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

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

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

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

Reasons for Performing Study: In order to evaluate its potential as an adjunct to inhalant anaesthesia in horses, the pharmacokinetics of fentanyl must first be determined., Objectives: To describe the pharmacokinetics of fentanyl and its metabolite, N-[1-(2-phenethyl-4-piperidinyl)maloanilinic acid (PMA), after i.v. administration of a single dose to horses that were awake in Treatment 1 and anaesthetised with isoflurane in Treatment 2., Methods: A balanced crossover design was used (n = 4/group). During Treatment 1, horses received a single dose of fentanyl (4 microg/kg bwt, i.v.) and during Treatment 2, they were anaesthetised with isoflurane and maintained at 1.2 x minimum alveolar anaesthetic concentration. After a 30 min equilibration period, a single dose of fentanyl (4 microg/kg bwt, i.v.) was administered to each horse. Plasma fentanyl and PMA concentrations were measured at various time points using liquid chromatography-mass spectrometry., Results: Anaesthesia with isoflurane significantly decreased mean fentanyl clearance (P < 0.05). The fentanyl elimination half-life, in awake and anaesthetised horses, was 1 h and volume of distribution at steady state was 0.37 and 0.26 l/kg bwt, respectively. Anaesthesia with isoflurane also significantly decreased PMA apparent clearance and volume of distribution. The elimination half-life of PMA was 2 and 1.5 h in awake and anaesthetised horses, respectively., Conclusions and Potential Relevance: Pharmacokinetics of fentanyl and PMA in horses were substantially altered in horses anaesthetised with isoflurane. These pharmacokinetic parameters provide information necessary for determination of suitable fentanyl loading and infusion doses in awake and isoflurane-anaesthetised horses.

Eight horses were fitted surgically with 8 ultrasonic sonomicrometer crystals each attached to their left ventricular pericardia and a left atrial catheter. Three horses returned to treadmill performance with a maximum rate of oxygen consumption similar to their presurgical values. These horses were evaluated to determine how well sonomicrometer estimates of cardiac output agreed with those obtained by a steady-state method, the Fick principle. Variance between the 2 was similar to the coefficient of variation (approximately 12.5%) of the Fick estimates. We conclude that left ventricular sonomicrometer measurements in horses appear to give a reasonable estimate of ventricular dimensions and can, therefore, be used potentially to evaluate such variables as diastolic flow.

Circulatory and respiratory effects of five h of constant 1.06 per cent alveolar halothane in oxygen were identified in eight healthy horses, which breathed spontaneously, were otherwise unmedicated and positioned in sternal recumbency. Only a few important significant (P less than 0.05) changes occurred with time. Total peripheral resistance was about 15 per cent lower after two hours of constant dose halothane than after 30 mins of constant dose (P less than 0.05) and accounted for the significant 10 per cent reduction in mean carotid arterial blood pressure. By 5 h, the reduction in resistance and arterial blood pressure was 20 and 25 per cent respectively. Heart rate increased progressively with time and the increase became significant at 5 h (15 per cent increase). However, the heart rate change was not large enough to alter cardiac output. There were no major time-related changes in PaO2 or PaCO2. Three of four horses recovered from anaesthesia had markedly elevated serum creatine kinase levels and clinical signs of severe post anaesthetic myopathy.

Arterial blood was collected from 25 clinically normal horses immediately before and serially throughout the first hour of halothane oxygen anaesthesia. Blood was analysed for oxygen and carbon dioxide partial pressure (PaO2, PaCO2). Measurements of inspired oxygen concentration during anaesthesia permitted direct correlation with blood gases. Horses were divided arbitrarily into two groups based on their age: two to seven years, n = 15; over seven years, n = 10. Average (+/- sd) PaO2 and PaCO2 was 14.1 +/- 1.5 kPa (106 +/- 11 mmHg) and 5.9 +/- 0.6 kPa (44.4 +/- 4.4 mmHg) respectively in conscious, young horses and 14.0 +/- 0.7 and 5.8 +/- 0.5 kPa (105 +/- 5 and 43.3 +/- 3.8 mmHg) respectively in conscious older horses. Arterial oxygen tension decreased to 9.3 +/- 1.0 and 8.5 +/- 1.4 kPa (69.6 +/- 7.8 and 63.7 +/- 10.4 mmHg) in young and older air breathing horses respectively immediately following intravenous anaesthetic induction, recumbency and orotracheal intubation. At this time, PaCO2 was 6.5 +/- 0.5 and 6.0 +/- 0.7 kPa (48.7 +/- 3.5 and 45.1 +/- 4.9 mmHg) respectively. By 30 mins after the start of halothane in oxygen (6 litres/min) anaesthesia PaO2 increased to a maximum in both study groups. Arterial PCO2 increased steadily during anaesthesia and 60 mins after induction PaCO2 was 10.5 +/- 2.4 kPa (78.5 +/- 17.8 mmHg) in the younger horses and 9.2 +/- 1.6 kPa (68.8 +/- 11.8 mmHg) in the older horses. During inhalation anaesthesia PaO2 tended to be greater at comparable time periods in the younger horses despite a slightly greater degree of hypoventilation.

High frequency jet ventilation (HFJV) is a recently developed mode of ventilation that delivers small tidal volumes at frequencies greater than 60 cycles per min via an injection catheter to the animal's airway. The construction of a high frequency jet ventilator suitable for use in adult horses is described. The effectiveness of this ventilator in maintaining normal arterial blood-gas tension was evaluated in five healthy adult horses. The horses were anaesthetised with intravenous acetylpromazine, guaifenesin, and thiamylal, positioned in lateral recumbency and baseline measurements were made during spontaneous ventilation. The horses were then paralysed with succinylcholine and ventilated for at least 20 mins with HFJV. Air was delivered from the ventilator to the animal by a polyethylene tube. The tip of this tube remained within and approximately 30 cm from the cuffed end of a standard 30 mm internal diameter large animal orotracheal tube. Frequency of flow interruption was 3 Hz with a constant source pressure of 275 kPa and an inspiratory to expiratory ratio of approximately 1:2.6. Gas delivery to the horse, as estimated with a resonator system was approximately 2 litres/breath. During HFJV, arterial carbon dioxide tension was significantly reduced and arterial oxygen tension significantly increased above measurements made when the horses were spontaneously breathing air.

Sequelae of routine orotracheal intubation under clinical conditions were characterised in 38 healthy horses presented at three veterinary medical teaching hospitals. Four of these were necropsied and their tissues studied histologically. To minimise variation, 30 mm id cuffed silicone endotracheal tubes or Cole cuffless tubes were used in all patients. Fibreoptic endoscopic examination of upper respiratory and tracheal areas was accomplished pre-intubation, immediately post extubation and after 24 h. Endoscopy revealed that intubation was associated with laryngeal and/or tracheal lesions in all horses. Observations included abundant tracheal mucus, epithelial ecchymoses, basement membrane haemorrhage and mucus covered diphtheritic membrane plaques. Histological examination of lesions from the upper respiratory system of the four necropsied horses confirmed that the damage was comparable to that associated with tracheal intubation and reported in other species.