Pharmacokinetics of intravenous and transdermal fentanyl in alpacas.

The purpose of the study was to determine pharmacokinetics of fentanyl after intravenous (i.v.) and transdermal (t.d.) administration to six adult alpacas. Fentanyl was administered i.v. (2 µg/kg) or t.d. (nominal dose: 2 µg kg-1  hr-1 ). Plasma concentrations were determined using liquid chromatography-mass spectrometry. Heart rate and respiratory rate were assessed. Extrapolated, zero-time plasma fentanyl concentrations were 6.0 ng/ml (1.7-14.6 ng/ml) after i.v. administration, total plasma clearance was 1.10 L hr-1  kg-1 (0.75-1.40 L hr-1  kg-1 ), volumes of distribution were 0.30 L/kg (0.10-0.99 L/kg), 1.10 L/kg (0.70-2.96 L/kg) and 1.5 L/kg (0.8-3.5 L/kg) for V1 , V2 , and Vss , respectively. Elimination half-life was 1.2 hr (0.5-4.3 hr). Mean residence time (range) after i.v. dosing was 1.30 hr (0.65-4.00 hr). After t.d. fentanyl administration, maximum plasma fentanyl concentration was 1.20 ng/ml (0.72-3.00 ng/ml), which occurred at 25 hr (8-48 hr) after patch placement. The area under the plasma fentanyl concentration-vs-time curve (extrapolated to infinity) after t.d. fentanyl was 61 ng*hr/ml (49-93 ng*hr/ml). The dose-normalized bioavailability of fentanyl from t.d. fentanyl in alpacas was 35.5% (27-64%). Fentanyl absorption from the t.d. fentanyl patch into the central compartment occurred at a rate of approximately 50 µg/hr (29-81 µg/hr) between 8 and 72 hr after patch placement.

Oxygenation, oxygen delivery and anaesthesia in the horse.

Horses are the most difficult of the common companion animals to anaesthetise. Hypoxaemia or inadequate oxygen delivery to peripheral tissues during anaesthesia would seem a potential cause of increased mortality, but no direct link has been established. A number of methods of increasing oxygenation and oxygen delivery have been reported, with varying results and potential applicability. The purpose of this article is to review the literature with regard to oxygenation, oxygen delivery and methods to improve each and to make recommendations for clinical application.

Use of sedation and ropivacaine-morphine epidural for femoral head and neck ostectomy in a dog.

A five-year-old male German shepherd dog presented with traumatic craniodorsal luxation of the right coxofemoral joint with pre-existing moderate hip dysplasia. A femoral head and neck ostectomy was performed. The patient was sedated with acepromazine and morphine administered intramuscularly. A lumbosacral epidural was performed using a combination of morphine and ropivacaine. Intraoperatively, an infusion of medetomidine, morphine, lidocaine, and ketamine was administered intravenously, and oxygen was administered via facemask. Heart rate, respiratory rate and oscillometric arterial blood pressures were monitored. Postoperatively, carprofen was administered once subcutaneously. On the day of hospital discharge, carprofen and tramadol were administered orally every 12 hours. Twenty-one days later, the dog was doing well and the surgical staples were removed. Sedation with acepromazine and morphine, administration of an epidural containing morphine and ropivacaine, and intraoperative sedation with medetomidine, morphine, lidocaine and ketamine were suitable for femoral head and neck ostectomy.

Pharmacokinetics of midazolam after intravenous administration to horses.

REASONS FOR PERFORMING THE STUDY: Midazolam is used to control seizures in horses and to enhance muscle relaxation, but its pharmacokinetics are unknown. OBJECTIVE: To determine the pharmacokinetics and sedative effects of midazolam in horses. STUDY DESIGN: Blinded, randomised, crossover design. METHODS: Midazolam was administered i.v. at either 0.05 or 0.1 mg/kg bwt to 6 horses on 2 occasions at least 7 days apart using a crossover design. Blood samples were collected before and at predetermined times through 24 h after administration. Serum midazolam concentrations were determined by a liquid chromatography tandem-mass spectrometry method. Heart and respiratory rates and indices of sedation, ataxia, and sensitivity to stimuli were recorded before and at predetermined times after midazolam administration. RESULTS: Pharmacokinetic analysis was performed on samples from 5 horses in each group. Median total clearance was 10.6 ml/min/kg (range 6.1-15.2 ml/min/kg) and 10.4 ml/min/kg (range 8.4-17.6 ml/min/kg), and median volume of distribution at steady state was 2094 ml/kg (range 2076-2413 ml/kg) and 2822 ml/kg (range 2270-7064 ml/kg) after the 0.05 mg/kg and 0.1 mg/kg bwt doses, respectively. Median distribution half-life was 24 min (range 6-42 min) and 39 min (range 33.6-72 min) and median terminal half-life was 216 min (range 120-248 min) and 408 min (range 192-924 min) after the 0.05 mg/kg and 0.1 mg/kg bwt doses, respectively. Cardiorespiratory parameters and sedation scores did not change. Midazolam caused agitation, postural sway, weakness, and one horse became recumbent after the 0.1 mg/kg bwt dose. CONCLUSIONS: Midazolam produces ataxia and postural sway of short duration after i.v. administration to horses. Sedation was not evident after midazolam administration. Drug redistribution is likely the primary mechanism for the termination of effect. POTENTIAL RELEVANCE: Midazolam produces muscle relaxation but not sedation in adult horses.

The use of sedatives, analgesic and anaesthetic drugs in the horse: an electronic survey of members of the American Association of Equine Practitioners (AAEP).

REASONS FOR PERFORMING STUDY: To determine the sedative, analgesic and anaesthetic drugs and techniques that are used by equine veterinarians. HYPOTHESIS OR OBJECTIVES: To provide equine veterinarians with information concerning veterinary use of anaesthetic techniques, a reflection of the collective experiences of the profession. METHODS: A survey was conducted of those members of the American Association of Equine Practitioners (AAEP) with an electronic mail address on file with the organisation using proprietary, web-based software. The survey was comprised of 30 questions divided into 8 sections: nonsteroidal anti-inflammatory drugs; local anaesthesia; alternative techniques; standing chemical restraint; epidural anaesthesia; short-term anaesthesia; long-term anaesthesia; and a place for the respondent to make comments. RESULTS: The response rate was 13.8% (952/6911) AAEP member veterinarians primarily use phenylbutazone and flunixin as anti-inflammatory drugs, and lidocaine and mepivacaine for local anaesthesia. Combinations of drugs are preferred for standing chemical restraint. While many veterinarians frequently utilise short-term anaesthesia, longer anaesthesia is less frequently performed. CONCLUSIONS: Most AAEP member veterinarians use sedatives in combination to provide standing chemical restraint. Extra-label use of drugs is a core component of current equine sedation and anaesthetic practice. POTENTIAL RELEVANCE: Equine veterinarians can compare their choices of anaesthetic drugs with others practising equine medicine and surgery and may be stimulated to investigate alternative methods of providing comfort to horses.

Effect of intravenous lidocaine administration on laminar inflammation in the black walnut extract model of laminitis.

REASONS FOR PERFORMING STUDY: Laminitis is a serious complication of horses suffering from sepsis/endotoxaemia-related events. Laminitis in horses and organ injury in human sepsis are both reported to involve inflammatory injury to the laminae/organs including early activation of endothelium and leucocytes leading to emigration of neutrophils into the tissue interstitium. In the black walnut extract (BWE) model, systemic inflammatory events coincide with marked increase in laminar mRNA concentrations of inflammatory genes including proinflammatory cytokines (i.e. IL-1beta, IL-6), COX-2, chemokines (i.e. IL-8) and endothelial adhesion molecules (i.e. ICAM-1 and E-selectin). In models of human sepsis, i.v. lidocaine has been reported to decrease leucocyte and endothelial activation, and the expression of proinflammatory cytokines and chemokines. OBJECTIVES: To evaluate the effect of i.v. lidocaine therapy on the inflammatory processes documented to occur in the BWE model of laminitis. METHODS: Twelve horses were administered BWE and treated immediately with either lidocaine (1.3 mg/kg bwt bolus, followed by 0.05 mg/kg bwt/min CRI, n=6) or saline (n=6) for 10 h. At 10 h post BWE administration, laminar samples were obtained under general anaesthesia for assessment of proinflammatory gene expression (using RT-qPCR) and leucocyte emigration (via CD13 immunohistochemistry). At 0, 3 and 10 h post BWE administration, skin samples were obtained for assessment of leucocyte emigration (via calprotectin immunohistochemistry). RESULTS: No significant differences between groups were noted for inflammatory gene mRNA concentrations (IL-1beta, IL-6, IL-8, COX-2) or for number of leucocytes present within the laminar interstitium or skin dermis. Increased (P<0.05) laminar E-selectin mRNA concentrations were present in the LD group (vs. SAL group). CONCLUSIONS: Continuous administration of i.v. lidocaine does not inhibit inflammatory events in either the laminae or skin in the horse administered black walnut extract. POTENTIAL RELEVANCE: This work questions the use of continuous i.v. administration of lidocaine as an effective anti-inflammatory therapy for systemic inflammation.

Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise.

REASON FOR PERFORMING STUDY: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. OBJECTIVES: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. METHODS: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatography-mass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. RESULTS: Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. CONCLUSIONS AND POTENTIAL RELEVANCE: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.

Antagonism of detomidine sedation in the horse using intravenous tolazoline or atipamezole.

REASONS FOR PERFORMING STUDY: The ability to shorten the duration of sedation would potentially improve safety and utility of detomidine. OBJECTIVES: To determine the effects of tolazoline and atipamezole after detomidine sedation. HYPOTHESIS: Administration of tolazoline or atipamezole would not affect detomidine sedation. METHODS: In a randomised, placebo-controlled, double-blind, descriptive study, detomidine (0.02 mg/kg bwt i.v.) was administered to 6 mature horses on 4 separate occasions. Twenty-five mins later, each horse received one of 4 treatments: Group 1 saline (0.9% i.v.) as a placebo control; Group 2 atipamezole (0.05 mg/kg bwt i.v.); Group 3 atipamezole (0.1 mg/kg bwt i.v.); and Group 4 tolazoline (4.0 mg/kg bwt i.v.). Sedation, muscle relaxation and ataxia were scored by 3 independent observers at 9 time points. Horses were led through an obstacle course at 7 time points. Course completion time was recorded and the ability of the horse to traverse the course was scored by 3 independent observers. Horses were videotaped before, during and after each trip through the obstacle course. RESULTS: Atipamezole and tolazoline administration incompletely antagonised the effects of detomidine, but the time course to recovery was shortened. CONCLUSIONS AND POTENTIAL RELEVANCE: Single bolus administration of atipamezole or tolazoline produced partial reversal of detomidine sedation and may be useful for minimising detomidine sedation.

Ureteral ligation prevents the haemodynamic effect of frusemide in pentobarbitol anaesthetised horses.

Frusemide reduces pulmonary vascular pressures in resting horses and attenuates exercise-induced increases in these pressures in exercising horses. The mechanism underlying these effects of frusemide is unclear. We tested the hypothesis that the haemodynamic effects of frusemide are dependent on diuresis by examining the effect of frusemide in anaesthetised horses in which diuresis was prevented by ligation of ureters. Twenty four horses were assigned randomly to one of 4 treatments: 1) frusemide (1 mg/kg bwt i.v.) and intact ureters; 2) frusemide and ligated ureters; 3) saline placebo and ligated ureters; and 4) frusemide and phenylbutazone (4.4 mg/kg bwt i.v. 12 h and 15 min before frusemide) and ligated ureters. Frusemide administration to anaesthetised horses with intact ureters increased plasma total protein concentration and reduced mean right atrial, pulmonary artery and aortic pressures. There was no significant effect of frusemide administration on haemodynamic variables or plasma total protein concentration in horses with ligated ureters. The combination of frusemide and phenylbutazone increased mean right atrial, pulmonary artery and aortic pressures in horses with ligated ureters. This study demonstrates that, in anaesthetised horses, the haemodynamic effect of frusemide is dependent upon diuresis. We interpret these results as providing further evidence that the haemodynamic effect of frusemide in horses is attributable to a reduction in plasma and blood volume.