Cardiovascular effects of intravenous vatinoxan (MK-467) in medetomidine-tiletamine-zolazepam anaesthetised red deer (Cervus elaphus).

OBJECTIVE: To determine the effect of intravenous vatinoxan administration on bradycardia, hypertension and level of anaesthesia induced by medetomidine-tiletamine-zolazepam in red deer (Cervus elaphus). STUDY DESIGN AND ANIMALS: A total of 10 healthy red deer were included in a randomised, controlled, experimental, crossover study. METHODS: Deer were administered a combination of 0.1 mg kg-1 medetomidine hydrochloride and 2.5 mg kg-1 tiletamine-zolazepam intramuscularly, followed by 0.1 mg kg-1 vatinoxan hydrochloride or equivalent volume of saline intravenously (IV) 35 minutes after anaesthetic induction. Heart rate (HR), mean arterial blood pressure (MAP), respiration rate (fR), end-tidal CO2 (Pe'CO2), arterial oxygen saturation (SpO2), rectal temperature (RT) and level of anaesthesia were assessed before saline/vatinoxan administration (baseline) and at intervals for 25 minutes thereafter. Differences within treatments (change from baseline) and between treatments were analysed with linear mixed effect models (p < 0.05). RESULTS: Maximal (81 ± 10 beats minute-1) HR occurred 90 seconds after vatinoxan injection and remained significantly above baseline (42 ± 4 beats minute-1) for 15 minutes. MAP significantly decreased from baseline (122 ± 10 mmHg) to a minimum MAP of 83 ± 6 mmHg 60 seconds after vatinoxan and remained below baseline until end of anaesthesia. HR remained unchanged from baseline (43 ± 5 beats minute-1) with the saline treatment, whereas MAP decreased significantly (112 ± 16 mmHg) from baseline after 20 minutes. Pe'CO2, fR and SpO2 showed no significant differences between treatments, whereas RT decreased significantly 25 minutes after vatinoxan. Level of anaesthesia was not significantly influenced by vatinoxan. CONCLUSIONS AND CLINICAL RELEVANCE: Vatinoxan reversed hypertension and bradycardia induced by medetomidine without causing hypotension or affecting the level of anaesthesia in red deer. However, the effect on HR subsided 15 minutes after vatinoxan IV administration. Vatinoxan has the potential to reduce anaesthetic side effects in non-domestic ruminants immobilised with medetomidine-tiletamine-zolazepam.

Pre-exposure to related substances induced place preference and self-administration of the NMDA receptor antagonist-benzodiazepine combination, zoletil.

Previously, we have reported that the N-methyl-D-aspartate (NMDA) receptor antagonist-benzodiazepine veterinary anesthetic combination, zoletil, produced reward and reinforcement, but only in rats repeatedly pretreated with the drug and not in drug-naïve rats. Therefore, we hypothesized that previous drug exposure plays an important role in the abuse of zoletil. In the present study, we examined whether pre-exposure to related substances, NMDA receptor antagonists (tiletamine, ketamine), and benzodiazepines (zolazepam, diazepam) predisposes animals to abuse zoletil. We examined whether animals repeatedly pretreated with tiletamine, ketamine, zolazepam, or diazepam, for 14 days, would show locomotor activation, place preference, and self-administration in response to zoletil. Place preference was observed in groups pretreated with either an NMDA receptor antagonist (ketamine) or a benzodiazepine (diazepam). However, locomotor activation and self-administration were only observed in rats pretreated with NMDA receptor antagonists (tiletamine and ketamine). These results show that pre-exposure to related substances might have induced neurobiological changes that consequently led to the expression of the rewarding and reinforcing effects of zoletil. This provides evidence that zoletil may be used as a substitute drug by abusers of NMDA receptor antagonists or benzodiazepines.

[Features of anesthesia in rats at abdominal operations].

Nowadays, in Russia, diethyl ether is the most popular narcosis for rodent and particular rats. We had tested the new methods based on Zoletil 100 + XylaVet (15 mg/kg and 15-10-5 mg/kg) respectively. 6 conventional female rats were treated with this narcosis. The rats, early have narcotized by diethyl ether were investigated as control group. All of 6 treated with new narcosis animals died in early post-operative time. Interestingly enough, that organ toxicity, except neurologic toxicity, was not described in literature and manuals. We assume that this new narcosis is the cause of portal thromboses.

Physiologic evaluation of capture and anesthesia with medetomidine-zolazepam-tiletamine in brown bears (Ursus arctos).

Physiologic variables during anesthesia with medetomidine-zolazepam-tiletamine were evaluated in 52 free-ranging brown bears (Ursus arctos) darted from a helicopter and in six captive brown bears darted at a zoo. During anesthesia, rectal temperature, respiratory rate, heart rate, and pulse oximetry derived hemoglobin oxygen saturation were recorded. Arterial blood samples were collected and immediately analyzed for evaluation of pulmonary gas exchange, acid-base status, and selected hematologic and plasma variables. At the end of anesthesia, atipamezole was administered intramuscularly at five times the medetomidine dose. Capture-induced hyperthermia and lactic acidemia were documented in free-ranging bears. Hypoxemia during anesthesia was documented in both free-ranging and captive bears. In free-ranging bears, rectal temperature, heart rate, lactate, hematocrit, and hemoglobin decreased significantly during anesthesia, whereas partial pressure of arterial carbon dioxide, pH, potassium, and glucose increased. Yearlings had a significantly higher heart rate, pH, base excess, bicarbonate, and glucose, and had a significantly lower rectal temperature, sodium, hematocrit, and hemoglobin when compared with subadult and adult brown bears. In conclusion, alterations in pulmonary gas exchange and acid-base status in brown bears during anesthesia with medetomidine-zolazepam-tiletamine with the doses and capture methods used in this study were identified. Oxygen supplementation is recommended to counteract hypoxemia during anesthesia.

Urinary cortisol responses to unusual events in captive chimpanzees (Pan troglodytes).

This study investigated the urinary cortisol stress response to one known stressor (anaesthesia) and three unusual events hypothesized to result in increases in cortisol (confinement to one half of an enclosure for several days due to a hurricane, an enrichment exercise, and a change in group composition) in young chimpanzees (Pan troglodytes). Although a cortisol stress response to a variety of laboratory experiences has been documented in captive animals, it is unclear whether other types of atypical events are stressful, including those that are not necessarily negative. Cortisol was measured in 519 urine samples collected from 20 awake, unrestrained chimpanzees; individuals were compared against their own baseline values. A significant increase in urinary cortisol concentration was found as a result of the stress of anaesthesia, but no significant change in urinary cortisol resulted from the three other potential stressors. A lack of a urinary cortisol response to these events may indicate that the events were not actually stressful for the chimpanzees, but may have resulted from the limited temporal resolution of measuring cortisol excretion as an indicator of integrated secretion, or from changes in rates of agonistic behaviors.

Arterial pH and blood gas values in rats under three types of general anesthesia: a chronobiological study.

The aim of study was to review the status of arterial pH, pO(2) and pCO(2) under general anesthesias in dependence on the light-dark (LD) cycle in spontaneously breathing rats. The experiments were performed using three- to four-month-old pentobarbital(P)-, ketamine/xylazine(K/X)- and zoletil(Z)-anesthetized female Wistar rats after a four-week adaptation to an LD cycle (12 h light:12 h dark). The animals were divided into three experimental groups according to the anesthetic agent used: P (light n=11; dark n=8); K/X (light n=13; dark n=11); and Z (light n=18; dark n=26). pH and blood gases from arterial blood were analyzed. In P anesthesia, LD differences in pH, pO(2), and pCO(2) were eliminated. In K/X anesthesia, parameters showed significant LD differences. In Z anesthesia, LD differences were detected for pH and pO(2) only. Acidosis, hypoxia, and hypercapnia have been reported for all types of anesthesia during the light period. In the dark period, except for P anesthesia, the environment was more stable and values fluctuated within normal ranges. From a chronobiological perspective, P anesthesia was not the most appropriate type of anesthesia in these rat experiments. It eliminated LD differences, and also produced a more acidic environment and more pronounced hypercapnia than K/X and Z anesthesias.

The abuse liability of the NMDA receptor antagonist-benzodiazepine (tiletamine-zolazepam) combination: evidence from clinical case reports and preclinical studies.

The tiletamine-zolazepam (TZ) combination is an anaesthetic drug commonly used in veterinary medicine. It is an equal amount combination of tiletamine, a dissociative anaesthetic pharmacologically classified as an N-methyl-D-aspartate (NMDA) receptor antagonist, and zolazepam, a benzodiazepine tranquilizer. There are concerns regarding the safety profile of this drug combination due to incidents of human misuse/abuse. In this paper, we discuss the abuse liability of this drug combination based on currently available scientific evidence. We performed an in-depth search of medical and scientific literature and found seven reported cases of human abuse of the TZ combination, two of which resulted in fatal outcomes. In most of these cases, drug administration was intentional indicating that the TZ combination was abused by humans. This finding is bolstered by the results of preclinical studies showing that the TZ combination produces rewarding effects in rats, although manifested only in pretreated subjects. Further studies revealed that the addictive effects of the TZ combination are influenced by pre-exposure to other psychoactive drugs. Pre-exposure to ketamine, diazepam, propofol, or ethanol facilitated the expression of the rewarding effects of the TZ combination. These findings support the hypothesis that the TZ combination was and can be used as a substitute or replacement drug. Altogether, the compiled evidence indicates that the TZ combination can potentially be abused by humans. Thus, careful use, dispensation, and monitoring of the TZ combination and associated substances are strongly advocated. Copyright © 2016 John Wiley & Sons, Ltd.

Efficacy of immobilizing free-ranging elk with Telazol and xylazine hydrochloride using transmitter-equipped darts.

From January 1999 to April 2002, 14 free-ranging elk were darted with a mixture of Telazol reconstituted with xylazine hydrochloride (HCl) in a forested habitat in southwestern Oklahoma and north-central Arkansas. Elk were darted from ground blinds, tree stands, or a vehicle at distances of 14-46 m and were recovered 37-274 m from the dart site. Elk were located using radiotelemetry with 3-cc disposable Pneu-dart transmitter darts. Mean+/-SD dose of Telazol and xylazine HCl was 590+/-192 mg/ml and 276+/-153 mg/ml, respectively, and mean time to standing after injection of reversal agent was 27 min (range: 1-65 min). The combination of Telazol and xylazine HCl successfully immobilized free-ranging elk, and transmitter-equipped darts permitted successful location of sedated elk by two people in areas of dense forest cover. The dose required to sedate elk appeared to vary depending on physiology and behavior, but no drug-induced mortality occurred despite the wide variance in the doses administered. We recommend 500 mg Telazol reconstituted with 300 mg xylazine HCl as an initial dose for a >or=200 kg elk. If needed to achieve full sedation, up to 3 additional ml of the mixture may be administered without adverse effects.

Chemical immobilization of crested porcupines with tiletamine HCl and zolazepam HCl (Zoletil) under field conditions.

The combination of tiletamine HCl and zolazepam HCl has been used on many species of wild mammals. Short induction time, low dosage, satisfactory safety margins, relatively constant immobilization time, and smooth recovery are benefits reported. This combination (Zoletil 100) was used during a study on behavioural ecology of the crested porcupine (Hystrix cristata) in a Mediterranean coastal area (Maremma Regional Park, Tuscany, Italy). We used this mixture 42 times on 31 individuals. Mean adult dose was (+/- SE) 7.24 +/- 0.37 mg/kg (74.0 +/- 3.0 mg/individual). Average adult induction time was 5.3 min (+/- 1.1) and average adult immobilization time was 22.6 min (+/- 6.0). One adult male porcupine died after chemical restraints. The use of tiletamine-zolazepam seems adequate for chemical immobilization of crested porcupines under field conditions, mainly because of its short induction time, small volume to be injected and wide safety margin.

Use of Telazol to immobilize female northern sea lions (Eumetopias jubatus) in Alaska.

Twenty-nine female northern sea lions (Eumetopias jubatus) were immobilized using Telazol in dosages ranging from 1.8 to 8.1 mg/kg. Best results were achieved with Telazol dosages ranging between 1.8 and 2.5 mg/kg which resulted in smooth induction and recovery. Optimal injection location was in the muscle mass of the lower back and hip. Dosages greater than 3.5 mg/kg resulted in a tendency toward hypothermia. Six mortalities occurred which were partially caused by the location of drug injection and perhaps the high dosage.

Use of tiletamine and zolazepam to immobilize captive Iberian wolves (Canis lupus).

A mixture of tiletamine and zolazepam (Zoletil) was used to immobilize 29 captive born Iberian wolves. Based on their excitability during handling procedures the animals were categorized as excited (n = 15) and unexcited (n = 14). We observed differences in the responses of these groups to the drugs. Although immobilized with higher doses (mean +/- SD of 6.94 +/- 2.13 versus 5.04 +/- 1.74 mg/kg for the unexcited) the excited individuals had an irregular and less predictable response, with five individuals needing additional dosages in the excited group compared to one animal in the unexcited group. Arousal time and duration of immobilization of excited wolves was not correlated to initial drug doses, but was in unexcited animals; the excited group had a poorer thermal regulation. Differences in arousal time and duration could be the a result of the different doses used. Excited wolves were older than unexcited (5.4 +/- 3.07 versus 2.86 +/- 2.11 years, respectively). For captive wolves, doses of about 5 mg/kg are recommended for non-excited and 10 mg/kg for excited individuals.

Response of wild subantarctic fur seal (Arctocephalus tropicalis) females to ketamine and tiletamine-zolazepam anesthesia.

This study is the first to compare the anesthetic effects of two cyclohexamines on free-ranging subantarctic fur seal (Arctocephalus tropicalis) females. From April to July 1999, 107 females were immobilized for tooth extraction and blood sampling, using either ketamine (Ketalar, n = 58) alone or tiletamine-zolazepam (Zoletil 100, n = 49) mixture. Animals were injected intramuscularly at mean doses of 2.1 mg/kg for ketamine and 1.1 mg/kg for tiletamine-zolazepam mixture. Individual response to both drugs was highly variable. The dosage required to achieve a satisfactory level of anesthesia was smaller for subantarctic fur seals than for most other species of seals and was less for animals in better body condition. Few side effects were observed during the trials, aside from mild tremors caused by ketamine, and respiratory depression or prolonged apnea caused by tiletamine-zolazepam. We recommend use of ketamine, especially by those with little experience in anesthesia of fur seals. However, precautionary measures should be taken, such as using low doses for animals in good body condition and being prepared for anesthetic emergencies to avoid any casualties.

Immobilisation of southern elephant seals and leopard seals with cyclohexamine anaesthetics and xylazine.

Ketamine and xylazine were given to 55 southern elephant seals (Mirounga leonina) for stomach lavaging, and to three leopard seals (Hydrurga leptonyx). The elephant seals showed prolonged apnoea and two of them died owing to aspiration of stomach contents. Two of the leopard seals died from unknown causes. Tiletamine and zolazepam were given to five elephant seals and one leopard seal. Two of the elephant seals and the leopard seal died from unknown causes. Xylazine alone was administered to 34 leopard seals. Sedation was poor at low dose rates (less than 1.7 mg/kg) but four of the seals given higher dose rates died owing to the aspiration of stomach contents.

Effects of tiletamine/zolazepam premedication on propofol anaesthesia in dogs.

The cardiovascular and pulmonary effects of tiletamine/zolazepam, propofol and tiletamine/zolazepam plus propofol were studied in five mongrel dogs. A cannula inserted into a raised carotid artery was used to measure mean arterial pressure (MAP) and heart rate continuously and to collect arterial blood for the determination of pH, PO2, PCO2, bicarbonate and base balance. Respiratory frequency and rectal temperature were also recorded. In the two propofol groups premedication had no significant effect on the time to rejection of an endotracheal tube and the return to sternal recumbency. The MAP and heart rate increased after tiletamine/zolazepam alone and after tiletamine/zolazepam plus propofol, although propofol alone reduced MAP and transiently increased heart rate. Respiratory frequency decreased transiently in both propofol groups in association with a significant increase in PaCO2 and decrease in PaO2. The most notable change was the hypoxaemia in the tiletamine/zolazepam plus propofol group in which the PaO2 was reduced. In all the dogs given tiletamine/zolazepam alone undesirable side effects were observed, effects which also occurred during the recovery of the dogs given tiletamine/zolazepam plus propofol.

The use of tiletamine hydrochloride and zolazepam hydrochloride for sedation of the mountain brushtial possum, Trichosurus caninus Ogilby (Phalangeridae: Marsupialia).

A combination of tiletamine hydrochloride and zolazepam hydrochloride in a 1:1 ration by weight was used successfully to sedate mountain brushtail possums, Trichosurus caninus, in the field. A standard total dose of 50 to 60 mg provided adequate sedation for the completion of a range of handling procedures. We describe the induction time, dose rate and side-effects associated with the use of tiletamine and zolazepam in T caninus.

Treatment of hypoxemia during xylazine-tiletamine-zolazepam immobilization of wapiti.

Hypoxemia is a commonly observed complication during the chemical immobilization of wild ruminants. If severe and left untreated, it can predispose animals to arrhythmias, organ failure, and capture myopathy. The following prospective study was designed to measure the degree of hypoxemia in wapiti that were immobilized with a combination of xylazine and tiletamine-zolazepam and to assess the response to nasal oxygen therapy. Pulse oximetry and arterial blood gas analysis were used to assess the degree of hypoxemia prior to nasal insufflation of oxygen and to demonstrate any beneficial effects of this intervention. All wapiti exhibited mild to marked hypoxemia (PaO2 = 43 +/- 11.8 mmHg) prior to treatment and showed marked improvement after 5 minutes of nasal insufflation of oxygen at 10 L/min (PaO2 = 207 +/- 60 mmHg). This inexpensive, noninvasive technique has great benefit in treating clinical hypoxemia under field conditions, and we recommend that nasal insufflation of oxygen be implemented during xylazine-tiletamine-zolazepam-induced immobilization of wapiti and other wild ruminants.

Capture, anesthesia, and disturbance of free-ranging brown bears (Ursus arctos) during hibernation.

We conducted thirteen immobilizations of previously collared hibernating two- to four-year-old brown bears (Ursus arctos) weighing 21-66 kg in central Sweden in winter 2010 and 2011 for comparative physiology research. Here we report, for the first time, an effective protocol for the capture and anesthesia of free-ranging brown bears during hibernation and an assessment of the disturbance the captures caused. Bears were darted in anthill, soil, or uprooted tree dens on eleven occasions, but two bears in rock dens fled and were darted outside the den. We used medetomidine at 0.02-0.06 mg/kg and zolazepam-tiletamine at 0.9-2.8 mg/kg for anesthesia. In addition, ketamine at 1.5 mg/kg was hand-injected intramuscularly in four bears and in six it was included in the dart at 1.1-3.0 mg/kg. Once anesthetized, bears were removed from the dens. In nine bears, arterial blood samples were analyzed immediately with a portable blood gas analyzer. We corrected hypoxemia in seven bears (PaO(2) 57-74 mmHg) with supplemental oxygen. We placed the bears back into the dens and antagonized the effect of medetomidine with atipamezole. Capturing bears in the den significantly increased the risk of den abandonment. One of twelve collared bears that were captured remained at the original den until spring, and eleven, left their dens (mean ± standard deviation) 3.2±3.6 (range 0.5-10.5) days after capture. They used 1.9±0.9 intermediate resting sites, during 6.2±7.8 days before entering a new permanent den. The eleven new permanent dens were located 730±589 m from the original dens. We documented that it was feasible and safe to capture hibernating brown bears, although they behaved differently than black bears. When doing so, researchers should use 25% of the doses used for helicopter darting during the active period and should consider increased energetic costs associated with den abandonment.