The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats

ObjectiveTo determine the cardiorespiratory and anesthetic effects of 0, 5, 15, and 50 mg kg^?1 intravenous (IV) alfaxalone in hydroxypropyl beta cyclodextrin (Alfaxan; Jurox Pty Ltd, Rutherford, NSW, Australia) in cats.Study designFour treatments of alfaxalone were administered in sequential order.AnimalsEight healthy adult cats (four male; four female) weighing between 3.71 and 5.91 kg.MethodsCats were instrumented for hemodynamic measurements. Four (0, 5, 15, and 50 mg kg^?1) IV doses of alfaxalone were administered over one minute, with a 3-hour washout period between doses 0, 5, and 15 mg kg^?1 on Day 0. The 50 mg kg^?1 treatment was administered 24 hours later. Measurements of heart rate, aortic systolic, mean, and diastolic blood pressures, pulmonary arterial and right atrial mean pressures, cardiac output, respiratory rate, tidal and minute volumes, and arterial blood pH and blood gases (PaO₂, PaCO₂) were performed at pre-determined intervals. Systemic vascular resistance and rate pressure product were calculated. The quality of induction, maintenance, and recovery from anesthesia and the response to noxious stimulation were categorically scored.ResultsAlfaxalone administration resulted in dose-dependent cardiorespiratory depression. Decreases in arterial blood pressure and increases in heart rate occurred at higher doses. Most variables returned to baseline by 15-30 minutes. Respiratory rate, minute volume, and PaO₂ decreased. Apnea was the most common side effect. Induction and maintenance quality were judged to be good to excellent at all doses and quality of recovery good to excellent at all but the 50 mg kg^?1 dose. The duration of anesthesia and unresponsiveness to noxious stimulation increased with dose. The administration of the 50 mg kg^?1 dose produced marked cardiorespiratory depression and apnea.Conclusions and clinical relevanceAlfaxalone produced dose-dependent anesthesia, cardiorespiratory depression and unresponsiveness to noxious stimulation in unpremedicated cats. Hypoventilation and apnea were the most common side effects.     

Cardiorespiratory and anesthetic effects produced by the combination of butorphanol,medetomidine and alfaxalone administered intramuscularly in Beagle dogs

This study evaluated anesthesia quality, degree of analgesia and cardiorespiratory parameters after intramuscular (IM) injection of a combination of butorphanol (0.1 mg/kg), medetomidine (10 µg/kg) and alfaxalone (1.5 mg/kg) in ten healthy adult Beagle dogs. Rectal temperature (T), heart rate (HR), respiratory rate (f_R), arterial pressure, arterial blood gases and M-mode echocardiographic left ventricular (LV) indices were measured before drug administration and every 10 min thereafter until extubation. Mean duration of anesthesia, recovery and analgesia were 89 ± 17, 6 ± 1 and 80 ± 12 min. HR, f_R, partial pressure of arterial CO₂ and O₂, arterial pressure, and LV contractility were significantly altered during anesthesia. IM administration of the drug combination provided acceptable anesthesia, but produced substantial cardiorespiratory suppression.     

Cardiopulmonary and anesthetic effects of the combination of butorphanol,midazolam and alfaxalone in Beagle dogs

ObjectiveTo evaluate the physiological variables, arterial blood gas values, induction of anesthesia quality, and recovery quality using the combination of butorphanol, midazolam and alfaxalone in dogs.AnimalsTen healthy adult Beagle dogs weighing 8.3 ± 3.1 kg.MethodsRectal temperature (T), pulse rate (PR), respiratory rate (f_R), mean arterial pressure (MAP), and arterial blood gases were measured and recorded prior to intravenous (IV) administration of butorphanol, prior to administration of both midazolam and alfaxalone IV 10 minutes later, then every 5 minutes for 20 minutes. M-mode echocardiographic left ventricular (LV) indices were measured before and 5 minutes after administration of alfaxalone. Qualitative scores for induction of anesthesia and recovery were allocated, duration of anesthesia and recovery were calculated, and adverse events were recorded.ResultsScores for induction and recovery quality were excellent. No significant adverse events were observed. Mean ± SD time from induction to extubation and to standing (full recovery) was 29 ± 6 and 36 ± 8 minutes, respectively. There were statistically significant changes in PR, f_R and MAP after drug administration. Transient hypercarbia developed after alfaxalone injection. The echocardiographic LV indices were reduced after alfaxalone injection, although those changes were not statistically significant.Conclusions and clinical relevanceThe combination of butorphanol, midazolam and alfaxalone provided excellent quality of induction of anesthesia and exerted minimal cardiopulmonary effects in healthy dogs.     

A comparison of cardiopulmonary and anesthetic effects of an induction dose of alfaxalone or propofol in dogs

ObjectiveTo compare the physiological parameters, arterial blood gas values, induction quality, and recovery quality after IV injection of alfaxalone or propofol in dogs.Study designProspective, randomized, blinded crossover.AnimalsEight random-source adult female mixed-breed dogs weighing 18.7 ± 4.5 kg.MethodsDogs were assigned to receive up to 8 mg kg^?1 propofol or 4 mg kg^?1 alfaxalone, administered to effect, at 10% of the calculated dose every 10 seconds. They then received the alternate drug after a 6-day washout. Temperature, pulse rate, respiratory rate, direct blood pressure, and arterial blood gases were measured before induction, immediately post-induction, and at 5-minute intervals until extubation. Quality of induction, recovery, and ataxia were scored by a single blinded investigator. Duration of anesthesia and recovery, and adverse events were recorded.ResultsThe mean doses required for induction were 2.6 ± 0.4 mg kg^?1 alfaxalone and 5.2 ± 0.8 mg kg^?1 propofol. After alfaxalone, temperature, respiration, and pH were significantly lower, and PaCO₂ significantly higher post-induction compared to baseline (p < 0.03). After propofol, pH, PaO₂, and SaO₂ were significantly lower, and PaCO₂, HCO₃, and PA-aO₂ gradient significantly higher post-induction compared to baseline (p < 0.03). Post-induction and 5-minute physiologic and blood gas values were not significantly different between alfaxalone and propofol. Alfaxalone resulted in significantly longer times to achieve sternal recumbency (p = 0.0003) and standing (p = 0.0004) compared to propofol. Subjective scores for induction, recovery, and ataxia were not significantly different between treatments; however, dogs undergoing alfaxalone anesthesia were more likely to have ≥1 adverse event (p = 0.041). There were no serious adverse events in either treatment.Conclusions and clinical relevanceThere were no clinically significant differences in cardiopulmonary effects between propofol and alfaxalone. A single bolus of propofol resulted in shorter recovery times and fewer adverse events than a single bolus of alfaxalone.     

Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs

ObjectiveTo compare the anaesthetic and cardiopulmonary effects of alfaxalone with propofol when used for total intravenous anaesthesia (TIVA) during ovariohysterectomy in dogs.Study designA prospective non-blinded randomized clinical study.AnimalsFourteen healthy female crossbred bitches, aged 0.5–5 years and weight 16–42 kg.MethodsDogs were premedicated with acepromazine 0.01 mg kg^?1 and morphine 0.4 mg kg^?1. Anaesthesia was induced and maintained with either propofol or alfaxalone to effect for tracheal intubation followed by an infusion of the same agent. Dogs breathed spontaneously via a ‘circle’ circuit, with oxygen supplementation. Cardiopulmonary parameters (respiratory and heart rates, end-tidal carbon dioxide, tidal volume, and invasive blood pressures) were measured continuously and recorded at intervals related to the surgical procedure. Arterial blood samples were analysed for blood gas values. Quality of induction and recovery, and recovery times were determined. Non-parametric data were tested for significant differences between groups using the Mann–Whitney U-test and repeatedly measured data (normally distributed) for significant differences between and within groups by anova.ResultsBoth propofol and alphaxalone injection and subsequent infusions resulted in smooth, rapid induction and satisfactory maintenance of anaesthesia. Doses for induction (mean ± SD) were 5.8 ± 0.30 and 1.9 ± 0.07 mg kg^?1 and for the CRIs, 0.37 ± 0.09 and 0.11 ± 0.01 mg kg^?1 per minute for propofol and alfaxalone respectively. Median (IQR) recovery times were to sternal 45 (33–69) and 60 (46–61) and to standing 74 (69–76) and 90 (85–107) for propofol and alphaxalone respectively. Recovery quality was good. Cardiopulmonary effects did not differ between groups. Hypoventilation occurred in both groups.Conclusions and clinical relevanceFollowing premedication with acepromazine and morphine, both propofol and alphaxalone produce good quality anaesthesia adequate for ovariohysterectomy. Hypoventilation occurs suggesting a need for ventilatory support during prolonged infusion periods with either anaesthetic agent.     

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.     

The bioequivalence of a single intravenous administration of the anesthetic alfaxalone in cyclodextrin versus alfaxalone in cyclodextrin plus preservatives in cats

To demonstrate the bioequivalence of alfaxalone in cyclodextrin (Reference Product) to a formulation of alfaxalone in cyclodextrin also containing the preservatives ethanol, chlorocresol, and benzethonium chloride (Test Product) when administered for the purpose of inducing anesthesia in the cat. Blinded, single‐dose, randomized, two‐period, two‐sequence, cross‐over bioequivalence study with a 7‐day washout period between treatments. Twenty‐four (12 neutered males and 12 intact females), healthy, adult cats weighing 4.1±0.9 kg. Cats were administered 5 mg/kg IV of alfaxalone in the Reference or Test Product using a randomized cross‐over design. One‐milliliter venous blood samples were collected at predetermined time points to 12 hr after drug administration to determine alfaxalone plasma concentration over time. Alfaxalone concentrations were determined by a validated analytical testing method using HPLC‐MS/MS. Plasma profiles of alfaxalone concentration against time were analyzed by noncompartmental analysis. The pivotal variables for bioequivalence were AUC_last and C_max. Equivalence was achieved if the 90% confidence interval for AUC_last and C_max fell into the asymmetric ±20% interval (0.80–1.25). Physiological variables, quality of anesthesia visual analog scale (VAS) scoring and anesthetic event times were recorded. ANOVA or ANCOVA (single time point), RMANOVA or RMANCOVA (multiple time point) was used for normally distributed data. GLIMMIX was used for nonnormally distributed data. VAS scores were analyzed as for blood bioequivalence data. Variables were evaluated for safety and assessed at alpha = 0.10. C_max and AUC_last for Reference and Test Products were statistically bioequivalent. No physiological variables except for a drug by time interaction for respiratory rate differed between treatment groups, and this difference was not clinically relevant. No anesthetic event times or VAS scores for quality of anesthesia were different between treatment groups. Neither formulation caused pain upon injection. The Reference and Test Products are pharmaceutically bioequivalent formulations when administered as a single intravenous administration for the purpose of induction of anesthesia in cats.     

Sedative and physiologic effects of low-dose intramuscular alfaxalone in dogs

Objective

To describe the sedative and physiologic effects of two doses of alfaxalone administered intramuscularly in dogs.

Effect of anesthetic induction with propofol,alfaxalone or ketamine on intraocular pressure in cats: a randomized masked clinical investigation

ObjectiveTo compare the effect of propofol, alfaxalone and ketamine on intraocular pressure (IOP) in cats.Study designProspective, masked, randomized clinical trial.AnimalsA total of 43 ophthalmologically normal cats scheduled to undergo general anesthesia for various procedures.MethodsFollowing baseline IOP measurements using applanation tonometry, anesthesia was induced with propofol (n = 15), alfaxalone (n = 14) or ketamine (n = 14) administered intravenously to effect. Then, midazolam (0.3 mg kg^?1) was administered intravenously and endotracheal intubation was performed without application of topical anesthesia. The IOP was measured following each intervention. Data was analyzed using one-way anova and repeated-measures mixed design with post hoc analysis. A p-value <0.05 was considered significant.ResultsMean ± standard error IOP at baseline was not different among groups (propofol, 18 ± 0.6; alfaxalone, 18 ± 0.7; ketamine, 17 ± 0.5 mmHg). Following induction of anesthesia, IOP increased significantly compared with baseline in the propofol (20 ± 0.7 mmHg), but not in the alfaxalone (19 ± 0.8 mmHg) or ketamine (16 ± 0.7 mmHg) groups. Midazolam administration resulted in significant decrease from the previous measurement in the alfaxalone group (16 ± 0.7 mmHg), but not in the propofol group (19 ± 0.7 mmHg) or the ketamine (16 ± 0.8 mmHg) group. A further decrease was measured after intubation in the alfaxalone group (15 ± 0.9 mmHg).Conclusions and clinical relevancePropofol should be used with caution in cats predisposed to perforation or glaucoma, as any increase in IOP should be avoided.     

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 (MIR_NM) in dogs.

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.

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

ObjectiveTo 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 designRandomized, blinded, crossover, experimental study.AnimalsA group of six adult Beagles.MethodsDogs 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.ResultsSedation 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 relevanceAdding alfaxalone to methadone and dexmedetomidine enhanced sedation and duration of recumbency. Although cardiopulmonary depression was limited, oxygen supplementation is advisable.     

Effects of different doses of dexmedetomidine on anaesthetic induction with alfaxalone – a clinical trial

ObjectiveTo document the effects of two doses of dexmedetomidine on the induction characteristics and dose requirements of alfaxalone.Study designRandomized controlled clinical trial.AnimalsSixty one client owned dogs, status ASA I-II.MethodsDogs were allocated randomly into three groups, receiving as pre-anaesthetic medication, no dexmedetomidine (D₀), 1 μg kg^?1 dexmedetomidine (D₁) intramuscularly (IM) or 3 μg kg^?1 dexmedetomidine IM (D₃). All dogs also received 0.2 mg kg^?1 methadone IM. Level of sedation was assessed prior to induction of anaesthesia. Induction of general anaesthesia was performed with alfaxalone administered intravenously to effect at a rate of 1 mg kg^?1 minute^?1; the required dose to achieve tracheal intubation was recorded. Anaesthesia was maintained with isoflurane in oxygen. Cardiopulmonary parameters were recorded throughout the anaesthetic period. Quality of intubation, induction and recovery of anaesthesia were recorded. Quantitative data were compared with one-way anova or Kruskal-Wallis test. Repeated measures were log-transformed and analysed with repeated measures anova (p < 0.05).ResultsTreatment groups were similar for categorical data, with exception of sedation level (p < 0.001). The doses (mean ± SD) of alfaxalone required for intubation were D₀ 1.68 ± 0.24, D₁ 1.60 ± 0.36 and D₃ 1.41 ± 0.43, the difference between D₀ and D₃ being statistically significant (p = 0.036). Heart and respiratory rates during the anaesthetic period were significantly different over time and between groups (p < 0.001); systolic arterial blood pressure was significantly different over time (p < 0.001) but not between groups (p = 0.833). Induction quality and recovery scores were similar between groups (p = 1.000 and p = 0.414, respectively).Conclusions and clinical relevanceThe administration of alfaxalone resulted in a good quality anaesthetic induction which was not affected by the dose of dexmedetomidine. Dexmedetomidine at 3 μg kg^?1 IM combined with methadone provides good sedation and enables a reduction of alfaxalone requirements.     

Evaluating the efficacy of alfaxalone in corn snakes (Pantherophis guttatus)

ObjectiveAlfaxalone is a popular veterinary anesthetic; however, research on this anesthetic in snakes has been limited to ball pythons, garter snakes and several Australian species. The objective was to evaluate the anesthetic effects of alfaxalone in corn snakes (Pantherophis guttatus), a popular pet snake.Study designProspective, randomized crossover study.AnimalsA total of eight corn snakes.MethodsIn phase I, snakes were subcutaneously administered three doses of alfaxalone (5, 10 and 15 mg kg^–1) in the cranial third of the body to determine the most effective dose. In phase II, a dose of 15 mg kg^–1 was administered in the cranial and caudal thirds of the snakes to determine if injection site affected anesthesia duration. Heart rate (HR), respiratory rate (f_R), righting reflex, escape response, tail pinch, needle prick and tongue flick were monitored at baseline and 5 minute intervals until the snakes fully recovered.ResultsDuration of anesthesia differed significantly, with higher doses lasting longer than lower doses: 5 mg kg^–1 [23.8 ± 4.4 (15–30) minutes]; 10 mg kg^–1 [40.6 ± 9.4 (25–55) minutes]; and 15 mg kg^–1 [56.9 ± 8.4 (50–70) minutes], mean ± standard deviation (range). The tail pinch reflex was not completely lost in phase 1. There was a significant change in f_R over time, but this was not related to dose. HR was not different by time or dose. Duration of anesthesia was not different after administration of alfaxalone (15 mg kg^–1) in the cranial third versus the caudal third of the body; however, there was a significant decrease in HR and f_R at this dose, regardless of injection site.Conclusions and clinical relevanceBased on these results, alfaxalone (15 mg kg^–1) provides adequate anesthesia for brief procedures or intubation; however, additional analgesia is required for painful procedures.     

Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU

OBJECTIVE: To determine the pharmacokinetic parameters of alfaxalone in dogs after the intravenous (IV) administration of clinical and supra-clinical doses of a 2-hydroxypropyl-beta-cyclodextrin (HPCD) alfaxalone formulation (Alfaxan-CD RTU). EXPERIMENTAL DESIGN: Prospective two-period crossover design. Animals Eight (four male and four female) young adult healthy Beagle dogs. Methods The steroid anaesthetic alfaxalone was administered IV at two doses in a crossover design (2 and 10 mg kg(-1)) with a washout period of 21 days. Blood samples were collected before and up to 8 hours after dosing. Plasma concentrations of alfaxalone were assayed using a liquid chromatograph/mass selective detector technique and analyzed to estimate the main pharmacokinetic parameters by noncompartmental analysis. Results were expressed as mean +/- SD. RESULTS: The mean duration of anaesthesia from endotracheal intubation to extubation was 6.4 +/- 2.9 and 26.2 +/- 7.5 minutes, for the 2 and 10 mg kg(-1) doses, respectively. The plasma clearance of alfaxalone for the 2 and 10 mg kg(-1) doses differed statistically at 59.4 +/- 12.9 and 52.9 +/- 12.8 mL kg(-1) minute(-1), respectively (p = 0.008) but this difference was deemed clinically unimportant; the harmonic mean plasma terminal half-lives (t(1/2)) were 24.0 +/- 1.9 and 37.4 +/- 1.6 minutes respectively. The volume of distribution was between 2 and 3 L kg(-1) and did not differ between the two doses. No sex effect was observed. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone, as an HPCD formulation (Alfaxan-CD RTU) administered in the dog provides rapid and smooth induction of anaesthesia, satisfactory conditions for endotracheal intubation and a short duration of anaesthesia. There was no clinically significant modification of the pharmacokinetic parameters between sexes and between the clinical (2 mg kg(-1)) and supra-clinical (10 mg kg(-1)) doses.     

Chronotropic effect of propofol or alfaxalone following fentanyl administration in healthy dogs

ObjectiveTo compare the effect of alfaxalone and propofol on heart rate (HR) and blood pressure (BP) after fentanyl administration in healthy dogs.Study designProspective, randomised clinical study.AnimalsFifty healthy client owned dogs (ASA I/II) requiring general anaesthesia for elective magnetic resonance imaging for neurological conditions.MethodsAll dogs received fentanyl 7 μg kg⁻¹ IV and were allocated randomly to receive either alfaxalone (n = 25) or propofol (n = 25) to effect until endotracheal (ET) intubation was possible. Heart rate and oscillometric BP were measured before fentanyl (baseline), after fentanyl (Time F) and after ET intubation (Time GA). Post-induction apnoea were recorded. Data were analysed using Fisher’s exact test, Mann Whitney U test and one-way anova for repeated measures as appropriate; p value <0.05 was considered significant.ResultsDogs receiving propofol showed a greater decrease in HR (-14 beat minute⁻¹, range -47 to 10) compared to alfaxalone (1 beat minute⁻¹, range -33 to 26) (p = 0.0116). Blood pressure decreased over the three time periods with no difference between groups. Incidence of post-induction apnoea was not different between groups.ConclusionFollowing fentanyl administration, anaesthetic induction with propofol resulted in a greater negative chronotropic effect while alfaxalone preserved or increased HR.Clinical relevanceFollowing fentanyl administration, HR decreases more frequently when propofol rather than alfaxalone is used as induction agent. However, given the high individual variability and the small change in predicted HR (-7.7 beats per minute after propofol), the clinical impact arising from choosing propofol or alfaxalone is likely to be small in healthy animals. Further studies in dogs with myocardial disease and altered haemodynamics are warranted.