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 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.

Sedative and cardiorespiratory effects of intranasal atomized alfaxalone in Japanese White rabbits.

OBJECTIVE: To investigate the sedative and cardiorespiratory effects of intranasal atomization (INA) of alfaxalone using a mucosal atomization device in Japanese White rabbits. STUDY DESIGN: Randomized, prospective, crossover study. ANIMALS: A total of eight healthy female rabbits, weighing 3.6-4.3 kg and aged 12-24 months. METHODS: Each rabbit was randomly assigned to four INA treatments administered 7 days apart: Control treatment, 0.15 mL 0.9% saline in both nostrils; treatment INA0.3, 0.15 mL 4% alfaxalone in both nostrils; treatment INA0.6, 0.3 mL 4% alfaxalone in both nostrils; treatment INA0.9, 0.3 mL 4% alfaxalone in left, then right, then left nostril. Sedation was scored 0-13 using a composite measure scoring system for rabbits. Simultaneously, pulse rate (PR), respiratory rate (fR), noninvasive mean arterial pressure (MAP), peripheral hemoglobin oxygen saturation (SpO2) and arterial blood gases were measured until 120 minutes. The rabbits breathed room air during the experiment and were administered flow-by oxygen when hypoxemia (SpO2 <90% or PaO2 <60 mmHg; 8.0 kPa) developed. Data were analyzed using the Fisher's exact test and the Friedman test (p < 0.05). RESULTS: No rabbit was sedated in treatments Control and INA0.3. All rabbits in treatment INA0.9 developed loss of righting reflex for 15 (10-20) minutes [median (25th-75th percentile)]. Sedation score significantly increased from 5 to 30 minutes in treatments INA0.6 and INA0.9 with maximum scores of 2 (1-4) and 9 (9-9), respectively. fR decreased in an alfaxalone dose-dependent manner and one rabbit developed hypoxemia in treatment INA0.9. No significant changes were observed in PR and MAP. CONCLUSIONS AND CLINICAL RELEVANCE: INA alfaxalone resulted in dose-dependent sedation and respiratory depression in Japanese White rabbits to values considered not clinically relevant. Further investigation of INA alfaxalone in combination with other drugs is warranted.

Comparison of two formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish (Daniorerio).

OBJECTIVE: To compare two commercial formulations of alfaxalone for immersion anaesthesia in laboratory zebrafish. STUDY DESIGN: Prospective, blinded, randomized study. ANIMALS: A total of 20 adult Danio rerio (Tuebingen strain). METHODS: Zebrafish were divided into two groups of 10 (five female, five male) and placed in individual immersion baths containing 10 mg L-1 of unpreserved alfaxalone (group 1) or preserved alfaxalone (group 2). Anaesthetists blinded to treatment used a composite score scale (CSS) (range 0-12) to assess fish every 30 seconds until induction of anaesthesia. Anaesthetic induction occurred when equilibrium and response to stimulus were lost. Fish were then placed in a clean water bath and scored every 60 seconds. Recovery from anaesthesia was defined as a CSS of ≤ 1. Time variables recorded were anaesthetic induction time (AIT), anaesthetic recovery time (ART) and total procedure time (TPT). Fish were observed for evidence of roupgross external pathology during the procedure. Following anaesthesia, four fish from each group were randomly chosen and euthanized for gill histopathology analysis immediately after recovery criteria were met. Data are presented as mean ± standard deviation. An independent t test was used to compare the difference in average anaesthetic time variables between groups (α = 0.05). RESULTS: There were no statistical differences between groups in reported variables. TPT, AIT and ART were 10.2 ± 1.2, 1.9 ± 0.9 and 8.3 ± 1.2 minutes for group 1 and 10.8 ± 2.9, 2.4 ± 1.2 and 8.4 ± 2.7 minutes for group 2. No gross external pathology was evident, and no fish died during the experimental period. Histopathology showed normal gill pathology and no difference between the groups. CONCLUSIONS AND CLINICAL RELEVANCE: Immersion anaesthesia using 10 mg L-1 of either formulation of alfaxalone resulted in anaesthesia of similar quality and duration.

Evaluation of alfaxalone total intravenous anesthesia in rabbits (Oryctolagus cuniculus) premedicated with dexmedetomidine or dexmedetomidine and buprenorphine.

OBJECTIVE: To evaluate alfaxalone for total intravenous anesthesia (TIVA) in rabbits premedicated with dexmedetomidine or dexmedetomidine and buprenorphine. STUDY DESIGN: Crossover study (part 1) with observational study (part 2). ANIMALS: A total of eight New Zealand White rabbits (Oryctolagus cuniculus), four female and four male, aged 12-16 weeks and weighing 2.8-3.5 kg in part 1. Separately, four additional rabbits in part 2. METHODS: Crossover study design with eight rabbits per treatment. Rabbits were administered treatment D, dexmedetomidine (0.2 mg kg-1), or treatment DB, dexmedetomidine (0.1 mg kg-1) and buprenorphine (0.05 mg kg-1) intramuscularly. Anesthesia was induced with alfaxalone intravenously until a supraglottic airway device was placed to deliver 100% oxygen. Anesthesia was maintained with alfaxalone (TIVA). Infusion rates were adjusted to achieve an absent pedal withdrawal reflex. Heart rate, respiratory rate, noninvasive blood pressure, end-tidal carbon dioxide partial pressure and peripheral hemoglobin oxygen saturation (SpO2) were recorded every 5 minutes. Subsequently, four rabbits underwent ovariohysterectomy using treatment DB and alfaxalone TIVA. RESULTS: The mean ± standard deviation alfaxalone infusion rate was 9.6 ± 2.6 and 4.5 ± 1.3 mg kg-1 hour-1 for treatments D and DB, respectively. In both treatments, blood pressure remained within acceptable range and SpO2 was > 95%. Postinduction apnea and respiratory depression were observed in both treatments and managed with manual positive pressure ventilation. Four separate rabbits underwent successful ovariohysterectomy with treatment DB and alfaxalone TIVA. One rabbit required supplementation with inhalant anesthesia; three rabbits were successfully maintained using alfaxalone TIVA alone. CONCLUSIONS AND CLINICAL RELEVANCE: Premedication with dexmedetomidine-buprenorphine combined with alfaxalone TIVA may be a viable alternative for performing abdominal surgery in the rabbit. The use of supplemental oxygen and ability to provide respiratory support are advised.

The utility of a novel formulation of alfaxalone in a remote delivery system.

OBJECTIVE: To quantify induction time, reliability, physiological effects, recovery quality and dart volume of a novel formulation of alfaxalone (40 mg mL-1) used in combination with medetomidine and azaperone for the capture and handling of wild bighorn sheep. STUDY DESIGN: Prospective clinical study. ANIMALS: A total of 23 wild bighorn sheep (Ovis canadensis) in Sheep River Provincial Park, AB, Canada. METHODS: Free-ranging bighorn sheep were immobilized using medetomidine, azaperone and alfaxalone delivered with a remote delivery system. Arterial blood was collected for measurement of blood gases, physiologic variables (temperature, heart and respiratory rates) were recorded and induction and recovery length and quality were scored. RESULTS: Data from 20 animals were included. Administered dose rates were alfaxalone (0.99 ± 0.20 mg kg-1; 40 mg mL-1), azaperone (0.2 ± 0.04 mg kg-1; 10 mg mL-1) and medetomidine (0.16 ± 0.03 mg kg-1; 30 mg mL-1). The mean drug volume injected was 1.51 mL. The median (range) induction time was 7.7 (5.8-9.7) minutes, and recovery was qualitatively smooth. CONCLUSIONS AND CLINICAL RELEVANCE: An increased concentration formulation of alfaxalone was administered in combination with medetomidine and azaperone, and resulted in appropriate anesthesia for the capture and handling of bighorn sheep. The dart volume was small, with potential for reducing capture-related morbidity.

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.

Hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats.

OBJECTIVE: To characterize the hemodynamic effects of subclinical, clinical and supraclinical plasma alfaxalone concentrations in cats. STUDY DESIGN: Experimental study. ANIMALS: A group of six adult healthy male neutered cats. METHODS: Cats were anesthetized with desflurane in oxygen for instrumentation. Catheters were placed in a medial saphenous vein for drug administration and in a carotid artery for arterial blood pressure measurement and blood collection. A thermodilution catheter was placed in the pulmonary artery via an introducer placed in a jugular vein for measurement of central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, cardiac output and core body temperature, and for sampling mixed venous blood. A lead II electrocardiogram was connected. Desflurane administration was discontinued and a target-controlled infusion system was used to administer alfaxalone to reach six plasma alfaxalone concentrations ranging from 1.0 to 30.4 mg L-1, with 7.6 mg L-1 considered a clinical concentration for anesthesia. Cardiovascular measurements were recorded, and arterial and mixed-venous blood samples were collected for blood-gas analysis and plasma alfaxalone concentration measurement at each target concentration. Data were analyzed using a repeated-measures analysis of variance and Dunnett's test for comparisons to the lowest target concentration. Significance was set at p < 0.05. RESULTS: Mean ± standard deviation plasma alfaxalone concentrations were 0.73 ± 0.32, 1.42 ± 0.41, 3.44 ± 0.40, 6.56 ± 0.43, 18.88 ± 6.81 and 49.47 ± 5.50 mg L-1 for the 1, 1.9, 3.8, 7.6, 15.2, and 30.4 mg L-1 target concentrations, respectively. PaCO2 increased with increasing target plasma alfaxalone concentrations and was 69.4 ± 14.2 mmHg (9.3 ± 1.9 kPa) at the 30.4 mg L-1 target. Some cardiovascular variables were statistically significantly affected by increasing target plasma alfaxalone concentrations. CONCLUSION AND CLINICAL RELEVANCE: Within the plasma concentration range studied, alfaxalone caused hypoventilation, but the cardiovascular effects were of small clinical significance.

Alfaxalone for total intravenous anaesthesia in horses.

OBJECTIVE: To determine the suitability of alfaxalone total intravenous (IV) anaesthesia in horses and concurrently evaluate infusion rates, cardiovascular effects, pharmacokinetics and the quality of the anaesthetic recovery period. STUDY DESIGN: Prospective, experimental study. ANIMALS: Eight Standardbred horses. METHODS: Horses were premedicated with IV acepromazine (0.03 mg kg-1) and xylazine (1 mg kg-1) and anaesthesia was induced with guaifenesin (35 mg kg-1) and alfaxalone (1 mg kg-1). Anaesthesia was maintained for 180 minutes using an IV infusion of alfaxalone at a rate determined by a horse's response to a supramaximal electrical noxious stimulus. Venous blood samples were regularly collected to determine alfaxalone plasma concentrations and for pharmacokinetic analysis. Cardiopulmonary variables were monitored and the quality of the anaesthetic recovery period scored. RESULTS: The median (range) alfaxalone infusion rate was 3.1 (2.4-4.3) mg kg-1 hour-1. The mean ± standard deviation plasma elimination half-life, plasma clearance and volume of distribution for alfaxalone were 41 minutes, 25 ± 6.3 mL minute-1 kg-1 and 1.6 ± 0.5 L kg-1, respectively. During anaesthesia, mean arterial blood pressure was maintained above 70 mmHg in all horses. Cardiac index reached a minimum value (68% of baseline values) immediately after induction of anaesthesia and was maintained between 74% and 90% of baseline values for the remainder of the anaesthetic protocol. Following the cessation of the alfaxalone infusion, six of eight horses exhibited muscle tremors and paddling. All horses stood without incident on the first or second attempt with a median recovery score of 4.5 (good to excellent). CONCLUSIONS AND CLINICAL RELEVANCE: Anaesthesia in horses can be maintained with an infusion of alfaxalone at approximately 3 mg kg-1 hour-1. The alfaxalone infusion rates used resulted in minimal haemodynamic changes and good recovery quality. Mean alfaxalone plasma concentration was stable over the infusion period and clearance rates were similar to previously published single-dose alfaxalone studies in horses.

Effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone preventing movement in dogs.

OBJECTIVE: To determine the effect of fentanyl on the induction dose and minimum infusion rate of alfaxalone required to prevent movement in response to a noxious stimulus (MIRNM) in dogs. STUDY DESIGN: Experimental crossover design. ANIMALS: A group of six healthy, adult, intact female mixed-breed dogs, weighing 19.7 ± 1.3 kg. METHODS: Dogs were randomly administered one of three treatments at weekly intervals: premedication with 0.9% saline (treatment A), fentanyl 5 µg kg-1 (treatment ALF) or fentanyl 10 µg kg-1 (treatment AHF), administered intravenously over 5 minutes. Anesthesia was induced 5 minutes later with incremental doses of alfaxalone to achieve intubation and was maintained for 90 minutes in A with alfaxalone (0.12 mg kg-1 minute-1), in ALF with alfaxalone (0.09 mg kg-1 minute-1) and fentanyl (0.1 µg kg-1 minute-1) and in AHF with alfaxalone (0.06 mg kg-1 minute-1) and fentanyl (0.2 µg kg-1 minute-1). The alfaxalone infusion was increased or decreased by 0.006 mg kg-1 minute-1 based on positive or negative response to antebrachium stimulation (50 V, 50 Hz, 10 ms). Data were analyzed using a mixed-model anova and presented as least squares means ± standard error. RESULTS: Alfaxalone induction doses were 3.50 ± 0.13 (A), 2.17 ± 0.10 (ALF) and 1.67 ± 0.10 mg kg-1 (AHF) and differed among treatments (p < 0.05). Alfaxalone MIRNM was 0.17 ± 0.01 (A), 0.10 ± 0.01 (ALF) and 0.07 ± 0.01 mg kg-1 minute-1 (AHF) and differed among treatments. ALF and AHF decreased the MIRNM by 44 ± 8% and 62 ± 5%, respectively (p < 0.05). Plasma alfaxalone concentrations at MIRNM were 5.82 ± 0.48 (A), 4.40 ± 0.34 (ALF) and 2.28 ± 0.09 µg mL-1 (AHF). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, significantly decreased the alfaxalone induction dose and MIRNM.

Pharmacokinetics of alfaxalone infusions, context-sensitive half-time and recovery times in male neutered cats.

OBJECTIVES: To determine the context-sensitive half-time of alfaxalone following intravenous infusions of various durations. To estimate the time necessary for plasma concentration to decrease by up to 95%. STUDY DESIGN: Prospective randomized and simulation studies. ANIMALS: A group of six 1-year-old male castrated research cats. METHODS: Cats were instrumented with catheters in a jugular and a medial saphenous vein. Alfaxalone was administered using a target-controlled infusion system, to target a plasma alfaxalone concentration of 7.6 mg L-1. The infusion lasted 30 (n = 2), 60 (n = 2) or 240 (n = 2) minutes. Blood samples were collected prior to drug administration, and at several times during and up to 8 hours after the infusion, for the determination of plasma alfaxalone concentration using liquid chromatography/tandem mass spectrometry. Compartment models were fitted to each time-concentration profile, and a population model was fitted to data from all individuals. The context-sensitive half-time was determined from each individual model. In addition, times for plasma alfaxalone concentration to decrease by 50-95% following bolus administration and target-controlled infusions or continuous rate infusions of 0.5-8 hours were estimated by simulation using the population model. RESULTS: Context-sensitive half-times were 2 and 8, 6 and 9, and 18 and 20 minutes for the 30, 60 and 240 minutes, respectively. Time for plasma alfaxalone concentration to decrease by 90% was predicted to range from 7 to 120 or 113 minutes following a bolus to an 8 hour target-controlled or continuous rate infusion, respectively. CONCLUSION AND CLINICAL RELEVANCE: Recovery time from alfaxalone anesthesia in cats is predicted to be influenced by the duration of target-controlled infusion.

Comparison of two intravenous anesthetic infusion regimens for alfaxalone in cats.

OBJECTIVE: To compare the performance of an alfaxalone constant rate intravenous (IV) infusion versus a 3-step IV infusion, both following a loading dose, for the maintenance of a target plasma alfaxalone concentration of 7.6 mg L-1 (effective plasma alfaxalone concentration for immobility in 99% of the population) in cats. STUDY DESIGN: Prospective randomized crossover study. ANIMALS: A group of six healthy, adult male neutered cats. METHODS: Catheters were placed in a jugular vein for blood sampling and in a medial saphenous vein for drug administration. An IV bolus of alfaxalone (2 mg kg-1) was administered, followed by either 0.2 mg kg-1 minute-1 for 240 minutes (single infusion; SI) or 0.4 mg kg-1 minute-1 for 10 minutes, then 0.3 mg kg-1 minute-1 for 30 minutes, and then 0.2 mg kg-1 minute-1 for 200 minutes (3-step infusion; 3-step). Plasma alfaxalone concentration was measured at six time points during the infusions. Measures of performance were calculated for each infusion regimen and compared using the paired Wilcoxon signed-rank test. RESULTS: Median (range) absolute performance error, divergence, median prediction error and wobble were 15 (8-19)%, -8 (-12 to -6)% hour-1, -12 (-19 to -7)% and 10 (8-19)%, respectively, in the SI treatment, and 6 (2-16)%, 0 (-13 to 2)% hour-1, 1 (-16 to 4)% and 4 (3-6)% respectively, in the 3-step treatment and were significantly smaller in the 3-step treatment than in the SI treatment. CONCLUSION AND CLINICAL RELEVANCE: After IV administration of a bolus dose, a 3-step infusion regimen can better maintain stable plasma alfaxalone concentrations close to the target concentration than a single constant rate infusion.

Effects of isoflurane, sevoflurane, propofol and alfaxalone on brain metabolism in dogs assessed by proton magnetic resonance spectroscopy (1H MRS).

BACKGROUND: The purpose of this study was to determine the effects of isoflurane, sevoflurane, propofol and alfaxalone on the canine brain metabolite bioprofile, measured with single voxel short echo time proton magnetic resonance spectroscopy at 3 Tesla. Ten adult healthy Beagle dogs were assigned to receive isoflurane, sevoflurane, propofol and alfaxalone at 3 different dose rates each in a randomized cross-over study design. Doses for isoflurane, sevoflurane, propofol and alfaxalone were FE'Iso 1.7 vol%, 2.1 vol%, 2.8 vol%, FE'Sevo 2.8 vol%, 3.5 vol% and 4.7 vol%, 30, 45 and 60 mg kg- 1 h- 1 and 10, 15 and 20 mg kg- 1 h- 1 respectively. A single voxel Point Resolved Spectroscopy Sequence was performed on a 3 T MRI scanner in three brain regions (basal ganglia, parietal and occipital lobes). Spectral data were analyzed with LCModel. Concentration of total N-acetylaspartate (tNAA), choline, creatine, inositol and glutamine and glutamate complex (Glx) relative to water content was obtained. Plasma concentration of lactate, glucose, triglycerides, propofol and alfaxalone were determined. Statistics were performed using repeated measures ANOVA or Wilcoxon Sign Rank test with alpha = 5%. RESULTS: Plasma glucose increased with isoflurane, sevoflurane and alfaxalone but decreased with propofol. Plasma lactate increased with all anesthetics (isoflurane > sevoflurane > propofol > alfaxalone). Cerebral lactate could not be detected. Only minor changes in cerebral metabolite concentrations of tNAA, choline, inositol, creatine and Glx occurred with anesthetic dose changes. CONCLUSION: The metabolomic profile detected with proton magnetic resonance spectroscopy at 3 Tesla of canine brain showed only minor differences between doses and anesthetics related to tNAA, choline, creatine, inositol and Glx.

Effective plasma alfaxalone concentration to produce immobility in male neutered cats.

OBJECTIVE: To determine the effective plasma alfaxalone concentration for the production of immobility in cats. STUDY DESIGN: Prospective up-and-down study. ANIMALS: Sixteen 1-2 year old male castrated research cats. METHODS: Cats were instrumented with catheters in a jugular and a medial saphenous vein. Alfaxalone was administered via the medial saphenous catheter, using a target-controlled infusion system. The infusion lasted for approximately 32 minutes. A noxious stimulus (tail clamp) was applied 30 minutes after starting the alfaxalone infusion, until the cat moved or 60 seconds had elapsed, whichever occurred first. The target alfaxalone concentration was set at 5 mg L-1 in the first cat and increased or decreased by 1 mg L-1 in subsequent cats, if the previous cat had moved or not moved in response to stimulation, respectively. This was continued until six independent crossovers (different responses in pairs of subsequent cats) had been observed. Blood samples were collected before alfaxalone administration, and 15 and 31 minutes after starting the administration, for the determination of plasma alfaxalone concentration using liquid chromatography/tandem mass spectrometry. The alfaxalone concentration yielding a probability of immobility in 50% (EC50), 95% (EC95) and 99% (EC99) of the population, and their respective 95% Wald confidence intervals were calculated. RESULTS: The EC50, EC95 and EC99 for alfaxalone-induced immobility were 3.7 (2.4-4.9), 6.2 (4.7-) and 7.6 (5.5-) mg L-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The effective plasma alfaxalone concentration for immobility in cats was determined. This value will help in the design of pharmacokinetic-based dosing regimens.

The pharmacological effects of intramuscular administration of alfaxalone combined with medetomidine and butorphanol in dogs.

The pharmacological effects of intramuscular (IM) administration of alfaxalone combined with medetomidine and butorphanol were evaluated in 6 healthy beagle dogs. Each dog received three treatments with a minimum 10-day interval between treatments. The dogs received an IM injection of alfaxalone 2.5 mg/kg (ALFX), medetomidine 2.5 µg/kg and butorphanol 0.25 mg/kg (MB), or their combination (MBA) 1 hr after the recovery from their instrumentation. Endotracheal intubation was attempted, and dogs were allowed to breath room air. Neuro-depressive effects (behavior changes and subjective scores) and cardiorespiratory parameters (rectal temperature, heart rate, respiratory rate, direct blood pressure, central venous pressure and blood gases) were evaluated before and at 2 to 120 min after IM treatment. Each dog became lateral recumbency, except for two dogs administered the MB treatment. The duration was longer in the MBA treatment compared with the ALFX treatment (100 ± 48 min vs 46 ± 13 min). Maintenance of the endotracheal tube lasted for 60 ± 24 min in five dogs administered the MBA treatment and for 20 min in one dog administered the ALFX treatment. Cardiorespiratory variables were maintained within clinically acceptable ranges, although decreases in heart and respiratory rates, and increases in central venous pressure occurred after the MBA and MB treatments. The MBA treatment provided an anesthetic effect that permitted endotracheal intubation without severe cardiorespiratory depression in healthy dogs.

Sedative effects of intramuscular alfaxalone administered to cats.

The sedative effects of intramuscular (IM) alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (alfaxalone-HPCD) were evaluated in cats. The cats were treated with alfaxalone-HPCD in five occasions with a minimum 14-day interval between treatments: an IM injection of 1.0 mg/kg (IM1), 2.5 mg/kg (IM2.5), 5 mg/kg (IM5) or 10 mg/kg (IM10), or an intravenous injection of 5 mg/kg (IV5). The sedative effects were evaluated subjectively using a composite measurement scoring system (a maximum score of 16). Cardio-respiratory variables were measured non-invasively. The median sedation scores peaked at 10 min (score 9), 15 min (score 14), 10 min (score 16), 10 to 20 min (score 16) and 2 to 5 min (score 16) after the IM1, IM2.5, IM5, IM10 and IV5 treatments, respectively. The IM5 treatment produced longer lasting sedation, compared to the IV5 treatment. Durations of maintenance of lateral recumbency after the IM10 treatment (115 ± 22 min) were longer than those after the IM2.5 (40 ± 15 min), IM5 (76 ± 21 min) and IV5 treatments (50 ± 5 min). Cardio-respiratory variables remained within clinically acceptable ranges, except for each one cat that showed hypotension (<60 mmHg) after the IM10 and IV5 treatments. Tremors, ataxia and opisthotonus-like posture were observed during the early recovery period after the IM2.5, IM5, IM10 and IV5 treatments. In conclusion, IM alfaxalone-HPCD produced dose-dependent and clinically relevant sedative effect at 2.5 to 10 mg/kg in healthy cats. Hypotension may occur at higher IM doses of alfaxalone-HPCD.

The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs.

The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone.

Clinical evaluation of alfaxalone to induce and maintain anaesthesia in cats undergoing neutering procedures.

This study looked at the use and efficacy of alfaxalone for total intravenous anaesthesia (TIVA) in cats. Following intramuscular medetomidine (20 µg/kg) and morphine (0.3 mg/kg) premedication, anaesthesia was induced and maintained with intravenous alfaxalone. Patients were breathing 100% oxygen. Heart rate (HR), respiratory rate (RR), end-tidal carbon dioxide, oxygen saturation of haemoglobin and indirect arterial blood pressure via Doppler (DAP) were recorded every 5 mins. Thirty-four cats (10 males and 24 females), between the age of 6 and 18 months, and weighing between 1.8 and 5.3 kg, and undergoing neutering procedures were included in this study. The results are presented as median (min, max) values. The time to first spontaneous movement (TS) was >30 mins in 19 cats, of which 12 received atipamezole for reversal of the effects of medetomidine. The TS was 53 (43, 130) mins in these 12 cats and 50 (40, 72) mins in the other seven cats. The body temperature in those 19 cats was significantly lower than the other cats (P = 0.05). The alfaxalone induction dose and maintenance infusion rate were1.7 (0.7, 3.0) mg/kg and 0.18 (0.06, 0.25) mg/kg/min, respectively. The HR, RR and DAP were 145 (68, 235) beats/min, 17 (5, 40) breaths/min and 110 (58, 210) mmHg, respectively. Apnoea was not observed in any cat. In conclusion, alfaxalone TIVA in combination with medetomidine and morphine premedication was effective in feral and domestic cats for the performance of neutering surgery; low body temperature might have resulted in longer recoveries in some cats.

Plasma pharmacokinetics and pharmacodynamics of alfaxalone in neonatal foals after an intravenous bolus of alfaxalone following premedication with butorphanol tartrate.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroid anaesthetic, alfaxalone, in neonatal foals after a single intravenous (IV) injection of alfaxalone following premedication with butorphanol tartrate. STUDY DESIGN: Prospective experimental study. ANIMALS: Five clinically healthy Australian Stock Horse foals of mean ± SD age of 12 ± 3 days and weighing 67.3 ± 12.4 kg. METHODS: Foals were premedicated with butorphanol (0.05 mg kg(-1) IV) and anaesthesia was induced 10 minutes later by IV injection with alfaxalone 3 mg kg(-1) . Cardiorespiratory variables (pulse rate, respiratory rate, direct arterial blood pressure, arterial blood gases) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and alfaxalone plasma concentrations were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. RESULTS: The harmonic, mean ± SD plasma elimination half life (t½) for alfaxalone was 22.8 ± 5.2 minutes. The observed mean plasma clearance (Cl(p) ) and volume of distribution (Vd) were 19.9 ± 5.9 mL minute kg(-1) and 0.6 ± 0.2 L kg(-1) , respectively. Overall, the quality of the anaesthetic inductions and recoveries was good and most monitored physiological variables were clinically acceptable in all foals, although some foals became hypoxaemic for a short period following recumbency. The mean durations of anaesthesia from induction to first movement and from induction to standing were 18.7 ± 7 and 37.2 ± 4.7 minutes, respectively. CONCLUSIONS: The anaesthetic protocol used provided a predictable and consistent plane of anaesthesia in the five foals studied, with minimal cardiovascular depression. In foals, as in the adult horse, alfaxalone has a short elimination half life. CLINICAL RELEVANCE: Alfaxalone appears to be an adequate anaesthetic induction agent in foals and the pharmacokinetics suggest that, with continuous infusion, it might be suitable to provide more prolonged anaesthesia. Oxygen supplementation is recommended.

The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of the neurosteroidal anaesthetic, alfaxalone, in horses after a single intravenous (IV) injection of alfaxalone, following premedication with acepromazine, xylazine and guaiphenesin. STUDY DESIGN: Prospective experimental study. ANIMALS: Ten (five male and five female), adult, healthy, Standardbred horses. METHODS: Horses were premedicated with acepromazine (0.03 mg kg(-1) IV). Twenty minutes later they received xylazine (1 mg kg(-1) IV), then after 5 minutes, guaiphenesin (35 mg kg(-1) IV) followed immediately by IV induction of anaesthesia with alfaxalone (1 mg kg(-1) ). Cardiorespiratory variables (pulse rate, respiratory rate, pulse oximetry) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Venous blood samples were collected at strategic time points and plasma concentrations of alfaxalone were assayed using liquid chromatography-mass spectrometry (LC/MS) and analysed by noncompartmental pharmacokinetic analysis. The quality of anaesthetic induction and recovery was scored on a scale of 1-5 (1 very poor, 5 excellent). RESULTS: The median (range) induction and recovery scores were 4 (3-5) (good: horse slowly and moderately gently attained recumbency with minimal or no rigidity or paddling) and 4 (1-5) (good: horse stood on first attempt with some knuckling and ataxia) respectively. The monitored cardiopulmonary variables were within the range expected for clinical equine anaesthesia. The mean ± SD durations of anaesthesia from induction to sternal recumbency and from induction to standing were 42.7 ± 8.4 and 47 ± 9.6 minutes, respectively. The mean ± SD plasma elimination half life (t(1/2) ), plasma clearance (Clp) and volume of distribution (V(d) ) for alfaxalone were 33.4 minutes, 37.1 ± 11.1 mL minute(-1) kg(-1) and 1.6 ± 0.4 L kg(-1) , respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone, in a 2-hydroxypropyl-beta-cyclodextrin formulation, provides anaesthesia with a short duration of recumbency that is characterised by a smooth induction and satisfactory recovery in the horse. As in other species, alfaxalone is rapidly cleared from the plasma in the horse.