Moxidectin is a candidate for use as an in vivo internal standard in pharmacokinetic studies, as demonstrated with use in simultaneous tissue cage and ultrafiltration fluid collection.

In vivo ultrafiltration has been used in veterinary pharmacokinetics since the early 2000's as an improvement on the tissue cage model which enables sampling of fluids from extra-circulatory compartments. Variability in analyte recovery from ultrafiltration samples, due to membrane fouling or tissue inflammation, has been a concern for this technique. Internal standards may be used to scale or verify the unknown result, such as is common in analytical extractions and in vivo microdialysis. Eight merino sheep were implanted with subcutaneous tissue cages and 2 weeks prior to the initiation of the study the sheep were injected with 0.2 mg/kg moxidectin subcutaneously. On the day of the study ultrafiltration probes were inserted subcutaneously. At time zero 4 mg/kg of carprofen was injected intravenously. Plasma, tissue cage, and ultrafiltration samples were taken 30 min before and 0.5, 1, 2, 3, 4, 5, 7, 24, 36, 48, 72 h after dosing. Carprofen and moxidectin concentrations were measured by LC-MS/MS. Pharmacokinetic parameters were estimated using Monolix for both the carprofen concentrations and the moxidectin corrected carprofen concentrations. The ultrafiltration probes failed to consistently produce enough sample volume to analyse. Moxidectin concentrations in the plasma and tissue cage fluid were stable throughout the 72 h sampling window. Moxidectin proved to be suitable as an in vivo internal standard for pharmacokinetic research using, tissue cages, plasma sampling and ultrafiltration probes, but the application of ultrafiltration techniques requires refinement.

The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep.

Introduction: Pharmacokinetic and pharmacodynamic models can be powerful tools for predicting outcomes. Many models are based on repetitive sampling of the vascular space, due to the simplicity of obtaining samples. As many drugs do not exert their effect in the vasculature, models have been developed to sample tissues outside the bloodstream. Tissue cages are hollow devices implanted subcutaneously, or elsewhere, that are filled with fluid allowing repetitive sampling to occur. The physical dimensions of the cage, namely, the diffusible surface area to volume ratio, would be expected to change the rate of drug movement into and out of tissue cages. Methods: Seven sheep were implanted with five pairs of tissue cages, subcutaneously. Each pair of cages had a different length but a fixed diffusible surface area, so the surface area to volume ratio differed. Carrageenan was injected into half of the cages in each animal during one sampling period in a cross-over design. Samples from each cage and the bloodstream were obtained at 14-time points during two sampling periods. The concentration of carprofen was measured using LC-MS/MS and the results were modeled using nonlinear mixed-effects techniques. Prostaglandin metabolites were also measured and the change over time was analyzed using linear mixed effect modeling. Results: The presence of carrageenan within an animal changed the systemic pharmacokinetics of carprofen. The rate of drug movement into and out of the tissue cages varied with the surface area to volume ratio. The concentration time curve for prostaglandin metabolites changed with cage size. Conclusion: The surface area volume ratio of tissue cages will influence the calculated pharmacokinetic parameters and may affect calculated pharmacodynamics, thus, it is an important factor to consider when using tissue cage data for dosing regimes.

Intravenous Acetaminophen Does Not Provide Adequate Postoperative Analgesia in Dogs Following Ovariohysterectomy.

(1) Objective: To investigate the analgesic effects of intravenous acetaminophen after intravenous administration in dogs presenting for ovariohysterectomy. (2) Methods: 14 ASA I client-owned female entire dogs. In this randomized, blinded, clinical study, dogs were given meperidine and acepromazine intramuscularly before induction of anesthesia with intravenous propofol. Anesthesia was maintained with isoflurane in oxygen. Intravenous acetaminophen 20 mg/kg or 0.9% NaCl was administered postoperatively. Pain assessments were conducted using the Glasgow Pain Scale short form before premedication and at 10, 20, 60, 120, and 180 min post-extubation or until rescue analgesia was given. The pain scores, times, and incidences of rescue analgesia between the groups was compared. Blood was collected before and 2, 5, 10, 20, 40, and 80 min after acetaminophen administration. Acetaminophen plasma concentration was quantified by liquid chromatography-mass spectrometry. The acetaminophen plasma concentration at the time of each pain score evaluation was subsequently calculated. (3) Results: There was no significant difference in pain scores at 10 min, highest pain scores, or time of rescue analgesia between groups. In each group, 3 dogs (43%) received rescue analgesia within 20 min. (4) Conclusions: Following ovariohysterectomy in dogs, there was no detectable analgesic effect of a 20 mg/kg dosage of intravenous acetaminophen administered at the end of surgery.

A Survey of Injuries That Occurred in Veterinary Teaching Hospitals during 2017.

Knowing the frequency, extent or severity of injuries that occur to students and staff within veterinary teaching hospitals (VTHs) is necessary for proactive management of their safety. This study surveyed contemporaneously-captured incident reports likely to cause or causing injury to students and staff of veterinary teaching hospitals in Europe, the United States of America (USA), Canada, Australia, and New Zealand, recorded in 2017. Four different severities of incident were evaluated within four different cohorts of people, precipitated by five categories for cause. Within each cause-category, further subdivision was based on the nature of the incident. All colleges of veterinary medicine accredited by the American Veterinary Medical Association (AVMA) Council on Education (COE) or the Australasian Veterinary Boards Council were surveyed. Responses were received from (7/7, 100%) schools in Australia and New Zealand, 12/30 (40%) the United States of America, 1/4 (25%) Canada, 1/1 (100%) Mexico, and 1/3 (33%) United Kingdom, and no responses were received from the AVMA-COE accredited schools in the European Union. The mean incidence of incidents caused by horses was (0.4/1,000 cases), followed by food animals (0.1/1,000 cases), other animals (0.1/1,000 cases), and small animals (0.074/1,000 cases). Within veterinary teaching hospitals at many institutions, veterinary students and veterinarians are particularly at risk of injuries caused by hand-held instruments, such as scalpels and needles. Non-veterinary staff are more at risk than students or veterinarians from injuries caused by small animals. Recording and reporting of incidents is not uniform and may be lacking in detail. Some institutions' systems for record management preclude easy evaluation, and therefore may be insufficient for proactive management of health and safety as required by accreditation bodies.

Study design synopsis: Designing and performing pharmacokinetic studies for systemically administered drugs in horses.

The goal of this editorial is to discuss best practice design, execution and reporting of a pharmacokinetic (PK) study in horses. Our target readers are clinicians who plan to perform this type of research, in a field, clinic or research setting but we also hope that this article might help readers of such work to appraise the articles and understand the quality of the studies. Our emphasis will be on appropriate study design and analytical method, drug and drug formulation choice and route of administration, animal choice, sample collection, storage and shipping, and reporting, rather than the PK data analysis itself.

Physiologically based modelling of the pharmacokinetics of three beta-lactam antibiotics after intra-mammary administration in dairy cows.

Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

A controlled randomized clinical trial to assess postoperative analgesia after thiopental-isoflurane anaesthesia or total intravenous anaesthesia with alfaxalone in dogs.

Alfaxalone, a synthetic neuroactive steroid, has been attributed with properties including sedation, anaesthesia and analgesia. The clinical relevance of any analgesic properties of alfaxalone has not been demonstrated. This study was a prospective, blinded, randomized, negative control clinical trial in 65 healthy dogs presented for ovariohysterectomy. Anaesthesia was induced and maintained, for Group 1 (TIVA) dogs (n = 30) with intravenous alfaxalone alone and for Group 2 dogs (n = 35) with thiopental followed by isoflurane in 100% oxygen inhalation. After ovariohysterectomy, quantitative measures of pain or nociception were recorded at 15 min intervals for 4 hr using three independent scoring systems, a composite measure pain scale (CMPS), von Frey threshold testing and measures of fentanyl rescue analgesia. The mean CMPS scores of Group 2 (THIO/ISO) dogs remained higher than Group 1 (TIVA) dogs from 15 to 135 min post-surgery but this difference was not statistically significant. There were no significant differences between groups in the proportions of dogs requiring rescue fentanyl analgesia, the total fentanyl dose used or the time to first fentanyl dose. The Von Frey threshold testing was found to be unsuitable for measurement of pain in this experimental model. When administered as total intravenous anaesthesia, alfaxalone did not provide analgesia in the postoperative period.

Two-point ultrasound-guided transversus abdominis plane injection in canine cadavers - a pilot study.

OBJECTIVE: This study evaluated the spread of a two-point transversus abdominis plane (TAP) injection in canine cadavers. Compared with previous techniques, the two-point TAP injection was developed to increase the consistency of local anaesthetic spread to the nerve segments T11, T12, L1, L2 and L3. STUDY DESIGN: Prospective experimental trial. ANIMALS: Five fresh canine cadavers. METHODS: Two-point TAP injections were performed under ultrasound guidance by a single trained individual in canine cadavers (15.7-43.0 kg). Each hemi-abdomen was infiltrated and evaluated independently for a total of 10 evaluations of the technique. The first injection was performed at the level of the costo-chondral junction of the thirteenth rib, and the second injection was performed cranial to the tuber coxae. Each injection comprised 0.3 mL kg-1 methylene blue solution (0.0015 mg mL-1). Ten minutes after the injections, abdominal wall dissection was performed, and any nerves stained for a minimum of 10 mm along their long axis were identified and recorded. RESULTS: During all injections, separation of the internal oblique and transversus abdominis muscles was observed on ultrasound. On dissection, branches of T12, T13, L1, L2 and L3 were adequately stained in 30%, 100%, 100%, 90% and 90% of injections, respectively. No staining of branches of T11 occurred in any of the cadavers. In one hemi-abdomen, branches of L1 and L3, but not L2, were stained. CONCLUSIONS AND CLINICAL RELEVANCE: This study indicates that the two-point TAP injection delivers consistent dye dispersion to adequately stain branches of T13, L1, L2 and L3, with no coverage of T11 and poor coverage of T12, in fresh canine cadavers. An in vivo study using local anaesthetic should be performed to evaluate the analgesic efficacy of this technique in mid to caudal abdominal surgeries.

Content validation of a Critical Appraisal Tool for Reviewing Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain.

INTRODUCTION: This article reports the content validation of a Critical Appraisal Tool designed to Review the quality of Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain and provide guidance as to the strengths and weakness of findings. The CATRAS quality items encompass 3 domains: level of evidence, methodological soundness, and grading of the pain assessment tool. OBJECTIVES: To validate a critical appraisal tool for reviewing analgesia studies involving subjects incapable of self-reporting pain. METHODS: Content validation was achieved using Delphi methodology through panel consensus. A panel of 6 experts reviewed the CATRAS in 3 rounds and quantitatively rated the relevance of the instrument and each of its quality items to their respective domains. RESULTS: Content validation was achieved for each item of the CATRAS and the tool as a whole. Item-level content validity index and kappa coefficient were at least greater than 0.83 and 0.81, respectively, for all items except for one item in domain 2 that was later removed. Scale-level content validity index was 97% (excellent content validity). CONCLUSIONS: This 67-item critical appraisal tool may enable critical and quantitative assessment of the quality of individual analgesia trials involving subjects incapable of self-reporting pain for use in systematic reviews and meta-analysis studies.

Determination of testosterone esters in the hair of male greyhound dogs using liquid chromatography-high resolution mass spectrometry.

The doping of greyhound dogs with testosterone is done in an attempt to improve their athletic performance, but such doping cannot easily be confirmed, especially in male dogs owing to the natural presence of endogenous testosterone. As testosterone is usually administered as its esters, their direct detection in hair would provide confirmatory evidence of the administration of a pharmaceutical product. This article demonstrates that the use of a liquid chromatography-high resolution mass spectrometry method with heated electrospray ionisation (HESI) combined with the use of amino solid-phase extraction (SPE) cartridges for sample clean-up, is suitable for the sensitive determination of propionate, phenyl propionate, isocaproate, decanoate, and enanthate esters of testosterone in greyhound hair. The method is linear over the range, 0.1 µg/kg-10 µg/kg, for all the testosterone esters analysed. The limits of detection (LOD) are 0.05 µg/kg for testosterone phenyl propionate, isocaproate, and decanoate, 0.025 µg/kg for testosterone propionate, and 0.25 µg/kg for testosterone enanthate. This method was applied to hair samples collected from male greyhounds before and after a single administration of a product containing several testosterone esters, each of which could be detected up to 100 days post-administration. The study also demonstrates that tail hair is the specimen of choice for the analysis of testosterone in dog hair and that washing of dogs does not impact the analysis of testosterone esters in hair. This method may be useful in racing regulation for the detection of illegitimate use of testosterone in all species.

Influence of two administration rates of alfaxalone at induction on its relative potency in cats: a pilot study.

Objectives The aim of the study was to evaluate, in a controlled, randomised, masked clinical trial, the influence of administration rate of alfaxalone at induction on its relative potency in cats and to report the incidence of cardiorespiratory adverse effects. Methods Twelve healthy female domestic cats admitted for ovariohysterectomy were premedicated with buprenorphine 20 µg/kg intramuscularly and alfaxalone 3.0 mg/kg subcutaneously. Sedation scores were established (using a published scale ranging from 1 [no sedation] to 5 [profound sedation]) prior to anaesthesia induction with alfaxalone intravenously at 2 mg/kg/min (group A2; n = 6) or 0.5 mg/kg/min (group A0.5; n = 6) to effect until orotracheal intubation was achieved. Sedation scores and alfaxalone induction doses were compared between the groups, using a Mann-Whitney exact test. Results are reported as median and range. Presence of apnoea (no breathing for more than 30 s) or hypotension (mean arterial blood pressure <60 mmHg) within 5 mins postintubation was also reported. Results Although sedation scores (1.5 [range 1.0-3.0] and 2.5 [range 1.0-3.0] for A2 and A0.5, respectively) were not significantly different ( P = 0.32), cats in group A2 required significantly more alfaxalone (4.3 mg/kg [range 3.4-7.0 mg/kg]) than group A0.5 (2.1 mg/kg [range 1.5-2.5 mg/kg]) ( P = 0.002). Two cats in each group presented postinduction apnoea, and two cats in group A2 and three cats in group A0.5 presented postinduction hypotension. Conclusions and relevance The use of a slower induction infusion rate resulted in an increase in the alfaxalone relative potency without obvious cardiorespiratory benefit.

Evaluation of the influence of atipamezole on the postoperative analgesic effect of buprenorphine in cats undergoing a surgical ovariohysterectomy.

OBJECTIVE: To evaluate the influence of atipamezole on postoperative pain scores in cats. STUDY DESIGN: Controlled, randomized, masked clinical trial. ANIMALS: Twelve healthy female domestic cats. METHODS: Cats admitted for ovariohysterectomy (OVH) surgery were randomly allocated to group atipamezole (n = 6) or group saline (n = 6) and were premedicated with buprenorphine 20 µg kg(-1) intramuscularly (IM) and alfaxalone 3.0 mg kg(-1) subcutaneously (SC). Anaesthesia was induced with alfaxalone intravenously (IV) to effect and maintained with isoflurane in oxygen. Ten minutes after extubation, cats from group atipamezole received IM atipamezole (0.0375 mg kg(-1) ) whereas group saline received an equivalent volume [0.0075 mL kg(-1) (0.003 mL kg(-1) IM)] of 0.9% saline. A validated multidimensional composite scale was used to assess pain prior to premedication and postoperatively (20 minutes after extubation). If postoperative pain scores dictated, rescue analgesia consisting of buprenorphine and meloxicam were administered. Pain score comparisons were made between the two groups using a Mann-Whitney exact test. Results are reported as the median and range. RESULTS: Preoperatively, all cats scored 0. At the postoperative pain evaluation, the pain scores from group atipamezole [16 (range, 12-20)] were not significantly different from group saline [18 (range, 15-23)] (p = 0.28). All cats required rescue analgesia post-operatively. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole (0.0375 mg kg(-1) IM) administration did not significantly affect the postoperative pain scores in cats after OVH. Preoperative administration of buprenorphine (20 µg kg(-1) IM) did not provide adequate postoperative analgesia for feline OVH.

Accidental alfaxalone overdose in a mature cat undergoing anaesthesia for magnetic resonance imaging.

Case summary This case report describes the clinical signs and treatment of an alfaxalone 10 times overdose in a 12-year-old cat undergoing anaesthesia for MRI. The cat was discharged from hospital following a prolonged recovery including obtunded mentation and cardiorespiratory depression for several hours following cessation of anaesthesia. The cat received supportive therapy that included supplemental oxygen via a face mask, intravenous crystalloid fluids and active rewarming. The benefits of using alfaxalone for maintenance of anaesthesia, its pharmacokinetics and previously reported lethal doses are discussed. Strategies for reducing the incidence of medication errors are presented. Relevance and novel information An unintentional overdose of alfaxalone by continuous rate infusion has not been reported previously in a cat. Treatment is supportive and directed towards maintenance of the cardiorespiratory systems. Whenever possible, smart pumps that have been designed to reduce human error should be used to help prevent medication errors associated with continuous rate infusions.

The bioavailability of medetomidine in eight sheep following oesophageal administration.

There is sound evidence that medetomidine is an effective analgesic for acute pain in sheep. In this study, 15 µg kg(-1) of medetomidine was administered intravenously, and into the oesophagus, in a cross-over study, using eight sheep. Following intravenous administration, medetomidine could be detected in the plasma of these sheep for 120-180 min but following oesophageal administration, medetomidine could not be detected in the plasma of any sheep at any of 17 time points over four days. It is suspected that this is due to high first pass metabolism in the liver. Consequently, we conclude that future studies investigating the use of analgesics in orally-administered osmotic pumps in sheep should consider higher doses of medetomidine (e.g. >100 µg kg(-1)), further investigations into the barriers of medetomidine bioavailability from the sheep gut, liver-bypass drug delivery systems, or other α2-adrenergic agonists (e.g. clonidine or xylazine).

A review of the pharmacology and clinical application of alfaxalone in cats.

Alfaxalone-2-hydroxpropyl-ß-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats.

Pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or intravenous infusion of penciclovir.

OBJECTIVE: To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir. ANIMALS: 6 cats. PROCEDURES: Cats received famciclovir (40 [n = 3] or 90 [3] mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration. RESULTS: Mean ± SD maximum plasma concentration (C(max)) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 µg/mL and 1.28 ± 0.42 µg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar C(max) and time to C(max) values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.

Dose determination of fondaparinux in healthy cats.

OBJECTIVE: To establish practical doses and administration frequencies of fondaparinux for cats that would approximate human therapeutic peak and trough plasma anti-factor Xa activities for thromboprophylaxis (TP) and thrombosis treatment (TT) protocols. ANIMALS: 6 healthy adult purpose-bred cats. PROCEDURES: Dosage protocols for TP and TT were selected on the basis of a single compartment pharmacokinetic model incorporating data from humans but modified to account for the higher body weight-normalized cardiac output of cats. Fondaparinux was administered at 0.06 mg/kg, SC, every 12 hours (TP) for 7 days in one session, and 0.20 mg/kg, SC, every 12 hours (TT) for 7 days in another, with a minimum of 1 week separating the sessions. Plasma anti-factor Xa activity was measured before fondaparinux administration (day 1) and at 2 (peak) and 12 (trough) hours after drug administration on days 1 and 7. Platelet aggregation and thromobelastographic (TEG) parameters were also measured 2 hours after drug administration on day 7. RESULTS: Peak plasma anti-factor Xa activities on day 7 for TP (median, 0.59 mg/L; range, 0.36 to 0.77 mg/L) and TT (median, 1.66 mg/L; range, 1.52 to 2.00 mg/L) protocols were within therapeutic ranges for humans. However, only the TP protocol achieved trough anti-factor Xa activity considered therapeutic in humans (median, 0.19 mg/L; range, 0.00 to 0.37 mg/L) on day 7. There were significant changes in the TEG parameters at peak for the TT protocol, suggesting a hypocoagulable state. No significant changes in platelet aggregation were evident for either protocol. CONCLUSIONS AND CLINICAL RELEVANCE: A fondaparinux dosage of 0.06 or 0.20 mg/kg, SC, every 12 hours, was sufficient to achieve a peak plasma anti-factor Xa activity in cats that has been deemed therapeutic in humans. This study provided preliminary data necessary to perform fondaparinux dose-determination and clinical efficacy studies.

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

OBJECTIVE: To 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 DESIGN: Four treatments of alfaxalone were administered in sequential order. ANIMALS: Eight healthy adult cats (four male; four female) weighing between 3.71 and 5.91 kg. METHODS: Cats 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 (PaO(2), PaCO(2)) 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. RESULTS: Alfaxalone 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 PaO(2) 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 RELEVANCE: Alfaxalone 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 of clinical and supraclinical doses of alfaxalone in dogs.

OBJECTIVE: To determine the cardiorespiratory and anesthetic effects of 2, 6, and 20 mg kg(-1) IV alfaxalone in hydroxypropyl beta cyclodextrin (Alfaxan) in dogs. STUDY DESIGN: Blinded four-way crossover randomized by dose. ANIMALS: Eight healthy adult purpose-bred mixed breed dogs (four male, four female) weighing between 12 and 28 kg. METHODS: Four (0, 2, 6, 20 mg kg(-1)) IV treatments of alfaxalone were administered to each dog with a 3-hour washout period between doses. 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, blood gases (PaO(2), PaCO(2)) were performed prior to and at predetermined intervals after drug administration. Systemic vascular resistance and rate pressure product were calculated. The quality of induction, maintenance, and recovery from anesthesia were categorically scored as was the response to noxious stimulation. RESULTS: The administration of alfaxalone resulted in dose-dependent changes in cardiovascular and respiratory parameters. Decreases in arterial blood pressure and increases in heart rate occurred at higher doses with most variables returning to baseline in 15-30 minutes. Respiratory rate, minute volume, and PaO(2) decreased and apnea was the most common side effect. The duration of anesthesia increased with dose, and induction, maintenance, and recovery were judged to be good to excellent with all doses studied. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone produced good to excellent short-term anesthesia in unpremedicated dogs. Cardiorespiratory effects were minimal at lower doses. Anesthesia was judged to be good to excellent and associated with unresponsiveness to noxious stimulation for the majority of anesthesia. Hypoventilation and apnea were the most prominent and dose-dependent effects.