Optimization of a tri-drug treatment against lung cancer using orthogonal design in preclinical studies.

A growing body of evidence suggests that anesthetics impact the outcome of patients with cancer after surgical intervention. However, the optimal dose and underlying mechanisms of co-administered anesthetics in lung tumor therapy have been poorly studied. Here, we aimed to investigate the role of combined anesthetics propofol, sufentanil, and rocuronium in treating lung cancer using an orthogonal experimental design and to explore the optimal combination of anesthetics. First, we evaluated the effects of the three anesthetics on the proliferation and invasion of A-549 cells using Cell Counting Kit 8 and Transwell migration and invasion assays. Subsequently, we applied the orthogonal experimental design (OED) method to screen the appropriate concentrations of the combined anesthetics with the most effective antitumor activity. We found that all three agents inhibited the proliferation of A-549 cells in a dose- and time-dependent manner when applied individually or in combination, with the highest differences in the magnitude of inhibition occurring 24 h after combined drug exposure. The optimal combination of the three anesthetics that achieved the strongest reduction in cell viability was 1.4 µmol/L propofol, 2 nmol/L sufentanil, and 7.83 µmol/L rocuronium. This optimal 3-drug combination produced a more beneficial result at 24 h than either single drug. Our results provide a theoretical basis for improving the efficacy of lung tumor treatment and optimizing anesthetic strategies.

A randomized clinical trial on effects of alfaxalone combined with medetomidine and midazolam in preventing stress-related neurohormonal and metabolic responses of isoflurane-anesthetized cats undergoing surgery.

OBJECTIVE: To evaluate the effects of IM and IV administration of alfaxalone alone and in combination with medetomidine, midazolam, or both on key stress-related neurohormonal and metabolic changes in isoflurane-anesthetized cats undergoing ovariohysterectomy or castration. ANIMALS: 72 client-owned mixed-breed cats undergoing ovariohysterectomy or castration between October 4, 2018, and January 10, 2020. PROCEDURES: For each type of surgery, cats were assigned to 1 of 6 premedication protocols groups, with 6 cats/group: physiologic saline (0.9% NaCl) solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IV); physiologic saline solution (0.5 mL, IM) and alfaxalone (5 mg/kg, IM); medetomidine (50 µg/kg, IM) and alfaxalone (5 mg/kg, IV); medetomidine (50 µg/kg, IM) and alfaxalone (5 mg/kg, IM); midazolam (0.5 mg/kg, IM), medetomidine (50 µg/kg, IM), and alfaxalone (5 mg/kg, IV); or midazolam (0.5 mg/kg, IM), medetomidine (50 µg/kg, IM), and alfaxalone (5 mg/kg, IM). Venous blood was taken before pretreatment, pre- and postoperatively during anesthesia with isoflurane and oxygen, and during early and complete recovery. RESULTS: Compared with baseline concentrations, plasma adrenaline and noradrenaline concentrations decreased during anesthesia in cats premedicated with alfaxalone alone and in combination with medetomidine. The combination of medetomidine, midazolam, and alfaxalone prevented an excessive increase in catecholamines during anesthesia and surgery in cats. Postoperative plasma cortisol concentration after ovariohysterectomy was lower for cats premedicated with the combination of medetomidine and alfaxalone or the combination of medetomidine, midazolam, and alfaxalone, compared with cats premedicated with alfaxalone alone. Cats treated with combinations that included medetomidine and midazolam had hyperglycemia during anesthesia. Cats treated with medetomidine or medetomidine and midazolam in combination with alfaxalone, compared with alfaxalone alone, had lower concentrations of nonesterified fatty acids during anesthesia. Behavioral recovery scores were lower (better) for cats that received medetomidine in addition to alfaxalone, compared with alfaxalone alone. CLINICAL RELEVANCE: Results indicated that pretreatments with medetomidine and alfaxalone or with medetomidine, midazolam, and alfaxalone were useful for preventing stress-related hormonal and metabolic responses, other than hyperglycemia, during isoflurane anesthesia and surgery in cats.

Comparison of the Cardiovascular Effects of Two Medetomidine Doses Combined with Tiletamine-Zolazepam for the Immobilization of Red Deer Hinds (Cervus elaphus).

Wild animal immobilization often requires high doses of α2-adrenoceptor agonists. Despite their desired sedative and analgetic effects, well-recognized cardiovascular side effects, such as hypertension and bradycardia, remain a major concern. We compared the effect of two medetomidine doses on intra-arterial blood pressure and heart rate in 13 captive, female red deer (Cervus elaphus) immobilized during winter. Each animal was randomly assigned to receive either 80 µg/kg (group L) or 100 µg/kg (group H) medetomidine, combined with 3 mg/kg tiletamine-zolazepam administered intramuscularly. Changes in cardiovascular variables over time and differences between the groups were analyzed using linear mixed-effect models. Induction time was faster in group L compared with group H; recovery time did not differ between groups. Initially, the arterial blood pressure was higher in group H compared with group L, but differences between groups diminished during anesthesia. Moreover, the decline in arterial blood pressure in group H was more rapid. Heart rate was significantly lower in group L, but bradycardia was not observed. The higher medetomidine dose did not reduce induction time, and initial hypertension was reduced by administering the lower dose. Therefore, although the sample size was small and, thus, the significance of results might be limited, we suggest using 80 µg/kg instead of 100 µg/kg medetomidine when combined with 3 mg/kg tiletamine-zolazepam for the immobilization of female red deer.

Characterization of brain-wide somatosensory BOLD fMRI in mice under dexmedetomidine/isoflurane and ketamine/xylazine.

Mouse fMRI under anesthesia has become increasingly popular due to improvement in obtaining brain-wide BOLD response. Medetomidine with isoflurane has become well-accepted for resting-state fMRI, but whether this combination allows for stable, expected, and robust brain-wide evoked response in mice has yet to be validated. We thus utilized intravenous infusion of dexmedetomidine with inhaled isoflurane and intravenous infusion of ketamine/xylazine to elucidate whether stable mouse physiology and BOLD response are obtainable in response to simultaneous forepaw and whisker-pad stimulation throughout 8 h. We found both anesthetics result in hypercapnia with depressed heart rate and respiration due to self-breathing, but these values were stable throughout 8 h. Regardless of the mouse condition, brain-wide, robust, and stable BOLD response throughout the somatosensory axis was observed with differences in sensitivity and dynamics. Dexmedetomidine/isoflurane resulted in fast, boxcar-like, BOLD response with consistent hemodynamic shapes throughout the brain. Ketamine/xylazine response showed higher sensitivity, prolonged BOLD response, and evidence for cortical disinhibition as significant bilateral cortical response was observed. In addition, differing hemodynamic shapes were observed between cortical and subcortical areas. Overall, we found both anesthetics are applicable for evoked mouse fMRI studies.

Effects of isoflurane and sevoflurane alone and in combination with butorphanol or medetomidine on the bispectral index in chickens.

BACKGROUND: The bispectral index (BIS) is an anaesthesia monitoring technique able to assess the level of central nervous system depression in humans and various animal species. In birds, it has been validated in chickens undergoing isoflurane anaesthesia. The aim of this study was to evaluate in an avian species the influence of isoflurane and sevoflurane on BIS, each at different minimum anaesthetic concentrations (MAC) multiples, alone or combined with butorphanol or medetomidine. Ten chickens (5 males and 5 females) underwent general anaesthesia with isoflurane or sevoflurane alone, and combined with either intramuscular administration of butorphanol (1 mg/kg) or medetomidine (0.1 mg/kg), in a prospective and cross-over study (i.e., 6 treatments per animal). BIS measurements were compared to heart rate (HR), non-invasive blood pressure (NIBP) and to a visual analogue scale (VAS) of anaesthesia depth. RESULTS: HR was significantly increased, and both NIBP and VAS were significantly reduced, with higher gas concentrations. NIBP (but not HR or VAS) was additionally affected by the type of gas, being lower at higher concentrations of sevoflurane. Butorphanol had no additional effect, but medetomidine led to differences in HR, NIBP, and in particular a reduction in VAS. With respect to deeper level of hypnosis at higher concentrations and the absence of difference between gases, BIS measurements correlated with all other measures (except with HR, where no significant relationship was found) The difference in BIS before (BISpre) and after stimulation (BISpost) did not remain constant, but increased with increasing MAC multiples, indicating that the BISpost is not suppressed proportionately to the suppression of the BISpre values due to gas concentration. Furthermore, neither butorphanol nor medetomidine affected the BIS. CONCLUSIONS: The difference of degree of central nervous system depression monitored by BIS compared with neuromuscular reflexes monitored by VAS, indicate that BIS records a level of anaesthetic depth different from the one deducted from VAS monitoring alone. BIS provided complementary information such as that medetomidine suppressed spinal reflexes without deepening the hypnotic state. As a consequence, it is concluded that BIS improves the assessment of the level of hypnosis in chickens, improving anaesthesia monitoring and anaesthesia quality in this species.

Comparison of anesthetic effects of tiletamine-zolazepam-medetomidine or ketamine-medetomidine in captive Amur leopard cats (Prionailurus bengalensis euptailurus).

OBJECTIVE: To evaluate the effects and utility of tiletamine-zolazepam-medetomidine (TZM) and ketamine-medetomidine (KM) for anesthesia of Amur leopard cats (Prionailurus bengalensis euptailurus). STUDY DESIGN: Prospective, randomized experimental trial. ANIMALS: A total of six female (3.70 ± 0.49 kg) and six male (5.03 ± 0.44 kg; mean ± standard deviation) Amur leopard cats aged 2-6 years. METHODS: Each animal was administered four protocols separated by ≥3 weeks. Each protocol included medetomidine (0.05 mg kg-1) combined with tiletamine-zolazepam (1 mg kg-1; protocol MTZLO); tiletamine-zolazepam (2 mg kg-1; protocol MTZHI); ketamine (2 mg kg-1; protocol MKLO); or ketamine (4 mg kg-1; MKHI) administered intramuscularly. At time 0 (onset of lateral recumbency) and 30 minutes, heart rate (HR), respiratory rate (fR), rectal temperature, noninvasive mean arterial pressure (MAP) and hemoglobin oxygen saturation (SpO2) were recorded. Times to onset of lateral recumbency, duration of anesthesia and time to standing were recorded. RESULTS: Overall, animals were anesthetized with all protocols within 10 minutes, anesthesia was maintained ≥57 minutes, and recovery (time from the first head lift to standing) was completed within 5 minutes. During anesthesia with all protocols, HR, fR, rectal temperature, SpO2 and MAP were 99-125 beats minute-1, 33-44 breaths minute-1, 37.6-39.4 °C, 90-95% and 152-177 mmHg, respectively. No adverse event was observed. CONCLUSIONS AND CLINICAL RELEVANCE: TZM and KM at various dosages resulted in rapid onset of anesthesia, duration of >57 minutes and rapid recovery without administration of an antagonist. Accordingly, all these combinations are useful for anesthetizing Amur leopard cats and for performing simple procedures. However, the low doses of the anesthetic agents are recommended because there was no difference in duration of anesthesia between the dose rates studied.

Comparison of the effects of methadone and butorphanol combined with acepromazine for canine gastroduodenoscopy.

OBJECTIVE: To evaluate the feasibility of gastroduodenoscopy in dogs premedicated with acepromazine in combination with butorphanol or methadone. STUDY DESIGN: Prospective, randomized, double-blinded clinical trial. ANIMALS: A group of 40 client-owned dogs. METHODS: Dogs were randomly allocated to one of two groups and give intramuscular acepromazine 0.02 mg kg-1 combined with either butorphanol 0.3 mg kg-1 (group ACEBUT) or methadone 0.2 mg kg-1 (group ACEMET). General anaesthesia was induced with propofol and ketamine and maintained with sevoflurane (2.3%) in oxygen. Cardiopulmonary variables were recorded at 5 minute intervals during anaesthesia. Feasibility of the entire gastroduodenoscopy was evaluated with a visual analogue scale (VAS) from 0 (best) to 100 (worst) (primary outcome of the study). Lower oesophageal sphincter dilatation and duodenal intubation were scored. Pylorus diameter was measured with standard endoscopic inflatable balloons. Overall cardiovascular stability was assessed during anaesthesia, using a VAS (0-100), as was the presence of fluid in the oesophagus, regurgitation, need for mechanical ventilation, and intraoperative and postoperative rescue analgesia (secondary outcomes of the study). Differences between treatments were analysed with Mann-Whitney U, Student t test, Fisher exact test or mixed model analysis of variance as appropriate. Subsequently, feasibility VAS of the gastroduodenoscopy was assessed for noninferiority between groups. The noninferiority margin was set as -10. RESULTS: All gastroduodenoscopies were successfully completed in both groups using an endoscope tip diameter of 12.8 mm in all but one dog. Feasibility of gastroduodenoscopy was evaluated as 2.9 ± 5.6 in group ACEBUT and 5.1 ± 5.8 in group ACEMET. No significant differences between groups were detected in any measured or assessed variables, and noninferiority was confirmed. CONCLUSION AND CLINICAL RELEVANCE: In our study population, the effects of methadone and butorphanol when combined with acepromazine were comparable.

Effects of intracoelomic alfaxalone-dexmedetomidine on righting reflex in common garter snakes (Thamnophis sirtalis): preliminary data.

OBJECTIVE: To evaluate the effect of dexmedetomidine on alfaxalone immobilization in snakes. STUDY DESIGN: Nonblinded, crossover study. ANIMALS: A total of eight mature common garter snakes (Thamnophis sirtalis). METHODS: Snakes were administered each of three treatments intracoelomically: alfaxalone (30 mg kg-1; treatment A), alfaxalone (30 mg kg-1) combined with dexmedetomidine (0.05 mg kg-1; treatment AD0.05); and alfaxalone (30 mg kg-1) combined with dexmedetomidine (0.10 mg kg-1; treatment AD0.10). A minimum of 10 days elapsed between experimental trials. Times to loss of righting reflex (LRR) and return of righting reflex (RRR) were recorded. Heart rate (HR) was recorded every 5 minutes throughout the period of LRR and averaged for each snake. Times to LRR and RRR, and mean HR in snakes that achieved LRR were reported. RESULTS: LRR occurred in eight (100%), five (63%) and three (38%) snakes in treatments A, AD0.05 and AD0.10, respectively. For all treatments, time to LRR ranged 3-20 minutes. Median (range) times to RRR were 39 (30-46), 89 (62-128) and 77 (30-185) minutes for treatments A, AD0.05 and AD0.10, respectively. In animals where righting reflex was lost, mean HR was lower in all dexmedetomidine treatments compared with treatment A. CONCLUSIONS AND CLINICAL RELEVANCE: In this pilot study, alfaxalone resulted in reliable immobilization, whereas dexmedetomidine and alfaxalone combinations resulted in highly variable durations of immobilization with low HR in immobilized animals. For snakes that achieved LRR, the addition of dexmedetomidine (0.05 mg kg-1) to alfaxalone appeared to extend the period of immobilization compared with alfaxalone alone.

Sedative effects of two doses of alfaxalone in combination with methadone and a low dose of dexmedetomidine in healthy Beagles.

OBJECTIVE: To evaluate the sedative effects of two doses of alfaxalone when added to a combination of dexmedetomidine and methadone injected intramuscularly (IM) in healthy Beagles. STUDY DESIGN: Randomized, blinded, crossover, experimental study. ANIMALS: A group of six adult Beagles. METHODS: Dogs were sedated on three different occasions with IM dexmedetomidine (3 µg kg-1) and methadone (0.3 mg kg-1) combined with two doses of alfaxalone (0.5 and 1 mg kg-1; A0.5 and A1, respectively) or saline (A0). Quality of sedation, response to tail clamping and rectal temperature were recorded at baseline, 5, 15, 25, 35 and 45 minutes. Pulse and respiratory rates, oxygen saturation of haemoglobin (SpO2) and noninvasive blood pressure (NIBP) were recorded every 5 minutes. Onset of sedation and duration of recumbency, response to venous catheterization and recovery quality were assessed. Physiological variables (analysis of variance) were analysed between treatments and within treatments compared with baseline (Student t test). Nonparametric data were analysed using Friedman and Cochran's Q tests. Significance was p < 0.05. RESULTS: Sedation scores were significantly higher when alfaxalone was co-administered (area under the curve; p = 0.024, A0.5; p = 0.019, A1), with no differences between doses. Onset of sedation was similar, but duration of recumbency was longer in A0.5 than in A0 [median (minimum-maximum), 43 (35-54) versus 30 (20-47) minutes, p = 0.018], but not in A1. Response to venous catheterization and tail clamping, and quality of recovery (acceptable) presented no differences between treatments. A decrease in all physiological variables (compared with baseline) was observed, except for NIBP, with no differences between treatments. All dogs required oxygen supplementation due to reduced SpO2. CONCLUSIONS AND CLINICAL RELEVANCE: Adding alfaxalone to methadone and dexmedetomidine enhanced sedation and duration of recumbency. Although cardiopulmonary depression was limited, oxygen supplementation is advisable.

Effects of constant rate infusions of dexmedetomidine, remifentanil and their combination on minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To evaluate the effects of constant rate infusions (CRIs) of dexmedetomidine and remifentanil alone and their combination on minimum alveolar concentration (MAC) of sevoflurane in dogs. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A total of six (three males, three females) healthy, adult neutered Beagle dogs weighing 12.6 ± 1.4 kg. METHODS: Anesthesia was induced with sevoflurane in oxygen until endotracheal intubation was possible and anesthesia maintained with sevoflurane using positive-pressure ventilation. Each dog was anesthetized five times and was administered each of the following treatments: saline (1 mL kg-1 hour-1) or dexmedetomidine at 0.1, 0.5, 1.0 or 5.0 µg kg-1 loading dose intravenously over 10 minutes followed by CRI at 0.1, 0.5, 1.0 or 5.0 µg kg-1 hour-1, respectively. Following 60 minutes of CRI, sevoflurane MAC was determined in duplicate using an electrical stimulus (50 V, 50 Hz, 10 ms). Then, CRI of successively increasing doses of remifentanil (0.15, 0.60 and 2.40 µg kg-1 minute-1) was added to each treatment. MAC was also determined after 30 minutes equilibration at each remifentanil dose. Isobolographic analysis determined interaction from the predicted doses required for a 50% MAC reduction (ED50) with remifentanil, dexmedetomidine and remifentanil combined with dexmedetomidine, with the exception of dexmedetomidine 5.0 µg kg-1 hour-1, obtained using log-linear regression analysis. RESULTS: The sevoflurane MAC decreased dose-dependently with increasing infusion rates of dexmedetomidine and remifentanil. Remifentanil ED50 values were lower when combined with dexmedetomidine than those obtained during saline-remifentanil. Synergistic interactions between dexmedetomidine and remifentanil for MAC reduction occurred with dexmedetomidine at 0.5 and 1.0 µg kg-1 hour-1. CONCLUSIONS AND CLINICAL RELEVANCE: Combined CRIs of dexmedetomidine and remifentanil synergistically resulted in sevoflurane MAC reduction. The combination of dexmedetomidine and remifentanil effectively reduced the requirement of sevoflurane during anesthesia in dogs.

Postanaesthetic effects of ketamine-midazolam and ketamine-medetomidine on gastrointestinal transit time in rabbits anaesthetised with isoflurane.

BACKGROUND: Gastrointestinal stasis is a common perianaesthetic complication in rabbits. The objective of this study was to assess the impact on gastrointestinal transit time of ketamine-midazolam (KMZ) versus ketamine-medetomidine (later antagonised by atipamezole) (KMT-A) in rabbits anaesthetised with isoflurane. METHODS: This was a cross-over, randomised, single-blinded, controlled, experimental trial. Seven healthy adult New Zealand White rabbits were used. Gastrointestinal transit time was assessed by contrast radiography in awake rabbits. Presence of contrast medium in the small intestine (gastric transit time), in the caecum (small intestinal transit time) and in faeces in the colon was assessed. One week later, 55 minutes isoflurane anaesthesia was induced with ketamine (15 mg/kg) and either midazolam (3 mg/kg) or medetomidine (0.25 mg/kg) by intramuscular injection. Thirty minutes after discontinuation of isoflurane, atipamezole (0.5 mg/kg) was administered only to rabbits in KMT-A treatment. Gastrointestinal transit time was then assessed in both treatment groups, beginning 30 minutes after cessation of isoflurane administration. Two weeks later, the treatment groups were interchanged. RESULTS: Gastric and small intestinal transit times were significantly longer with KMT-A (92±109 minutes and 214±119 minutes, respectively) than with KMZ (1±0 minutes and 103±6 minutes, respectively) and in the awake state (7±7 minutes and 94±32 minutes, respectively). CONCLUSION: Clinicians should therefore be aware of the potential gastrointestinal side effects of KMT-A, particularly in rabbits at risk for gastrointestinal stasis.

The effect of intramuscular dexmedetomidine-butorphanol combination on tear production in dogs.

This study assessed the effects of a combination of dexmedetomidine and butorphanol on the Schirmer tear test I (STT I) values in dogs. Ninety-eight dogs were sedated with an intramuscular injection of a combination of dexmedetomidine, 5 µg/kg body weight (BW), and butorphanol, 0.2 mg/kg BW. The effects of dexmedetomidine were reversed by administering atipamezole at the end of the procedure. The combination of dexmedetomidine and butorphanol significantly decreased tear production 15 minutes after sedation. The STT I values 15 minutes after reversal of dexmedetomidine with atipamezole were significantly higher than the STT I values 15 minutes after sedation but were significantly lower than the STT I values before sedation. Gender, weight, duration of sedation, right or left eye did not affect STT I values after sedation. It is recommended that dogs sedated with a combination of dexmedetomidine and butorphanol be treated with a tear substitute to combat decreased tear production.

Effet de l'association dexmédétomidin-butorphanol intramusculaire sur la production lacrymale chez le chien. L'étude vise à déterminer les effets de l'association dexmédétomidine-butorphanol sur les résultats du test de Schirmer I (STT I) chez le chien. Quatre-vingt-dix-huit chiens ont été sédatés avec l'association dexmédétomidine (5 µg/kg) butorphanol (0,2 mg/kg) intramusculaire. La dexmédétomidine a été antagonisée avec de l'atipamezole en fin de procédure. L'association dexmédétomidine-butorphanol diminue significativement la production lacrimale 15 minutes post-sédation. Les valeurs de STT I 15 minutes post-antagonisation de la dexmédétomidine étaient significativement plus élevées que celles de STT I 15 minutes post-sédation, mais significativement inférieures aux STT I pré-sédation. Les variables genre, poids, durée de la sédation, oeil droit/gauche, n'ont pas significativement influencé les valeurs de STT I post-sédation. L'association dexmédétomidine-butorphanol diminuant significativement leur production lacrimale il est recommandable de traiter les chiens avec des substituts lacrimaux pour éviter la sécheresse oculaire.(Traduit par les auteurs).

Comparison of alfaxalone-medetomidine and tiletamine-zolazepam in rescued common palm civets (Paradoxurus musangus).

Forty rescued common palm civets were anesthetized. Twenty animals received intramuscular injections of alfaxalone 5 mg/kg and medetomidine 0.05 mg/kg (A-M group), whereas twenty animals received 5 mg/kg of tiletamine and zolazepam (T-Z group). The A-M group was reversed with atipamazole 0.25 mg/kg. There were no significant differences in the time from anesthetic injection to induction and intubation between the A-M and T-Z groups. The time from the injection of reversal in the A-M group and the time from cessation of isoflurane in the T-Z group to extubation, first response to recovery and ambulation were longer (P<0.05) in the T-Z group. The T-Z group recorded lower (P<0.05) rectal temperatures compared to the A-M group. This study showed that both drug combinations can be used effectively for the immobilization of civets. The A-M combination provided better anesthetic depth, but with higher incidence of bradycardia and hypoxemia. The recovery time was reduced significantly as atipamezole was used as a reversal agent in the A-M combination.

A clinical study to evaluate the cardiopulmonary characteristics of two different anaesthetic protocols for immobilization of healthy chimpanzees (Pan troglodytes).

OBJECTIVE: To characterize the cardiopulmonary characteristics of two different anaesthetic protocols (tiletamine/zolazepam ± medetomidine) and their suitability for the immobilization of healthy chimpanzees undergoing cardiac assessment. STUDY DESIGN: Prospective, clinical, longitudinal study. ANIMALS: Six chimpanzees (Pan troglodytes) aged 4-16 years weighing 19.5-78.5 kg were anaesthetized on two occasions. METHODS: Anaesthesia was induced with tiletamine/zolazepam (TZ) (3-4 mg kg-1) or tiletamine/zolazepam (2 mg kg-1) and medetomidine (0.02 mg kg-1) (TZM) via blow dart [intramuscular (IM)] and maintained with intermittent boluses of ketamine (IV) or zolazepam/tiletamine (IM) as required. The overall quality of the anaesthesia was quantified based on scores given for: quality of induction, degree of muscle relaxation and ease of intubation. The time to achieve a light plane of anaesthesia, number of supplemental boluses needed and recovery characteristics were also recorded. Chimpanzees were continuously monitored and heart rate (HR), pulse rate (PR), respiratory rate (fR) oxygen saturation of haemoglobin (SpO2), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), rectal temperature, mucous membrane colour and capillary refill time recorded. During the first procedure (TZ) animals underwent a 12-channel electrocardiogram (ECG), haematology, biochemistry and cardiac biomarker assessment to rule out the presence of pre-existing cardiovascular disease. A detailed echocardiographic examination was carried out by the same blinded observer during both procedures. Data were compared using Student's paired t-test or Wilcoxon rank tests as appropriate. RESULTS: There was a significant difference for the area under the curves between anaesthetic protocols for HR, SAP, MAP and fR. No significant differences in the echocardiographic measurements were evident. Quality of anaesthesia was significantly better with TZM and no additional boluses were required. The TZ protocol required multiple supplemental boluses. CONCLUSIONS AND CLINICAL RELEVANCE: Both combinations are suitable for immobilization and cardiovascular evaluation of healthy chimpanzees. Further work is required to evaluate the effect of medetomidine in cardiovascular disease.

Efficacy of a Butorphanol, Azaperone, and Medetomidine Combination for Helicopter-Based Immobilization of Bison ( Bison bison).

Decreased access to potent narcotics for wildlife applications has stimulated the need to explore alternative drug combinations for ungulate immobilizations. A combination of butorphanol, azaperone, and medetomidine (BAM) has been used for some ungulate species, but information on its use in bison ( Bison bison) is limited. We conducted field trials using BAM, in conjunction with atipamezole and naltrexone as antagonists, for reversible field immobilization of bison during ground- and helicopter-based operations. We compared times to induction and recovery, vital rates (rectal temperature and respiration rate), and the quality of induction, immobilization, and recovery between ground- and helicopter-based immobilizations of bison. Overall, 15 of 21 bison were induced with the volume we used (mean±SD=3.4±0.6 mL); two other animals darted from a helicopter required a full second dose, and four others (two darted from the ground and two from a helicopter) required a supplemental partial dose to achieve induction. All immobilizations achieved a sufficient plane of anesthesia to permit minor invasive procedures (e.g., skin biopsy and blood sampling). All animals recovered, and most (17 of 21) were reversed in ≤5 min. The mean time to induction was 10.8±7.3 min while that for recovery was 5.0±2.1 min. We found few differences in vital rates or the quality of immobilizations between ground- and helicopter-based captures. The drug combination provided good immobilization and was reliably reversed; however, inconsistent inductions at the doses we used may limit its use in field immobilizations of bison, particularly those animals being darted from a helicopter.

Effects of transdermal lidocaine or lidocaine with prilocaine or tetracaine on mechanical superficial sensation and nociceptive thermal thresholds in horses.

OBJECTIVE: To evaluate the transdermal local anaesthetic effect of lidocaine or lidocaine combined with prilocaine or tetracaine in horses. STUDY DESIGN: Experimental, randomized study. ANIMALS: A total of five healthy adult warmblood horses. METHODS: Horses were clipped bilaterally at the withers, cranial saddle area and caudal saddle area. Baseline measurements for mechanical superficial sensation via von Frey filaments and nociceptive thermal thresholds were performed. A 5% lidocaine patch (12 hour exposure, treatment L), a lidocaine/prilocaine cream (each 2.5%, treatment LP) and a lidocaine/tetracaine cream (each 7%, treatment LT) were applied (both 2 hour exposure). The same product was applied at the same location bilaterally, but on the right side an epidermal micro-perforation (dermaroller, 1200 needles) was performed prior to application. A total of five more measurements were performed at each location, immediately at the end of exposure time followed by hourly measurements. Thermal thresholds normalized to thermal excursion were analysed. One- or two-way anova and the Wilcoxon signed-rank test were used for statistical analysis with p<0.05 considered significant. RESULTS: Epidermal micro-perforation had no enhancing effect. Treatments L, LP, and LT resulted in increased thermal excursion (%) immediately (84.7±12.9; 100.0±0.0; 100.0±0.0) and 1 hour (81.7±66; 86.0±17.7; 87.7±14.4) after the removal of the respective product compared to baseline (66.1±9.3; 69.9±8.3; 76.5±7.8). Superficial mechanical sensation was decreased by the lidocaine-and-tetracaine cream at all time points, and by the lidocaine patch and lidocaine-and-prilocaine cream for three measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Eutectic mixtures of lidocaine with either prilocaine or tetracaine led to a reduction in thermal nociception and mechanical sensation for up to 2 hours.

Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs.

OBJECTIVE: To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs. STUDY DESIGN: Randomized, crossover, blinded study. ANIMALS: Ten female Beagle dogs, aged 11-13 months and weighing 7.2-8.6 kg. METHODS: The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone+acepromazine and butorphanol (ALF-AB), propofol (PRO) and propofol+AB (PRO-AB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg-1). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality. RESULTS: A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PRO-AB and ALF-AB before doxapram. All dogs in PRO-AB and ALF-AB with <20% increase in RGSA before doxapram had ≥20% increase in RGSA after doxapram. Examination quality was significantly better in PRO-AB and ALF-AB. CONCLUSIONS AND CLINICAL RELEVANCE: The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion.

Evaluation of injectable anaesthesia with five medetomidine-midazolam based combinations in Egyptian fruit bats ( Rousettus aegyptiacus).

Egyptian fruit bats are increasingly used as model animals in neuroscience research. Our aim was to characterize suitable injectable anaesthesia for this species, possibly replacing inhalant anaesthesia, thus minimizing occupational health hazards. Eight bats were randomly assigned by a crossover design for subcutaneously administered combinations of medetomidine-midazolam with: saline (MM-Sal), ketamine (MM-Ket), fentanyl (MM-Fen), morphine (MM-Mor), or butorphanol (MM-But). The anaesthetic depth and vital signs were monitored at baseline and every 10 min until bats recovered. If after 180 min the bats did not recover, atipamezole was administered. Mean induction times were 7-11.5 min with all combinations. Twitching during induction was common. All combinations produced anaesthesia, with significantly decreased heart rate (from 400 to 200 bpm) and respiratory rate (from 120-140 to 36-65 rpm). Arrhythmia and irregular breathing patterns occurred. MM-Fen, MM-Mor, and MM-But depressed respiration significantly more than MM-Sal. Time to first movement with MM-Ket and MM-But lasted significantly longer than with MM-Sal. Recovery time was significantly shorter in the MM-Sal (88 min) in comparison to all other treatments, and it was significantly longer in the MM-But (159 min), with atipamezole administered to four of the eight bats. In conclusion, all five anaesthetic protocols are suitable for Egyptian fruit bats; MM-Ket produces long anaesthesia and minimal respiratory depression, but cannot be antagonized completely. MM-Fen, MM-Mor, and MM-But depress respiration, but are known to produce good analgesia, and can be fully antagonized. Administration of atipamezole following the use of MM-But in Egyptian fruit bats is recommended.

Cardiovascular, respiratory and sedative effects of intramuscular alfaxalone, butorphanol and dexmedetomidine compared with ketamine, butorphanol and dexmedetomidine in healthy cats.

Objectives The aim of the study was to evaluate the cardiorespiratory effects, quality of sedation and recovery of intramuscular alfaxalone-dexmedetomidine-butorphanol (ADB) and ketamine-dexmedetomidine-butorphanol (KDB), in cats. Methods Nine adult, healthy cats (6.63 ± 1.42 kg) were enrolled in a blinded, randomized, crossover experimental design. Cats were sedated twice intramuscularly, once with ADB (alfaxalone 1 mg/kg, dexmedetomidine 0.005 mg/kg, butorphanol 0.2 mg/kg), and once with KDB (ketamine 5 mg/kg, dexmedetomidine 0.005 mg/kg, butorphanol 0.2 mg/kg), in random order. Data collected included heart rate (HR), arterial blood pressure and blood gas analysis, respiratory rate and sedation score. Analysis of variance with Bonferroni post-hoc correction was used for parametric data, and a Wilcoxon signed rank test was used for non-parametric data. Significance was set at P <0.05. Results Total sedation time was shorter for ADB (90.71 ± 15.12 mins vs 147.00 ± 47.75 mins). Peak sedation was observed within 15 mins in both groups. Quality of recovery was excellent in both groups. HR decreased over time in both groups. Diastolic and mean arterial pressure decreased over time for ADB, becoming significant after 30 mins. All cardiovascular variables were within the clinically acceptable range in both groups. Arterial partial pressure of oxygen was significantly decreased from baseline for KDB at all time points (73 ± 2.5 mmHg [9.7 ± 0.3 kPa] vs ADB 83 ± 2.6 mmHg [11 ± 0.3 kPa]). Hypoventilation was not observed. Conclusions and relevance Both protocols produced acceptable cardiovascular stability. Sedation and recovery quality were good, albeit sedation was shorter with ADB. Although oxygenation was better maintained in the ADB group, all sedated cats should receive oxygen supplementation.