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BackgroundThe effects of anesthesia on the equine electroencephalogram (EEG) after administration of various drugs for sedation, induction, and maintenance are known, but not that the effect of inhaled anesthetics alone for EEG recording.ObjectiveTo determine the effects of isoflurane and halothane, administered as single agents at multiple levels, on the EEG and quantitative EEG (qEEG) of normal horses.AnimalsSix healthy horses.MethodsProspective study. Digital EEG with video and quantitative EEG (qEEG) were recorded after the administration of one of the 2 anesthetics, isoflurane or halothane, at 3 alveolar doses (1.2, 1.4 and 1.6 MAC). Segments of EEG during controlled ventilation (CV), spontaneous ventilation (SV), and with peroneal nerve stimulation (ST) at each MAC multiple for each anesthetic were selected, analyzed, and compared. Multiple non-EEG measurements were also recorded.ResultsSpecific raw EEG findings were indicative of changes in the depth of anesthesia. However, there was considerable variability in EEG between horses at identical MAC multiples/conditions and within individual horses over segments of a given epoch. Statistical significance for qEEG variables differed between anesthetics with bispectral index (BIS) CV MAC and 95% spectral edge frequency (SEF95) SV MAC differences in isoflurane only and median frequency (MED) differences in SV MAC with halothane only.Conclusions and clinical importanceUnprocessed EEG features (background and transients) appear to be beneficial for monitoring the depth of a particular anesthetic, but offer little advantage over the use of changes in mean arterial pressure for this purpose.

BackgroundPrevious study of the diagnostic validity of electroencephalography (EEG) to detect abnormalities in equine cerebral cortical function relied on the administration of various drugs for sedation, induction, and maintenance of general anesthesia but used identical criteria to interpret recordings.ObjectivesTo determine the effects of 2 inhalation anesthetics on the EEG of healthy horses.AnimalsSix healthy horses.MethodsProspective study. After the sole administration of one of either isoflurane or halothane at 1.2, 1.4, and 1.6 times the minimum alveolar concentration, EEG was recorded during controlled ventilation, spontaneous ventilation, and nerve stimulation.ResultsBurst suppression was observed with isoflurane, along with EEG events that resembled epileptiform discharges. Halothane results were variable between horses, with epileptiform-like discharges and bursts of theta, alpha, and beta recorded intermittently. One horse died and 2 were euthanized as the result of anesthesia-related complications.Conclusions and clinical importanceThe results of this study indicate that the effects of halothane and isoflurane on EEG activity in the normal horse can be quite variable, even when used in the absence of other drugs. It is recommended that equine EEG be performed without the use of these inhalation anesthetics and that general anesthesia be induced and maintained by other contemporary means.

The purpose of this study was to evaluate selected physiological and behavioral responses to xylazine (XYL)–butorphanol (BUTOR) supplemented propofol (PROP) anesthesia in horses and the influence of BUTOR dose on outcome. Eight horses [13 ± 2 (mean ± SE) year], weighing 524 ± 9 kg were anesthetized three times with at least 3 weeks between each anesthesia. After collecting pre-drug data, horses were always medicated with 0.5 mg kg[sup -1] XYL IV. Five minutes later, BUTOR was administered IV according to a randomized order of three doses: 0.025, 0.05, and 0.075 mg kg[sup -1] ; all horses received the complete dose set. Five minutes after BUTOR, anesthesia was induced with PROP, 2 mg kg[sup -1] IV. The resultant data were grouped by treatment and parameter and analyzed by RM anova; p < 0.05 considered significant. The pre-drug values within a treatment group were not significantly different. The combined pre-drug values were heart rate (HR) = 32 ± 1 beats minute[sup -1] , respiratory frequency (f ) = 11 ± 1 breaths minute[sup -1] , PaO[sub 2] = 66.6 ± 1.5 mm Hg (Mexico City is 2240 m above sea level; yearly average P[sub BAR] = 582 mm Hg), PaCO[sub 2] = 36.2 ± 0.7 mm Hg and pH[sub a] = 7.42 ± 0.01. During 20 minutes of anesthesia HR, f and PaCO[sub 2] were not significantly different from pre-drug values. The PaO[sub 2] decreased by an average of 12 mm Hg during anesthesia but returned to the pre-drug values within 15 minutes after the horses stood. The quality of anesthetic induction varied and brief paddling limb movements occurred occasionally after recumbency regardless BUTOR dose. Recovery from anesthesia was subjectively graded good to excellent. The BUTOR dose did not significantly influence recumbency time (33 ± 2 minutes for all studies). The BUTOR dose did not markedly influence study results. However, some physiological effects likely were confounded by the notably low PaO[sub 2] that was influenced... [ABSTRACT FROM AUTHOR]

Aims to quantify changes in ventilation as a function of isoflurane (ISO) dose in the horse. Research methodology; Magnitude of respiratory depression in equidae anesthesized with ISO; Respiratory rate; Tidal volume.

The purpose of this study was to characterize urine flow and biochemical parameters in horses given xylazine (XYL) and anesthetized with ketamine and isoflurane. Nine mares [9 ± 2 (mean ± SE) years; 492 ± 17 kg] were studied. They were anesthetized for 2 hours in support of a campus-approved, laboratory-based orthopedic study. The day prior to anesthesia, a venous blood sample was obtained for biochemical analysis from each unmedicated mare. The urinary bladder was catheterized and emptied, and urine collected over the next three hours to quantitate the pre-drug values. The next day the mares were similarly catheterized. After obtaining urine and venous blood samples, XYL (1.1 mg kg[sup -1] IV) was administered. Anesthesia was induced 5 minutes later with ketamine (2.2 mg kg[sup -1] IV) and diazepam (0.04 mg kg[sup -1] IV) and maintained with isoflurane in O[sub 2] . Lactated Ringer's solution (10 mL kg[sup -1] hours[sup -1] ) was administered IV and dobutamine infused as required to maintain mean arterial blood pressure between 70 and 80 mm Hg. Mechanical ventilation maintained PaCO[sub 2] between 48 and 52 mm Hg and PaO[sub 2] > 200 mm Hg. Blood and urine were collected at 30, 60, and 120 minutes during anesthesia, and at 1 hour postanesthesia. Data were analyzed with RM anova; with p < 0.05. Control urine flow was 0.92 ± 0.17 mL kg[sup -1] hour[sup -1] . Urine flow was significantly increased at 30 and 60 minutes following XYL (2.14 ± 0.59 and 2.86 ± 0.97 mL kg[sup -1] hour[sup -1] , respectively), but returned to control levels by the end of anesthesia. The most notable biochemical change was an initial significant increase in serum glucose from 121 ± 4 to 167 ± 8 mg dL[sup -1] at 30 minutes post-XYL that was not accompanied by a significant glucosuria (control value 4 ± 1 mg dL[sup -1] ). We conclude that urine output increases in anesthetized horses following XYL, but this increase is not as a result of glucosuria. [ABSTRACT FROM AUTHOR]

Alpha-2 agonists cause transient dose-related increase in urine flow in normal horses. Although important clinically, effects of these drugs in dehydrated animals are not known. The purpose of this study was to describe the influence of xylazine (XYL) and detomidine (DET) on urine flow in mares deprived of food and water for 24 hours. Six clinically normal mares [12.5 ± 3.3 (mean ± SE) years] weighing 471 ± 23 kg were each studied four times; each study was separated by at least 7 days. The morning following fasting, the urinary bladder was catheterized (Foley) and emptied. Urine was then collected for 2 hours and a composite urine sample along with a sample of jugular venous blood provided baseline values. Shortly after emptying the bladder, saline, 0.5 or 1.0 mg kg[sup -1] XYL or 0.03 mg kg[sup -1] DET was injected IV (treatment randomly assigned) and urine and blood samples obtained over the next 2 hours. Data were analyzed by RM anova followed by Dunnett's test for pairwise comparisons p < 0.05; indicated by (S). Pretreatment urine flow was 0.30 ± 0.03 mL kg[sup -1] hour[sup -1] , urine specific gravity (SG) was 1.032 ± 0.001, packed cell volume (PCV) was 37.8 ± 1.0%, and total plasma solids (TP) was 6.85 ± 0.12 g dL[sup -1] ; values for four treatment periods within a grouping did not differ. At 1 hour post-treatment, urine flow (mL kg[sup -1] hour[sup -1] ) was 0.31 ± 0.04, 1.09 ± 0.48, 2.33 ± 0.89[sup (S)] , and 2.14 ± 0.58 [sup (S)] for saline, 0.5 XYL, 1.0 XYL and DET, respectively. By 2 hours, urine flow was at or returning to baseline with all treatments except DET where a further increase was noted (8.28 ± 0.92[sup (S)] ). A time related decrease in urine specific gravity (e.g. 1.010–1.021 at 1 hour post-treatment) was associated with the increase in urine flow but PCV and TP did not change significantly with time or treatment. These data indicate that XYL and DET cause an important... [ABSTRACT FROM AUTHOR]

Minimum alveolar concentration (MAC) of an inhalant is an indicator of its anesthetic potency. Individuals vary in their sensitivity to anesthetic agents as demonstrated by different individual MAC values. We hypothesized that individual animal sensitivity would be maintained with different inhalant anesthetics. As part of separate studies, six female DSH cats, aged 24 ± 2.5 (mean ± SD) months and weighing 3.5 ± 0.3 kg, were studied similarly on three separate occasions over a 12-month period to determine the MAC of isoflurane (ISO), sevoflurane (SEVO), and desflurane (DES), respectively. In each study, chamber induction was followed by orotracheal intubation, and anesthesia was maintained via a nonrebreathing circuit. ECG, pulse oximetry, Doppler systolic blood pressure, end-tidal gases, and esophageal temperature were monitored. End-tidal gases were hand-sampled from a catheter whose tip lay level with the distal end of the ET tube. Gases were analyzed by Raman spectrometry and, for each agent, the analyzer was calibrated with at least three gas standards. MAC was determined in triplicate using standard tail-clamp technique. Data were analyzed by two-way anova followed by Tukey's test and significant differences were found. Average MACs (%) for ISO, SEVO, and DES were 1.90 ± 0.18, 3.41 ± 0.65, and 10.27 ± 1.06, respectively. Body temperatures, Doppler systolic blood pressure, and SpO2 were recorded at the time of MAC determinations for ISO, SEVO, and DES were 38.3 ± 0.3, 38.6 ± 0.1, 38.3 ± 0.35 °C; 71 ± 8, 75 ± 16, 88 ± 12 mm Hg; 99 ± 1, 99 ± 1, 99 ± 1%, respectively. Both the anesthetic agent and the individual cat had significant effects on MAC (p = 0.0001 and 0.0185, respectively). MAC varied between individuals and cats were consistent in their order of sensitivity to inhalant anesthetics across the three agents. Within this group of cats, the relationship of individual MAC to the group MAC for each of the three inhalant agents was maintained. This suggests that any individual may be consistently more or less sensitive to a variety of inhalant agents. [ABSTRACT FROM AUTHOR]

Isoflurane (ISO) is the most commonly administered feline inhalant anesthetic in North America. A newer agent, sevoflurane (SEVO), may provide faster induction and recovery from anesthesia based on its physical characteristics. Accordingly, we compared some induction and recovery characteristics of ISO and SEVO in healthy cats. Six female DSH cats (17.9 ± 9.0 (mean ± SD) months, 3.7 ± 0.3 kg) received four randomly assigned treatments: ISO for 1 hour (IS), SEVO for 1 hour (SS), ISO for 5 hours (IL), and SEVO for 5 hours (SL). Anesthesia was induced in a chamber into which ISO or SEVO was delivered at 2.7 times the individual's MAC (determined previously) in 6 L minute-1 O2 . Measured (Rascal II, Ohmeda) anesthetic concentration was reported after correction using a multiple gas, standard-defined calibration curve. For induction, time (seconds) from introduction of inhalant to onset of incoordinated movement (IM), recumbency with movement (RM), recumbency without movement, loss of pedal reflex (PD), and intubation (ET) were recorded. Following intubation, anesthesia was maintained for the required time at 1.25 times the individual's MAC. For recovery, time (seconds) from discontinuation of the inhalant (with continuation of O2 ) to first movement, extubation (EXT), start of incoordinated movement, head-lift, sternal recumbency (SR), crawl, stand/walk with incoordination, and jump without incoordination were recorded. Esophageal normothermia was maintained. Data were analyzed by paired t -test (induction) or One-way Repeated Measures anova followed, when appropriate, by Tukey's test (recovery). p < 0.05 was regarded as significant. For induction, IM was not significantly different between ISO and SEVO (118 ± 28 seconds vs. 104 ± 28 seconds). All other induction times were significantly shorter with SEVO vs. ISO, e.g. RM (181 ± 31 seconds vs. 213 ± 31 seconds), PD (426 ± 68 seconds vs. 504 ± 70 seconds), and ET (434 ± 66 seconds vs. 515 ± 69 seconds). For recovery, there were no differences between ISO and SEVO for any stage of recovery, e.g. EXT (IS 588 ± 163 seconds vs. SS 425 ± 109 seconds), SR (IS 735 ± 215 seconds vs. SS 655 ± 337 seconds), and IL (710 ± 658 seconds vs. SL 807 ± 465 seconds). We concluded that quantitative recovery characteristics did not depend on whether cats are anesthetized with equipotent amounts of SEVO or ISO, but some induction end-points were reached more quickly with SEVO. [ABSTRACT FROM AUTHOR]

As a cerebral vasodilator, isoflurane (ISO) can interfere with normal cerebrovascular autoregulation and may exacerbate cerebral perfusion pressure (CPP) changes in horses brought about by drugs that decrease mean arterial pressure (MAP) and by body positions that alter the hydrostatic gradient between brain and heart. It was, therefore, hypothesized that ISO-anesthetized horses in lateral recumbency would have increased intracranial pressure (ICP) and decreased CPP compared to standing, unmedicated horses. Anesthesia was induced and maintained in six healthy horses in left lateral recumbency using only ISO in oxygen. Central venous pressure (CVP) from the right atrium and MAP from the right carotid artery were recorded on a calibrated physiograph. A Codman Microsensor ICP transducer was placed in the subarachnoid space through a right parietal craniotomy. The PaO[sub 2] , PaCO[sub 2] , and pH[sub a] were obtained using an automated blood gas analyzer with values corrected to tonometrically derived standard curves. Horses were ventilated to 18–22 cm H[sub 2] O inspiratory pressure and 0–2 cm H[sub 2] O end-expiratory pressure. End-tidal isoflurane was measured by calibrated gas analyzers and maintained at 1.57%, or 1.2 times minimum alveolar concentration. Measurements in laterally recumbent horses were made at least 20 minutes following constant end-tidal isoflurane conditions. Measurements in awake horses were made 1 hour following standing recovery from anesthesia. The following data were obtained from anesthetized and awake horses, respectively (mm Hg; mean ± SD): MAP = 71 ± 6 and 133 ± 17, CVP = 9 ± 3 and 4 ± 14, ICP = 24 ± 5 and 2 ± 4, CPP = 48 ± 4 and 102 ± 26. Paired t -tests showed significant differences between anesthetized and awake horses for MAP (p < 0.0005), ICP (p < 0.00005), and CPP (p < 0.005), but not for CVP. In both groups, PaCO[sub 2] ranged between 34 and 43 mm Hg, and PaO[sub 2]... [ABSTRACT FROM AUTHOR]

This study was conducted to determine the isoflurane (ISO) minimum alveolar concentration (MAC) reduction induced by nitrous oxide in cats. Twelve cats (four females, eight males; 3.8–8.8 kg; 2–3 years) were anesthetized with only ISO in O[sub 2] . Ventilation was spontaneous. The MAC of ISO was determined at four concentrations of N[sub 2] O (0, 30, 50, and 70%) using the tail-clamp technique. The dose order of N[sub 2] O was randomly assigned. The average of three measurements was considered MAC at each N[sub 2] O concentration. Prior to each MAC measurement, heart rate (HR), direct arterial blood pressure (ABP), respiratory frequency (f ), PaO[sub 2] , PaCO[sub 2] , pH[sub a] , PCV, total protein concentration, and the bispectral index (BIS) were determined. The esophageal temperature was kept constant [38.5 ± 0.35 °C (mean ± SD)]. A negative linear relationship between N[sub 2] O and ISO[sub MAC] was demonstrated by four cats (Group 1), but not by the other eight cats (Group 2). Gender did not appear to influence these results. The ISO[sub MAC] (%) for Group 1 was 2.06 ± 0.08, 1.90 ± 0.17, 1.83 ± 0.07, and 1.58 ± 0.22 at 0, 30, 50, and 70% N[sub 2] O, respectively, and similarly, ISO[sub MAC] for Group 2 was 1.86 ± 0.22, 1.80 ± 0.23, 1.84 ± 0.19, and 1.85 ± 0.22 at 0, 30, 50, and 70% N[sub 2] O, respectively. The relationships between N[sub 2] O concentration and ISO[sub MAC] were significantly different for the two groups of cats (p < 0.0001). The MAC at 70% N[sub 2] O in Group 1 was significantly less than that at 0, 30, and 50% N[sub 2] O. The relationships between N[sub 2] O concentration and other physiological variables were not statistically different for the two groups of cats, so the values for the two groups were combined. In this case, an increase in HR, ABP, PCV, f , and BIS values was associated with an increase in N[sub 2] O concentration and values at 70% were significantly... [ABSTRACT FROM AUTHOR]

Although morphine has demonstrated antinociceptive effects in horses, its administration has been associated with dose-dependent adverse effects. In humans and rats, part of the analgesic effect of morphine has been attributed to the active metabolite, morphine-6-glucuronide (M6G). Although morphine can cause several undesirable effects, M6G has a more favorable safety profile. The objective of this study was to characterize the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of M6G following intravenous administration to a small group of horses. In Part 1 of the study, 3 horses received a single intravenous administration of saline, 0.5 mg/kg body weight (BW) M6G, or 0.5 mg/kg BW morphine in a 3-way crossover design. Blood samples were collected up to 96 hours post-administration, concentrations of drug and metabolites measured, and pharmacokinetics determined. Behavioral and physiological effects were then recorded. In Part 2 of the study, 2 horses scheduled to be euthanized for other reasons, were administered 0.5 mg/kg BW M6G. Blood, cerebrospinal fluid (CSF), and various tissue samples were collected post-administration and concentrations of drug were determined. The clearance of M6G was more rapid and the volume of distribution at steady state was smaller for M6G compared to morphine. A reaction characterized by head shaking, pawing, and slight ataxia was observed immediately following administration of both morphine and M6G to horses. After M6G administration, these behaviors subsided rapidly and were followed by a longer period of sedation. Following administration, M6G was detected in the kidney, liver, CSF, and regions of the brain. Results of this study encourage further investigation of M6G in order to assess its clinical feasibility as an analgesic in horses., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Objective: To evaluate the effects of combined infusions of vatinoxan and dexmedetomidine on inhalant anesthetic requirement and cardiopulmonary function in dogs., Study Design: Prospective experimental study., Methods: A total of six Beagle dogs were anesthetized to determine sevoflurane minimum alveolar concentration (MAC) prior to and after an intravenous (IV) dose (loading, then continuous infusion) of dexmedetomidine (4.5 μg kg -1 hour -1 ) and after two IV doses of vatinoxan in sequence (90 and 180 μg kg -1 hour -1 ). Blood was collected for plasma dexmedetomidine and vatinoxan concentrations. During a separate anesthesia, cardiac output (CO) was measured under equivalent MAC conditions of sevoflurane and dexmedetomidine, and then with each added dose of vatinoxan. For each treatment, cardiovascular variables were measured with spontaneous and controlled ventilation. Repeated measures analyses were performed for each response variable; for all analyses, p < 0.05 was considered significant., Results: Dexmedetomidine reduced sevoflurane MAC by 67% (0.64 ± 0.1%), mean ± standard deviation in dogs. The addition of vatinoxan attenuated this to 57% (0.81 ± 0.1%) and 43% (1.1 ± 0.1%) with low and high doses, respectively, and caused a reduction in plasma dexmedetomidine concentrations. Heart rate and CO decreased while systemic vascular resistance increased with dexmedetomidine regardless of ventilation mode. The co-administration of vatinoxan dose-dependently modified these effects such that cardiovascular variables approached baseline., Conclusions and Clinical Relevance: IV infusions of 90 and 180 μg kg -1 hour -1 of vatinoxan combined with 4.5 μg kg -1 hour -1 dexmedetomidine provide a meaningful reduction in sevoflurane requirement in dogs. Although sevoflurane MAC-sparing properties of dexmedetomidine in dogs are attenuated by vatinoxan, the cardiovascular function is improved. Doses of vatinoxan >180 μg kg -1 hour -1 might improve cardiovascular function further in combination with this dose of dexmedetomidine, but beneficial effects on anesthesia plane and recovery quality may be lost., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Although controversial, due to its reported effectiveness in attenuating bleeding associated with exercise-induced pulmonary hemorrhage (EIPH), furosemide is currently a permitted race day medication in most North American racing jurisdictions. The objective of this study was to assess the efficacy of furosemide in reducing the presence and severity of EIPH when administered 24 hr prior to strenuous treadmill exercise. Eight exercised Thoroughbred horses received saline or 250 mg of furosemide either 4 or 24 hr prior to high-speed treadmill exercise in a balanced 3-way cross-over design. Blood samples were collected for determination of furosemide, lactate, hemoglobin, blood gas, and electrolyte concentrations. Heart rate and pulmonary arterial pressure were measured throughout the run and endoscopic examination and bronchoalveolar lavage (BAL) performed. Horses were assigned an EIPH score and the number of red blood cells in BAL fluid determined. Although not significantly different, endoscopic EIPH scores were lower in the 4-hr versus the 24-hr and saline groups. RBC counts were not significantly different between the treatment groups. Pulmonary arterial pressures were significantly increased at higher speeds; however, there were no significant differences between dose groups when controlling for speed. A small sample size and unknown bleeding history warrant a larger-scale study., (© 2020 John Wiley & Sons Ltd.)

Background: Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3-8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated., Results: Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138-1.58 ± 0.280 L/kg and 18.0 ± 1.4-22.8 ± 3.60 mL/min/kg, respectively for 0.5-1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg)., Conclusions: Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.

The objective of the current study was to describe and characterize the pharmacokinetics and selected pharmacodynamic effects of morphine and its two major metabolites in horses following several doses of morphine. A total of ten horses were administered a single intravenous dose of morphine: 0.05, 0.1, 0.2, or 0.5 mg/kg, or saline control. Blood samples were collected up to 72 hr, analyzed for morphine, and metabolites by LC/MS/MS, and pharmacokinetic parameters were determined. Step count, heart rate and rhythm, gastrointestinal borborygmi, fecal output, packed cell volume, and total protein were also assessed. Morphine-3 glucuronide (M3G) was the predominant metabolite detected, with concentrations exceeding those of morphine-6 glucuronide (M6G) at all time points. Maximal concentrations of M3G and M6G ranged from 55.1 to 504 and 6.2 to 28.4 ng/ml, respectively, across dose groups. The initial assessment of morphine pharmacokinetics was done using noncompartmental analysis (NCA). The volume of distribution at steady-state and systemic clearance ranged from 9.40 to 16.9 L/kg and 23.3 to 32.4 ml min -1  kg -1 , respectively. Adverse effects included signs of decreased gastrointestinal motility and increased central nervous excitation. There was a correlation between increasing doses of morphine, increases in M3G concentrations, and adverse effects. Findings from this study support direct administration of purified M3G and M6G to horses to better characterize the pharmacokinetics of morphine and its metabolites and to assess pharmacodynamic activity of these metabolites., (© 2019 John Wiley & Sons Ltd.)

OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

Objective: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral α 2 -adrenoceptor antagonist, MK-467, on sevoflurane minimum alveolar concentration (MAC) in dogs., Study Design: Crossover experimental study., Animals: Six healthy, adult Beagle dogs weighing 12.6±0.9 kg (mean±standard deviation)., Methods: Dogs were anesthetized with sevoflurane in oxygen. After a 60-minute instrumentation and equilibration period, the MAC of sevoflurane was determined in triplicate using the tail clamp technique. PaCO 2 and temperature were maintained at 40±5 mmHg (5.3±0.7 kPa) and 38±0.5 ºC, respectively. After baseline MAC determination, dogs were administered two incremental loading and infusion doses of either dexmedetomidine (1.5 μg kg -1 then 1.5 μg kg -1  hour -1 and 4.5 μg kg -1 then 4.5 μg kg -1  hour -1 ) or MK-467 (90 μg kg -1 then 90 μg kg -1  hour -1 and 180 μg kg -1 then 180 μg kg -1  hour -1 ); loading doses were administered over 10 minutes. MAC was redetermined in duplicate starting 30 minutes after the start of drug administration at each dose. End-tidal sevoflurane concentrations were corrected for calibration and adjusted to sea level. A repeated-measures analysis was performed and comparisons between doses were conducted using Tukey's method. Statistical significance was considered at p<0.05., Results: Sevoflurane MAC decreased significantly from 1.86±0.3% to 1.04±0.1% and 0.57±0.1% with incremental doses of dexmedetomidine. Sevoflurane MAC significantly increased with high dose MK-467, from 1.93±0.3% to 2.29±0.5%., Conclusions and Clinical Relevance: Dexmedetomidine caused a dose-dependent decrease in sevoflurane MAC, whereas MK-467 caused an increase in MAC at the higher infusion dose. Further studies evaluating the combined effects of dexmedetomidine and MK-467 on MAC and cardiovascular function may elucidate potential benefits of the addition of a peripheral α 2 -adrenergic antagonist to inhalation anesthesia in dogs., (Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Reasons for Performing Study: Tramadol is an analgesic agent used in man and a number of veterinary species. The pharmacokinetics and behavioural effects of tramadol and its active metabolite have been described in mature horses, but not in young foals., Objectives: To characterise the pharmacokinetics, metabolism and some induced behavioural and physiological responses following i.v. tramadol administration in the same group of foals on 4 different occasions, from a few days after birth to age 43 days., Study Design: Experimental., Methods: Tramadol was administered i.v. (3 mg/kg bwt) to a group of 8 foals on 4 separate occasions at ages 6–8, 13–15, 20–22 and 40–43 days. Blood samples were collected prior to administration and at multiple times until 48 h post administration. Blood samples were analysed for tramadol and metabolite concentrations and pharmacokinetics determined at each age. Behavioural and physiological effects were also assessed., Results: The average volume of distribution was 5.10, 4.63, 4.02 and 3.84 l/kg bwt and clearance 3.44, 3.08, 3.14 and 2.69 l/h/kg bwt when foals were aged 6–8, 13–15, 20–22 and 40–43 days, respectively. There was not a significant difference in the elimination half-life between age groups (1.52, 1.73, 1.13 and 1.51 for ages 6–8, 13–15, 20–22 and 40–43 days, respectively). The metabolites produced were the same as in mature horses; however, glucuronidation capability, appeared to increase with increasing age. Tramadol administration was well tolerated at all ages studied with sedation noted in the 3 older age groups., Conclusions: Tramadol appears to be consistently well tolerated following i.v. administration of 3 mg/kg bwt to foals ranging in age from 1 to 6 weeks. Although analgesic concentrations in foals have yet to be established, the results of this study support further study of tramadol for clinical use in foals.

Uterine vascular elastosis in mares is characterized by degeneration of uterine vasculature through thickening of the elastin layers. Factors commonly associated with this degeneration include age, parity, and chronic uterine endometritis. Affected mares have also been shown to exhibit decreases in uterine blood flow and perfusion of the uterus. Due to the increased thickness of the elastin layers, we hypothesize that vasodilatation of the uterine vasculature is also impaired. To test the functionality of these vessels, we evaluated the vasodilatory effects of estradiol on the uterine vascular bed in mares with normal vasculature and mares with severe elastosis. Both groups were tested in estrus and diestrus. Fluorescent microspheres were used to determine basal blood perfusion, followed by the intravenous administration of 1.0 μg/kg of 17β-estradiol. After 90 min, perfusion was measured once again to determine the vascular response to estradiol. Control mares in estrus displayed a significant increase in total uterine blood flow after the administration of estradiol when compared to baseline levels. No other group had a significant increase in total blood flow and perfusion after estradiol administration. The administration of estradiol in control mares induced regional increases in perfusion in the uterine horns and uterine body during estrus and only in the uterine horns during diestrus. Mares affected by elastosis exhibited no regional differences in perfusion levels post-estradiol administration. The difference in the vasodilatory response induced by estradiol between reproductively healthy mares and mares affected with elastosis indicates that the functionality of the affected vessels is compromised., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Reasons for Performing Study: Foal responses to a broader range of plasma fentanyl concentrations than currently reported are desirable to support (or not) clinical use., Objectives: To describe fentanyl plasma concentrations following an escalating i.v. fentanyl dosing schedule in foals aged 5-13 days and describe selected, associated dose- and time-related behavioural and physiological responses to plasma fentanyl concentration., Study Design: Experimental., Methods: Fentanyl was administered i.v. in an escalating fashion (2, 4, 8, 16 and 32 μg/kg bwt) at 10-min intervals. Blood samples were collected before and at selected times until 24 h post administration. Blood samples were analysed for fentanyl and metabolite concentrations and correlated with behavioural and physiological observations and selected blood analytes., Results: Foals mostly appeared to be unaffected following 2 μg/kg bwt (1.09 ± 0.41 μg/l; average maximal plasma concentration) of fentanyl, but 6 of the 8 foals appeared to be sedated following 4 μg/kg bwt (3.07 ± 1.11 μg/l). Ataxia with increased locomotor activity, muscle rigidity and head pressing posture was observed in many foals at 8 (7.24 ± 3.22 μg/l) and 16 μg/kg bwt (17.4 ± 5.67 μg/l). All foals were heavily sedated after 32 μg/kg bwt (34.5 ± 10.3 μg/l); 3 of the 8 foals became recumbent. The average (± s.d.) terminal half-life following administration of the final dose was 44.2 ± 9.85 min., Conclusions: Behavioural and physiological responses to i.v. fentanyl in young foals are dose related. As with mature horses, the window of fentanyl plasma concentrations related to possible clinically desirable actions appears relatively narrow., (© 2014 EVJ Ltd.)

In the uterus of the mare, data obtained using transrectal Doppler ultrasonography indicate that uterine blood flow (UBF) is dynamic and changes throughout the estrous cycle. Degenerative lesions in the uterus are associated with subfertility and infertility. Among these lesions, vascular elastosis has been reported in aged, multiparous, and infertile mares. Angiosis of the uterine vasculature could potentially compromise UBF. The objectives of this experiment are to determine levels of UBF and perfusion of reproductively healthy mares and compare them to levels of subfertile/infertile mares affected by uterine vascular elastosis. Twenty mares were classified on the basis of degree of vascular degeneration and stage of cycle. A fluorescent microsphere technique was used to measure reproductive organ perfusion, where microspheres were injected into the left ventricle of the heart and became trapped in capillary beds in proportion to blood flow and tissue perfusion. The reproductive tract was removed, sectioned, and the fluorescent intensity evaluated to measure blood flow and perfusion. Additionally, full-thickness samples of the uterine wall were examined postmortem to further assess the degree of vascular degeneration in all layers of uterine wall. The mean value of uterine perfusion for the control mares during estrus (n = 5) was higher (P < 0.01) than that during diestrus (n = 5); 17.6 and 11.9 mL/min/100g, respectively. For the subfertile/infertile mares, the mean value of tissue perfusion was not different (P > 0.05) during estrus (n = 5) and diestrus (n = 5); 5.9 and 7.2 mL/min/100g, respectively. Uterine perfusion in subfertile/infertile mares affected by elastosis was lower than that of control mares during both estrus (P < 0.01) and diestrus (P < 0.01). The differences in baseline levels of perfusion between the control and elastosis groups indicate that elastosis of the uterine vasculature is associated with decreased uterine perfusion during both phases of the estrous cycle. In the uterus, a compromise in UBF could have implications in endometrial glandular development, postbreeding endometritis, uterine clearance, development of the conceptus, and overall fertility., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of the study was to describe the pharmacokinetics and selected pharmacodynamics of intravenous dexmedetomidine in horses. Eight adult horses received 5 μg/kg dexmedetomidine IV. Blood samples were collected before and for 10 h after drug administration to determine dexmedetomidine plasma concentrations. Pharmacokinetic parameters were calculated using noncompartmental analysis. Data from one outlier were excluded from the statistical summary. Behavioral and physiological responses were recorded before and for 6 h after dexmedetomidine administration. Dexmedetomidine concentrations decreased rapidly (elimination half-life of 8.03 ± 0.84 min). Time of last detection varied from 30 to 60 min. Bradycardia was noted at 4 and 10 min after drug administration (26 ± 8 and 29 ± 8 beats/min respectively). Head height decreased by 70% at 4 and 10 min and gradually returned to baseline. Ability to ambulate was decreased for 60 min following drug administration, and mechanical nociceptive threshold was increased during 30 min. Blood glucose peaked at 30 min (134 ± 24 mg/dL) and borborygmi were decreased for the first hour after dexmedetomidine administration. Dexmedetomidine was quickly eliminated as indicated by the rapid decrease in plasma concentrations. Physiological, behavioral, and analgesic effects observed after dexmedetomidine administration were of short duration., (© 2014 John Wiley & Sons Ltd.)

Reasons for Performing Study: The use of fentanyl is limited in adult horses, in part due to potential for central nervous system excitation. The pharmacokinetics and the plasma concentration-related behavioural actions of fentanyl have not been described for young foals., Objectives: The goal of the present study was to describe the pharmacokinetics and behavioural effects of fentanyl following administration to the same group of foals at 3 different ages., Study Design: Experimental study in healthy foals., Methods: Fentanyl was administered i.v. (4 μg/kg bwt) to a group of 9 foals on 3 separate occasions at 6–8, 20–22 and 41–42 days of age. Blood samples were collected prior to administration and at multiple times until 24 h post administration. Blood samples were analysed for fentanyl concentrations and pharmacokinetics determined at each age. Behavioural and physiological effects were also assessed., Results: The average volume of distribution was 3.55, 1.53 and 1.82 l/kg bwt and clearance 50.2, 40.7 and 35.7 ml/min/kg bwt when foals were 6–8, 20–22 and 41–42 days of age, respectively. The elimination half-life was slightly prolonged (49.3 min) at 6–8 days relative to 20–22 and 41–42 days of age (25.8 and 33.7 min, respectively). The primary metabolite detected in blood samples was the same as for adult horses. While the onset and duration varied widely between foals, sedation was observed at all ages studied., Conclusions: Fentanyl appears to be consistently well tolerated following i.v. administration of 4 μg/kg bwt to foals ranging in age from 1 to 6 weeks. The results of this study support further study of fentanyl for clinical use in foals.

The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL · min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro-excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3-glucuronide contribute to the dose-dependent excitation observed at high morphine doses., (© 2014 John Wiley & Sons Ltd.)

Background: This study investigated the antinociceptive effects of a constant rate infusion (CRI) of lidocaine during xylazine and ketamine anesthesia in horses and aimed to correlate these effects with cardiorespiratory variables, bispectral index (BIS) and plasma lidocaine concentrations. Six adult crossbred mares weighing 320-400 kg were anesthetized on three different occasions. Sedation was performed with xylazine (0.75 mg/kg IV) and anesthetic induction with guaifenesin (75 mg/kg IV) and ketamine (2 mg/kg IV). Anesthesia was maintained with 37.5 μg/kg/min of xylazine and 87.5 μg/kg/min of ketamine both administered intravenously for 75 min. The three treatments consisted of: lidocaine (loading dose: 5 mg/kg, CRI: 100 μg/kg/min; THL); lidocaine (loading dose: 2.5 mg/kg; CRI: 50 μg/kg/min: TLL); and saline (TS); all given 15 min after induction and maintained for 1 h. Antinociception was measured by response to electrical stimulation and bispectral index (BIS) was recorded during anesthesia. Parametric and non-parametric data were compared using ANOVA followed by Student-Newman-Keuls and Friedman tests, respectively., Results: Plasma lidocaine concentrations peaked at the end of lidocaine loading dose and was greater in THL (9.61 ± 2.75 μg/mL) vs TLL (4.50 ± 3.34 μg/mL). Electrical noxious stimulation caused purposeful movement in all horses from TS, but no response in THL. The BIS was decreased in THL only and was less when compared to the other treatments throughout anesthesia. Blood pressure, PaO2 and PaCO2 increased and heart rate (HR), respiratory rate (RR), pH, total plasma protein and temperature decreased during anesthesia in all treatments. PaCO2 and HR were greater and RR and pH less in THL compared to TLL and TS at 30 min during anesthesia. All recoveries were considered excellent. Time to standing was longer after THL (60 ± 20 min) than following TLL and TS (32 ± 17 and 30 ± 15 min, respectively)., Conclusions: At the highest dose administered (THL) lidocaine CRI during xylazine/ketamine anesthesia decreased BIS and motor response to noxious stimulation, and prolonged recovery time without significant added cardiorespiratory depression.

Reasons for Performing Study: Both the potential analgesic effect and the conflicting reports describing tramadol disposition in the horse warrant further study of the pharmacokinetics of tramadol in this species., Objectives: To describe the pharmacokinetics of tramadol and its metabolites, O-desmethyltramadol and N-desmethyltramadol, following i.v. administration of 3 doses to the horse., Methods: Nine adult horses received a single i.v. dose of 0.5, 1.5 and 3 mg/kg bwt tramadol. Blood samples were collected prior to and at various times up to 72 h post administration. Plasma samples were analysed using liquid chromatography-mass spectrometry and data analysed using noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, step count and gastrointestinal activity were also assessed., Results: Maximal measured plasma tramadol concentrations were 454 ± 101.6, 1086.7 ± 330.7 and 1697.9 ± 406.1 ng/ml for 0.5, 1.5 and 3 mg/kg bwt, respectively. Depending on the dose administered, the tramadol clearance, volume of distribution and half-life ranged from 24.6 to 25.0 ml/min/kg, 2.66 to 3.33 l/kg and 2.17 to 3.05 h, respectively. Following administration of 0.5, 1.5 and 3 mg/kg bwt tramadol, the maximal measured plasma concentrations of the active metabolite, O-desmethyltramadol, were 3.9 ± 1.9, 9.6 ± 4.8 and 12.9 ± 5.2 ng/ml, respectively. Muscle fasiculations and tremors were seen following administration of the 2 high doses. No significant changes in chin-to-ground distance, heart rate and rhythm, step count and gastrointestinal activity were observed., Conclusions and Potential Relevance: This study confirms and extends previous studies describing the pharmacokinetics of tramadol following i.v. administration to the horse. Plasma tramadol concentrations exceeded those necessary for analgesia in human patients; however, further studies are necessary to determine plasma concentrations of tramadol necessary for analgesic efficacy in the horse. These results support further investigation of the analgesic efficacy of tramadol in the horse., (© 2012 EVJ Ltd.)