Comparison of Two Different Alfaxalone Concentrations Combined with Midazolam to Anesthetize Cynomolgus Macaques (Macaca fascicularis) for Plethysmography.

Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.

A Comparison of Three Anesthetic Drug Combinations for Use in Inducing Surgical Anesthesia in Female Guinea Pigs (Cavia porcellus).

Guinea pigs are often used in translational research, but providing them with safe and effective anesthesia is a challenge. Common methods like inhalant anesthesia and injectable ketamine/xylazine induce surgical anesthesia but can negatively affect cardiovascular, respiratory, and thermoregulatory systems and complicate the interpretation of research outcomes. Several alternative anesthetic regimens have been investigated, but none have consistently achieved a surgical plane of anesthesia. Therefore, identifying an anesthetic regimen that achieves a stable state of the surgical plane of anesthesia while preserving cardiorespiratory function would be a valuable contribution. To address this issue, we compared the efficacy of 3 anesthetic combinations in female Dunkin-Hartley guinea pigs: 1) alfaxalone, dexmedetomidine, and fentanyl (ADF); 2) alfaxalone, midazolam, and fentanyl (AMF); and 3) alfaxalone, midazolam, fentanyl, and isoflurane (AMFIso). We monitored anesthetic depth, heart rate, oxygenation, respiratory rate, respiratory effort, blood pressure, and body temperature every 15 min from injection to recovery. We also recorded the time to loss of righting reflex, duration of anesthesia, and time to achieve a surgical plane. The results showed no statistically significant differences in induction and recovery times among the groups. In the AMFIso group, 100% of the animals achieved a surgical plane of anesthesia, whereas only 10% of the animals in the AMF group reached that level. None of the animals in ADF group reached a surgical plane of anesthesia. Respiratory rate was significantly lower in the AMFIso as compared with the ADF group (P < 0.001) but was not different between the AMF and ADF groups. Temperature was significantly lower in the AMFIso group as compared with both the ADF and AMF groups (P < 0.001). In conclusion, both combinations of solely injectable anesthetics assessed in this study can be used for short, nonpainful procedures without significant cardiorespiratory depression. However, for mildly to moderately painful surgical procedures, the addition of an inhalant anesthetic like isoflurane is necessary for female guinea pigs.

A dose characterization study evaluating the pharmacodynamics and safety of a concentrated alfaxalone solution (4%) as an intramuscular sedative in dogs.

Alfaxalone is a commonly employed veterinary anaesthetic induction and sedation agent. A 4% w/v preserved, aqueous formulation of alfaxalone 'RD0387' (A4%) has recently been developed. To evaluate the sedative effects of A4%, three doses, 5 mg kg-1 (A5); 7.5 mg kg-1 (A7.5) and 10 mg kg-1 (A10) were administered intramuscularly into the epaxial musculature of six healthy adult mixed-breed dogs in an experimental, randomized, blinded, crossover study. Sedation time variables, quality of sedation (including onset of sedation and recovery), physiological variables, response to cephalic vein catheterization and frequency of undesirable events were recorded. Continuous variables were analysed between treatments (one-way ANOVA or restricted maximum likelihood modelling) and within treatments compared with baseline (Tukey's test). Categorical data were analysed between treatments (Kruskal-Wallis' test) and within treatments from baseline (Dunn's test). Significance was set at p < .05. All dogs became sedated (laterally recumbent) and sedation onset was significantly faster in groups A7.5 (9.8 ± 5.3 min) and A10 (9.1 ± 5.6 min) compared to A5 (25.6 ± 16.1 min) (p = .033, p = .027, respectively). Duration of sedation was significantly longer in A10 (168.5 ± 70.6 min) and A7.5 (143.8 ± 58 min) compared to A5 (63.8 ± 28.2 min) (p = .005 and p = .003, respectively). Dogs in A10 had a superior quality of onset of sedation compared to A5 (p = .028). Sedation scores and quality of recovery from sedation were not significantly different between doses. Two dogs (2/6) in A5 were insufficiently sedated for cephalic catheterization. Ataxia was the most frequently observed undesirable event with an overall frequency of 78% (14/18) and 89% (16/18) during sedation onset and recovery, respectively. Overall, A4% administered IM in dogs at 7.5 and 10 mg kg-1 resulted in sufficient sedation for IV catheterization in dogs. To improve the speed and quality of the sedation, it is recommended that future research focuses on combining A4% with other sedative or analgesic drugs.

Comparison between three dosages of intramuscular alfaxalone and a ketamine-dexmedetomidine-midazolam-tramadol combination in golden-headed lion tamarins (Leontopithecus chrysomelas).

OBJECTIVES: To characterize the cardiopulmonary and anesthetic effects of alfaxalone at three dose rates in comparison with a ketamine-dexmedetomidine-midazolam-tramadol combination (KDMT) for immobilization of golden-headed lion tamarins (GHLTs) (Leontopithecus chrysomelas) undergoing vasectomy. STUDY DESIGN: Prospective clinical trial. ANIMALS: A total of 19 healthy, male, wild-caught GHLTs. METHODS: Tamarins were administered alfaxalone intramuscularly (IM) at 6, 12 or 15 mg kg-1, or KDMT, ketamine (15 mg kg-1), dexmedetomidine (0.015 mg kg-1), midazolam (0.5 mg kg-1) and tramadol (4 mg kg-1) IM. Immediately after immobilization, lidocaine (8 mg kg-1) was infiltrated subcutaneously (SC) at the incision site in all animals. Physiologic variables, anesthetic depth and quality of immobilization were assessed. At the end of the procedure, atipamezole (0.15 mg kg-1) was administered IM to group KDMT and tramadol (4 mg kg-1) SC to the other groups; all animals were injected with ketoprofen (2 mg kg-1) SC. RESULTS: A dose-dependent increase in sedation, muscle relaxation and immobilization time was noted in the alfaxalone groups. Despite the administration of atipamezole, the recovery time was longer for KDMT than all other groups. Muscle tremors were noted in some animals during induction and recovery with alfaxalone. No significant differences were observed for cardiovascular variables among the alfaxalone groups, whereas an initial decrease in heart rate and systolic arterial blood pressure was recorded in KDMT, which increased after atipamezole administration. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone dose rates of 12 or 15 mg kg-1 IM with local anesthesia provided good sedation and subjectively adequate pain control for vasectomies in GHLTs. KDMT induced a deeper plane of anesthesia and should be considered for more invasive or painful procedures. All study groups experienced mild to moderate hypothermia and hypoxemia; therefore, the use of more efficient heating devices and oxygen supplementation is strongly recommended when using these protocols.

Sedation Characteristics of Intranasal Alfaxalone in Adult Yucatan Swine.

Compared with intravenous and intramuscular methods, intranasal administration of sedatives is a less invasive and nonpainful technique. In this prospective, randomized, crossover study, we evaluated the sedative characteristics of 2 doses (1 and 2 mg/kg) of alfaxalone administered intranasally to 7 adult Yucatan swine. We compared sedation scores before and after administration of alfaxalone and between groups by using a composite sedation scoring system (range, 0 to 12, with 12 being the highest level of sedation)). Pigs were randomly assigned to receive 2 doses of intranasal alfaxalone (1 mg/kg [A1]); 2 mg/kg [A2]) as 2 separate events in a crossover design with a 60-d washout period. Categories scored were posture, palpebral droop, uninhibited behavior, drowsiness, and acceptance of anesthetic facemask. Sedation scores were collected before sedation was administered and then every 3 min for 30 min afterward. Instilled volumes (mean ± 1 SD) were 5.7 ± 0.5 and 11.3 ± 0.8 mL for A1 and A2, respectively. Both alfaxalone doses produced significant increases in sedation scores compared with baseline. Median sedation scores for A1 (6; range, 4-12) were not different from those for A2 (6; range, 6 to 12). Intranasal administration of alfaxalone as the sole sedative agent increased sedation scores from baseline, achieving peak sedation at 6 to 9 min after instillation of A2. However, sedation scores were similar between the 2 groups, and neither dose produced sufficient sedation to facilitate handling or the performance of any clinical procedures. Given the concentration of alfaxalone solution currently available, volume is the major limiting factor regarding testing higher doses of this drug for its use as a sole sedative agent in swine.

EVALUATION OF TWO MEDETOMIDINE-AZAPERONE-ALFAXALONE COMBINATIONS IN CAPTIVE ROCKY MOUNTAIN ELK (CERVUS ELAPHUS NELSONI).

Alfaxalone has been successfully used intramuscularly (im) combined with medetomidine and azaperone for immobilization of small ungulates. An experimental 40 mg/ml alfaxalone solution (RD0387) was recently formulated for reduced injection volume. The objective of this study was to assess the efficacy and cardiopulmonary effects of high-concentration alfaxalone combined with medetomidine and azaperone for the intramuscular immobilization of captive Rocky Mountain elk (Cervus elaphus nelsoni). Seven adult female elk were used in a crossover design in which they were administered alfaxalone 1 mg/kg, medetomidine 0.05 mg/kg, and azaperone 0.1 mg/kg or alfaxalone 0.5 mg/kg, medetomidine 0.1 mg/kg, and azaperone 0.1 mg/kg im approximately 3 wk apart. Drugs were delivered to each elk in a chute by hand injection. Once recumbent, elk were placed in sternal recumbency for a period of 30 min, during which time level of sedation, response to minor procedures, heart rate, respiratory rate, rectal temperature, oxygen saturation, and direct arterial blood pressures were recorded every 5 min. Arterial blood gases were performed every 15 min. At 30 min, elk were administered atipamezole 0.25 or 0.5 mg/kg im and recovery quality and times were recorded. Statistical comparisons were made by t test, Wilcoxon signed rank test, and repeated measures analysis (significance level P < 0.05). Both drug combinations provided effective immobilization for 30 min, with induction and recovery time and quality similar to other medetomidine-based combinations used in elk. Cardiopulmonary effects included bradycardia, hypertension, and hypoxemia that resolved with oxygen supplementation. The average injection volume in the low-dose alfaxalone combination was approximately 5 ml. These combinations provided deep sedation and the ability to perform minor procedures in captive elk, with acceptable cardiopulmonary parameters as long as supplemental oxygen was provided.

SEDATIVE AND CARDIORESPIRATORY EFFECTS OF INTRAMUSCULAR ALFAXALONE AND BUTORPHANOL AT TWO DOSAGES IN FERRETS (MUSTELA PUTORIUS FURO).

Veterinary care of ferrets often requires chemical restraint. This study hypothesized that IM alfaxalone and butorphanol would result in clinically useful sedation without clinically relevant cardiorespiratory effects. Twelve healthy 15-mo-old ferrets of equal sexes weighing 0.75 to 1.66 kg were enrolled. Using a prospective, blinded design, ferrets randomly received either IM alfaxalone 2.5 mg/kg and butorphanol 0.2 mg/kg (low dose [LD]) or IM alfaxalone 5 mg/kg and butorphanol 0.2 mg/kg (high dose [HD]) (n = 6/group). Sedation times and induction and recovery scores were recorded by a blinded observer. Anesthetic monitor placement was attempted in all recumbent ferrets, and physiologic parameters and reflexes were recorded every 5 min until return of spontaneous movement. Data were assessed for normality using a Shapiro-Wilk normality test and analyzed by two-sample t test or Mann-Whitney U test; one ferret in HD was excluded. Ferrets in LD and HD exhibited moderate and marked sedation, with one of six and four of five ferrets tolerating monitor placement, respectively. Mean ± SD time to first effects, recumbency, and recovery in LD and HD was 2.30 ± 1.13 and 2.054 ± 1.12 (P = 0.7240), 2.87 ± 1.25 and 2.72 ± 1.41 (P = 0.8529), and 65.43 ± 32.43 and 52.30 ± 13.19 (P = 0.4212), respectively. Median (range) duration of recumbency in LD and HD was 31.12 (25.58-115.72) and 35.47 (28.27-44.42) min (P = 0.3290), respectively. Among monitored ferrets, transient mild hypotension and hypoxemia were observed. Intramuscular alfaxalone 5 mg/kg with butorphanol 0.2 mg/kg provided clinically useful sedation in ferrets with mild transient cardiorespiratory derangements.

Effects of alfaxalone on cerebral blood flow and intrinsic neural activity of rhesus monkeys: A comparison study with ketamine.

OBJECTIVE: Alfaxalone has been used increasingly in biomedical research and veterinary medicine of large animals in recent years. However, its effects on the cerebral blood flow (CBF) physiology and intrinsic neuronal activity of anesthetized brains remain poorly understood. METHODS: Four healthy adult rhesus monkeys were anesthetized initially with alfaxalone (0.125 mg/kg/min) or ketamine (1.6 mg/kg/min) for 50 min, then administrated with 0.8% isoflurane for 60 min. Heart rates, breathing beats, and blood pressures were continuously monitored. CBF data were collected using pseudo-continuous arterial spin-labeling (pCASL) MRI technique and rsfMRI data were collected using single-shot EPI sequence for each anesthetic. RESULTS: Both the heart rates and mean arterial pressure (MAP) remained more stable during alfaxalone infusion than those during ketamine administration. Alfaxalone reduced CBF substantially compared to ketamine anesthesia (grey matter, 65 ± 22 vs. 179 ± 38 ml/100g/min, p<0.001; white matter, 14 ± 7 vs. 26 ± 6 ml/100g/min, p < 0.05); In addition, CBF increase was seen in all selected cortical and subcortical regions of alfaxalone-pretreated monkey brains during isoflurane exposure, very different from the findings in isoflurane-exposed monkeys pretreated with ketamine. Also, alfaxalone showed suppression effects on functional connectivity of the monkey brain similar to ketamine. CONCLUSION: Alfaxalone showed strong suppression effects on CBF of the monkey brain.The residual effect of alfaxalone on CBF of isoflurane-exposed brains was evident and monotonous in all the examined brain regions when used as induction agent for inhalational anesthesia. In particular, alfaxalone showed similar suppression effect on intrinsic neuronal activity of the brain in comparison with ketamine. These findings suggest alfaxalone can be a good alternative to veterinary anesthesia in neuroimaging examination of large animal models. However, its effects on CBF and functional connectivity should be considered.

Intramuscular alfaxalone and methadone with or without ketamine in healthy cats: effects on sedation and echocardiographic measurements.

OBJECTIVE: To evaluate the effect of alfaxalone and methadone administered intramuscularly (IM), with or without ketamine, on sedation and echocardiographic measurements in healthy cats. STUDY DESIGN: A randomized, blinded, clinical study. ANIMALS: A group of 24 client-owned cats. METHODS: Baseline echocardiographic evaluation (bEchoCG) was performed. Cats were given IM alfaxalone (2 mg kg-1) and methadone (0.3 mg kg-1) with (AMK group) or without (AM group) ketamine (1 mg kg-1). A sedation score (0-5, indicating none to good sedation) was assigned at 5 (T5), 10 (T10) and 15 (T15) minutes after IM injection. At T15, a second echocardiographic evaluation (sEchoCG) was performed. Data are shown as median (range). Significance was p < 0.05. RESULTS: Finally, 21 cats were included. Sedation score was significantly higher in the AMK (11 cats) than in the AM group (10 cats): 4 (1-5) versus 0.5 (0-4) at T5 (p = 0.003); 4 (1-5) versus 1.5 (0-5) at T10 (p = 0.043); and 4 (1-5) versus 2 (0-5) at T15 (p = 0.024). All echocardiographic measurements obtained were within reference ranges. Between the groups, aortic root area (p = 0.009) and end-diastolic aortic dimension (p = 0.011) were significantly higher in the AM group at bEchoCG and sEchoCG, respectively. Within each group, values at bEchoCG and sEchoCG showed no significant differences, except for pulmonary peak velocity (0.85 m second-1; p = 0.028) in the AMK group and ejection time (154 m second; p = 0.03) in the AM group; both variables decreased after sedation. CONCLUSIONS AND CLINICAL RELEVANCE: In this population of healthy cats, neither protocol produced clinically meaningful effects on the echocardiographic variables evaluated. Alfaxalone with methadone produced mild sedation, whereas the addition of 1 mg kg-1 ketamine induced adequate sedation for diagnostic procedures.

Intraperitoneal Alfaxalone and Alfaxalone-Dexmedetomidine Anesthesia in Sprague-Dawley Rats (Rattus norvegicus).

Due to their unpredictability and variable effects, injectable anesthetic regimens in laboratory rodent species warrant refinement. In our study we sought to evaluate alfaxalone, which has gained recent popularity in veterinary medicine, alone and in combination with dexmedetomidine to evaluate their anesthetic ability in Sprague-Dawley rats when administered intraperitoneally. Three doses of alfaxalone only and 4 dose combinations of alfaxalone-dexmedetomidine were tested in males and female rats. The time to induction, anesthetic duration, pulse rate, respiratory rate, temperature, and time to recovery were recorded by a blind observer. The level of anesthesia induced by the various anesthetic protocols was assessed by using pedal withdrawal reflex to a noxious stimulus and scored according to the response. Dependent on the treatment group, atipamezole or saline was administered intraperitoneally once animals reached 60 min of anesthesia. Regardless of the dose, alfaxalone alone achieved only a sedative level of anesthesia, whereas all alfaxalone-dexmedetomidine combinations led to a surgical level of anesthesia in all animals. Anesthesia regimens using alfaxalone alone and in combination with dexmedetomidine demonstrated sex-associated differences, with female rats maintaining longer durations of sedation or anesthesia than their male counterparts. Both male and female rats displayed decreases in physiologic parameters consistent with the effects of dexmedetomidine. Given the results described herein, we recommend 20 mg/kg alfaxalone for sedation and 30 mg/kg alfaxalone combined with 0.05 mg/kg dexmedetomidine for surgical anesthesia in female rats. Appropriate doses of alfaxalone only and alfaxalone-dexmedetomidine for male rats were not determined in this study and need further evaluation.

Anesthetic agents affect urodynamic parameters and anesthetic depth at doses necessary to facilitate preclinical testing in felines.

Urodynamic studies, used to understand bladder function, diagnose bladder disease, and develop treatments for dysfunctions, are ideally performed with awake subjects. However, in small and medium-sized animal models, anesthesia is often required for these procedures and can be a research confounder. This study compared the effects of select survival agents (dexmedetomidine, alfaxalone, and propofol) on urodynamic (Δpressure, bladder capacity, bladder compliance, non-voiding contractions, bladder pressure slopes) and anesthetic (change in heart rate [∆HR], average heart rate [HR], reflexes, induction/recovery times) parameters in repeated cystometrograms across five adult male cats. The urodynamic parameters under isoflurane and α-chloralose were also examined in terminal procedures for four cats. Δpressure was greatest with propofol, bladder capacity was highest with α-chloralose, non-voiding contractions were greatest with α-chloralose. Propofol and dexmedetomidine had the highest bladder pressure slopes during the initial and final portions of the cystometrograms respectively. Cats progressed to a deeper plane of anesthesia (lower HR, smaller ΔHR, decreased reflexes) under dexmedetomidine, compared to propofol and alfaxalone. Time to induction was shortest with propofol, and time to recovery was shortest with dexmedetomidine. These agent-specific differences in urodynamic and anesthetic parameters in cats will facilitate appropriate study-specific anesthetic choices.

Anesthetic Effects of Intramuscular Alfaxalone-Ketamine in Naked Mole Rats (Heterocephalus glaber).

In this study, adult intact male and female (n = 10) naked mole rats (Heterocephalus glaber) were anesthetized by using a combination of ketamine (20 mg/kg IM), and alfaxalone (4.0 mg/kg IM). Induction and recovery times were recorded. Vital parameters, including heart rate, respiratory rate, and reflexes, were monitored every 5 min during the anesthetic period. Anesthetic induction was smooth and rapid. Induction time was significantly longer in male rats (median, 325 s; range, 180 to 385 s) than in females (median, 145 s; range, 118 to 180 s). In addition, overall duration of loss of righting reflex was shorter in male mole rats (median, 50 min; range, 36 to 65 min) than females (median, 70 min; range, 60 to 85 min). Males largely had intact withdrawal reflexes, whereas females showed variable loss of both forelimb and hindlimb withdrawal reflexes. Neither recovery time (mean ± 1 SD, 16 ± 13 min) nor vital parameters differed between sexes. None of animals showed any anesthesia-related adverse responses. According to these findings, intramuscular AK is a safe and effective protocol that provides brief, light anesthesia in male naked mole rats and deeper anesthesia in females. We recommend adding analgesics when this AK protocol is used for pain-inducing or invasive procedures, and further studies evaluating higher doses and different combinations are indicated.

Hypoventilation following oxygen administration associated with alfaxalone-dexmedetomidine-midazolam anesthesia in New Zealand White rabbits.

OBJECTIVE: To investigate the relationship between oxygen administration and ventilation in rabbits administered intramuscular alfaxalone-dexmedetomidine-midazolam. STUDY DESIGN: Prospective, randomized, blinded study. ANIMALS: A total of 25 New Zealand White rabbits, weighing 3.1-5.9 kg and aged 1 year. METHODS: Rabbits were anesthetized with intramuscular alfaxalone (4 mg kg-1), dexmedetomidine (0.1 mg kg-1) and midazolam (0.2 mg kg-1) and randomized to wait 5 (n = 8) or 10 (n = 8) minutes between drug injection and oxygen (100%) administration (facemask, 1 L minute-1). A control group (n = 9) was administered medical air 10 minutes after drug injection. Immediately before (PREoxy/air5/10) and 2 minutes after oxygen or medical air (POSToxy/air5/10), respiratory rate (fR), pH, PaCO2, PaO2, bicarbonate and base excess were recorded by an investigator blinded to treatment allocation. Data [median (range)] were analyzed with Wilcoxon, Mann-Whitney U and Kruskal-Wallis tests and p < 0.05 considered significant. RESULTS: Hypoxemia (PaO2 < 88 mmHg, 11.7 kPa) was observed at all PRE times: PREoxy5 [71 (61-81) mmHg, 9.5 (8.1-10.8) kPa], PREoxy10 [58 (36-80) mmHg, 7.7 (4.8-10.7) kPa] and PREair10 [48 (32-64) mmHg, 6.4 (4.3-8.5) kPa]. Hypoxemia persisted when breathing air: POSTair10 [49 (33-66) mmHg, 6.5 (4.4-8.8) kPa]. Oxygen administration corrected hypoxemia but was associated with decreased fR (>70%; p = 0.016, both groups) and hypercapnia (p = 0.016, both groups). Two rabbits (one per oxygen treatment group) were apneic (no thoracic movements for 2.0-2.5 minutes) following oxygen administration. fR was unchanged when breathing air (p = 0.5). PaCO2 was higher when breathing oxygen than air (p < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Early oxygen administration resolved anesthesia-induced hypoxemia; however, fR decreased and PaCO2 increased indicating that hypoxemic respiratory drive is an important contributor to ventilation using the studied drug combination.

Evaluation of anaesthetic and cardiorespiratory effects after intramuscular administration of alfaxalone alone, alfaxalone-ketamine and alfaxalone-butorphanol-medetomidine in common marmosets (Callithrix jacchus).

BACKGROUND: Anaesthesia is often required in common marmosets undergoing various procedures. The aim of this study was to evaluate anaesthetic and cardiopulmonary effects of alfaxalone, alfaxalone-ketamine and alfaxalone-butorphanol-medetomidine in common marmosets. METHODS: The following treatments were repeatedly administered to seven female common marmosets: Treatment A, alfaxalone (12 mg kg-1 ) alone; treatment AK, alfaxalone (1 mg animal-1 ) plus ketamine (2.5 mg animal-1 ); treatment AMB, alfaxalone (4 mg kg-1 ), medetomidine (50 µg kg-1 ) plus butorphanol (0.3 mg kg-1 ); and treatment AMB-Ati, AMB with atipamezole at 45 minutes. RESULTS AND CONCLUSIONS: Marmosets became laterally recumbent and unresponsive for approximately 30 minutes in A and AK and for approximately 60 minutes in AMB. The animals showed rapid recovery following atipamezole injection in AMB-Ati. The decrease in heart rate and SpO2 was significantly greater in AMB compared to A and AK. Oxygen supplementation, anaesthetic monitors and atipamezole should be available especially when AMB is administered.

A Comparison of the Efficacy and Cardiopulmonary Effects of 3 Different Sedation Protocols in Otolemur garnettii.

The Northern greater galago (Otolemur garnettii) is a prosimian primate most commonly used to study the evolutionary development of vision and somatosensation. This study aimed to investigate the efficacy and cardiopulmonary effects of 3 sedation protocols commonly used in other primate species: 1) alfaxalone (Alf; 8 mg/kg IM) 2) ketamine alone (Ket; 20 mg/kg IM) and 3) ketamine + dexmedetomidine (Ket+Dex; 4 mg/kg + 25 µg/kg IM) with reversal (atipamezole; 250 µg/kg IM). A total of 34 animals were evaluated, including 11 juveniles and 23 adults. Cardiopulmonary parameters such as indirect blood pressure, heart rate, respiratory rate, and SpO2 were measured, and blood was collected for blood gas analysis and a chemistry panel. To examine the efficacy of each sedation protocol, induction time, immobilization time, and recovery time were recorded. Subjective measures of quality and efficacy included quality of induction, pedal withdrawal reflex, palpebral reflex, muscle tension, rectal temperature, and quality of recovery. All 3 protocols successfully immobilized the animals and all animals recovered from sedation. Heart rates were highest among the Ket group and the lowest for the Ket+Dex group. On average, the Alf group was immobilized for twice as long as either the Ket or Ket+Dex groups. The Ket+Dex group had the fastest average recovery time and subjectively had the best quality of recovery. Based on these results, Ket+Dex is recommended over Alf or Ket alone for brief sedation of healthy galagos.

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.

EVALUATION OF TWO ANESTHETIC COMBINATIONS IN LOWLAND NYALA (TRAGELAPHUS ANGASII).

Fourteen lowland nyala (Tragelaphus angasii) in managed care were successfully anesthetized for a total of 17 anesthetic events using either a combination of butorphanol (0.75 ± 0.15 mg/kg), azaperone (0.25 ± 0.05 mg/kg), and medetomidine (0.30 ± 0.06 mg/kg) (BAM) or medetomidine (0.17 ± 0.01 mg/kg), azaperone (0.22 ± 0.02 mg/kg), and alfaxalone (0.52 ± 0.08 mg/kg) (MAA) delivered intramuscularly via dart. Mean time to initial effect, sternal recumbency, lateral recumbency, handling, and intubation were recorded. The nyala were maintained in sternal recumbency with supplemental oxygenation until 60 min after initial injection. Cardiopulmonary effects were recorded every 5 min after handling until reversal. Arterial blood samples were collected every 15 min for analysis. Level of sedation and quality of recovery were scored. Anesthesia was antagonized with atipamezole (at 5 mg per mg of medetomidine) for both protocols and naltrexone (at 2 mg per mg of butorphanol) for the BAM protocol delivered intramuscularly via hand injection. Mean time to extubation, head control, and standing post reversal were recorded. No hyperthermia, acidemia, apnea, or tachycardia occurred; however, animals did display hypoxemia. Two animals in the BAM cohort required supplementation to facilitate handling. These drug combinations provided satisfactory levels of sedation in most cases for safe handling and minor procedures in lowland nyala under managed care.

Sedative and physiological effects of alfaxalone intramuscular administration in cynomolgus monkeys (Macaca fascicularis).

To evaluate the sedative and physiological effects of alfaxalone intramuscular (IM) administration, 12 healthy cynomolgus monkeys were administered single IM doses of alfaxalone at 0.625 mg/kg (ALFX0.625), 1.25 mg/kg (ALFX1.25), 2.5 mg/kg (ALFX2.5), 5 mg/kg (ALFX5), 7.5 mg/kg (ALFX7.5), or 10 mg/kg (ALFX10); saline was used as the control (CONT). The sedative effects were subjectively evaluated using a composite measure scoring system in six animals. Changes in respiratory rate, pulse rate, non-invasive blood pressure, percutaneous oxygen-hemoglobin saturation (SpO2), and rectal temperature were observed after IM treatments in the other six animals. All animals were allowed to lay down following the ALFX5, ALFX7.5, and ALFX10 treatments, whereas lateral recumbency was achieved in only two animals after ALFX2.5 treatment and none after the CONT, ALFX 0.625, and ALFX1.25 treatments. The median time (interquartile range) to lateral recumbency was 6.5 min (5.3-7.8), 4.0 min (4.0-4.0), and 3.0 min (3.0-3.8), and the duration of immobilization was 27.5 min (19.0-33.8), 56.0 min (42.3-60.8), and 74.5 min (62.8-78.0) after the ALFX5, ALFX7.5, and ALFX10 treatments, respectively. Endotracheal intubation was achieved in all six animals after the ALFX7.5 and ALFX10 treatments. Dose-dependent decreases in respiratory rate, non-invasive blood pressure, SpO2, and rectal temperature were observed, and the quality of recovery was smooth in all animals after the ALFX5, ALFX7.5, and ALFX10 treatments. Thus, alfaxalone IM induced a dose-dependent sedative effect in cynomolgus monkeys, but at higher doses, hypotension, hypoxemia, and hypothermia could be induced.

Field immobilization using alfaxalone and alfaxalone-medetomidine in free-ranging koalas (Phascolarctos cinereus): a randomized comparative study.

OBJECTIVE: To characterize and compare two intramuscular drug protocols using alfaxalone and alfaxalone-medetomidine combination for the field immobilization of free-ranging koalas. STUDY DESIGN: Blinded, randomized, comparative field study. ANIMALS: A total of 66 free-ranging koalas from the Mount Lofty Ranges, South Australia. METHODS: Koalas were randomly allocated into two groups. Group A animals were given alfaxalone alone at 3.5 mg kg-1. Group AM animals were given alfaxalone 2 mg kg-1 and medetomidine 40 µg kg-1, reversed with atipamezole at 0.16 mg kg-1. Blinded operators recorded heart rate (HR), respiratory rate (fR), cloacal temperature, depth of sedation and times to: first effect, sedation suitable for clinical interventions, first arousal and full recovery. Data were analysed using independent t test, Mann-Whitney U test, chi-square analysis and log-rank test at 5% level of significance. RESULTS: Suitable immobilization for clinical examination and sample collection was achieved in all animals. In groups A and AM, median time to working depth was 6.5 minutes (range: 3.4-15) and 8.1 minutes (range: 4.3-24) and time to complete recovery was 66 minutes (range: 12-138) and 34 minutes (range: 4-84), respectively, following reversal. Time to first effect was significantly shorter in group A (p = 0.013), whereas time to full arousal was significantly shorter in group AM (p = 0.007) probably due to the administration of atipamezole. Maximum HR was 117 ± 28 beats minute-1 in group A, which was a significant increase from baseline values (p < 0.0001), whereas group AM showed a significant tachypnoea of 67 ± 25 (normal fR 10-15; p < 0.0001). CONCLUSIONS AND CLINICAL RELEVANCE: Both the protocols produced immobilization, enabling clinical examination and sample collection; however, protocol AM was more suitable for field work due to shorter recovery times.

Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABAA currents, but are not neurotoxic to the developing rat brain.

BACKGROUND: The most currently used general anaesthetics are potent potentiators of γ-aminobutyric acid A (GABAA) receptors and are invariably neurotoxic during the early stages of brain development in preclinical animal models. As causality between GABAA potentiation and anaesthetic-induced developmental neurotoxicity has not been established, the question remains whether GABAergic activity is crucial for promoting/enhancing neurotoxicity. Using the neurosteroid analogue, (3α,5α)-3-hydroxy-13,24-cyclo-18,21-dinorchol-22-en-24-ol (CDNC24), which potentiates recombinant GABAA receptors, we examined whether this potentiation is the driving force in inducing neurotoxicity during development. METHODS: The neurotoxic potential of CDNC24 was examined vis-à-vis propofol (2,6-diisopropylphenol) and alphaxalone (5α-pregnan-3α-ol-11,20-dione) at the peak of rat synaptogenesis. In addition to the morphological neurotoxicity studies of the subiculum and medial prefrontal cortex (mPFC), we assessed the extra-, pre-, and postsynaptic effects of these agents on GABAergic neurotransmission in acute subicular slices from rat pups. RESULTS: CDNC24, like alphaxalone and propofol, caused dose-dependent hypnosis in vivo, with a higher therapeutic index. CDNC24 and alphaxalone, unlike propofol, did not cause developmental neuroapoptosis in the subiculum and mPFC. Propofol potentiated post- and extrasynaptic GABAA currents as evidenced by increased spontaneous inhibitory postsynaptic current (sIPSC) decay time and prominent tonic currents, respectively. CDNC24 and alphaxalone had a similar postsynaptic effect, but also displayed a strong presynaptic effect as evidenced by decreased frequency of sIPSCs and induced moderate tonic currents. CONCLUSIONS: The lack of neurotoxicity of CDNC24 and alphaxalone may be at least partly related to suppression of presynaptic GABA release in the developing brain.