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.

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.

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.

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.

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.

Sedative and analgesic effects of buprenorphine, combined with either acepromazine or dexmedetomidine, for premedication prior to elective surgery in cats and dogs.

OBJECTIVE: To evaluate the sedative and analgesic effects of intramuscular buprenorphine with either dexmedetomidine or acepromazine, administered as premedication to cats and dogs undergoing elective surgery. STUDY DESIGN: Prospective, randomized, blinded clinical study. ANIMALS: Forty dogs and 48 cats. METHODS: Animals were assigned to one of four groups, according to anaesthetic premedication and induction agent: buprenorphine 20 µg kg(-1) with either dexmedetomidine (dex) 250 µg m(-2) or acepromazine (acp) 0.03 mg kg(-1), followed by alfaxalone (ALF) or propofol (PRO). Meloxicam was administered preoperatively to all animals and anaesthesia was always maintained using isoflurane. Physiological measures and assessments of pain, sedation and mechanical nociceptive threshold (MNT) were made before and after premedication, intraoperatively, and for up to 24 hours after premedication. Data were analyzed with one-way, two-way and mixed between-within subjects anova, Kruskall-Wallis analyses and Chi squared tests. Results were deemed significant if p ≤ 0.05, except where multiple comparisons were performed (p ≤ 0.005). RESULTS: Cats premedicated with dex were more sedated than cats premedicated with acp (p < 0.001) and ALF doses were lower in dex cats (1.2 ± 1.0 mg kg(-1) ) than acp cats (2.5 ± 1.9 mg kg(-1)) (p = 0.041). There were no differences in sedation in dogs however PRO doses were lower in dex dogs (1.5 ± 0.8 mg kg(-1) ) compared to acp dogs (3.3 ± 1.1 mg kg(-1) ) (p < 0.001). There were no differences between groups with respect to pain scores or MNT for cats or dogs. CONCLUSION: Choice of dex or acp, when given with buprenorphine, caused minor, clinically detectable, differences in various characteristics of anaesthesia, but not in the level of analgesia. CLINICAL RELEVANCE: A combination of buprenorphine with either acp or dex, followed by either PRO or ALF, and then isoflurane, accompanied by an NSAID, was suitable for anaesthesia in dogs and cats undergoing elective surgery. Choice of sedative agent may influence dose of anaesthetic induction agent.

Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats.

OBJECTIVE: To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats. STUDY DESIGN: Randomized, prospective, blinded, three period crossover experiment. ANIMALS: Six healthy adult cats weighing 4.1±0.5 kg. METHODS: Buprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics. RESULTS: TT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: I.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.

A study to evaluate buprenorphine at 40 µg kg(-1) compared to 20 µg kg(-1) as a post-operative analgesic in the dog.

OBJECTIVE: Comparison of the analgesic effect of buprenorphine at 20 or 40 µg kg(-1) . STUDY DESIGN: An investigator 'blinded', randomised study. ANIMALS: Twenty six dogs presented for ovariohysterectomy. METHODS: Dogs were premedicated intramuscularly with acepromazine 0.03 mg kg(-1) and buprenorphine at either 20 (B20, n = 12) or 40 µg kg(-1) (B40, n = 14) followed by anaesthetic induction with propofol and maintenance with isoflurane. During anaesthesia non invasive blood pressure, heart rate, respiratory rate, blood oxygen saturation, inspired and expired volatile agent, end-tidal carbon dioxide and ECG were recorded. Pain and sedation were assessed using interactive VAS scores; mechanical nociceptive thresholds were measured at the wound and hindlimb--all were assessed before and up to 22 hours after administration. Carprofen was used for rescue analgesia. RESULTS: There were no significant differences between the two groups for any of the parameters examined. Rescue analgesia was required around 5 hours after administration of buprenorphine in a significant number of animals. Sedation was good preoperatively and scores decreased over time postoperatively. Hock thresholds did not change over time; wound thresholds decreased significantly compared to the baseline value from 3 hours onwards. CONCLUSIONS: Administration of buprenorphine at either 20 or 40 µg kg(-1) IM with acepromazine provided good pre-operative sedation. Cardiovascular and respiratory values remained within clinically acceptable limits during anaesthesia. There was no evidence that increasing dose increased adverse events that may be associated with opioid administration (e.g. bradycardia and respiratory depression). CLINICAL RELEVANCE: Increasing the dose of buprenorphine from 20 to 40 µg kg(-1) did not provide any benefits with respect to analgesia after ovariohysterectomy as assessed using the VAS scoring system.

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.

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.

Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone.

OBJECTIVE: To evaluate the sedative and antinociceptive effects of combinations of dexmedetomidine and buprenorphine in cats. STUDY DESIGN: Experimental randomized study. ANIMALS: Twelve purpose-bred neutered domestic short-hair cats (4 male and 8 female) weighing 4.6 kg (range 3.7-5.5 kg) aged from 2 to 5 years. METHODS: Six cats per group were administered buprenorphine (B) at 10 (B10) or 20 microg kg(-1) (B20) or dexmedetomidine (D) at 20 (D20) or 40 microg kg(-1) (D40) or a combination of B10/D20. A feline thermal nociceptive threshold testing device was used to evaluate the antinociceptive effects of the drugs before and up to 24 hours after drug treatment. Sedation was scored using a 100 mm visual analogue scale (VAS). RESULTS: Thermal thresholds increased significantly after administration of all but D20. Area under the curve (AUC, hours degrees C) for the first 6 hours (mean +/- SD) for B20 (281 +/- 17.8) was significantly greater than B10 (260 +/- 11.4), D20 (250 +/- 7.9) and D40 (255 +/- 11.4). The AUC for B10/D20 (273 +/- 12.2) was significantly greater than D20 but not the other treatments. No sedation was seen after administration of B10 or B20 and maximal sedation was seen for all animals in the D40 and B10/D20 groups and most animals in the D20 group. CONCLUSIONS: D20 alone had the smallest analgesic effect; B10 alone provided no sedation but their combination gave good sedation with analgesia comparable with B20. CLINICAL RELEVANCE: This combination could be a useful multimodal sedative/analgesic regimen in cats.

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.

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.

Antinociceptive effects of tramadol and acepromazine in cats.

Effects of tramadol and acepromazine on pressure and thermal thresholds were examined in eight cats. After baseline measurements, subcutaneous (SC) tramadol 1 mg/kg, acepromazine 0.1 mg/kg, tramadol 1 mg/kg with acepromazine 0.1 mg/kg, or saline 0.3 ml were given. Serial measurements were made for 24 h. Mean thermal thresholds did not change significantly [analysis of variance (ANOVA)] from baseline. The maximum thermal threshold increase above baseline was 2.8+/-2.8 degrees C at 6 h (P>0.05) after tramadol; it was above the 95% confidence interval (CI) at 0.75, 3 and 6 h. Pressure thresholds increased above baseline from 0.25 to 2 h after acepromazine (P<0.05) and from 0.5 to 3 h after the combination (P<0.05), with a maximum increase of 132+/-156 mmHg 0.25 h after acepromazine and 197+/-129 mmHg 0.5 h after the combination. Pressure thresholds were above the 95% CI from 0.25 to 2 h after acepromazine and from 0.5 to 3 h after the combination. SC tramadol at 1 mg/kg in cats had limited effect on thermal and pressure nociception, but this was enhanced by acepromazine. Acepromazine alone had pressure antinociceptive effects.

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?'