RESUMO
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.
Assuntos
Anestésicos Inalatórios , Dexmedetomidina , Animais , Dexmedetomidina/farmacologia , Cães , Estudos Prospectivos , Quinolizinas , SevofluranoRESUMO
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.
Assuntos
Analgésicos Opioides/farmacologia , Analgésicos Opioides/farmacocinética , Meperidina/farmacologia , Meperidina/farmacocinética , Administração Intravenosa/veterinária , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Cavalos , Temperatura Alta , Masculino , Meperidina/administração & dosagem , Meperidina/efeitos adversos , Meperidina/análogos & derivados , Meperidina/sangue , Meperidina/urina , Nociceptividade/efeitos dos fármacos , UrticáriaRESUMO
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.
Assuntos
Diuréticos/farmacologia , Furosemida/farmacologia , Condicionamento Físico Animal , Privação de Água , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Diuréticos/administração & dosagem , Esquema de Medicação , Feminino , Furosemida/administração & dosagem , Cavalos , Ácido Láctico/sangue , MasculinoRESUMO
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.
Assuntos
Analgésicos Opioides/farmacocinética , Cavalos/sangue , Derivados da Morfina/urina , Morfina/farmacocinética , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/urina , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Injeções Intravenosas , Masculino , Morfina/administração & dosagem , Morfina/urinaRESUMO
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.
Assuntos
Anestesia por Inalação/veterinária , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/farmacologia , Dexmedetomidina/farmacologia , Éteres Metílicos/administração & dosagem , Quinolizinas/farmacologia , Anestesia por Inalação/métodos , Anestésicos Combinados/administração & dosagem , Anestésicos Combinados/farmacologia , Anestésicos Inalatórios/análise , Anestésicos Intravenosos/administração & dosagem , Animais , Dexmedetomidina/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Feminino , Masculino , Éteres Metílicos/análise , Alvéolos Pulmonares/química , Quinolizinas/administração & dosagem , SevofluranoRESUMO
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.
Assuntos
Analgesia/veterinária , Anestésicos Locais/farmacologia , Cavalos , Ketamina/farmacologia , Lidocaína/farmacologia , Xilazina/farmacologia , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/farmacologia , Anestésicos Locais/administração & dosagem , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Feminino , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Injeções Intravenosas , Ketamina/administração & dosagem , Lidocaína/administração & dosagem , Xilazina/administração & dosagemRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Cavalos/sangue , Cavalos/fisiologia , Imidazóis/farmacologia , Imidazóis/farmacocinética , Ioimbina/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Interações Medicamentosas , Frequência Cardíaca/efeitos dos fármacos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Imidazóis/administração & dosagem , Ioimbina/administração & dosagemRESUMO
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.
Assuntos
Anestesia por Inalação/veterinária , Anestésicos Inalatórios , Dióxido de Carbono/uso terapêutico , Cavalos , Isoflurano , Éteres Metílicos , Período de Recuperação da Anestesia , Anestesia por Inalação/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Animais , Feminino , Cavalos/fisiologia , Hipercapnia/veterinária , Hipoventilação/veterinária , Intubação Intratraqueal/veterinária , Isoflurano/efeitos adversos , Masculino , Éteres Metílicos/efeitos adversos , Taxa Respiratória/efeitos dos fármacos , SevofluranoRESUMO
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.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Cavalos/sangue , Hipnóticos e Sedativos/farmacocinética , Imidazóis/farmacocinética , Ioimbina/farmacocinética , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/sangue , Animais , Área Sob a Curva , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Meia-Vida , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Imidazóis/administração & dosagem , Imidazóis/sangue , Masculino , Ioimbina/administração & dosagem , Ioimbina/sangueRESUMO
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.
Assuntos
Analgesia/veterinária , Analgésicos não Narcóticos/farmacocinética , Medetomidina/farmacocinética , Analgesia/métodos , Analgésicos não Narcóticos/sangue , Analgésicos não Narcóticos/farmacologia , Animais , Glicemia/análise , Bradicardia/induzido quimicamente , Bradicardia/veterinária , Feminino , Frequência Cardíaca/efeitos dos fármacos , Cavalos/metabolismo , Injeções Intravenosas/veterinária , Masculino , Medetomidina/sangue , Medetomidina/farmacologia , Taxa Respiratória/efeitos dos fármacosRESUMO
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).
Assuntos
Analgésicos Opioides , Glucuronídeos , Administração Intravenosa/veterinária , Animais , Cavalos , Morfina/farmacologia , Derivados da Morfina/farmacocinética , Ratos , Distribuição TecidualRESUMO
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.
Assuntos
Anestesia Geral/veterinária , Anestésicos Inalatórios/farmacocinética , Cavalos/fisiologia , Lidocaína/farmacocinética , Éteres Metílicos/farmacocinética , Alvéolos Pulmonares/metabolismo , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/sangue , Animais , Interações Medicamentosas , Feminino , Frequência Cardíaca , Infusões Intravenosas/veterinária , Lidocaína/administração & dosagem , Lidocaína/sangue , Masculino , Éteres Metílicos/administração & dosagem , SevofluranoRESUMO
OBJECTIVE: To compare cardiovascular effects of sevoflurane alone and sevoflurane plus an IV infusion of lidocaine in horses. Animals-8 adult horses. PROCEDURES: Each horse was anesthetized twice via IV administration of xylazine, diazepam, and ketamine. During 1 anesthetic episode, anesthesia was maintained by administration of sevoflurane in oxygen at 1.0 and 1.5 times the minimum alveolar concentration (MAC). During the other episode, anesthesia was maintained at the same MAC multiples via a reduced concentration of sevoflurane plus an IV infusion of lidocaine. Heart rate, arterial blood pressures, blood gas analyses, and cardiac output were measured during mechanical (controlled) ventilation at both 1.0 and 1.5 MAC for each anesthetic protocol and during spontaneous ventilation at 1 of the 2 MAC multiples. RESULTS: Cardiorespiratory variables did not differ significantly between anesthetic protocols. Blood pressures were highest at 1.0 MAC during spontaneous ventilation and lowest at 1.5 MAC during controlled ventilation for either anesthetic protocol. Cardiac output was significantly higher during 1.0 MAC than during 1.5 MAC for sevoflurane plus lidocaine but was not affected by anesthetic protocol or mode of ventilation. Clinically important hypotension was detected at 1.5 MAC for both anesthetic protocols. CONCLUSIONS AND CLINICAL RELEVANCE: Lidocaine infusion did not alter cardiorespiratory variables during anesthesia in horses, provided anesthetic depth was maintained constant. The IV administration of lidocaine to anesthetized nonstimulated horses should be used for reasons other than to improve cardiovascular performance. Severe hypotension can be expected in nonstimulated horses at 1.5 MAC sevoflurane, regardless of whether lidocaine is administered.
Assuntos
Anestesia Geral/veterinária , Anestésicos Inalatórios/administração & dosagem , Cavalos/fisiologia , Lidocaína/administração & dosagem , Éteres Metílicos/farmacologia , Anestésicos Inalatórios/sangue , Animais , Gasometria , Pressão Sanguínea , Débito Cardíaco , Interações Medicamentosas , Feminino , Frequência Cardíaca , Infusões Intravenosas/veterinária , Lidocaína/sangue , Masculino , Éteres Metílicos/administração & dosagem , SevofluranoRESUMO
OBJECTIVE: To test a hypothesis predicting that isoflurane would interfere with cerebrovascular autoregulation in horses and to evaluate whether increased mean arterial blood pressure (MAP) would increase cerebral blood flow and intracranial pressure (ICP) during isoflurane anesthesia. ANIMALS: 6 healthy adult horses. PROCEDURES: Horses were anesthetized with isoflurane at a constant end-tidal concentration sufficient to maintain MAP at 60 mm Hg. The facial, carotid, and dorsal metatarsal arteries were catheterized for blood sample collection and pressure measurements. A sub-arachnoid transducer was used to measure ICP Fluorescent microspheres were injected through a left ventricular catheter during MAP conditions of 60 mm Hg, and blood samples were collected. This process was repeated with different-colored microspheres at the same isoflurane concentration during MAP conditions of 80 and 100 mm Hg achieved with IV administration of dobutamine. Central nervous system tissue samples were obtained after euthanasia to quantify fluorescence and calculate blood flow. RESULTS: Increased MAP did not increase ICP or blood flow in any of the brain tissues examined. However, values for blood flow were low for all tested brain regions except the pons and cerebellum. Spinal cord blood flow was significantly decreased at the highest MAP. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that healthy horses autoregulate blood flow in the CNS at moderate to deep planes of isoflurane anesthesia. Nonetheless, relatively low blood flows in the brain and spinal cord of anesthetized horses may increase risks for hypoperfusion and neurologic injury.
Assuntos
Anestesia Geral/veterinária , Anestésicos Inalatórios/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Cavalos/fisiologia , Isoflurano/farmacologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Feminino , MasculinoRESUMO
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.
Assuntos
Analgésicos Opioides/farmacologia , Anestesia por Inalação/veterinária , Anestésicos Inalatórios/farmacologia , Gatos , Metadona/farmacologia , Éteres Metílicos/farmacologia , Movimento/efeitos dos fármacos , Analgésicos Opioides/sangue , Período de Recuperação da Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas/veterinária , Masculino , Metadona/sangue , Estudos Prospectivos , Alvéolos Pulmonares , Sevoflurano , Fatores de TempoRESUMO
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.
Assuntos
Anestesia por Inalação/veterinária , Modelos Animais de Doenças , Cães , Ligamentos/fisiopatologia , Ovário/fisiopatologia , Dor Pélvica , Alvéolos Pulmonares/metabolismo , Anestésicos Inalatórios/farmacocinética , Animais , Feminino , Laparoscopia/veterinária , Éteres Metílicos/farmacocinética , Estudos Prospectivos , Reprodutibilidade dos Testes , SevofluranoRESUMO
OBJECTIVE: To characterize cardiovascular, respiratory and biochemical effects and recovery behavior associated with a 3-hour continuous infusion of a micellar microemulsion propofol formulation in horses. STUDY DESIGN: Prospective experimental trial. ANIMALS: Six healthy adult horses, 9 +/- 2 years old and weighing 557 +/- 14 kg. METHODS: All horses received xylazine (1 mg kg(-1), IV) 5 minutes prior to anesthetic induction. Each horse was anesthetized on two occasions with a 5% micellar microemulsion propofol formulation (2 mg kg(-1), IV); first as a single bolus (phase I) and then as a 3-hour continuous infusion (phase II). Propofol pharmacokinetics were obtained from phase I and used to determine the starting infusion rates in phase II. Anesthetic induction and recovery characteristics were quantitatively and qualitatively assessed. Cardiovascular, respiratory and biochemical parameters were monitored during anesthesia and recovery. RESULTS: Induction quality varied, ranging from good to poor. Standing and overall recovery quality scores were consistently excellent in phase I but more variability was observed among horses in phase II. Heart rate (HR) and mean arterial pressure (MAP) were adequately maintained but marked hypoventilation developed. There were only minimal changes in blood biochemical analytes following anesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: The micellar microemulsion propofol formulation, administered as a 3-hour continuous infusion, showed similar results compared to those previously described with a commercially available propofol preparation. However, based on present findings, use of propofol as a primary anesthetic in horses for prolonged periods of anesthesia requires further study to determine the limits of safety and clinical applicability.
Assuntos
Anestesia Intravenosa/veterinária , Cavalos , Propofol , Anestesia Intravenosa/métodos , Animais , Gasometria/veterinária , Pressão Sanguínea/efeitos dos fármacos , Proteínas Sanguíneas/análise , Temperatura Corporal/efeitos dos fármacos , Esquema de Medicação/veterinária , Feminino , Frequência Cardíaca/efeitos dos fármacos , Hematócrito/veterinária , Cavalos/fisiologia , Infusões Intravenosas/veterinária , Injeções Intravenosas/veterinária , Masculino , Propofol/administração & dosagem , Propofol/farmacologia , Taxa Respiratória/efeitos dos fármacosRESUMO
OBJECTIVE: To verify the isoflurane anesthetic minimum alveolar concentration (MAC)-sparing effect of a previously administered target plasma fentanyl concentration of 16 ng/mL and characterize an anticipated further sparing in isoflurane MAC associated with higher target plasma fentanyl concentrations. ANIMALS: 8 horses. PROCEDURES: Horses were assigned 2 of 3 target plasma fentanyl concentrations (16, 24, and 32 ng/mL), administered in ascending order. Following determination of baseline MAC, horses received a loading dose of fentanyl followed by a constant rate infusion; MAC determination was performed in triplicate at baseline and at each fentanyl concentration. Venous blood samples were collected throughout the study for determination of actual plasma fentanyl concentrations. Recovery from anesthesia was monitored, and behaviors were rated as excellent, good, fair, or poor. RESULTS: Mean + or - SD fentanyl plasma concentrations were 13.9 + or - 2.6 ng/mL, 20.1 + or - 3.6 ng/mL, and 24.1 + or - 2.4 ng/mL for target concentrations of 16, 24, and 32 ng/mL, respectively. The corresponding changes in the MAC of isoflurane were -3.28%, -6.23%, and +1.14%. None of the changes were significant. Recovery behavior was variable and included highly undesirable, potentially injurious excitatory behavior. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the study did not verify an isoflurane-sparing effect of fentanyl at a plasma target concentration of 16 ng/mL. Furthermore, a reduction in MAC was not detected at higher fentanyl concentrations. Overall, results did not support the routine use of fentanyl as an anesthetic adjuvant in adult horses.