Data Collection for the Fourth Multicentre Confidential Enquiry into Perioperative Equine Fatalities (CEPEF4) Study: New Technology and Preliminary Results.

It is almost 20 years since the largest observational, multicentre study evaluating the risks of mortality associated with general anaesthesia in horses. We proposed an internet-based method to collect data (cleaned and analysed with R) in a multicentre, cohort, observational, analytical, longitudinal and prospective study to evaluate peri-operative equine mortality. The objective was to report the usefulness of the method, illustrated with the preliminary data, including outcomes for horses seven days after undergoing general anaesthesia and certain procedures using standing sedation. Within six months, data from 6701 procedures under general anaesthesia and 1955 standing sedations from 69 centres were collected. The results showed (i) the utility of the method; also, that (ii) the overall mortality rate for general anaesthesia within the seven-day outcome period was 1.0%. In horses undergoing procedures other than exploratory laparotomy for colic ("noncolics"), the rate was lower, 0.6%, and in "colics" it was higher, at 3.4%. For standing sedations, the overall mortality rate was 0.2%. Finally, (iii) we present some descriptive data that demonstrate new developments since the previous CEPEF2. In conclusion, horses clearly still die unexpectedly when undergoing procedures under general anaesthesia or standing sedation. Our method is suitable for case collection for future studies.

Sevoflurane or isoflurane anaesthesia? A prospective, randomised blinded clinical trial in horses undergoing elective surgery.

BACKGROUND: Isoflurane is the only volatile anaesthetic agent licensed for equine use in the United Kingdom, but sevoflurane is also commonly used. The two agents have rarely been compared for use in clinical elective surgery. METHODS: This single centre, prospective, randomised, blinded clinical investigation recruited 101 healthy client owned horses undergoing elective surgery. Anaesthesia was standardised and horses randomly assigned to receive isoflurane (I) or sevoflurane (S) for maintenance of anaesthesia in 100% oxygen. Horses were ventilated to normocapnia and received intravenous fluid therapy and haemodynamic support with dobutamine to maintain mean arterial blood pressure above 60 mm Hg. Recovery was timed and video-recorded to allow offline evaluation by two experienced clinicians unaware of the volatile agent used. No post-anaesthetic sedation was administered. RESULTS: There was no significant difference between groups in terms of haemodynamic support required during anaesthesia nor in quality or duration of recovery. Inotropic support to maintain MAP above 60 mm Hg was required by 67 of 101 (67%) of horses. Five horses in the I group required additional ketamine or thiopentone to improve the plane of anaesthesia. CONCLUSIONS: Haemodynamic support needed during anaesthesia as well as the duration and quality of recovery were similar with isoflurane and sevoflurane.

Comparing paracetamol/codeine and meloxicam for postoperative analgesia in dogs: a non-inferiority trial.

BACKGROUND: There are limited published data on the analgesic efficacy of paracetamol/codeine in dogs. METHODS: Prospective, randomised, blinded, positive-controlled clinical trial with 70 dogs (paracetamol/codeine, n=46; meloxicam, n=24) undergoing surgery. Drugs were administered orally 2 hours before and for 48 hours after surgery at the licensed dose. Anaesthesia was standardised. Dogs received buprenorphine 6 hourly for the first 24 hours after surgery. Outcome assessments were made pretrial and at regular intervals up to 48 hours after extubation and comprised the Glasgow Composite Measure Pain Score-Short Form, visual analogue scale for sedation and inflammation and mechanical nociceptive threshold (MNT). Non-inferiority of paracetamol/codeine compared with meloxicam was defined using a non-inferiority margin (Δ) against the 95 per cent confidence interval of the difference between the treatment means. RESULTS: Pain scores were low in both treatment groups. With the exception of MNT all upper 95 per cent confidence intervals for the differences between outcome variable treatment means were within +Δ for each variable, establishing non-inferiority for each outcome variable. CONCLUSIONS: Paracetamol/codeine is a useful perioperative analgesic that within the context of the perioperative analgesia regimen studied (methadone premedication, buprenorphine for the first 24 hours after surgery) shows non-inferiority to the NSAID meloxicam.

Mechanical nociceptive thresholds in endurance horses.

BACKGROUND: Alteration of limb sensitivity is forbidden in equine sports but difficult to enforce. We aimed to develop an objective field method to assess mechanical nociceptive threshold (MNT) in endurance horses. METHODS: A remotely controlled pneumatic actuator (1 mm tip) was used to measure forelimb pastern MNT in 108 endurance horses. RESULTS: Median (IQR) MNT at rest was 1.9 N (0.9-3.5). Icing had no significant effect on limb sensitivity. MNT measured at weekly intervals increased from week 1 (1.2 N (0.6-1.8)) to week 3 (1.9 N (1.2-2.8)) (P<0.05). In 17 horses without impaired sensitivity, MNT increased from 1.2 N (0.6-2.3) before to 2.4 N (1.2-5.2) after racing (P=0.0017). In desensitised horses, MNT after racing was higher (8 limbs-23.1 N (21.4 to >25)) than in horses without impaired sensitivity (42 limbs-2.2 N (1.2-4.3)) (P<0.0001). Desensitisation with mepivacaine increased MNT to above the safety cut-off (25 N) at 10 minutes; sensitivity return to baseline varied between individuals but was restored by 330 minutes. None of the horses became averse to the technique. CONCLUSION: MNT was practical, non-traumatic, repeatable and well tolerated under field conditions in endurance horses. The technique differentiated postracing MNT in horses with normal sensitivity from those with impaired sensitivity.

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).

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.

Drawing the line in clinical treatment of companion animals: recommendations from an ethics working party.

Modern veterinary medicine offers numerous options for treatment and clinicians must decide on the best one to use. Interventions causing short-term harm but ultimately benefitting the animal are often justified as being in the animal's best interest. Highly invasive clinical veterinary procedures with high morbidity and low success rates may not be in the animal's best interest. A working party was set up by the European College of Veterinary Anaesthesia and Analgesia to discuss the ethics of clinical veterinary practice and improve the approach to ethically challenging clinical cases. Relevant literature was reviewed. The 'best interest principle' was translated into norms immanent to the clinic by means of the 'open question argument'. Clinical interventions with potential to cause harm need ethical justification, and suggest a comparable structure of ethical reflection to that used in the context of in vivo research should be applied to the clinical setting. To structure the ethical debate, pertinent questions for ethical decision-making were identified. These were incorporated into a prototype ethical tool developed to facilitate clinical ethical decision-making. The ethical question 'Where should the line on treatment be drawn' should be replaced by 'How should the line be drawn?'

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.

Sedative and cardiopulmonary effects of dexmedetomidine infusions randomly receiving, or not, butorphanol in standing horses.

Dexmedetomidine (DEX) alone, or combined with butorphanol (BUT), may be administered by constant rate infusions (CRIs) in standing horses. This blinded, randomised, crossover study in six healthy adult horses aimed to determine the sedative and cardiopulmonary effects of DEX (dexmedetomidine (3.5 µg/kg+5 µg/kg/hour CRI) and DEX/BUT (dexmedetomidine (3.5 µg/kg+3.5 µg/kg/hour CRI) and butorphanol (20 µg/kg+24 µg/kg/hour CRI)). Head height above ground (HHAG), ataxia, responses to tactile/auditory stimuli and cardiopulmonary variables were recorded before, at 5/15/30/60/90 minutes and after CRIs terminated (15/30/60 minutes). Repeated measures analysis of variance with Tukey-Kramer test were used for cardiopulmonary values (mean±SD) and HHAG reduction (per cent), and Friedman's and Dunn's for non-parametric data (P<0.05). Maximum HHAG reductions of 54 per cent (DEX) and 58 per cent (DEX/BUT) occurred at 15 minutes, with ataxia for 15 minutes in both treatments. Responses to stimuli were reduced for 30 minutes in both treatments, and auditory up to 60 minutes in DEX. Cardiopulmonary effects typical of α2-agonists were observed, with no differences between treatments. At the doses and rates reported here, both regimens provided clinically sufficient sedation for only 30 minutes.

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.

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.

Effect of intramuscular methadone on pharmacokinetic data and thermal and mechanical nociceptive thresholds in the cat.

Objectives The aim of the study was to assess simultaneous pharmacokinetics and thermal and mechanical antinociception after intramuscular methadone (0.6 mg/kg) in 10 cats. Methods Thermal and mechanical threshold (TT and MT, respectively) testing and blood collection were conducted at baseline and up to 24 h after administration. Methadone plasma concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated by a non-compartmental method. TT and MT were analysed using ANOVA ( P <0.05). Time of maximum plasma concentration (Tmax), time of onset of antinociception and time of reaching cut-out threshold (TT 55°C; MT 30 Newtons [N]) were determined. Results TT and MT increased above baseline from 20-240 mins and 5-40 mins, respectively, after intramuscular (IM) administration ( P <0.005). Mean maximum delta T (measured as TT minus baseline threshold) was 7.9°C (95% confidence interval [CI] 4.3-11.6) at 60 mins and mean maximum delta F (measured as MT minus baseline threshold) was 4.2 (95% CI 1.6-6.7) N at 45 mins. IM methadone concentration-time data decreased curvilinearly, and gave a clearance estimate of mean 9.1 ml/kg/min (range 5.2-15.7) with median Tmax at 20 mins (range 5-360 mins). Conclusions and relevance IM data followed classical disposition and elimination in all cats. Plasma concentrations after IM administration were associated with an antinociceptive effect, including negative hysteresis. These data can be used for devising dosing schedules for methadone in clinical feline practice.

Injectable anaesthesia for adult cat and kitten castration: effects of medetomidine, dexmedetomidine and atipamezole on recovery.

Objectives Rapid recovery from injectable anaesthesia benefits cat shelter neutering programmes. The effects of medetomidine, dexmedetomidine and atipamezole on recovery were evaluated in adult cats and kittens (⩽6 months old). Methods One hundred healthy male cats (age range 2-66 months, weight range 0.7-5.3 kg) admitted forneutering were randomly allocated to groups of 25. Anaesthesia was induced with 60 mg/m2 ketamine, 180 µg/m2 buprenorphine, 3 mg/m2 midazolam and either 600 µg/m2 medetomidine (groups M and MA) or 300 µg/m2 dexmedetomidine (groups D and DA) intramuscularly (IM). Groups MA and DA also received 1.5 mg/m2 atipamezole IM after 40 mins. Preparation time, surgical time, and times to sternal recumbency and standing were recorded. Data were analysed using the Kruskall-Wallis test, unpaired t-tests and ANOVA. Statistical significance was deemed to be P ⩽0.05. Results Groups did not differ significantly in age, body weight, preparation or surgical time. The time to sternal recumbency in group MA (64 ± 34 mins) was less than in group M (129 ± 32 mins), and in group DA it was less than in group D (54 ± 6 mins vs 110 ± 27 mins) ( P <0.001). There were no differences in duration of recovery to sternal recumbency between groups M and D or MA and DA. The time to standing in group MA (79 ± 51 mins) was less than in group M (150 ± 38 mins) ( P <0.001), and in group DA it was less than in group D (70 ± 22 mins vs 126 ± 27 mins) ( P <0.01). Time to standing in group D (126 ± 27 mins) was less than in group M (150 ± 38 mins) (P <0.05). Time to standing in groups DA and MA were not different. Kittens recovered faster than adults after atipamezole. Minimal adverse effects were seen. Conclusions and relevance Atipamezole reliably reduced recovery time after anaesthesia incorporating either dexmedetomidine or medetomidine; however, the choice of dexmedetomidine or medetomidine had little effect. Recovery was faster in kittens.

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.

Pharmacokinetic and pharmacodynamic evaluation of high doses of buprenorphine delivered via high-concentration formulations in cats.

OBJECTIVES: To evaluate the potential benefits of high-dose buprenorphine formulations for analgesia in cats, serial and crossover studies were undertaken to investigate their pharmacokinetics and thermal antinociceptive effects. METHODS: Twelve healthy adult domestic shorthair cats (6.0 ± 1.1 kg body weight) were studied. Aqueous solutions of buprenorphine hydrochloride at 0, 0.02, 0.06, 0.12 and 0.24 mg/kg body weight and formulations containing 0, 0.3, 0.6 and 1.2 mg/ml with and without preservatives were given subcutaneously. Blood samples were taken and thermal threshold (TT) measured prior to and at regular time points up to 72 h after dosing. Descriptive statistics and analyses of variance were applied as appropriate. RESULTS: Baseline TT was 47.6 ± 4.1°C, which increased in all groups treated with all buprenorphine dosages and formulations. After doses of 0.12 mg/kg and above, TT was significantly higher than baseline at most time points from 1-30 h post-treatment. The time to maximum effect (Tmax) ranged between 0.25 and 2.00 h; and plasma concentrations associated with maximum antinociceptive effect (Cmax) were 1.01-1.72 ng/ml after the 0.02 mg/kg dose, 1.4-4.9 ng/ml after the 0.06 mg/kg dose, 4.6-51.4 ng/ml after the 0.12 mg/kg dose and 5.3-22.3 ng/ml after the 0.24 mg/kg dose. The range of estimates for the buprenorphine elimination half-life were as follows: 0.02 mg/kg = 1.35-5.33 h; 0.06 mg/kg = 16.1-31.2 h; 0.12 mg/kg = 10.1-34.0 h; and 0.24 = mg/kg 16.1-31.6 h. The mean 'plasma concentration for the offset of analgesia' was 2.3 ± 2.0 ng/ml. No adverse effects were seen. The addition of preservatives to a high-concentration buprenorphine formulation had no impact on antinociception nor any side effects. CONCLUSIONS AND RELEVANCE: Aqueous high-concentration buprenorphine formulations administered at 0.12 or 0.24 mg/kg have potential for clinical use in cats, providing prolonged antinociception in a single subcutaneous injection of minimal dose volume.

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.

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.

Evoked temporal summation in cats to highlight central sensitization related to osteoarthritis-associated chronic pain: a preliminary study.

In cats, osteoarthritis causes significant chronic pain. Chronicity of pain is associated with changes in the central nervous system related to central sensitization, which have to be quantified. Our objectives were 1) to develop a quantitative sensory testing device in cats for applying repetitive mechanical stimuli that would evoke temporal summation; 2) to determine the sensitivity of this test to osteoarthritis-associated pain, and 3) to examine the possible correlation between the quantitative sensory testing and assessment using other pain evaluation methods. We hypothesized that mechanical sub-threshold repetitive stimuli would evoke temporal summation, and that cats with osteoarthritis would show a faster response. A blinded longitudinal study was performed in 4 non-osteoarthritis cats and 10 cats with naturally occurring osteoarthritis. Quantification of chronic osteoarthritis pain-related disability was performed over a two week period using peak vertical force kinetic measurement, motor activity intensity assessment and von Frey anesthesiometer-induced paw withdrawal threshold testing. The cats afflicted with osteoarthritis demonstrated characteristic findings consistent with osteoarthritis-associated chronic pain. After a 14-day acclimation period, repetitive mechanical sub-threshold stimuli were applied using a purpose-developed device. Four stimulation profiles of predetermined intensity, duration and time interval were applied randomly four times during a four-day period. The stimulation profiles were different (P<0.001): the higher the intensity of the stimulus, the sooner it produced a consistent painful response. The cats afflicted with osteoarthritis responded more rapidly than cats osteoarthritis free (P = 0.019). There was a positive correlation between the von Frey anesthesiometer-induced paw withdrawal threshold and the response to stimulation profiles #2 (2N/0.4 Hz) and #4 (2N/0.4 Hz): Rhos = 0.64 (P = 0.01) and 0.63 (P = 0.02) respectively. This study is the first report of mechanical temporal summation in awake cats. Our results suggest that central sensitization develops in cats with naturally occurring osteoarthritis, providing an opportunity to improve translational research in osteoarthritis-associated chronic pain.