Pharmacokinetics and adverse effects of butorphanol administered by single intravenous injection or continuous intravenous infusion in horses

OBJECTIVE: To determine an infusion rate of butorphanol tartrate in horses that would maintain therapeutic plasma drug concentrations while minimizing development of adverse behavioral and gastrointestinal tract effects. ANIMALS: 10 healthy adult horses. PROCEDURE: Plasma butorphanol concentrations were determined by use of high-performance liquid chromatography following administration of butorphanol by single IV injection (0.1 to 0.13 mg/kg of body weight) or continuous IV infusion (loading dose, 17.8 microg/kg; infusion dosage, 23.7 microg/kg/h for 24 hours). Pharmacokinetic variables were calculated, and changes in physical examination data, gastrointestinal tract transit time, and behavior were determined over time. RESULTS: A single IV injection of butorphanol was associated with adverse behavioral and gastrointestinal tract effects including ataxia, decreased borborygmi, and decreased defecation. Elimination half-life of butorphanol was brief (44.37 minutes). Adverse gastrointestinal tract effects were less apparent during continuous 24-hour infusion of butorphanol at a dosage that resulted in a mean plasma concentration of 29 ng/ml, compared with effects after a single IV injection. No adverse behavioral effects were observed during or after continuous infusion. CONCLUSIONS AND CLINICAL RELEVANCE: Continuous IV infusion of butorphanol for 24 hours maintained plasma butorphanol concentrations within a range associated with analgesia. Adverse behavioral and gastrointestinal tract effects were minimized during infusion, compared with a single injection of butorphanol. Continuous infusion of butorphanol may be a useful treatment to induce analgesia in horses.     

Effects of atracurium administered by continuous intravenous infusion in halothane-anesthetized horses

Atracurium (0.4 mg/ml in isotonic NaCl solution) was administered by IV infusion to 7 healthy adult horses for 2 hours. Over the 2-hour period, a 95 to 99% reduction of train-of-four hoof-twitch response was maintained by 0.17 +/- 0.01 mg of atracurium/kg of body weight/h, for a total of 161 +/- 6 mg of atracurium (mean +/- SEM) for horses 1 to 4, 6, and 7. Horse 5, a mare in estrus, required 0.49 mg of atracurium/kg/h to maintain comparable relaxation. Hoof-twitch recovery time from 10 to 75% of baseline strength was 19.8 +/- 2.5 minutes for all horses. The 10 to 75% recovery time for horse 5 was 18 minutes. Recovery time from discontinuation of halothane until standing was 86 +/- 14 minutes (range, 55 to 165 minutes). Horse 5 had a 165-minute recovery. Regarding recovery from anesthesia, 3 recoveries were rated as excellent, 1 recovery good, and 2 recoveries as fair. Horse 5 laid quietly until she stood with 1 strong, smooth effort.     

Medetomidine continuous rate intravenous infusion in horses in which surgical anaesthesia is maintained with isoflurane and intravenous infusions of lidocaine and ketamine

ObjectiveTo evaluate medetomidine as a continuous rate infusion (CRI) in horses in which anaesthesia is maintained with isoflurane and CRIs of ketamine and lidocaine.Study designProspective, randomized, blinded clinical trial.AnimalsForty horses undergoing elective surgery.MethodsAfter sedation and induction, anaesthesia was maintained with isoflurane. Mechanical ventilation was employed. All horses received lidocaine (1.5 mg kg^?1 initially, then 2 mg kg^?1 hour^?1) and ketamine (2 mg kg^?1 hour^?1), both CRIs reducing to 1.5 mg kg^?1 hour^?1 after 50 minutes. Horses in group MILK received a medetomidine CRI of 3.6 μg kg^?1 hour^?1, reducing after 50 minutes to 2.75 μg kg^?1 hour^?1, and horses in group ILK an equal volume of saline. Mean arterial pressure (MAP) was maintained above 70 mmHg using dobutamine. End-tidal concentration of isoflurane (FE′ISO) was adjusted as necessary to maintain surgical anaesthesia. Group ILK received medetomidine (3 μg kg^?1) at the end of the procedure. Recovery was evaluated. Differences between groups were analysed using Mann-Whitney, Chi-Square and anova tests as relevant. Significance was taken as p < 0.05.ResultsFE′ISO required to maintain surgical anaesthesia in group MILK decreased with time, becoming significantly less than that in group ILK by 45 minutes. After 60 minutes, median (IQR) FE′ISO in MILK was 0.65 (0.4–1.0) %, and in ILK was 1 (0.62–1.2) %. Physiological parameters did not differ between groups, but group MILK required less dobutamine to support MAP. Total recovery times were similar and recovery quality good in both groups.Conclusion and clinical relevanceA CRI of medetomidine given to horses which were also receiving CRIs of lidocaine and ketamine reduced the concentration of isoflurane necessary to maintain satisfactory anaesthesia for surgery, and reduced the dobutamine required to maintain MAP. No further sedation was required to provide a calm recovery.     

Effects of intravenous infusion of guaifenesin on electroencephalographic variables in pigs

OBJECTIVE: To investigate the sedative effects of guaifenesin in pigs by use of electroencephalography. ANIMALS: 10 Norwegian Landrace pigs (5 castrated males and 5 sexually intact females). PROCEDURE: Guaifenesin (150 mg/kg of body weight, IV) was administered during a 5-minute period. Using a 2-channel referential electrode configuration, electroencephalograms were recorded before, during, and after infusion of guaifenesin. Changes in spectral edge frequency 95% (SEF), median frequency (MED), and total power were evaluated. RESULTS: After administration of guaifenesin, SEF decreased significantly, and total power increased significantly; however, MED did not change significantly. Analysis of the data did not reveal differences between pigs on the basis of sex. CONCLUSIONS AND CLINICAL RELEVANCE: We concluded that guaifenesin synchronized the patterns of electroencephalograms. This is a strong indication that the drug has a sedative effect in pigs.     

Effects of intravenous administration of formaldehyde on platelet and coagulation variables in healthy horses

OBJECTIVES: To assess safety and determine effects of IV administration of formaldehyde on hemostatic variables in healthy horses. ANIMALS: 7 healthy adult horses. PROCEDURE: Clinical signs and results of CBC, serum biochemical analyses, and coagulation testing including template bleeding time (TBT) and activated clotting time (ACT) were compared in horses given a dose of 0.37% formaldehyde or lactated Ringer's solution (LRS), IV, in a 2-way crossover design. In a subsequent experiment, horses received an infusion of 0.74% formaldehyde or LRS. In another experiment, horses were treated with aspirin to impair platelet responses prior to infusion of formaldehyde or LRS. RESULTS: Significant differences were not detected in any variable measured between horses when given formaldehyde or any other treatment. Infusion of higher doses of formaldehyde resulted in adverse effects including muscle fasciculations, tachycardia, tachypnea, serous ocular and nasal discharge, agitation, and restlessness. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous infusion of formaldehyde at doses that do not induce adverse reactions did not have a detectable effect on measured hemostatic variables in healthy horses.     

Development of a romifidine constant rate infusion with or without butorphanol for standing sedation of horses

ObjectiveTo determine constant rate infusion (CRI) protocols for romifidine (R) and romifidine combined with butorphanol (RB) resulting in constant sedation and romifidine plasma concentrations.Study designBlinded randomized crossover study.AnimalsTen adult research horses.MethodsPart I: After determining normal height of head above ground (HHAG = 100%), loading doses of romifidine (80 μg kg^?1) with butorphanol (RB: 18 μg kg^?1) or saline (R) were given intravenously (IV). Immediately afterwards, a butorphanol (RB: 25 μg kg^?1 hour^?1) or saline (R) CRI was administered for 2 hours. The HHAG was used as marker of sedation depth. Sedation was maintained for 2 hours by additional romifidine (20 μg kg^?1) whenever HHAG > 50%. The dose rate of romifidine (μg kg^?1 hour^?1) required to maintain sedation was calculated for both treatments. Part II: After loading doses, the romifidine CRIs derived from part I were administered in parallel to butorphanol (RB) or saline (R). Sedation and ataxia were evaluated periodically. Romifidine plasma concentrations were measured by HPLC-MS-MS at 0, 5, 10, 15, 30, 45, 60, 90, 105, and 120 minutes. Data were analyzed using paired t-test, Fisher's exact test, Wilcoxon signed rank test, and two-way anova for repeated measures (p < 0.05).ResultsThere was no significant difference in romifidine requirements (R: 30; RB: 29 μg kg^?1 hour^?1). CRI protocols leading to constant sedation were developed. Time to first additional romifidine bolus was significantly longer in RB (mean ± SD, R: 38.5 ± 13.6; RB: 50.5 ± 11.7 minutes). Constant plasma concentrations of romifidine were achieved during the second hour of CRI. Ataxia was greater when butorphanol was added.ConclusionRomifidine bolus, followed by CRI, provided constant sedation assessed by HHAG. Butorphanol was ineffective in reducing romifidine requirements in unstimulated horses, but prolonged the sedation caused by the initial romifidine bolus.Clinical relevanceBoth protocols need to be tested under clinical conditions.     

Development of a xylazine constant rate infusion with or without butorphanol for standing sedation of horses

ObjectiveTo elaborate constant rate infusion (CRI) protocols for xylazine (X) and xylazine/butorphanol (XB) which will result in constant sedation and steady xylazine plasma concentrations.Study designBlinded randomized experimental study.AnimalsTen adult research horses.MethodsPart I: After normal height of head above ground (HHAG = 100%) was determined, a loading dose of xylazine (1 mg kg^?1) with butorphanol (XB: 18 μg kg^?1) or saline (X: equal volume) was given slowly intravenously (IV). Immediately afterwards, a CRI of butorphanol (XB: 25 μg kg^?1 hour^?1) or saline (X) was administered for 2 hours. The HHAG was used as a marker of depth of sedation. Sedation was maintained for 2 hours by additional boluses of xylazine (0.3 mg kg^?1) whenever HHAG >50%. The dose of xylazine (mg kg^?1 hour^?1) required to maintain sedation was calculated for both groups. Part II: After the initial loading dose, the calculated xylazine infusion rates were administered in parallel to butorphanol (XB) or saline (X) and sedation evaluated. Xylazine plasma concentrations were measured by HPLC-MS-MS at time points 0, 5, 30, 45, 60, 90, and 120 minutes. Data were analyzed using paired t-test, Wilcoxon signed rank test and a 2-way anova for repeated measures (p < 0.05).ResultsThere was no significant difference in xylazine requirements (X: 0.69, XB: 0.65 mg kg^?1 hour^?1) between groups. With treatment X, a CRI leading to prolonged sedation was developed. With XB, five horses (part I: two, part II: three) fell down and during part II four horses appeared insufficiently sedated. Xylazine plasma concentrations were constant after 45 minutes in both groups.ConclusionXylazine bolus, followed by CRI, provided constant sedation. Additional butorphanol was ineffective in reducing xylazine requirements and increased ataxia and apparent early recovery from sedation in unstimulated horses.Clinical relevanceData were obtained on unstimulated healthy horses and extrapolation to clinical conditions requires caution.     

Combination of continuous intravenous infusion using a mixture of guaifenesin-ketamine-medetomidine and sevoflurane anesthesia in horses

The anesthetic and cardiovascular effects of a combination of continuous intravenous infusion using a mixture of 100 g/L guaifenesin-4 g/L ketamine-5 mg/L medetomidine (0.25 ml/kg/hr) and oxygen-sevoflurane (OS) anesthesia (GKM-OS anesthesia) in horses were evaluated. The right carotid artery of each of 12 horses was raised surgically into a subcutaneous position under GKM-OS anesthesia (n=6) or OS anesthesia (n=6). The end-tidal concentration of sevoflurane (EtSEV) required to maintain surgical anesthesia was around 1.5% in GKM-OS and 3.0% in OS anesthesia. Mean arterial blood pressure (MABP) was maintained at around 80 mmHg under GKM-OS anesthesia, while infusion of dobutamine (0.39+/-0.10 microg/kg/min) was necessary to maintain MABP at 60 mmHg under OS anesthesia. The horses were able to stand at 36+/-26 min after cessation of GKM-OS anesthesia and at 48+/-19 minutes after OS anesthesia. The cardiovascular effects were evaluated in 12 horses anesthetized with GKM-OS anesthesia using 1.5% of EtSEV (n=6) or OS anesthesia using 3.0% of EtSEV (n=6). During GKM-OS anesthesia, cardiac output and peripheral vascular resistance was maintained at about 70% of the baseline value before anesthesia, and MABP was maintained over 70 mmHg. During OS anesthesia, infusion of dobutamine (0.59+/-0.24 microg/kg/min) was necessary to maintain MABP at 70 mmHg. Infusion of dobutamine enabled to maintaine cardiac output at about 80% of the baseline value; however, it induced the development of severe tachycardia in a horse anesthetized with sevoflurane. GKM-OS anesthesia may be useful for prolonged equine surgery because of its minimal cardiovascular effect and good recovery.     

Pharmacokinetics of butorphanol and evaluation of physiologic and behavioral effects after intravenous and intramuscular administration to neonatal foals

Background: Despite frequent clinical use, information about the pharmacokinetics (PK), clinical effects, and safety of butorphanol in foals is not available. Objectives: The purpose of this study was to determine the PK of butorphanol in neonatal foals after IV and IM administration; to determine whether administration of butorphanol results in physiologic or behavioral changes in neonatal foals; and to describe adverse effects associated with its use in neonatal foals. Animals: Six healthy mixed breed pony foals between 3 and 12 days of age were used. Methods: In a 3‐way crossover design, foals received butorphanol (IV and IM, at 0.05 mg/kg) and IV saline (control group). Butorphanol concentrations were determined by high‐performance liquid chromatography and analyzed using a noncompartmental PK model. Physiologic data were obtained at specified intervals after drug administration. Pedometers were used to evaluate locomotor activity. Behavioral data were obtained using a 2‐hour real‐time video recording. Results: The terminal half‐life of butorphanol was 2.1 hours and C₀ was 33.2 ± 12.1 ng/mL after IV injection. For IM injection, C_max and T_max were 20.1 ± 3.5 ng/mL and 5.9 ± 2.1 minutes, respectively. Bioavailability was 66.1 ± 11.9%. There were minimal effects on vital signs. Foals that received butorphanol spent significantly more time nursing than control foals and appeared sedated. Conclusions and Clinical Importance: The disposition of butorphanol in neonatal foals differs from that in adult horses. The main behavioral effects after butorphanol administration to neonatal foals were sedation and increased feeding behavior.     

Pharmacokinetics and clinical effects of a subanesthetic continuous rate infusion of ketamine in awake horses

OBJECTIVE: To determine the pharmacokinetics and clinical effects of a subanesthetic, continuous rate infusion of ketamine administered to healthy awake horses. ANIMALS: 8 adult horses. PROCEDURES: Ketamine hydrochloride was administered to 2 horses, in a pilot study, at rates ranging from 0.4 to 1.6 mg/kg/h for 6 hours to determine an appropriate dose that did not cause adverse effects. Ketamine was then administered to 6 horses for a total of 12 hours (3 horses at 0.4 mg/kg/h for 6 hours followed by 0.8 mg/kg/h for 6 hours and 3 horses at 0.8 mg/kg/h for 6 hours followed by 0.4 mg/kg/h for 6 hours). Concentration of ketamine in plasma, heart rate, respiratory rate, blood pressure, physical activity, and analgesia were measured prior to, during, and following infusion. Analgesic testing was performed with a modified hoof tester applied at a measured force to the withers and radius. RESULTS: No signs of excitement and no significant changes in the measured physiologic variables during infusion rates of 0.4 and 0.8 mg of ketamine/kg/h were found. At 6 hours following infusions, heart rate and mean arterial pressure were decreased, compared with preinfusion measurements. An analgesic effect could not be demonstrated during or after infusion. Pharmacokinetic variables for 0.4 and 0.8 mg/kg/h infusions were not significantly different. CONCLUSIONS AND CLINICAL RELEVANCE: Ketamine can be administered to awake horses at 0.4 or 0.8 mg/kg/h without adverse behavioral effects. The observed pharmacokinetic values are different than those reported for single-dose IV bolus administration of this drug.     

The minimum infusion rate (MIR) of propofol for total intravenous anesthesia after premedication with xylazine in horses

To investigate an adequate infusion rate of propofol for total intravenous anesthesia (TIVA) in horses, the minimum infusion rate (MIR) comparable to the minimum alveolar anesthetic concentration (MAC) of inhalation anesthetic was determined under constant ventilation condition by intermittent positive pressure ventilation (IPPV). In addition, arterial propofol concentration was measured to determine the concentration corresponding to the MIR (concentration preventing reaction to stimulus in 50% of population, Cp(50)). Further, 95% effective dose (ED(95)) was estimated as infusion rate for acquiring adequate anesthetic depth. Anesthetic depth was judged by the gross purposeful movement response to painful stimulus. MIR and Cp(50) were 0.10 +/- 0.02 mg/kg/min and 5.3 +/- 1.4 microg/ml, respectively. ED(95) was estimated as 0.14 mg/kg/min (1.4MIR).     

Influence of gastrointestinal tract disease on pharmacokinetics of lidocaine after intravenous infusion in anesthetized horses

OBJECTIVE: To determine the disposition of lidocaine after IV infusion in anesthetized horses undergoing exploratory laparotomy because of gastrointestinal tract disease. ANIMALS: 11 horses (mean +/- SD, 10.3 +/- 7.4 years; 526 +/- 40 kg). PROCEDURE: Lidocaine hydrochloride (loading infusion, 1.3 mg/kg during a 15-minute period [87.5 microg/kg/min]; maintenance infusion, 50 microg/kg/min for 60 to 90 minutes) was administered IV to dorsally recumbent anesthetized horses. Blood samples were collected before and at fixed time points during and after lidocaine infusion for analysis of serum drug concentrations by use of liquid chromatography-mass spectrometry. Serum lidocaine concentrations were evaluated by use of standard noncompartmental analysis. Selected cardiopulmonary variables, including heart rate (HR), mean arterial pressure (MAP), arterial pH, PaCO2, and PaO2, were recorded. Recovery quality was assessed and recorded. RESULTS: Serum lidocaine concentrations paralleled administration, increasing rapidly with the initiation of the loading infusion and decreasing rapidly following discontinuation of the maintenance infusion. Mean +/- SD volume of distribution at steady state, total body clearance, and terminal half-life were 0.70 +/- 0.39 L/kg, 25 +/- 3 mL/kg/min, and 65 +/- 33 minutes, respectively. Cardiopulmonary variables were within reference ranges for horses anesthetized with inhalation anesthetics. Mean HR ranged from 36 +/- 1 beats/min to 43 +/- 9 beats/min, and mean MAP ranged from 74 +/- 18 mm Hg to 89 +/- 10 mm Hg. Recovery quality ranged from poor to excellent. CONCLUSIONS AND CLINICAL RELEVANCE: Availability of pharmacokinetic data for horses with gastrointestinal tract disease will facilitate appropriate clinical dosing of lidocaine.     

Effects of intravenous ethyl pyruvate on cardiopulmonary variables and quality of recovery from anesthesia in horses

ObjectiveTo determine the effects of intravenous ethyl pyruvate, an anti-inflammatory with putative benefits in horses with endotoxemia, on cardiopulmonary variables during anesthesia and the quality of anesthetic recovery.Study designRandomized, crossover, blinded experimental design.AnimalsA total of six healthy Standardbred geldings, aged 13 ± 3 years and weighing 507 ± 66 kg (mean ± standard deviation).MethodsHorses were anesthetized for approximately 90 minutes on two occasions with a minimum of 2 weeks apart using xylazine for sedation, ketamine and diazepam for induction, and isoflurane in oxygen for maintenance. Lactated Ringer’s solution (LRS; 10 mL kg^–1 hour^–1) was administered during anesthesia. Treatments were randomized and administered starting approximately 30 minutes after induction of anesthesia and infused over 60 minutes: LRS (1 L) or ethyl pyruvate (150 mg kg^–1 in 1 L LRS). Invasive arterial pressures, heart rate, respiratory rate and end-tidal carbon dioxide tensions were recorded every 5 minutes for the duration of anesthesia. Arterial blood gases, glucose and lactate concentrations were measured every 20 minutes. Anesthetic recovery was video recorded, stored, and subsequently rated by two individuals blinded to treatments. Total recovery time, time to extubation, number of attempts and time to sternal recumbency, number of attempts to stand and time to stand were recorded. Quality of recovery was analyzed. Data between treatments and within a treatment were assessed using two-way repeated-measures anova and a Pearson correlation coefficient, significant at p < 0.05.ResultsAll horses completed the study. No significant differences were detected between the ethyl pyruvate and LRS treatments for either the cardiopulmonary variables or quality of recovery from anesthesia.Conclusions and clinical relevanceThe results suggest that intravenous ethyl pyruvate can be administered to healthy anesthetized horses with minimal impact on the cardiopulmonary variables studied or the quality of recovery from anesthesia.     

Evaluation of a romifidine constant rate infusion protocol with or without butorphanol for dentistry and ophthalmologic procedures in standing horses

ObjectiveTo compare the clinical usefulness of constant rate infusion (CRI) protocols of romifidine with or without butorphanol for sedation of horses.Study designProspective ‘blinded’ controlled trial using block randomization.AnimalsForty healthy Freiberger stallions.MethodsThe horses received either intravenous (IV) romifidine (loading dose: 80 μg kg^?1; infusion: 30 μg kg^?1 hour^?1) (treatment R, n = 20) or romifidine combined with butorphanol (romifidine loading: 80 μg kg^?1; infusion: 29 μg kg^?1 hour^?1, and butorphanol loading: 18 μg kg^?1; infusion: 25 μg kg^?1 hour^?1) (treatment RB, n = 20). Twenty-one horses underwent dentistry and ophthalmic procedures, while 19 horses underwent only ophthalmologic procedure and buccal examination. During the procedure, physiologic parameters and occurrence of head/muzzle shaking or twitching and forward movement were recorded. Whenever sedation was insufficient, additional romifidine (20 μg kg^?1) was administered IV. Recovery time was evaluated by assessing head height above ground. At the end of the procedure, overall quality of sedation for the procedure was scored by the dentist and anaesthetist using a visual analogue scale. Statistical analyses used two-way anova or linear mixed models as relevant.ResultsSedation quality scores as assessed by the anaesthetist were R: median 7.55, range: 4.9–9.0 cm, RB: 8.8, 4.7–10.0 cm, and by the dentist R: 6.6, 3.0–8.2 cm, RB: 7.9, 6.6–8.8 cm. Horses receiving RB showed clinically more effective sedation as demonstrated by fewer poor scores and a tendency to reduced additional drug requirements. More horses showed forward movement and head shaking in treatment RB than treatment R. Three horses (two RB, one R) had symptoms of colic following sedation.Conclusions and clinical relevanceThe described protocols provide effective sedation under clinical conditions but for dentistry procedures, the addition of butorphanol is advantageous.     

The pharmacokinetics of ketamine after a continuous infusion under halothane anaesthesia in horses

The pharmacodynamics and pharmacokinetics of ketamine, when administered by infusion as an adjunct to halothane anaesthesia in horses, were investigated in 5 equine patients presented for routine castration. Anaesthesia was induced with detomidine, 20 μg/kg, followed by ketamine, 2.2 mg/kg bwt, the trachea intubated and the horses allowed to breathe halothane in oxygen. Five minutes later, a constant rate infusion of ketamine, 40 μg/kg min, was commenced and the halothane vaporiser concentration adjusted to maintain a light plane of anaesthesia. The mean infusion duration was 62 min (range 40–103). The ketamine was switched off approximately 15 min before the halothane. Plasma ketamine and norketamine levels, determined by high performance liquid chromatography, ranged from 0.74–2.04 μg/ml and 0.15–0.75 μg/ml, respectively, during the infusion period. The harmonic mean elimination half-life of ketamine was 46.1 min, mean volume of distribution at steady state (Vdss) was 1365 (271) ml/kg, mean body clearance (Cl) was 32.3 (9.1) ml/min.kg, and average mean residence time for the infusion (MRTinf) was 105.9 (20.4) min, respectively. Following termination of halothane, mean times to sternal recumbency and standing were 21.1 (6.9) and 41.6 (17.0) min, respectively. Surgical conditions were considered highly satisfactory, and physiological parameters were well preserved in most animals.