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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)., (© 2019 John Wiley & Sons Ltd.)

The objective of this review was to perform a literature compilation of all the equine publications that used dexmedetomidine as the first article on this topic was published, in 2005. We also aimed to answer the question whether the use of dexmedetomidine can currently be justified. For that, we compiled information from databases, such as PubMed, Google Scholar and Web of Science and the proceedings of the last veterinary anaesthesiology meetings. Dexmedetomidine is an attractive drug to be used in horses, mainly due to its pharmacokinetic profile and pharmacodynamics that favour its use as intravenous constant rate infusion (CRI). Nowadays, its clinical use is popular for sedation in prolonged standing procedures and during partial intravenous anaesthesia (PIVA) and total intravenous anaesthesia (TIVA). However, legal requirements for its use should be taken into account., (© 2017 John Wiley & Sons Ltd.)

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd ss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone., (© 2017 John Wiley & Sons Ltd.)

Reasons for Performing Study: To validate a model for investigating the effects of analgesic drugs on mechanical, thermal and electrical stimulation testing., Objectives: To investigate repeatability, sensitivity and specificity of nociceptive tests., Study Design: Randomised experiment with 2 observers in 2 phases., Methods: Mechanical (M), thermal (TL) and electrical (E) stimuli were applied to the dorsal metacarpus (M-left and TL-right) and coronary band of the left thoracic limb (E) and a thoracic thermal stimulus (TT) was applied caudal to the withers in 8 horses (405 ± 43 kg). Stimuli intensities were increased until a clear avoidance response was detected without exceeding 20 N (M), 60°C (TL and TT) and 15 V (E). For each set of tests, 3 real stimuli and one sham stimulus were applied (32 per animal) using a blinded, randomised, crossover design repeated after 6 months. A distribution frequency and, for each stimulus, Chi-square and McNemar tests compared both the proportion of positive responses detected by 2 observers and the 2 study phases. The κ coefficients estimated interobserver agreement in determining endpoints. Sensitivity (384 tests) and specificity (128 tests) were evaluated for each nociceptive stimulus to assess the evaluators' accuracy in detecting real and sham stimuli., Results: Nociceptive thresholds were 3.1 ± 2 N (M), 8.1 ± 3.8 V (E), 51.4 ± 5.5°C (TL) and 55.2 ± 5.3°C (TT). The level of agreement after all tests, M, E, TL and TT, was 90, 100, 84, 98 and 75%, respectively. Sensitivity was 89, 100, 89, 98 and 70% and specificity 92, 97, 88, 91 and 94%, respectively., Conclusions: The high interobserver agreement, sensitivity and specificity suggest that M, E and TL tests are valid for pain studies in horses and are suitable tools for investigating antinociceptive effects of analgesics in horses., (© 2014 EVJ Ltd.)

Halothane depresses cardiorespiratory function and activates the pituitary-adrenal axis, increasing beta endorphin. In horses, beta endorphin may enhance the anaesthetic-associated cardiorespiratory depression and mortality risk. The authors studied endogenous opioid effects on cardiorespiratory function and pituitary-adrenal activity in halothane-anaesthetised ponies by investigating opioid antagonism by naloxone. Six ponies were anaesthetised three times (crossover design). Anaesthesia was induced with thiopentone and maintained with 1.2 per cent halothane for 2 hours. Immediately after induction, naloxone was administered either intravenously (0.5 mg kg(-1)bolus then 0.25 mg kg(-1)hour(-1)for 2 hours) or intrathecally (0.5 mg) or was replaced by saline as control. Pulse and respiratory rates, arterial blood gases, cardiac output and plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations were measured. All groups developed cardiorespiratory depression (40 per cent decrease in cardiac output) and plasma cortisol increased. Plasma ACTH concentration was higher in ponies treated with intrathecal naloxone. Endogenous opioids may inhibit ACTH secretion, attenuating the stress response to halothane anaesthesia in equidae., (Copyright 2001 Harcourt Publishers Ltd.)

Objective: To compare detomidine hydrochloride and romifidine as premedicants in horses undergoing elective surgery., Animals: 100 client-owned horses., Procedure: After administration of acepromazine (0.03 mg/kg, IV), 50 horses received detomidine hydrochloride (0.02 mg/kg of body weight, IV) and 50 received romifidine (0.1 mg/kg, IV) before induction and maintenance of anesthesia with ketamine hydrochloride (2 mg/kg) and halothane, respectively. Arterial blood pressure and blood gases, ECG, and heart and respiratory rates were recorded. Induction and recovery were timed and graded., Results: Mean (+/- SD) duration of anesthesia for all horses was 104 +/- 28 minutes. Significant differences in induction and recovery times or grades were not detected between groups. Mean arterial blood pressure (MABP) decreased in both groups 30 minutes after induction, compared with values at 10 minutes. From 40 to 70 minutes after induction, MABP was significantly higher in detomidine-treated horses, compared with romifidine-treated horses, although more romifidine-treated horses received dobutamine infusions. In all horses, mean respiratory rate ranged from 9 to 11 breaths/min, PaO2 from 200 to 300 mm Hg, PaCO2 from 59 to 67 mm Hg, arterial pH from 7.33 to 7.29, and heart rate from 30 to 33 beats/min, with no significant differences between groups., Conclusions and Clinical Relevance: Detomidine and romifidine were both satisfactory premedicants. Romifidine led to more severe hypotension than detomidine, despite administration of dobutamine to more romifidine-treated horses. Both detomidine and romifidine are acceptable alpha2-adrenoceptor agonists for use as premedicants before general anesthesia in horses; however, detomidine may be preferable when maintenance of blood pressure is particularly important.

Objective: To evaluate the effect of changing the mode of ventilation from spontaneous to controlled on the arterial-to-end-tidal CO2 difference [P(a-ET)CO2] and physiological dead space (VD(phys)/VT) in laterally and dorsally recumbent halothane-anesthetized horses. STUDY DESIGN; Prospective, experimental, nonrandomized trial., Animals: Seven mixed breed adult horses (1 male and 6 female) weighing 320 +/- 11 kg., Methods: Horses were anesthetized in 2 positions-right lateral and dorsal recumbency-with a minimum interval of 1 month. Anesthesia was maintained with halothane in oxygen for 180 minutes. Spontaneous ventilation (SV) was used for 90 minutes followed by 90 minutes of controlled ventilation (CV). The same ventilator settings were used for both laterally and dorsally recumbent horses. Arterial blood gas analysis was performed every 30 minutes during anesthesia. End-tidal CO2 (PETCO2) was measured continuously. P(a-ET)CO2 and VD(phys)NT were calculated. Statistical analysis included analysis of variance for repeated measures over time, followed by Student-Newman-Keuls test. Comparison between groups was performed using a paired t test; P < .05 was considered significant., Results: P(a-ET)CO2 and VD(phys)/VT increased during SV, whereas CV reduced these variables. The variables did not change significantly throughout mechanical ventilation in either group. Dorsally recumbent horses showed greater P(a-ET)CO2 and VD(phys)/VT values throughout. PaCO2 was greater during CV in dorsally positioned horses., Conclusions and Clinical Relevance: Changing the mode of ventilation from spontaneous to controlled was effective in reducing P(a-ET)CO2 and physiological dead space in both laterally and dorsally recumbent halothane-anesthetized horses. Dorsal recumbency resulted in greater impairment of effective ventilation. Capnometry has a limited value for accurate estimation of PaCO2 in anesthetized horses, although it may be used to evaluate pulmonary function when paired with arterial blood gas analysis.

Glucose was infused intravenously into six ponies during halothane anaesthesia, to evaluate its effect on their endocrine response to anaesthesia. The ponies were premedicated with acepromazine, and anaesthesia was induced with thiopentone and maintained with halothane in oxygen for two hours. Glucose was infused to maintain the plasma glucose concentration above 20 mmol/litre. Anaesthesia was associated with hypothermia, a decrease in haematocrit, hypotension, hyperoxaemia, respiratory acidosis and an increase in the plasma concentrations of lactate and arginine vasopressin. The concentration of beta-endorphin in plasma increased transiently after 20 minutes but there were no changes in concentrations of adrenocorticotrophic hormone, dynorphin, cortisol or catecholamines. These data suggest that the glucose infusion attenuated the normal adrenal response of ponies to halothane anaesthesia.

This prospective clinical study compared the physiological effects of two commonly used anaesthetic induction techniques in horses maintained with halothane. One hundred horses admitted for elective surgery were randomly allocated to receive either guaiphenesin (to effect) and thiopentone (5 mg/kg), or detomidine (20 microg/kg) and ketamine (2 mg/kg) for the induction of anaesthesia after acepromazine premedication. Anaesthesia was maintained with halothane in oxygen. There were no significant differences in breed, age, sex, weight, type of surgery and duration of anaesthesia between the groups. Immediately after induction of anaesthesia heart rate was higher after guaiphenesin and thiopentone, and arterial blood pressure was higher after detomidine and ketamine. Thereafter hypotension, often necessitating an infusion of dobutamine, developed in both groups. Arterial blood gases and respiratory rates were similar in the two groups. There were no significant differences between the groups in the subjectively scored quality of induction and recovery, or in recovery time.

Monthly radiography was performed to study distal radial physeal closure in ten male and ten female Thoroughbred horses. The height, thoracic circumference and metacarpus circumference were also measured. Distal radial physeal closure time was sooner in females than males, and took 701 +/- 37 and 748 +/- 55 days respectively.

Objective: To investigate the effects of inhalation and total IV anesthesia on pituitary-adrenal activity in ponies., Animals: 9 healthy ponies: 5 geldings and 4 mares., Procedure: Catheters were placed in the cavernous sinus below the pituitary gland and in the subarachnoid space via the lumbosacral space. After 72 hours, administration of acepromazine was followed by induction of anesthesia with thiopentone and maintenance with halothane (halothane protocol), or for the IV protocol, anesthesia induction with detomidine and ketamine was followed by maintenance with IV infusion of a detomidine-ketamine-guaifenesin combination. Arterial blood pressure and gas tensions were measured throughout anesthesia. Peptide and catecholamine concentrations were measured in pituitary effluent, peripheral plasma, and CSF. Peripheral plasma cortisol, glucose, and lactate concentrations also were measured., Results: Intravenous anesthesia caused less cardiorespiratory depression than did halothane. ACTH, metenkephalin, arginine vasopressin, and norepinephrine pituitary effluent and peripheral plasma concentrations were higher during halothane anesthesia, with little change during intravenous anesthesia. Pituitary effluent plasma beta-endorphin and peripheral plasma cortisol concentrations increased during halothane anesthesia only. Dynorphin concentrations did not change in either group. Hyperglycemia developed during intravenous anesthesia only. Minimal changes occurred in CSF hormonal concentrations during anesthesia., Conclusion: The pituitary gland has a major role in maintaining circulating peptides during anesthesia. Compared with halothane, IV anesthesia appeared to suppress pituitary secretion.

Six Welsh gelding ponies were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) prior to induction of anaesthesia with midazolam at 0.2 mg/kg and ketamine at 2 mg/kg i.v.. Anaesthesia was maintained for 2 h using 1.2% halothane concentration in oxygen. Heart rate, electrocardiograph (ECG), arterial blood pressure, respiratory rate, blood gases, temperature, haematocrit, plasma arginine vasopressin (AVP), dynorphin, beta-endorphin, adrenocorticotropic hormone (ACTH), cortisol, dopamine, noradrenaline, adrenaline, glucose and lactate concentrations were measured before and after premedication, immediately after induction, every 20 min during anaesthesia, and at 20 and 120 min after disconnection. Induction was rapid, excitement-free and good muscle relaxation was observed. There were no changes in heart and respiratory rates. Decrease in temperature, hyperoxia and respiratory acidosis developed during anaesthesia and slight hypotension was observed (minimum value 76 +/- 10 mm Hg at 40 mins). No changes were observed in dynorphin, beta-endorphin, ACTH, catecholamines and glucose. Plasma cortisol concentration increased from 220 +/- 17 basal to 354 +/- 22 nmol/L at 120 min during anaesthesia; plasma AVP concentration increased from 3 +/- 1 basal to 346 +/- 64 pmol/L at 100 min during anaesthesia and plasma lactate concentration increased from 1.22 +/- 0.08 basal to 1.76 +/- 0.13 mmol/L at 80 min during anaesthesia. Recovery was rapid and uneventful with ponies taking 46 +/- 6 min to stand. When midazolam/ketamine was compared with thiopentone or detomidine/ketamine for induction before halothane anaesthesia using an otherwise similar protocol in the same ponies, it caused slightly more respiratory depression, but less hypotension. Additionally, midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.

Six Welsh gelding ponies (weight 246 +/- 6 kg) were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) followed by 0.02 mg/kg of detomidine i.v. Anaesthesia was induced with 2 mg/kg of ketamine i.v. Ponies were intubated and lay in left lateral recumbency. On one occasion anaesthesia was maintained for 2 h using 1.2% halothane in oxygen. The same group of ponies were anaesthetized 1 month later using the same induction regime and anaesthesia was maintained with a combination of detomidine, ketamine and guaiphenesin, while the ponies breathed oxygen-enriched air. Electrocardiogram, heart rate, mean arterial blood pressure, cardiac output, respiratory rate, blood gases, temperature, haematocrit, glucose, lactate and cortisol were measured and cardiac index and systemic vascular resistance were calculated in both groups. Beta-endorphin, met-enkephalin, dynorphin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH) and catecholamines were measured in the halothane anaesthesia group only and 11-deoxycortisol during total intravenous anaesthesia (TIVA) only. Cardiorespiratory depression was more marked during halothane anaesthesia. Hyperglycaemia developed in both groups. Lactate and AVP increased during halothane anaesthesia. Cortisol increased during halothane and decreased during TIVA. There were no changes in the other hormones during anaesthesia. Recovery was smooth in both groups. TIVA produced better cardiorespiratory performance and suppressed the endocrine stress response observed during halothane anaesthesia.

Pharmacokinetics and some pharmacological effects of anaesthesia induced by a combination of detomidine, ketamine and guaiphenesin were investigated in eight ponies. Cardiopulmonary function was studied and plasma met-enkephalin, dynorphin, beta-endorphin, arginine vasopressin, adrenocorticotrophin, cortisol, 11-deoxycortisol and catecholamine concentrations were measured. The combination produced slight cardiorespiratory depression, hyperglycaemia and a reduction in haematocrit. There were no changes in plasma opioids, pituitary peptides or catecholamines. Plasma cortisol concentration decreased and plasma 11-deoxycortisol increased indicating a suppression of steroidogenesis. Steady state ketamine and guaiphenesin concentrations were attained during the infusion period, and ketamine concentrations likely to provide adequate analgesia for surgical operations were achieved (more than 2.2 micrograms ml-1). Steady state detomidine concentration was not attained. The ponies took on average 68 minutes to recover to standing and the recovery was uneventful.

The effect of thiopentone/halothane anaesthesia on the release of endogenous opioid, adrenocorticotrophin, arginine vasopressin, cortisol and catecholamine was investigated in ponies. The contribution made by halothane itself was studied by maintaining six ponies with a constant 1.2 per cent end tidal halothane concentration and five with a concentration ranging between 0.8 and 1.2 per cent. Cardiorespiratory depression was more prolonged in the ponies receiving a constant 1.2 per cent end tidal halothane concentration than in those which received less halothane. Plasma lactate concentration increased and haematocrit decreased during halothane anaesthesia. The concentrations of met-enkephalin, dynorphin and catecholamines did not change and those of beta-endorphin, adrenocorticotrophin, arginine vasopressin and cortisol increased during halothane anaesthesia. Halothane appeared to be a major stimulus to pituitary adrenocortical activation because the adrenocortical secretion was proportional to the amount of halothane inhaled. Beta-endorphin increased proportionally more than adrenocorticotrophin and their plasma concentrations were not correlated, suggesting that they have independent secretion mechanisms.

A combination of 0.5 mg/kg of methotrimeprazine, 0.1 mg/kg of midazolam and 100 mg/kg of a 10 per cent guaiphenesin solution was investigated for the induction of recumbency in 15 horses; the addition of 1.6 mg/kg of ketamine was also evaluated in 15 horses and anaesthesia was maintained with halothane in oxygen. The horses became recumbent quickly and smoothly and they recovered quietly, with little ataxia. Tachycardia occurred after induction, but no other changes from pre-operative values were observed until halothane in oxygen had been given, when hypothermia, hypotension, bradypnoea, hyperoxaemia, respiratory acidosis and decreased respiratory minute volume developed. Horses given ketamine in addition to methotrimeprazine, midazolam and guaiphenesin were easier to intubate and recovered more quickly than horses receiving only methotrimeprazine, midazolam and guaiphenesin.

Atipamezole antagonism of xylazine sedation was evaluated in six ponies. Atipamezole (0.15 mg/kg) or saline was injected intravenously 15 minutes after the ponies had been sedated with xylazine (1.0 mg/kg). Arterial blood pressure and gases, pulse and respiratory rates, the electrocardiogram, nose-to-ground distance and a subjective sedation score were recorded. The pretreatment nose-to-ground distance and PaO2 returned to normal sooner after atipamezole than after saline and the ponies' appetite and normal locomotion also recovered sooner. No significant differences were observed between the effects of saline and atipamezole on the other measurements.