Preliminary study of the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of morphine 6-glucuronide (M6G) following intravenous administration to horses.

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.

Bien que la morphine ait démontré des effets antinociceptifs chez les chevaux, son administration a été associée avec des effets non-désirés d'une manière dose-dépendante. Chez les humains et les rats, une partie de l'effet analgésique de la morphine a été attribuée au métabolite actif, morphine-6-glucuronide (M6G). Bien que la morphine puisse causer plusieurs effets indésirables, M6G a un profil de sécurité plus favorable. L'objectif de cette étude était de caractériser la pharmacocinétique, la distribution tissulaire, et le comportement et sélectionner des effets physiologiques de M6G suivant son administration intraveineuse à un petit groupe de chevaux. Dans la Partie 1 de l'étude, trois chevaux ont reçu l'administration intraveineuse d'une dose unique de saline, 0,5 mg/kg de poids corporel (BW) de M6G, ou 0,5 mg/kg BW de morphine selon un essai croisé à trois voies. Des échantillons sanguins ont été prélevés jusqu'à 96 h post-administration, les concentrations de drogues et de métabolites mesurées, et les pharmacocinétiques déterminées. Les effets physiologiques et sur le comportement ont par la suite été notés. Dans la Partie 2 de l'étude, deux chevaux devant être euthanasiés pour d'autres raisons, ont reçu 0,5 mg/kg BW de M6G. Du sang, du liquide céphalo-rachidien (CSF), et différents échantillons de tissu ont été prélevés post-administration et les concentration de drogue furent déterminées. La clairance de M6G a été plus rapide et le volume de distribution à l'état d'équilibre était plus petit pour M6G comparativement à la morphine. Une réaction caractérisée par le tremblement de la tête, du piaffage, et une légère ataxie a été observée immédiatement à la suite de l'administration soit de morphine ou de M6G aux chevaux. Après administration de M6G, ces comportements diminuèrent rapidement et furent suivis par une période plus longue de sédation. À la suite de l'administration, M6G a été détecté dans les reins, le foie, le CSF, et des régions du cerveau. Les résultats de cette étude incitent à réaliser des études additionnelles sur M6G afin d'évaluer son potentiel clinique comme analgésique chez les chevaux.(Traduit par Docteur Serge Messier).

Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs.

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.

Meperidine pharmacokinetics and effects on physiologic parameters and thermal threshold following intravenous administration of three doses to horses.

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.

Physiologic effects of furosemide in combination with water restriction when administered at 4 and 24 hours prior to high-intensity treadmill training.

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.

Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses.

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.

Pharmacokinetics and selected pharmacodynamics of trazodone following intravenous and oral administration to horses undergoing fitness training.

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.

Effects of constant rate infusions of dexmedetomidine or MK-467 on the minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To determine the effects of low and high dose infusions of dexmedetomidine and a peripheral α2-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. PaCO2 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 α2-adrenergic antagonist to inhalation anesthesia in dogs.

Cardiorespiratory and antinociceptive effects of two different doses of lidocaine administered to horses during a constant intravenous infusion of xylazine and ketamine.

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.

Effect of yohimbine on detomidine induced changes in behavior, cardiac and blood parameters in the horse.

OBJECTIVE: To describe selected pharmacodynamic effects of detomidine and yohimbine when administered alone and in sequence. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses aged 9 ± 4 years and weighing 561 ± 56 kg. METHODS: Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV, 2) 0.2 mg kg(-1) yohimbine IV and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV. Each horse received all three treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume and plasma proteins were monitored. RESULTS: Yohimbine rapidly reversed the sedative effects of detomidine in the horse. Additionally, yohimbine effectively returned heart rate and the percent of atrio-ventricular conduction disturbances to pre-detomidine values when administered 15 minutes post-detomidine administration. Plasma glucose was significantly increased following detomidine administration. The detomidine induced hyperglycemia was effectively reduced by yohimbine administration. Effects on packed cell volume and plasma proteins were variable. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of yohimbine effectively reversed detomidine induced sedation, bradycardia, atrio-ventricular heart block and hyperglycemia.

Effects of hypercapnic hyperpnea on recovery from isoflurane or sevoflurane anesthesia in horses.

OBJECTIVE: To test the hypothesis that hypercapnic hyperpnea produced using endotracheal insufflation with 5-10% CO(2) in oxygen could be used to shorten anesthetic recovery time in horses, and that recovery from sevoflurane would be faster than from isoflurane. STUDY DESIGN: Randomized crossover study design. ANIMALS: Eight healthy adult horses. METHODS: After 2 hours' administration of constant 1.2 times MAC isoflurane or sevoflurane, horses were disconnected from the anesthetic circuit and administered 0, 5, or 10% CO(2) in balance O(2) via endotracheal tube insufflation. End-tidal gas samples were collected to measure anesthetic washout kinetics, and arterial and venous blood samples were collected to measure respiratory gas partial pressures. Horses recovered in padded stalls without assistance, and each recovery was videotaped and evaluated by reviewers who were blinded to the anesthetic agent and insufflation treatment used. RESULTS: Compared to isoflurane, sevoflurane caused greater hypoventilation and was associated with longer times until standing recovery. CO(2) insufflation significantly decreased anesthetic recovery time compared to insufflation with O(2) alone without significantly increasing PaCO(2) . Pharmacokinetic parameters during recovery from isoflurane with CO(2) insufflation were statistically indistinguishable from sevoflurane recovery without CO(2). Neither anesthetic agent nor insufflation treatment affected recovery quality from anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Hypercapnic hyperpnea decreases time to standing without influencing anesthetic recovery quality. Although the lower blood gas solubility of sevoflurane should favor a shorter recovery time compared to isoflurane, this advantage is negated by the greater respiratory depression from sevoflurane in horses.

The effects of yohimbine on the pharmacokinetic parameters of detomidine in the horse.

OBJECTIVE: To describe the pharmacokinetics of detomidine and yohimbine when administered in combination. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses aged 9 ± 4 years and weighing of 561 ± 56 kg. METHODS: Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV (D), 2) 0.2 mg kg(-1) yohimbine IV (Y) and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV (DY). Each horse received all three dose regimens with a minimum of 1 week in between subsequent regimens. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Data were analyzed using both non-compartmental and compartmental analysis. RESULTS: The maximum measured detomidine concentrations were 76.0 and 129.9 ng mL(-1) for the D and DY treatments, respectively. Systemic clearance and volume of distribution of detomidine were not significantly different for either treatment. There was a significant increase in the maximum measured yohimbine plasma concentrations from Y (173.9 ng mL(-1)) to DY (289.8 ng mL(-1)). Both the Cl and V(d) for yohimbine were significantly less (6.8 mL minute(-1) kg(-1) (Cl) and 1.7 L kg(-1) (V(d) )) for the DY as compared to the Y treatments (13.9 mL minute(-1) kg(-1) (Cl) and 2.7 L kg(-1) (V(d))). Plasma concentrations were below the limit of quantitation (0.05 and 0.5 ng mL(-1)) by 18 hours for both detomidine and yohimbine. CONCLUSION AND CLINICAL RELEVANCE: The Cl and V(d) of yohimbine were affected by prior administration of detomidine. The elimination half life of yohimbine remained unaffected when administered subsequent to detomidine. However, the increased plasma concentrations in the presence of detomidine has the potential to cause untoward effects and therefore further studies to assess the physiologic effects of this combination of drugs are warranted.

Evaluation of infusions of xylazine with ketamine or propofol to modulate recovery following sevoflurane anesthesia in horses.

OBJECTIVE: To determine whether infusion of xylazine and ketamine or xylazine and propofol after sevoflurane administration in horses would improve the quality of recovery from anesthesia. ANIMALS: 6 healthy adult horses. PROCEDURES: For each horse, anesthesia was induced by administration of xylazine, diazepam, and ketamine and maintained with sevoflurane for approximately 90 minutes (of which the last 60 minutes were under steady-state conditions) 3 times at 1-week intervals. For 1 anesthetic episode, each horse was allowed to recover from sevoflurane anesthesia; for the other 2 episodes, xylazine and ketamine or xylazine and propofol were infused for 30 or 15 minutes, respectively, after termination of sevoflurane administration. Selected cardiopulmonary variables were measured during anesthesia and recovery. Recovery events were monitored and subjectively scored. RESULTS: Cardiopulmonary variables differed minimally among treatments, although the xylazine-propofol infusion was associated with greater respiratory depression than was the xylazine-ketamine infusion. Interval from discontinuation of sevoflurane or infusion administration to standing did not differ significantly among treatments, but the number of attempts required to stand successfully was significantly lower after xylazine-propofol infusion, compared with the number of attempts after sevoflurane alone. Scores for recovery from anesthesia were significantly lower (ie, better recovery) after either infusion, compared with scores for sevoflurane administration alone. CONCLUSIONS AND CLINICAL RELEVANCE: Xylazine-ketamine or xylazine-propofol infusion significantly improved quality of recovery from sevoflurane anesthesia in horses. Xylazine-ketamine or xylazine-propofol infusions may be of benefit during recovery from sevoflurane anesthesia in horses for which a smooth recovery is particularly critical. However, oxygenation and ventilation should be monitored carefully.

Pharmacokinetics and pharmacodynamics of intravenous medetomidine in the horse.

OBJECTIVE: To describe the pharmacodynamics and pharmacokinetics following an intravenous (IV) bolus dose of medetomidine in the horse. STUDY DESIGN: Prospective experimental trial. ANIMALS: Eight, mature healthy horses age 11.7 ± 4.6 (mean ± SD) years, weighing 557 ± 54 kg. METHODS: Medetomidine (10 µg kg(-1) ) was administered IV. Blood was sampled at fixed time points from before drug administration to 48 hours post administration. Behavioral, physiological and biochemical data were obtained at predetermined time points from 0 minutes to 24 hours post administration. An algometer was also used to measure threshold responses to noxious stimuli. Medetomidine concentrations were determined by liquid chromatography-Mass Spectrometry and used for calculation of pharmacokinetic parameters using noncompartmental and compartmental analysis. RESULTS: Pharmacokinetic analysis estimated that medetomidine peaked (8.86 ± 3.87 ng mL(-1) ) at 6.4 ± 2.7 minutes following administration and was last detected at 165 ± 77 minutes post administration. Medetomidine had a clearance of 39.6 ± 14.6 mL kg(-1) minute(-1) and a volume of distribution of 1854 ± 565 mL kg(-1). The elimination half-life was 29.1 ± 12.5 minutes. Glucose concentration reached a maximum of 176 ± 46 mg dL(-1) approximately 1 hour post administration. Decreased heart rate, respiratory rate, borborygmi, packed cell volume, and total protein concentration were observed following administration. Horses lowered their heads from 107 ± 12 to 20 ± 10 cm within 10 minutes of drug administration and gradually returned to normal. Horse mobility decreased after drug administration. An increased mechanical threshold was present from 10 to 45 minutes and horses were less responsive to sound. CONCLUSION AND CLINICAL RELEVANCE: Behavioral and physiological effects following intravenous administration positively correlate with pharmacokinetic profiles from plasma medetomidine concentrations. Glucose concentration gradually transiently increased following medetomidine administration. The analgesic effect of the drug appeared to have a very short duration.

Anesthetic induction with guaifenesin and propofol in adult horses.

OBJECTIVE: To evaluate whether guaifenesin can prevent adverse anesthetic induction events caused by propofol and whether a guaifenesin-propofol induction combination has brief cardiovascular effects commensurate with rapid drug washout. ANIMALS: 8 healthy adult horses. PROCEDURES: Guaifenesin was administered IV for 3 minutes followed by IV injection of a bolus of propofol (2 mg/kg). Additional propofol was administered if purposeful movement was detected. Anesthesia was maintained for 2 hours with isoflurane or sevoflurane at 1.2 times the minimum alveolar concentration with controlled normocapnic ventilation. Normotension was maintained via a dobutamine infusion. Plasma concentrations of propofol and guaifenesin were measured every 30 minutes. RESULTS: Mean ± SD guaifenesin and propofol doses inducing anesthesia in half of the horses were 73 ± 18 mg/kg and 2.2 ± 0.3 mg/kg, respectively. No adverse anesthetic induction events were observed. By 70 minutes, there was no significant temporal change in the dobutamine infusion rate required to maintain normotension for horses anesthetized with isoflurane or sevoflurane. Mean plasma guaifenesin concentrations were 122 ± 30 µM, 101 ± 33 µM, 93 ± 28 µM, and 80 ± 24 µM at 30, 60, 90, and 120 minutes after anesthetic induction, respectively. All plasma propofol concentrations were below the limit of quantitation. CONCLUSIONS AND CLINICAL RELEVANCE: Guaifenesin prevented adverse anesthetic induction events caused by propofol. Guaifenesin (90 mg/kg) followed by propofol (3 mg/kg) should be sufficient to immobilize > 99% of calm healthy adult horses. Anesthetic drug washout was rapid, and there was no change in inotrope requirements after anesthesia for 70 minutes.

Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs.

OBJECTIVE: To determine the anesthetic-sparing effect of maropitant, a neurokinin 1 receptor antagonist, during noxious visceral stimulation of the ovary and ovarian ligament in dogs. ANIMALS: Eight 1-year-old female dogs. PROCEDURES: Dogs were anesthetized with sevoflurane. Following instrumentation and stabilization, the right ovary and ovarian ligament were accessed by use of laparoscopy. The ovary was stimulated with a traction force of 6.61 N. The minimum alveolar concentration (MAC) was determined before and after 2 doses of maropitant. RESULTS: The sevoflurane MAC value was 2.12 ± 0.4% during stimulation without treatment (control). Administration of maropitant (1 mg/kg, IV, followed by 30 µg/kg/h, IV) decreased the sevoflurane MAC to 1.61 ± 0.4% (24% decrease). A higher maropitant dose (5 mg/kg, IV, followed by 150 µg/kg/h, IV) decreased the MAC to 1.48 ± 0.4% (30% decrease). CONCLUSIONS AND CLINICAL RELEVANCE: Maropitant decreased the anesthetic requirements during visceral stimulation of the ovary and ovarian ligament in dogs. Results suggest the potential role for neurokinin 1 receptor antagonists to manage ovarian and visceral pain.

Determination of the sevoflurane sparing effect of methadone in cats.

OBJECTIVE: To determine the magnitude and duration of sevoflurane minimum alveolar concentration (MAC) reduction following a single intravenous (IV) dose of methadone in cats. STUDY DESIGN: Prospective experimental study. ANIMALS: Eight (four females and four males) healthy mixed-breed adult (1-2 years) cats weighing 5.82 ± 0.42 kg. METHODS: Anesthesia was induced and maintained with sevoflurane. Intravenous catheters facilitated administration of methadone and lactated Ringer's solution. After baseline MAC determination in triplicate using a tail clamp technique, 0.3 mg kg(-1) of methadone was administered IV. End-tidal sevoflurane concentration (e'SEVO) was reduced and MAC was redetermined. In an effort to determine the duration of MAC reduction, measurements were repeated in a stepwise manner until MAC values returned to baseline. After the last stimulation, the e'SEVO was increased to 1.2 individual MAC for 15 minutes, then sevoflurane was discontinued and cats were allowed to recover from anesthesia. RESULTS: Baseline sevoflurane MAC was 3.18 ± 0.06%. When compared with baseline the sevoflurane MAC after methadone administration was significantly reduced by 25, 15 and 7% at 26, 76 and 122 minutes, respectively. The final MAC value (3.09 ± 0.07%) determined 156 minutes after methadone administration was not significantly different from baseline. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous methadone (0.3 mg kg(-1)) significantly decreased MAC of sevoflurane in cats but the effect was short-lived.

A dog model to study ovary, ovarian ligament and visceral pain.

OBJECTIVE: A dog model was developed to study visceral pain by stimulating the ovarian ligament. STUDY DESIGN: Prospective experimental trial. ANIMALS: Twelve 1-year old female hound dogs weighing 25.7 ± 3.6 kg. METHODS: Dogs were anesthetized with sevoflurane. The right ovary was accessed via laparoscopy. A suture was placed around the ovarian ligament and exteriorized through the abdominal wall for stimulation. The noxious stimulus consisted of pulling the ovary and ovarian ligament with a force transducer. The response to noxious stimulation was determined using the anesthetic minimum alveolar concentration requirement (MAC) for sevoflurane. The ovarian MAC was compared to the standardized somatic noxious stimulation tail clamp MAC. The results are depicted as mean ± SD and corrected to sea-level. RESULTS: The stimulus-response curve during ovarian stimulation in three dogs was hyperbolic and best represented by a three-parameter logistic growth curve model. The curve plateaued at 7.12 ± 4.19 N. From the stimulus-response curve, we chose 6.61 N to test the consistency and repeatability of the model in nine dogs. The ovarian stimulation MAC for sevoflurane in these dogs was 2.16 ± 0.46%. The ovarian stimulation confidence interval and limits are comparable to the results from tail stimulation MAC. The tail stimulation MACs before and after laparoscopy surgery were not different (1.86 ± 0.28% and 1.77 ± 0.38% respectively; p > 0.05) but lower when compared to the ovarian MAC (p < 0.01). The dogs recovered from anesthesia without complications. CONCLUSIONS AND CLINICAL RELEVANCE: The ovarian stimulation model is an adequate and repeatable means of producing visceral stimulation to determine MAC. The model may provide a humane mechanism to study the effectiveness of analgesics for acute ovarian pain.

Effects of intravenous administration of lidocaine on the minimum alveolar concentration of sevoflurane in horses.

OBJECTIVE: To determine effects of a continuous rate infusion of lidocaine on the minimum alveolar concentration (MAC) of sevoflurane in horses. ANIMALS: 8 healthy adult horses. PROCEDURES: Horses were anesthetized via IV administration of xylazine, ketamine, and diazepam; anesthesia was maintained with sevoflurane in oxygen. Approximately 1 hour after induction, sevoflurane MAC determination was initiated via standard techniques. Following sevoflurane MAC determination, lidocaine was administered as a bolus (1.3 mg/kg, IV, over 15 minutes), followed by constant rate infusion at 50 µg/kg/min. Determination of MAC for the lidocaine-sevoflurane combination was started 30 minutes after lidocaine infusion was initiated. Arterial blood samples were collected after the lidocaine bolus, at 30-minute intervals, and at the end of the infusion for measurement of plasma lidocaine concentrations. RESULTS: IV administration of lidocaine decreased mean ± SD sevoflurane MAC from 2.42 ± 0.24% to 1.78 ± 0.38% (mean MAC reduction, 26.7 ± 12%). Plasma lidocaine concentrations were 2,589 ± 811 ng/mL at the end of the bolus; 2,065 ± 441 ng/mL, 2,243 ± 699 ng/mL, 2,168 ± 339 ng/mL, and 2,254 ± 215 ng/mL at 30, 60, 90, and 120 minutes of infusion, respectively; and 2,206 ± 329 ng/mL at the end of the infusion. Plasma concentrations did not differ significantly among time points. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine could be useful for providing a more balanced anesthetic technique in horses. A detailed cardiovascular study on the effects of IV infusion of lidocaine during anesthesia with sevoflurane is required before this combination can be recommended.