T. Whittem

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.

The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses

This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin alfaxalone formulation (Alfaxan), Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h).

Effect of intravenous dose escalation with alfaxalone and propofol on occurrence of apnoea in the dog.

Spontaneous ventilation after induction of anaesthesia with intravenous alfaxalone or propofol was evaluated in a dose escalation study using 6 dogs. Each dog was dosed at 1×, 2×, 5×, 10× and 20× multiples of the labelled doses (2mg/kg for alfaxalone; 6.5mg/kg for propofol), until apnoea was observed. For each administration, the entire calculated dose was delivered over 1 min. All 6 dogs ventilated spontaneously after labelled (1×) doses of each drug but became apnoeic at 5× dose of propofol versus 20× dose of alfaxalone. For propofol at 2× and 5× doses, 4 and 0 dogs ventilated spontaneously respectively. For alfaxalone at 2×, 5× and 10× doses all 6, 4 and 1 dog ventilated spontaneously, respectively. The median dose which induced apnoea was higher for alfaxalone (5×) than for propofol (2×) (p=0.05). We concluded that induction of anaesthesia with propofol is more likely to induce apnoea than with alfaxalone.

Clinical evaluation of alfaxalone as an anaesthetic induction agent in dogs less than 12 weeks of age.

OBJECTIVE To assess the efficacy of alfaxalone as an anaesthetic induction agent for dogs aged less than 12 weeks. MATERIALS AND METHODS The study group comprised 25 juvenile dogs aged less than 12 weeks that were presented for surgical desexing. Dogs were aged by dentition, examined and weighed prior to premedication with acepromazine, atropine and morphine. At 20-30 min after premedication, animals were anaesthetised with intravenous alfaxalone administered to effect, using a target maximum expected dose of 2  mg/kg. Dogs were intubated and anaesthesia was maintained with isoflurane in oxygen administered with a non-rebreathing system. Subjective measures of anaesthetic quality and vital signs were recorded from enrollment to recovery. Descriptive and comparative statistics were used to analyse and present collected data. RESULTS The mean (± SD) dose of alfaxalone for induction was 1.7 (± 0.3) mg/kg body weight. Subjective measures of anaesthetic quality indicated acceptable induction, maintenance and recovery standards. Measured cardiovascular and respiratory parameters were well maintained. CONCLUSION Alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (Alfaxan®) is a suitable injectable anaesthetic induction agent for dogs aged less than 12 weeks requiring anaesthesia.

Report of the third Havemeyer workshop on infection control in equine populations

Infectious diseases are an ever present threat to the health of individual horses, local, regional and national herds and the equine industry as a whole. Treating infectious disease has always been one of the foundations of veterinary medicine. However, infectious disease prevention is becoming increasingly important because of the high visibility of recent outbreaks of infectious disease, the increasing frequency and ease of national and international horse movement and emergence and re-emergence of equine pathogens. This is especially true in large, transient horse populations. For many veterinarians and facility managers, infection control remains a subject they are reluctant to discuss for fear of it reflecting poorly on them, yet management of infectious diseases is an unavoidable issue that must be addressed by all equine practitioners regarding every equine population under their care. The field of veterinary infection control, although still young compared with equivalent efforts in human medicine, has advanced considerably in the last decade thanks to those that have willingly and openly shared their experiences – both good and bad – with regard to hospital and field-based outbreaks of infectious diseases and subsequent mitigation efforts. In veterinary hospitals, infection control is often not considered until after individual patient care is addressed and thus prevention of infectious disease transmission can become a secondary activity relative to the treatment of individual horses and a tertiary activity relative to the care of the larger hospital population. Thus infection control has often been largely reactive rather than proactive in many equine facilities. Control efforts are sometimes hurriedly implemented after a disease outbreak is well underway, rather than being used to prevent sporadic cases from escalating into an outbreak. It is clear that outbreaks of infectious disease can occur with alarming frequency, even in highly controlled environments such as veterinary teaching hospitals. A survey of personnel responsible for infection control at 38 American Veterinary Medical Association (AVMA) accredited veterinary teaching hospitals found that 82% had identified at least one outbreak of hospital-associated disease in the previous 5 years with 32% reporting outbreaks so significant that hospital closure was utilised to aid in mitigation efforts [1]. Outbreaks are undoubtedly under-reported in the scientific literature but a variety of organisms have been previously documented as causes of epidemic disease in equine hospitals, including Salmonella enterica [2–5], methicillin-resistant Staphylococcus aureus (MRSA) [6–8], equine herpesvirus type 1 [9–11] and Cryptosporidium [12]. However, equine infectious diseases are not solely associated with veterinary hospitals. The last decade has seen the epidemic spread of West Nile virus in North America, a major equine influenza epidemic in Australia, outbreaks of contagious equine metritis in the USA and South Africa, the re-emergence of piroplasmosis in the USA and dramatically increasing concerns regarding equine herpesvirus myeloencephalopathy and multidrug resistant bacterial pathogens (e.g. MRSA). There are several significant differences with regard to the practice of infection control in equine populations outside of veterinary hospitals (i.e. ‘in the field’). The focus in field situations is likely to be the protection of a relatively healthy population of horses from disease incursion, rather than protection of hospitalised patients with varying degrees of compromised health. The differences are similar to those between protection of public health in the community and infection control in human hospitals. Infection control in the field has often focused heavily on vaccination; however, effective vaccines cannot fully protect all horses as vaccines are not available for many diseases and vaccination cannot be used to control emerging diseases. A fundamental shift in the mindset of clinicians and horse owners must occur whereby vaccination is considered a last line of defence and overall infection prevention emphasises implementation of other control measures. This is particularly critical in large, transient horse populations that gather for specific events due to the potential for serious and widespread repercussions when these populations disperse, as was seen following the National Cutting Horse Association Western National Championship in Ogden, Utah, in May 2011. It is likely that exposure to a single horse shedding equine herpesvirus-1 (EHV-1) at this event resulted in over 165 horses developing clinical disease that was known or suspected to be caused by EHV-1 and at least 13 of these horses were subjected to euthanasia. The outbreak spanned at least 10 western US states and 2 Canadian provinces ([13], P.S. Morley, personal communication 2012). Clearly infectious diseases have a tremendous impact on equine populations and efforts to control and prevent spread are critical to the well-being of individual horses and horse populations. The Dorothy Russell Havemeyer Foundation Inc. (http://www.havemeyerfoundation. org) is a private foundation that supports scientific efforts to improve the health and welfare of horses. To this end, the foundation conducts workshops in a variety of different subject areas, including the control of infectious diseases. The most recent Havemeyer workshop conducted on infection control in equine populations was held in September 2010, bringing together a diverse group of internationally recognised experts in fields related to infection control. The overarching goal of the workshop was to advance the discipline by providing guidance and inspiration to those currently involved in equine infection control and insight to those who may still be on its periphery. More specifically, the objective of this workshop was to identify the most urgent and critical priorities in equine infection control so that these might be targeted for research and resource development. In this report, we summarise the consensus opinions, major ideas and recommendations developed during the workshop. In working to summarise the discussion and major conclusions of this workshop, several common themes became apparent that were deemed essential to the future progress of the discipline of infection control. Specifically, these included ethical obligations and standards of practice regarding infection control, improvements and standardisation for surveillance methods, developing better education and training programmes, standardisation and development of new diagnostic tests for important contagious pathogens, objectively quantifying the costs and benefits of infection control programmes, expanding knowledge necessary for design of control programmes for important contagious pathogens, developing and promoting multicentre studies and promoting judicious antimicrobial use practices. Approaches that can be used for development of infection control programmes (the ‘how to’ of infection control) were discussed in previous Havemeyer workshops and have been reviewed in detail elsewhere [14–17]. Issues regarding the detection and control of specific agents were discussed and were used as examples during the meeting but the focus of this document is on the future needs of infection control in a broader context, not in relation to specific diseases.

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

Alfaxalone-2-hydroxpropyl-β-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.

Clinical evaluation of alfaxalone as an anaesthetic induction agent in cats less than 12 weeks of age: Small Animals

OBJECTIVE To assess the clinical suitability of alfaxalone as an anaesthetic induction and maintenance agent for kittens aged less than 12 weeks. MATERIALS AND METHODS The study group comprised 34 kittens aged less than 12 weeks that were presented for surgical desexing. They were aged by dentition, examined and weighed prior to premedication with acepromazine, atropine and morphine. At 20-30 min after premedication, animals were anaesthetised with intravenous alfaxalone administered to effect, using a target maximum expected dose of 5 mg/kg. All cats were intubated: 25 were maintained with isoflurane in oxygen administered with a non-rebreathing circuit and 8 were maintained by supplemental intravenous administration of alfaxalone. Subjective measures of anaesthetic quality and vital signs were recorded from enrolment to recovery. Cats receiving supplemental alfaxalone for maintenance were evaluated for time to first supplemental dose and the total dose of supplemental alfaxalone (mg/kg/h). Descriptive and comparative statistics were used to analyse and present collected data. RESULTS The mean (± SD) dose of alfaxalone for induction was 4.7 ± 0.5 mg/kg body weight. Subjective measures of anaesthetic quality indicated acceptable induction, maintenance and recovery standards. Measured cardiovascular and respiratory parameters were well maintained. CONCLUSION Alfaxalone in 2-hydroxypropyl-beta-cyclodextrin (Alfaxan®) is a suitable injectable anaesthetic induction agent for juvenile cats aged less than 12 weeks requiring anaesthesia. Maintenance of anaesthesia with supplemental doses of alfaxalone may be a suitable alternative in kittens when the use of inhalant anaesthetic maintenance is not feasible.

PRINCIPLES OF ANTIMICROBIAL THERAPY

It has been 2500 years since the Chinese began applying moldy soybean curd to cure skin infections. Technology today has refined the benefits of antibiotic-forming molds and bacteria and has greatly increased the number of antimicrobial drugs available to combat infection. Understanding the principles fundamental to rational therapy with these drugs will ensure the best of possible outcomes.

Dihydrostreptomycin or streptomycin in combination with penicillin G in dairy cattle therapeutics: A review and re-analysis of published data Part 1: Clinical pharmacology

Combination formulations of penicillin G salts and dihydrostreptomycin were developed during the 1960s and are currently marketed in New Zealand for parenteral and intramammary use in dairy cattle. In this paper, the clinical indications and efficacy, pharmacokinetics and potential for antimicrobial synergy of penicillin and dihydrostreptomycin or streptomycin, when combined, are discussed.

A systematic review and meta-analysis of the efficacy of furosemide for exercise-induced pulmonary haemorrhage in Thoroughbred and Standardbred racehorses

REASONS FOR PERFORMING STUDY Furosemide is the most commonly used medication for exercise-induced pulmonary haemorrhage (EIPH); however, critical evaluation of the strength of evidence for efficacy of furosemide is lacking and is warranted so that evidence-based treatment decisions can be made. OBJECTIVES To evaluate the efficacy of furosemide to reduce the severity or frequency of detection of EIPH in Thoroughbred and Standardbred racehorses. STUDY DESIGN Systematic review with meta-analyses. METHODS Primary studies were identified via searches of electronic databases, relevant texts and reference lists of published articles. Studies were not restricted by date or publication status. Only studies published in English were eligible for inclusion. Searches were performed using a predetermined search string. Randomised controlled trials, nonrandomised trials and observational studies were included. Three authors independently assessed each study using the Cochrane collaboration guidelines and Grading of Recommendations Assessment, Development and Evaluation recommendations for rating quality of evidence. Meta-analysis of studies was performed with pooled data to determine whether furosemide reduced the frequency of detection of EIPH (yes or no) as evaluated by tracheobronchoscopy or bronchoalveolar lavage fluid red blood cell number, or if furosemide reduced the severity of EIPH by at least one tracheobronchoscopic grade. RESULTS Seventeen studies fulfilled the inclusion criteria. The relative risk of detecting any EIPH by tracheobronchoscopy after administration of furosemide was 0.88 (pooled data from 11 studies, n = 5780; 95% confidence interval 0.79-0.97, P = 0.01). When data from only high-quality randomised controlled trials (2 studies, n = 405) were used, the relative risk of detecting endoscopically evident EIPH was 0.68 (95% confidence interval 0.58-0.79, P<0.001). The proportion of horses previously diagnosed with EIPH having a reduction of at least one EIPH grade after furosemide was 68% (2 studies, n = 405; 95% confidence interval 61-78%). CONCLUSIONS There is high-quality evidence, albeit limited, that administration of furosemide reduces the incidence and severity of EIPH in Thoroughbred or Standardbred racehorses.