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Clinical and Pharmacokinetic Evaluation of S Casoni et al. Acta Veterinaria Scandinavica (2015) 57:21 DOI 10.1186/s13028-015-0112-4 RESEARCH Open Access Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration Daniela Casoni1*, Claudia Spadavecchia1, Beat Wampfler2, Wolfgang Thormann3 and Olivier L Levionnois1 Abstract Background: Intravenous anaesthetic drugs are the primary means for producing general anaesthesia in equine practice. The ideal drug for intravenous anaesthesia has high reliability and pharmacokinetic properties indicating short elimination and lack of accumulation when administered for prolonged periods. Induction of general anaesthesia with racemic ketamine preceded by profound sedation has already an established place in the equine field anaesthesia. Due to potential advantages over racemic ketamine, S-ketamine has been employed in horses to induce general anaesthesia, but its optimal dose remains under investigation. The objective of this study was to evaluate whether 2.5 mg/kg S-ketamine could be used as a single intravenous bolus to provide short-term surgical anaesthesia in colts undergoing surgical castration, and to report its pharmacokinetic profile. Results: After premedication with romifidine and L-methadone, the combination of S-ketamine and diazepam allowed reaching surgical anaesthesia in the 28 colts. Induction of anaesthesia as well as recovery were good to excellent in the majority (n = 22 and 24, respectively) of the colts. Seven horses required additional administration of S-ketamine to prolong the duration of surgical anaesthesia. Redosing did not compromise recovery quality. Plasma concentration of S-ketamine decreased rapidly after administration, following a two-compartmental model, leading to the hypothesis of a consistent unchanged elimination of the parent compound into the urine beside its conversion to S-norketamine. The observed plasma concentrations of S-ketamine at the time of first movement were various and did not support the definition of a clear cut-off value to predict the termination of the drug effect. Conclusions: The administration of 2.5 mg/kg IV S-ketamine after adequate premedication provided good quality of induction and recovery and a duration of action similar to what has been reported for racemic ketamine at the dose of 2.2 mg/kg. Until further investigations will be provided, close monitoring to adapt drug delivery is mandatory, particularly once the first 10 minutes after injection are elapsed. Taking into account rapid elimination of S-ketamine, significant inter-individual variability and rapid loss of effect over a narrow range of concentrations a sudden return of consciousness has to be foreseen. Keywords: S-ketamine, Horses, Intravenous anesthesia, Field castration, Plasma level, Pharmacokinetic Background racemic ketamine has been gaining hedging popularity The administration of racemic ketamine and diazepam due to its safety and reliability in allowing most surgical following the premedication with an α-2 agonist for pro- procedures and rapid recoveries. However, undesirable ducing short term anaesthesia represents one of the most psychomimetic effects during the emergence from general significant events in equine anaesthesia in the last fifty anaesthesia have been reported. years [1]. Since its introduction in the early Seventies, Racemic ketamine is the mixture of two enantiomers: S (+) ketamine and R (−) ketamine: recently, it has been * Correspondence: [email protected] recognized that each ketamine enantiomer can evoke dif- 1Anesthesiology and Pain Therapy Division, Department of Veterinary Clinical ferent effects. In humans, when compared to R- and ra- Science of the Vetsuisse Faculty of Berne, Länggassstrasse 124, CH-3012 Berne, Switzerland cemic ketamine at clinical anaesthetic doses, S-ketamine Full list of author information is available at the end of the article was found to evoke shorter and fewer psychomimetic © 2015 Casoni et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Casoni et al. Acta Veterinaria Scandinavica (2015) 57:21 Page 2 of 10 effects after general anaesthesia [2] and for comparable were fasted for 6 hours before anaesthesia, but free ac- anaesthetic depth the S-enantiomer was associated with a cess to the water was granted. more rapid recovery of psychomotor skills than the ra- cemic mixture [3]. Furthermore, a different pharmacoki- Experimental protocol netic profile for the two enantiomers was described in After clinical examination and weight assessment, every humans [4] as well as in dogs and ponies [5,6]. The extent horse was premedicated with romifidine at 0.1 mg/kg of pharmacokinetic enantioselectivity has been shown to (Sedivet® Boehringer Ingelheim, Switzerland) injected in be species-specific and dependent on drugs concomitantly the right jugular vein. Five to ten minutes after pre- administered [7]. If administered alone, S-ketamine has a medication, a 13 G. indwelling catheter (Provet AG/ higher clearance than in the racemic mixture resulting in Petco AG Heiland, Switzerland) was placed in the left quicker elimination, shorter duration of action and faster jugular vein. Immediately after catheter placement, − recovery from anaesthesia [4,8,9]. L-methadone/fenpipramide 50/2.5 μgkg 1 IV (Polamivet ®, In horses, ataxia, excitation, and residual muscle rigidity Intervet, Switzerland) was administered and the horses increase the risk for complications during the recovery were walked from their box to the induction area. Sedation phase. Since trained assistance is minimal under field con- quality was scored including response to tactile and audi- ditions, a single injection of an anaesthetic should ideally tory stimuli (Table 1) at least 5 minutes after catheter allow for completion of a standard surgical procedure. To placement and not more than 30 minutes after romifidine extend the duration of anaesthesia, re-dosing should be administration. If the sedation score was higher than 2, possible, but without compromising its safety and overall additional romifidine was administered (0.03 mg/kg IV) quality. Due to its favorable pharmacological profile, com- and the sedation reassessed after 5 minutes. If the sedation pared to the racemic ketamine, S-ketamine might result in score remained higher than 2, a third dose (0.015 mg/kg) a smoother quality of induction and in a better quality of was allowed, but if still judged insufficient, the horse would recovery. Data in the literature are still insufficient to de- be excluded from the trial. The overall quality of sedation termining an appropriate anaesthetic protocol based on achieved was evaluated using a visual analogue scale (VAS) S-ketamine for surgical anaesthesia in horses. Several from 0 (best possible sedation) to 100 mm (worst possible studies have shown that the ratio of anaesthetic potency sedation). Heart rate (HR), pulse rate (PR) and respiratory between S-ketamine and racemic ketamine can be up to rate (RR) were then recorded. 1:3 [10-12]. In dogs, a potency ratio of 1:1.3 has been re- General anaesthesia was induced with diazepam ported under experimental conditions [13] and 1:1.5 under 0.05 mg/kg IV (Valium, Roche, Basel, Switzerland) and clinical conditions [14]. The results from Rossetti et al. S- ketamine 2.5 mg/kg IV (Keta-S Graeub AG, Bern, [15] suggested a similar potency ratio in horses. In a previ- Switzerland) administered in sequence. Anaesthesia on- ous clinical trial 2 mg/kg S-ketamine was found by the au- set time (T_onset) was defined as the time elapsing from thors as being insufficient to obtain surgical anaesthesia the end of injection until lateral recumbency and re- (unpublished data). corded. Induction quality was scored (Table 2) and This study aimed at evaluating whether S-ketamine assessed using a VAS (from 0 corresponding to best in- could be used as a single bolus to provide short-term duction to 100 mm corresponding to worst induction). − surgical anaesthesia in horses undergoing castration, and Oxygen was then supplemented (10 L min 1) via a nasal at reporting the pharmacokinetic profile of S-ketamine tube (10 mm ED) introduced in the ventral meatus of and its main active metabolite, S-norketamine. We hy- the dependent nostril, up to the lateral canthus of the pothesized that S-ketamine at 2.5 mg/kg given as a sin- eye. In case of apnea lasting for more than 1 minute, gle bolus would be appropriate to perform surgical endo-tracheal intubation would be performed and venti- castration in healthy colts under field conditions. lation assisted by using a Hudson valve. The time elapsed between the end of S-ketamine administration (in- Methods duction) and first surgical incision (T_incision), first This prospective clinical trial was reviewed and approved (T_testis_1) and second (T_testis_2) testicle removal, end by the Committee for Animal Experimentation of the of surgery (T_surgery), as well as appearance of brisk pal- Canton Bern, Switzerland (BE 11/43). pebral reflex (T_palpebral), first purposeful movement (T_movement), sternal recumbency (T_sternal)
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