ANESTHESIA IN CAPTIVE GIANT PANDAS (AILUROPODA MELANOLEUCA) WITH MEDETOMIDINE-KETAMINE.

One male and one female giant panda (Ailuropoda melanoleuca) from a Belgian zoo were anesthetized on eight different occasions over a course of 4 yr for electro-ejaculation (n = 3) or artificial insemination (n = 5). Medetomidine (0.03-0.04 mg/kg) and ketamine (2.5-3 mg/kg) were administered by intramuscular remote injection. Animals gained sternal recumbency with the loss of response to external stimuli after 4.9 ± 1.6 min (mean ± SD). The trachea was intubated with a 14-mm-internal diameter endotracheal tube; anesthesia was maintained with isoflurane in oxygen adjusted according to the required depth of anesthesia with a small-animal circle system. Physiological variables (heart rate, respiratory rate, oxygenation, end tidal carbon dioxide partial pressure and non-invasive blood pressure) were measured and remained within an acceptable range throughout anesthesia. Atipamezole (0.17-0.25 mg/kg) was administered intramuscularly after anesthesia. Recoveries were rapid and uneventful. Medetomidine 0.03 mg/kg and ketamine 2.5 mg/kg IM appeared to be the preferred doses for giant pandas.

Screening for gene doping transgenes in horses via the use of massively parallel sequencing.

Throughout the history of horse racing, doping techniques to suppress or enhance performance have expanded to match the technology available. The next frontier in doping, both in the equine and human sports areas, is predicted to be genetic manipulation; either by prohibited use of genome editing, or gene therapy via transgenes. By using massively-parallel sequencing via a two-step PCR method we can screen for multiple doping targets at once in pooled primer sets. This method has the advantages of high scalability through combinational indexing, and the use of reference standards with altered sequences as controls. Custom software produces transgene-specific amplicons from any Ensembl-annotated genome to facilitate rapid assay design. Additional scripts batch-process FASTQ data from experiments, automatically quality-filtering sequences and assigning hits based on discriminatory motifs. We report here our experiences in establishing the workflow with an initial 31 transgene and vector feature targets. To evaluate the sensitivity of parallel sequencing in a real-world setting, we performed an intramuscular (IM) administration of a control rAAV vector into two horses and compared the detection sensitivity between parallel sequencing and real-time qPCR. Vector was detected by all assays on both methods up to 79 h post-administration, becoming sporadic after 96 h.

Pharmacokinetics of paracetamol in the Thoroughbred horse following an oral multi-dose administration.

Paracetamol is a widely used, non-opioid analgesic and antipyretic drug. Scientific evidence suggests that it is an effective pain treatment in equine medicine. However, there is very little published information about the pharmacokinetics of the drug in the horse. The aim of the research was to determine the pharmacokinetics of paracetamol in equine plasma and urine to inform treatment of Thoroughbred racehorses. In this multi-dose study, paracetamol was administered orally at 20 mg/kg to six Thoroughbred horses. Pre- and post-administration urine and plasma samples were collected and analysed using a quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic analysis of urine and plasma paracetamol clearance profiles was carried out, which enabled the calculation of possible screening limits (SL) that can regulate for a detection time of 120 h. Additionally, an estimation of orthocetamol concentration levels in urine was carried out to investigate any underlying relationship between the para- and ortho-isomers as both were suspected to contribute to basal levels, possibly due to environmental feed sources.

A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

Sedative and antinociceptive effects of different combinations of detomidine and methadone in standing horses.

OBJECTIVE: To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects. STUDY DESIGN: Randomized, placebo-controlled, blinded, crossover. ANIMALS: A group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg. METHODS: A total of six treatments were administered IV: saline (SAL); detomidine (5 µg kg-1; DET); methadone (0.2 mg kg-1; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) µg kg-1]. Thermal, mechanical and electrical nociceptive thresholds were measured, and sedation, head height above ground (HHAG), cardiopulmonary variables and intestinal motility were evaluated at 5, 15, 30, 45, 60, 75, 90, 120 and 180 minutes. Normal data were analyzed by mixed-model analysis of variance and non-normal by Kruskal-Wallis (p < 0.05). RESULTS: Nociceptive thresholds in horses administered methadone with the higher doses of detomidine (MMD, MHD) were increased above baseline to a greater degree and for longer duration (MMD: 15-30 minutes, MHD: 30-60 minutes) than in horses administered low dose with methadone or detomidine alone (MLD, DET: 5-15 minutes). No increases in nociceptive thresholds were recorded in SAL or MET. Compared with baseline, HHAG was lower for 30 minutes in MMD and DET, and for 45 minutes in MHD. No significant sedation was observed in SAL, MET or MLD. Intestinal motility was reduced for 75 minutes in MHD and for 30 minutes in all other treatments. CONCLUSIONS: Methadone (0.2 mg kg-1) potentiated the antinociception produced by detomidine (5 µg kg-1), with minimal sedative effects. CLINICAL RELEVANCE: Detomidine (5 µg kg-1) with methadone (0.2 mg kg-1) produced antinociception without the adverse effects of higher doses of detomidine.

DETOMIDINE AND BUTORPHANOL FOR STANDING SEDATION IN A RANGE OF ZOO-KEPT UNGULATE SPECIES.

General anesthesia poses risks for larger zoo species, like cardiorespiratory depression, myopathy, and hyperthermia. In ruminants, ruminal bloat and regurgitation of rumen contents with potential aspiration pneumonia are added risks. Thus, the use of sedation to perform minor procedures is justified in zoo animals. A combination of detomidine and butorphanol has been routinely used in domestic animals. This drug combination, administered by remote intramuscular injection, can also be applied for standing sedation in a range of zoo animals, allowing a number of minor procedures. The combination was successfully administered in five species of nondomesticated equids (Przewalski horse [ Equus ferus przewalskii; n = 1], onager [ Equus hemionus onager; n = 4], kiang [ Equus kiang ; n = 3], Grevy's zebra [ Equus grevyi ; n = 4], and Somali wild ass [ Equus africanus somaliensis; n = 7]), with a mean dose range of 0.10-0.17 mg/kg detomidine and 0.07-0.13 mg/kg butorphanol; the white ( Ceratotherium simum simum; n = 12) and greater one-horned rhinoceros ( Rhinoceros unicornis ; n = 4), with a mean dose of 0.015 mg/kg of both detomidine and butorphanol; and Asiatic elephant bulls ( Elephas maximus ; n = 2), with a mean dose of 0.018 mg/kg of both detomidine and butorphanol. In addition, the combination was successfully used for standing sedation in six species of artiodactylids: giraffe ( Giraffa camelopardalis reticulata; n = 3), western bongo ( Tragelaphus eurycerus eurycerus; n = 2), wisent ( Bison bonasus ; n = 5), yak ( Bos grunniens ; n = 1), water buffalo ( Bubalus bubalis ; n = 4) and Bactrian camel ( Camelus bactrianus ; n = 5). The mean dose range for artiodactylid species except bongo was 0.04-0.06 mg/kg detomidine and 0.03-0.06 mg/kg butorphanol. The dose in bongo, 0.15-0.20 mg/kg detomidine and 0.13-0.15 mg/kg butorphanol, was considerably higher. Times to first effect, approach, and recovery after antidote were short. The use of detomidine and butorphanol has been demonstrated to be a reliable, safe alternative to general anesthesia for a number of large ungulate species.

Equine anaesthesia-associated mortality: where are we now?

OBJECTIVES: To review the literature concerning mortality associated with general anaesthesia in horses and to assess whether there is evidence for a reduction in mortality over the 20 years since the Confidential Enquiry into Perioperative Equine Fatalities (CEPEF). DATABASES USED: PubMed, Scopus, Google Scholar. Search terms used: horse; pony; equine; anaesthesia; anesthesia; recovery; morbidity, and mortality. CONCLUSIONS: The most recent studies, in which isoflurane and sevoflurane have been more commonly used for anaesthesia maintenance, report fewer intraoperative cardiac arrests than older studies in which halothane was favoured. Catastrophic fractures, however, have become the greatest cause of recovery-associated mortality.

Preliminary investigation comparing a detomidine continuous rate infusion combined with either morphine or buprenorphine for standing sedation in horses.

OBJECTIVE: To compare sedative and analgesic properties of buprenorphine or morphine for standing procedures combined with a detomidine continuous rate infusion (CRI). STUDY DESIGN: Blinded, prospective, randomized clinical pilot study. ANIMALS: Ten horses presented for dental or sinus procedures. METHODS: Horses received 0.02 mg kg(-1) acepromazine intravenously (IV), followed 30 minutes later by detomidine 10 µg kg(-1) IV. Five minutes later, buprenorphine 0.01 mg kg(-1) (n = 6) or morphine 0.1 mg kg(-1) (n = 4) was administered IV. Detomidine was administered by CRI (0.2 µg kg(-1) minute(-1)) and adjusted to maintain appropriate sedation. Heart rate, respiratory frequency, gastrointestinal motility and rectal temperature were measured; pain, ataxia and sedation were scored. Sedation, pain scores and ataxia scores were analysed using a mixed linear model. Detomidine dose and procedure success scores were compared using Wilcoxon's rank sum test. Complications between groups were analysed using Fisher's exact test. RESULTS: Two horses had incomplete data. Weights and ages were not different between groups (p = 0.15 and p = 0.42, respectively). The dose rate for detomidine was not different between groups (0.33 ± 0.02 µg kg(-1) minute(-1) in the buprenorphine group and 0.33 ± 0.05 µg kg(-1) minute(-1), in the morphine group p = 0.89). Intraoperative visual analogue scale scores were greater after buprenorphine than morphine (mean ± SD, buprenorphine 48 ± 4, morphine 40 ± 5, p = 0.0497). Procedure duration was not different between groups (buprenorphine 142 ± 33, morphine 140 ± 12 minutes). All horses treated with buprenorphine experienced complications compared with none in the morphine group (p = 0.0286). CONCLUSIONS AND CLINICAL RELEVANCE: At the doses used, buprenorphine produced greater sedation but more post-operative complications than morphine. However, Type I or Type II errors cannot be excluded and larger studies are required to confirm these findings.

Factors affecting mechanical nociceptive thresholds in healthy sows.

OBJECTIVE: To describe anatomical and methodological factors influencing mechanical nociceptive thresholds (MNTs) and intra-site variability in healthy sows. STUDY DESIGN: Prospective, randomized validation. ANIMALS: Eight pregnant, healthy, mixed-parity sows (176-269 kg). METHODS: Repeated MNT measurements were taken: 1) with a hand-held probe and a limb-mounted actuator connected to a digital algometer; 2) at nine landmarks on the limbs and tail; and 3) at 1 and 3 minute intervals. Data were analysed using linear mixed regression models. RESULTS: The MNTs (±SEM) of the limbs were lower with the probe (14.7 ± 1.2 N) than with the actuator (21.3 ± 1.2 N; p < 0.001), in the pelvic versus the thoracic limbs (16.7 ± 1.2 versus 19.2 ± 1.2 N; p < 0.001), and in the lateral versus the dorsal metatarsi and metacarpi (17.6 ± 1.2 versus 18.4 ± 1.2 N; p = 0.002). MNTs were higher in all subsequent measurements compared with the first (p < 0.001) and in the morning compared with the afternoon (p = 0.04). We found no evidence of MNT differences based on interval between consecutive measurements (1 versus 3 minutes). Variability was lower in the thoracic limbs [mean back-transformed log10 coefficient of variation (CV) ± SE = 25.5 ± 1.5% versus 30.6 ± 1.5% in the pelvic limbs; p < 0.001], with the actuator (22.7 ± 1.5% versus 33.4 ± 1.5% with the probe; p < 0.001), and on the left (CV = 26.9 ± 1.5% versus 29.3 ± 1.5% on the right; p = 0.01). Tail data (probe only) were analysed separately: mean MNT (± SE) was 11.7 (±1.8); MNT increased in days 3-6 of testing compared with day 1 (p < 0.001). The mean CV (±SE) was 38.9% (±1.1%). CONCLUSIONS AND CLINICAL RELEVANCE: MNTs and intra-site variability in healthy sows were affected by several factors, indicating that this methodology requires considerable attention to detail.

Clinical effects and pharmacokinetic variables of romifidine and the peripheral α2 -adrenoceptor antagonist MK-467 in horses.

OBJECTIVES: To investigate the effects of MK-467 on sedation quality, and cardiopulmonary and pharmacokinetic variables in horses sedated intravenously (IV) with romifidine. STUDY DESIGN: Experimental, randomized, crossover design. ANIMALS: Seven healthy mares. METHODS: Romifidine (80 µg kg-1 ; R) and MK-467 (200 µg kg-1 ; MK) were administered IV alone and in combination (R + MK). Levels of sedation and borborygmi were scored. Heart rate (HR), direct arterial blood pressure (ABP) and respiratory rate (fR ) were recorded. Arterial and venous blood gas analyses were performed and venous plasma drug concentrations were measured. Pharmacokinetic parameters were calculated. Linear mixed modelling for repeated measures, contrasts of least square means by Bonferroni correction tests, one-way anova for repeated measures with Bonferroni multiple comparison tests and paired Student's t-tests were used to compare results within and between treatments as appropriate. Significance was set at p < 0.05. RESULTS: After R, ABP increased and HR and fR decreased significantly. After R + MK, HR, fR , systolic and mean ABP decreased. MK alone increased both HR and fR . After R, ABP was significantly higher than after R + MK. HR and fR were significantly higher after MK than after R and R + MK. Areas under the curve for sedation time were similar after R and R + MK. Intestinal activity decreased markedly after R and less after R + MK. Volume of distribution and clearance of romifidine were significantly higher and area under the concentration time curve extrapolated to infinity significantly lower after R + MK than after R. CONCLUSIONS: Combined romifidine and MK-467 prevented the cardiovascular changes commonly seen with romifidine but did not affect sedation quality. CLINICAL RELEVANCE: Combined IV romifidine and MK-467 can be used to attenuate the cardiovascular effects of romifidine, such as in horses with colic or undergoing general anaesthesia.

Mechanical nociceptive thresholds using four probe configurations in horses.

OBJECTIVE: To examine the relationship between probe tip size and force readings of mechanical nociceptive thresholds (MTs) to identify appropriate probes for horses. STUDY DESIGN: Randomized, crossover study. ANIMALS: Eight adult, mixed-breed horses aged 5-10 years, weighing 268-460 kg. METHODS: Four probe configurations (PCs) were used in random sequence: 1.0 mm diameter (SHARP); 3.2 mm (BLUNT); spring-mounted 1.0 mm (SPRING), and 3 × 2.5 mm (3PIN). A remote-controlled unit on the horse increased force (1.2 N second(-1)) in a pneumatic actuator on the metacarpus. Mean MT for each PC was calculated from 10 readings for each horse. Data were log-transformed for analysis using mixed-effects anova/linear regression (p < 0.05). Variability of data for each PC was assessed using the coefficient of variation (CV). RESULTS: Mean ± standard deviation MTs were: SHARP, 5.6 ± 2.3 N; BLUNT, 11.4 ± 3.4 N; 3PIN, 9.6 ± 4.6 N, and SPRING 6.4 ± 1.8 N. Mean MT for SHARP was significantly lower than for BLUNT (p < 0.001) and 3PIN (p < 0.001), but not different from SPRING (p > 0.05). Mean MT was significantly higher for BLUNT than for 3PIN (p < 0.05) and SPRING (p < 0.001). Mean MT for 3PIN was significantly higher than for SPRING (p < 0.001). Larger contact area PCs produced higher MTs than smaller PCs, but the relationship was not linear. BLUNT (area: 10-fold greater) gave a MT two-fold higher than SHARP. 3PIN (area: 20-fold greater) produced more variable MTs, less than two-fold higher than SHARP. SPRING was similar to SHARP. CVs were: SHARP, 22.9%; BLUNT, 72.3%; 3PIN, 44.2%, and SPRING, 28.7%. CONCLUSIONS AND CLINICAL RELEVANCE: The PC has nonlinear effects on MT. Therefore, it is important to define PC when measuring MT. Smaller probe tips may be preferable as MT data are less variable.

Refinement and partial validation of the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in horses.

BACKGROUND: Quantification of pain plays a vital role in the diagnosis and management of pain in animals. In order to refine and validate an acute pain scale for horses a prospective, randomized, blinded study was conducted. Twenty-four client owned adult horses were recruited and allocated to one of four following groups: anaesthesia only (GA); pre-emptive analgesia and anaesthesia (GAA,); anaesthesia, castration and postoperative analgesia (GC); or pre-emptive analgesia, anaesthesia and castration (GCA). One investigator, unaware of the treatment group, assessed all horses at time-points before and after intervention and completed the pain scale. Videos were also obtained at these time-points and were evaluated by a further four blinded evaluators who also completed the scale. The data were used to investigate the relevance, specificity, criterion validity and inter- and intra-observer reliability of each item on the pain scale, and to evaluate construct validity and responsiveness of the scale. RESULTS: Construct validity was demonstrated by the observed differences in scores between the groups, four hours after anaesthetic recovery and before administration of systemic analgesia in the GC group. Inter- and intra-observer reliability for the items was only satisfactory. Subsequently the pain scale was refined, based on results for relevance, specificity and total item correlation. CONCLUSIONS: Scale refinement and exclusion of items that did not meet predefined requirements generated a selection of relevant pain behaviours in horses. After further validation for reliability, these may be used to evaluate pain under clinical and experimental conditions.

Ranking the harm of non-medically used prescription opioids in the UK.

A panel of nine experts applied multi-criteria decision analysis (MCDA) to determine the relative overall harm to users and harms to others of street heroin (injected and smoked) and eleven non-medically used prescription opioids. The experts assessed harm scores for each of the 13 opioids on each of 20 harm criteria, weighted the criteria and explored the resulting weighted harm scores for each opioid. Both forms of heroin scored very high: overall harm score of 99 for injected heroin and 72 for smoked heroin on a scale of 0-100. The main feature that distinguishes both forms of street heroin use is that their harm to others is more than five times that of the other eleven opioids. The overall harm score of fentanyl (including injection of fentanyl extracted from patches) and diamorphine (medically prescribed form of heroin) was 54 and 51, respectively, whereas that of orally used opioids ranged from 32 (pethidine) to 11 (codeine-containing pharmaceuticals). Injected street heroin, fentanyl and diamorphine emerged as most harmful to users, with the latter two very low in harm to others. Pethidine, methadone, morphine and oxycodone are also low in harm to others, while moderate in harm to users. We conclude that the overall harms of non-medically used prescription opioids are less than half that of injected street heroin. These data may give a basis for precautionary regulatory measures that should be considered if the rising trend in non-medical use of prescription opioids were to become evident in the UK.

Comparison of midazolam and diazepam as co-induction agents with ketamine for anaesthesia in sedated ponies undergoing field castration.

OBJECTIVE: To compare intravenous (IV) midazolam and diazepam administered with ketamine for induction of anaesthesia in ponies, already sedated with detomidine, undergoing field castration. STUDY DESIGN: Prospective, randomised, 'blinded', clinical study. ANIMALS: Twenty Welsh pony yearlings. METHODS: After IV injection of detomidine (20 µg kg(-1) ) and phenylbutazone (4.4 mg kg(-1) ) ponies were allocated to receive either IV midazolam (group M) or diazepam (group D) (both 0.06 mg kg(-1) ) with ketamine (2.2 mg kg(-1) ) for induction of anaesthesia. Using simple descriptive scales, quality of sedation, induction, endotracheal intubation, surgical conditions and recovery were scored by observers blinded to treatment. Time from sedation to induction of anaesthesia, IV injection to lateral recumbency, induction to start of surgery, induction to first head lift and to standing, and total surgical time were measured. Cardiorespiratory function was assessed every 5 minutes. Time, number and total quantity of additional IV ketamine as well as any adverse effects were documented. Data were tested for normality and analysed using two-way anova with Bonferroni post hoc tests, unpaired t-tests and Mann-Whitney U tests as appropriate. Significance was set at p < 0.05. RESULTS: There were no significant group differences in any of the measured variables except bodyweight (mean ± SD: group M 163 ± 12 kg; group D 150 ± 7 kg; p = 0.01). One pony in group M required ketamine 15 minutes after induction of anaesthesia. Surgical conditions were good in all cases; time from induction to standing was 50 ± 11 minutes in group M and 48 ± 12 minutes in group D. There were no adverse effects. Recoveries were uneventful with minimal ataxia. CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam and diazepam at 0.06 mg kg(-1) can be used interchangeably in combination with ketamine for IV induction of short term anaesthesia in ponies.

Pharmacokinetic-pharmacodynamic modelling of intravenous buprenorphine in conscious horses.

OBJECTIVE: Describe the pharmacokinetics of buprenorphine and norbuprenorphine in horses and to relate the plasma buprenorphine concentration to the pharmacodynamic effects. STUDY DESIGN: Single phase non-blinded study. ANIMALS: Six dedicated research horses, aged 3-10 years and weighing 480-515 kg. METHODS: Thermal and mechanical nociceptive thresholds, heart and respiratory rates and locomotor activity were measured before and 15, 30, 45 & 60 minutes and 2, 4, 6, 8, 12 & 24 hours post-administration of 10 µg kg(-1) buprenorphine IV. Intestinal motility was measured 1, 6, 12 & 24 hours after buprenorphine administration. Venous blood samples were obtained before administration of buprenorphine 10 µg kg(-1) IV and 1, 2, 4, 6, 10, 15, 30, 45 & 60 minutes, and 2, 4, 6, 8, 12 & 24 hours afterwards. Plasma buprenorphine and norbuprenorphine concentrations were measured using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay with solid-phase extraction. A non-compartmental method was used for analysis of the plasma concentration-time data and plasma buprenorphine concentrations were modelled against two dynamic effects (change in thermal threshold and mechanical threshold) using a simple Emax model. RESULTS: Plasma buprenorphine concentrations were detectable to 480 minutes in all horses and to 720 minutes in two out of six horses. Norbuprenorphine was not detected. Thermal thresholds increased from 15 minutes post-buprenorphine administration until the 8-12 hour time points. The increase in mechanical threshold ranged from 3.5 to 6.0 Newtons (median: 4.4 N); and was associated with plasma buprenorphine concentrations in the range 0.34-2.45 ng mL(-1) . CONCLUSIONS AND CLINICAL RELEVANCE: The suitability of the use of buprenorphine for peri-operative analgesia in the horse is supported by the present study.

Evaluation of sedation for standing clinical procedures in horses using detomidine combined with buprenorphine.

OBJECTIVES: To examine the effect of including buprenorphine with detomidine for sedation of horses undergoing clinical procedures. STUDY DESIGN: Partially blinded, randomised, prospective clinical field trial. ANIMALS: Eighty four client-owned horses scheduled for minor surgery or diagnostic investigation under standing sedation. METHODS: The effects of buprenorphine (5 µg kg(-1) ) (Group B, n = 46) or placebo (5% glucose solution) (Group C, n = 38) in combination with detomidine (10 µg kg(-1) ) were compared in standing horses undergoing minor clinical procedures. The primary outcome measure was successful completion of the procedure. The degree of sedation and ataxia were scored using simple descriptive scales. Heart and respiratory rates were recorded at 15-30 minute intervals. Parametric data from each group were compared using anova or t-test and non parametric data using the Mann-Whitney U test. RESULTS: The procedure was carried out successfully in 91% of Group B and 63% of Group C (p < 0.01). Repeat dosing was required in 24% of Group B and 32% of Group C (p < 0.05). Sedation was more profound and lasted longer (60 versus 45 minutes) in Group B (p < 0.01). Ataxia occurred after detomidine, increased after buprenorphine but not glucose administration, was more profound in group B and lasted longer (60 versus 30 minutes) p < 0.001). Heart and respiratory rates remained within normal limits in both groups and there were no serious adverse events. CONCLUSIONS AND CLINICAL RELEVANCE: Buprenorphine 5 and 10 µg kg(-1) enhanced the sedation produced by detomidine 10 and 20 µg kg(-1) with minor side effects similar to other alpha2 agonist/opioid combinations. Detomidine-buprenorphine sedation is suitable for standing procedures in horses.

Thermal and mechanical nociceptive threshold testing in pregnant sheep.

OBJECTIVE: Analgesic regimes were compared in pregnant ewes after laparotomy by measuring thermal (TT) and mechanical (MT) nociceptive thresholds. STUDY DESIGN: Prospective randomised experimental study. ANIMALS: Pregnant ewes at 121 days gestation underwent laparotomy as part of another research project. METHODS: Thermal and mechanical thresholds were measured before, and 2, 6, 24 and 48 hours after surgery. Thermal stimuli were delivered to the lateral aspect of the metatarsus via a skin-mounted probe, and mechanical stimuli to the contralateral site via a pneumatically driven 1.5 mm diameter pin. Each test was performed five times, alternating thermal and mechanical stimuli, with ten minutes between thermal stimuli. At the end of surgery ewes received either: 75 µg hour(-1) transdermal fentanyl patch (medial thigh) (group FP) (n = 8), or 3 µg kg(-1 ) hour(-1) intra-peritoneal medetomidine via an osmotic pump (group IPM) (n = 8) inserted immediately prior to closure. Data were analysed using the Kruskal-Wallis RS Test (p < 0.05). Once a significant effect was identified, pairwise comparisons were performed using paired Wilcoxon RS tests. To compensate for multiple hypotheses testing, p < 0.005 was considered significant. RESULTS: Prior to surgery mean ± SD TT was 56.1 ± 5.0 °C (FP) and 55.6 ± 5.0 °C (IPM); MT was 5.3 ± 2.6 N (FP) and 8.0 ± 5.0 N (IPM). In FP there was no significant change in either TT or MT over time. In IPM there was no significant change in MT over time but TT increased at two hours to 59.2 ± 3.0 °C (p = 0.003). Skin temperature (ST) ranged from 33.0 to 34.7 °C and did not change over time. There were no significant differences between groups in TT, MT or ST. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of intra-peritoneal medetomidine (3 µg kg(-1 ) hour(-1) ) by an osmotic pump increases the thermal nociceptive threshold in the immediate post operative period in pregnant sheep, suggesting that this agent may have a role in providing post-operative analgesia.

The influence of various confounding factors on mechanical nociceptive thresholds in the donkey.

OBJECTIVE: To evaluate a mechanical nociceptive threshold (MNT) testing device in the donkey, and to investigate the influence of potential confounders on MNTs generated. STUDY DESIGN: Prospective, randomised. ANIMALS: Sixteen castrated male donkeys aged 4-9 years, weighing 105-170 kg. METHODS: Mechanical nociceptive thresholds were measured using an actuator with three pins placed on the dorsal aspect of the distal limb, connected to a force meter. The pins (surface area 15 mm(2) ) were extruded onto the limb by pressurising an air-filled syringe, until the MNT force (when foot-lift was observed) or 25 N (cut-off force) was reached. Effect on MNT of presence of a companion donkey, the limb tested, rate of application of force, testing location, level of distraction, ambient temperature and hair cover at the test site was evaluated. Long and short-term repeatability of MNT was assessed. Data were analysed using general linear models and Mann-Whitney U tests, p < 0.05 was considered significant. RESULTS: Increasing the rate of force application significantly increased the mean ± SD MNT from 9.2 ± 2.0 N when applied at 0.4 N sec(-1) to 10.6 ± 2.1 N when applied at 1.2 N sec(-1) (p = 0.001). No other factors significantly influenced MNT. Mean MNT remained stable over a 3 week period, however MNTs were significantly (p = 0.006) higher (12.8 ± 3.0 N cf 10.3 ± 1.9 N) after a 12 month interval. CONCLUSIONS AND CLINICAL RELEVANCE: When designing studies measuring MNT in donkeys, rate of application of force must be standardised. Donkeys' MNTs have good short-term stability suggesting this technique is appropriate for short-term analgesiometry studies; however variability of MNTs over the long-term is greater.

Detection of FG-4592 and metabolites in equine plasma, urine and hair following oral administration.

FG-4592 is a hypoxia-inducible factor inhibitor that has been approved for therapeutic use in some countries. This class of compounds can increase the oxygen carrying capacity of the blood and thus have the potential to be used as performance enhancing agents in sports. The purpose of this study was to investigate the detection of FG-4592 and metabolites in equine plasma and mane hair following a multiple dose oral administration to two Thoroughbred racehorses, to identify the best analytical targets for doping control laboratories. Urine samples were also analysed, and the results compared to previously published urine data. Liquid chromatography-high resolution mass spectrometry was used for metabolite identification in urine and plasma. Liquid chromatography-tandem mass spectrometry was used for full sample analysis of urine, plasma and hair samples and generation of urine and plasma profiles. FG-4592 and a mono-hydroxylated metabolite were detected in plasma. FG-4592 was detected with the greatest abundance and gave the longest duration of detection, up to 312 h post-administration, and would be the recommended target in routine doping samples. FG-4592 was detected in all mane hair samples collected post-administration, up to 166 days following the final dose, showing extended detection can be achieved with this matrix. To the best of the authors' knowledge, this is the first report of FG-4592 and metabolites in equine plasma and hair samples. Urine results were consistent with the previously published data, with FG-4592 offering the best target for detection and longest detection periods.