Use of nalbuphine as a substitute for butorphanol in combination with dexmedetomidine and tiletamine/zolazepam: a randomized non-inferiority trial.

OBJECTIVES: The goal of this study was to determine whether a drug combination using nalbuphine with dexmedetomidine and tiletamine/zolazepam is non-inferior to one that uses butorphanol. METHODS: All healthy cats presenting solely for gonadectomy to two trap-neuter-return mobile clinic days were randomly assigned to induction with a combination of tiletamine/zolazepam 3 mg/kg, dexmedetomidine 7.5 µg/kg and either butorphanol or nalbuphine at 0.15 mg/kg. All participants were blinded to the identity of the combinations. The primary endpoint was clinician satisfaction, comprised of the mean of four satisfaction ratings on a 7-point Likert scale (highly dissatisfied through to highly satisfied) recorded for induction, maintenance of anesthesia, surgery and recovery. Exploratory endpoints included each individual score, number of injections, duration of induction, duration of recovery and need for reversal agent. To assess non-inferiority for the primary endpoint and individual scores, the difference and 95% confidence intervals (CIs) of the difference between the mean clinical scores for the nalbuphine and butorphanol-based combinations were calculated and compared with a prespecified non-inferiority margin of 20% (1.4 points). RESULTS: Seventy-two cats were enrolled, 36 in each group. The mean ± SD composite score for the combination with nalbuphine was 6.06 ± 0.59 (95% CI 5.86-6.25) points, while the combination with butorphanol was 6.22 ± 0.62 (95% CI 6.01-6.43). The difference between mean scores was 0.17 (-0.12 to 0.45), which did not exceed the prespecified boundary of 1.4, establishing the non-inferiority of nalbuphine. No individual clinical score for nalbuphine was inferior to butorphanol, and there were no significant differences for any secondary endpoints. CONCLUSIONS AND RELEVANCE: The clinical experience of the nalbuphine-based combination was non-inferior to the butorphanol-based combination. Nalbuphine is an effective substitute for butorphanol, providing another option if butorphanol is unavailable due to shortage, controlled status or cost, without requiring a change in anesthetic workflow.

Effect of Anesthetics on Efficiency of Remote Ischemic Preconditioning.

Remote ischemic preconditioning of hind limbs (RIPC) is an effective method for preventing brain injury resulting from ischemia. However, in numerous studies RIPC has been used on the background of administered anesthetics, which also could exhibit neuroprotective properties. Therefore, investigation of the signaling pathways triggered by RIPC and the effect of anesthetics is important. In this study, we explored the effect of anesthetics (chloral hydrate and Zoletil) on the ability of RIPC to protect the brain from injury caused by ischemia and reperfusion. We found that RIPC without anesthesia resulted in statistically significant decrease in neurological deficit 24 h after ischemia, but did not affect the volume of brain injury. Administration of chloral hydrate or Zoletil one day prior to brain ischemia produced a preconditioning effect by their own, decreasing the degree of neurological deficit and lowering the volume of infarct with the use of Zoletil. The protective effects observed after RIPC with chloral hydrate or Zoletil were similar to those observed when only the respective anesthetic was used. RIPC was accompanied by significant increase in the level of brain proteins associated with the induction of ischemic tolerance such as pGSK-3ß, BDNF, and HSP70. However, Zoletil did not affect the level of these proteins 24 h after injection, and chloral hydrate caused increase of only pGSK-3ß. We conclude that RIPC, chloral hydrate, and Zoletil produce a significant neuroprotective effect, but the simultaneous use of anesthetics with RIPC does not enhance the degree of neuroprotection.

Effect of tiletamine-zolazepam on the intraocular pressure of the dog.

OBJECTIVE: To determine the effect of tiletamine-zolazepam (TZ) on canine intraocular pressure (IOP). ANIMALS STUDIED: Six healthy dogs without ocular abnormalities were used in this study. PROCEDURES: The study was carried out as a crossover experimental trial with a 7-day interval between treatments. TZ combination was administered intravenously (IV) at a dose of 5, 10, and 20 mg/kg (TZ5, TZ10, and TZ20, respectively). Following preanesthetic baseline readings of IOP, each dog received IV TZ and then the IOP values were measured every 10 min for 40 min in all treatments. RESULTS: The baseline IOP values (mean ± standard deviation) for TZ5, TZ10, and TZ20 were 12.7 ± 0.8, 14.4 ± 1.2, and 15.3 ± 1.7 mmHg, and each IOP changed to 11.1 ± 1.1, 13.1 ± 1.4 and 13.5 ± 1.7 mmHg after intravenous administration of each TZ treatment, respectively. However, there were no statistical differences between baseline and post-treatment values. CONCLUSIONS: The TZ combination had no clinically significant effect on IOP of the dog. This could be an option for induction or surgical procedures in dogs with ophthalmic problems when an increase in IOP is undesirable.

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.

Effects of premedication with tiletamine/zolazepam/medetomidine during general anesthesia using sevoflurane/fentanyl in swine undergoing pancreas transplantation.

OBJECTIVE: To assess cardiac and hemodynamic responses and body temperature during long-term general anesthesia using sevoflurane/fentanyl after premedication with a tiletamine/zolazepam/medetomidine combination in swine undergoing experimental pancreas transplantation. MATERIALS AND METHODS: Twelve Landrace female pigs of means weight 46.4 +/- 5.1 kg were premedicated by intramuscular administration of tiletamine/zolazepam (3.5 mg/kg), medetomidine (0.03 mg/kg), and atropine (0.02 mg/kg), before anesthesia with 0.75 minimum alveolar concentration sevoflurane and continuous intravenous fentanyl infusion (5.7 +/- 0.7 microg/kg/h). Assessment of heart rate, arterial blood pressure, and temperature in pigs undergoing allogenic pancreas transplant surgery were registered at the start of anesthesia (T0), as well as at 60 (T60), 120 (T120), and 180 (T180) minutes after T0, and finally at the end of anesthesia (T anesthesia end), when we switched off the sevoflurane vaporizer. Analysis of variance was used to determine differences between times with P < .05 considered significant. Results are given as mean values +/- standard deviations. RESULTS: Arterial blood pressure significantly decreased from T120 to the end of anesthesia, while a significantly decreased heart rate was only evident at T60. Body temperature decreased significantly from T60 to the end of anesthesia. These decreases, however, lacked clinical relevance; all parameters were within normal range. No major anesthetic complications were observed in this study. CONCLUSIONS: The administration of a tiletamine/zolazepam/medetomidine combination as premedication in swine subjected to pancreas transplantation allowed for a safe reduction of sevoflurane/fentanyl requirements during long-term general anesthesia. Despite arterial blood pressure and body temperature evidencing a decrease during anesthetic maintenance, all parameters remained within normal range values.

Chemical immobilization of adult female Weddell seals with tiletamine and zolazepam: effects of age, condition and stage of lactation.

BACKGROUND: Chemical immobilization of Weddell seals (Leptonychotes weddellii) has previously been, for the most part, problematic and this has been mainly attributed to the type of immobilizing agent used. In addition to individual sensitivity, physiological status may play an important role. We investigated the use of the intravenous administration of a 1:1 mixture of tiletamine and zolazepam (Telazol) to immobilize adult females at different points during a physiologically demanding 5-6 week lactation period. We also compared performance between IV and IM injection of the same mixture. RESULTS: The tiletamine:zolazepam mixture administered intravenously was an effective method for immobilization with no fatalities or pronounced apnoeas in 106 procedures; however, there was a 25 % (one animal in four) mortality rate with intramuscular administration. Induction time was slightly longer for females at the end of lactation (54.9 +/- 2.3 seconds) than at post-parturition (48.2 +/- 2.9 seconds). In addition, the number of previous captures had a positive effect on induction time. There was no evidence for effects due to age, condition (total body lipid), stage of lactation or number of captures on recovery time. CONCLUSION: We suggest that intravenous administration of tiletamine and zolazepam is an effective and safe immobilizing agent for female Weddell seals. Although individual traits could not explain variation in recovery time, we suggest careful monitoring of recovery times during longitudinal studies (> 2 captures). We show that physiological pressures do not substantially affect response to chemical immobilization with this mixture; however, consideration must be taken for differences that may exist for immobilization of adult males and juveniles. Nevertheless, we recommend a mass-specific dose of 0.50-0.65 mg/kg for future procedures with adult female Weddell seals and a starting dose of 0.50 mg/kg for other age classes and other phocid seals.

Anesthesia of wood bison with medetomidine-zolazepam/tiletamine and xylazine-zolazepam/tiletamine combinations.

This study was designed to evaluate 2 combinations for immobilization of bison. Seven wood bison received 1.5 mg/kg body weight (BW) of xylazine HCl + 1.5 mg/kg BW of zolazepam HCl and 1.5 mg/kg BW of tiletamine HCl on one occasion. The bison received 60 micrograms/kg BW of medetomidine HCl + 0.6 mg/kg BW of zolazepam HCl and 0.6 mg/kg BW of tiletamine HCL on another occasion. Xylazine was antagonized with 3 mg/kg BW of tolazoline HCl and medetomidine HCl was antagonized with 180 micrograms/kg (BW) of atipamezole HCl. Temporal characteristics of immobilization and physiological effects (acid-base status, thermoregulatory, cardiovascular, and respiratory effects) of the drug combinations were compared. Induction was significantly faster with xylazine HCl-zolazepam HCl/tiletamine HCl. Recovery following antagonist administration was significantly faster with medetomidine HCl-zolazepam HCl/tiletamine HCl. The average drug volumes required were 7.00 mL of xylazine HCl-zolazepam HCl/tiletamine HCL and 2.78 mL of medetomidine HCl-zolazepam HCl/tiletamine HCl. Hypoxemia, hypercarbia, and rumenal tympany were the major adverse effects with both drug combinations.