketamine combination were evaluated during twenty immobilizations of sixteen Baird's tapirs (Tapirus bairdii) between March 1996 and January of 1998 in Corcovado National Park (Costa Rica). The animals were attracted to a bait site and darted from tree platforms. The tapirs were estimated to weigh between 200 to 300 kg. Actual weights of three tapirs taken at later dates fell within the estimated range. A butorphanol, 48+/-1.84 (x +/- SE) mg/animal IM, and xylazine, 101+/-2.72 mg/animal IM, combination was used to immobilize the animals. In some instances, ketamine was used either IM or IV at 187+/-40.86 mg/animal to prolong the immobilization period in addition to the butorphanol/xylazine combination. Naltrexone was used IM to reverse butorphanol at 257+/-16.19 mg/animal. Either yohimbine, 34+/-0.61 or tolazoline at 12+/-10.27 mg/animal, was used to reverse xylazine. The mean time from dart impact to first visible effect was 4.63+/-0.50 min (x +/- SE). Mean time to sternal recumbency was 12.21+/-1.08 min. Mean time the tapirs were immobilized was 45.63+/-3.6 min. Mean time to return to sternal recumbency and standing in animals that received yohimbine and naltrexone was 3.16+/-1.06 and 5.33+/-1.45 min, respectively. Mean time to return to sternal recumbency and standing in animals that received tolazoline and naltrexone was 1.57+/-0.39 and 3.14+/-0.51 min, respectively. Cardiopulmonary parameters including heart rate, respiratory rate, body temperature, electrocardiogram, percent oxygen satoration, and indirect blood pressure were recorded. Arterial blood gas analysis was performed on four animals. A mild degree of hypoxemia was evidenced by low arterial oxygen saturations. Five of 14 (36%) animals measured had oxygen saturations below 90%. Bradycardia (heart rates <45 BPM) was an expected finding in 11 (55%) immobilizations. Induction, recovery and muscle relaxation of each immobilization was graded. Premature arousal, which occurred in six (30%) animals, was the only problem associated with the immobilizations. Butorphanol/xylazine is a recommended protocol for immobilization of calm, free-ranging tapirs lasting less than 30 min. Supplemental intravenous administration of ketamine is recommended for longer procedures. Nasal insufflation of oxygen is recommended.     

Early effects of tribromoethanol, ketamine/xylazine, pentobarbitol, and isoflurane anesthesia on hepatic and lymphoid tissue in ICR mice

We investigated the effects of various anesthetic agents on hepatic and splenic injury in mice. Three and six hours after intraperitoneal injection of TBE, intramuscular injection of ketamine/xylazine combination (K/X), intraperitoneal injection of pentobarbital (PB), and inhalation of isoflurane (IF), or intraperitoneal and intramuscular injection of control saline, mice were exsanguinated and serum was obtained for measurement of hepatic aspartate transaminase (AST), alanine transaminase (ALT) and gamma-glutamyltransferase (GGT). The spleen and liver also were obtained, and sections were examined by use of routine light microscopy for pathologic changes and for apoptosis, as determined by use of the in situ terminal deoxynucleotidyl transferase-mediated dUPT nick-end-labeling (TUNEL) histochemical analysis. Three hours after TBE or K/X administration, AST activity increased three- to fourfold above that in untreated and saline-injected control animals, and remained high at six hours. Administration of PB did not effect AST activity at three hours, but there was a significant increase at six hours. Activity of ALT was non-significantly increased three hours after TBE and K/X, but not PB administration. Administration of IF had no effect on hepatic enzyme activities, and GGT was not increased after administration of any of the agents. Markedly increased apoptosis was observed in splenic follicles and in hepatic Kupffer and endothelial cells at three hours after TBE and K/X administration, but apoptosis decreased to control levels by six hours. Increased apoptosis was not observed after IF administration. Administration of TBE and K/X causes injury to lymphocytes and to hepatic Kupffer and endothelial cells within three hours, and PB administration induces changes within six hours. Thus, use of these anesthetic agents should be avoided when experiments are being designed to test short-term effects of an experimental intervention on the spleen and possibly on all lymphoid tissues. In addition, they also should be avoided in experiments testing effects on hepatic tissue.     

Comparison of ketmine with the combination of ketamine and xylazine for effective anesthesia in the rhesus monkey (Macaca mulatta).

The addition of xylazine to ketamine hydrochloride was found to enhance analgesia, anesthesia, and muscle relaxation in rhesus monkeys. At 0.10 ml/kg body weight, this combination provided adequate anesthesia for such procedures as cisternal puncture, lumbar spinal puncture, insertion of urinary catheters, finger amputations, and tattooing. The combination of ketamine and xylazine did depress the heart rate, respiration rate, and body temperature more than the administration of ketamine alone. The period of anesthesia also was prolonged, but the monkeys regained consciousness more rapidly at the end of the anesthetic period.     

Effects of yohimbine on bradycardia and duration of recumbency in ketamine/xylazine anesthetized ferrets

Eleven adult ferrets (Mustela putorius furo) were anesthetized with ketamine hydrochloride (25 mg/kg, IM) and xylazine hydrochloride (2 mg/kg, IM). Fifteen minutes post-ketamine/xylazine injection, ferrets were treated with yohimbine hydrochloride at a dose of 0.5 mg/kg, or an equal volume of physiologic saline, intramuscularly. Each ferret served as its own control by randomly receiving both treatments with a minimum interval of 2 weeks between treatments on any one ferret. At 15 minutes post-ketamine/xylazine injection, mean heart rate measurements for both treatment groups were 27% less than the mean heart rate measurement reported for unanesthetized ferrets. Intramuscular administration of yohimbine antagonized the ketamine/xylazine induced bradycardia in 10 of the 11 ferrets, (p = 0.0001). In yohimbine treated ferrets, an increase in mean heart rate measurement was noted 5 minutes after the intramuscular administration of yohimbine, and followed, over the next 15 minutes, by a progressive increase in mean heart rate. However, a corresponding decrease in mean heart rate measurement was observed in saline treated controls. Fifteen minutes after the injection of yohimbine, the mean heart rate measurement of yohimbine treated animals had increased to 194 beats per minute. This mean heart rate measurement is nearly 30% greater than the mean heart rate of 150 beats per minute measured at 15 minutes post-saline injection in saline treated controls. Also, yohimbine treatment significantly reduced duration of recumbency in 10 of 11 ferrets (p = 0.0001). Mean duration of recumbency for yohimbine treated ferrets was 41 +/- 9.7 minutes, whereas mean duration of recumbency for saline treated ferrets was determined to be 80 +/- 11.4 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle necrosis in Syrian hamsters resulting from intramuscular injections of ketamine and xylazine

To assess tissue damage resulting from intramuscular injection of mixtures of ketamine and xylazine, 48 hamsters were given 100, 150 or 200 mg/kg ketamine and 10 mg/kg xylazine in one hind leg and an equal volume of sterile physiologic saline in the other leg. Four hamsters from each group were killed 1, 3, 7 and 14 days after injection and the tissues at the injection sites were examined. There was grossly apparent muscle necrosis in most of the ketamine-xylazine injected legs. By light microscopy, 47 of 48 legs injected with ketamine-xylazine had moderate to extensive muscle necrosis with an acute to chronic inflammatory response, depending on the time elapsed since injection. Microscopic slides of the injection sites were coded, randomized and scored for severity of muscle lesions. Lesion scores for ketamine-xylazine injected legs were significantly higher than controls at all post-injection times. These findings indicate that intramuscular injection of ketamine with xylazine can cause extensive muscle necrosis in hamsters and should not be used for anesthesia in survival procedures.     

Total intravenous anesthesia with midazolam, ketamine, and xylazine or detomidine following induction with tiletamine, zolazepam, and xylazine in red deer (Cervus elaphus hippelaphus) undergoing surgery

Sixteen captive female red deer were successfully anesthetized to surgically implant a telemetry system. The deer were immobilized with (mean±SD) 1.79±0.29 mg/kg xylazine and 1.79±0.29 mg/kg tiletamine/zolazepam given intramuscularly with a dart gun. Anesthesia was maintained for 69±2 min using a total intravenous protocol with a catheter placed in the jugular vein. Group X received xylazine (0.5±0.055 mg/kg/hr) and group D, detomidine (2±0.22 μg/kg/hr), both in combination with ketamine (2±0.02 mg/kg/hr) and midazolam (0.03±0.0033 mg/kg/hr), as a constant rate infusion. Anesthesia was reversed with 0.09±0.01 mg/kg atipamezole and 8.7±1.21 μg/kg sarmazenil given intravenously in both groups. These drug combinations provided smooth induction, stable anesthesia for surgery, and rapid recovery. Respiratory depression and mild hypoxemia were seen, and we, therefore, recommend using supplemental intranasal oxygen.     

Thermoregulation during pentobarbital and ketamine anesthesia in rats

1.) Core temperature, tail temperature, metabolic heat production, and evaporative heat loss were measured in rats exposed to various ambient temperature conditions. 2.) Control rats increased heat production in the cold and heat loss in a warm environment, thus maintaining a relatively constant core temperature. 3.) Pentobarbital anesthesia reduced the thermoregulatory responses and caused core temperature to vary considerably with ambient temperature. Ketamine anesthesia resulted in minor thermoregulatory deficits. 4.) It is concluded that ketamine can be used in thermal physiological studies that require an anesthetised preparation, although it is not completely devoid of inhibitory effects on thermoregulatory responses.