Stereoselective Pharmacokinetics of Ketamine Administered at a Low Dose in Awake Dogs.

The present study aimed to examine the stereoselective pharmacokinetics of racemic ketamine in dogs at low doses. The secondary aims were to identify associated behavioural effects and propose a ketamine infusion rate. The study was conducted on nine intact male beagles, with each dog undergoing two treatments (BOL and INF). For treatment BOL, an intravenous bolus of 1 mg/kg was administered over 2 min. The treatment INF involved an initial bolus of 0.5 mg/kg given over 1 min, followed by an infusion at 0.01 mg/kg/min for 1 h. Blood samples were collected for pharmacokinetic analysis. The median R/S enantiomer ratio of ketamine remained close to 1 throughout the study. Levels of S-norketamine were significantly higher than those of R-norketamine across all time points. Based on the collected data, the infusion rate predicted to achieve a steady-state racemic ketamine plasma concentration of 150 ng/mL was 0.028 mg/kg/min. Higher scores for behavioural effects were observed within the first five minutes following bolus administration. The most common behaviours observed were disorientation, head movements and staring eyes. Furthermore, employing ROC curve analysis, a racemic ketamine plasma concentration of 102 ng/mL was defined as the cut-off value, correlating with the occurrence of undesirable behavioural patterns.

Colon constipation in horses after sustained-release buprenorphine administration.

OBJECTIVE: To investigate the pharmacological profile and side effects of buprenorphine administered as a sustained-release formulation in horses. STUDY DESIGN: Pilot trial. ANIMALS: A total of four experimental horses, aged 18-27 years and weighing 508-578 kg. METHODS: Buprenorphine (0.1 mg kg-1) was mixed as a freshly prepared sterile solution with a sustained-release drug carrier. It was administered by the subcutaneous (n = 2) or intramuscular (n = 2) route. During the experiment, the horses were closely monitored, equipped with a step counter and blood samples were collected for quantification of buprenorphine in plasma. RESULTS: All four horses developed colon constipation requiring medical therapy, together with increased locomotor activity. One horse, requiring surgical treatment of colon constipation, was euthanized during recovery from anaesthesia for weakness and severe lower airway obstruction. The three other horses recovered fully within 5-7 days. Plasma buprenorphine concentrations were between 1 and 8 ng mL-1 for approximately 48 hours. No local reaction was observed at the injection sites. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of the sustained-release formulation of buprenorphine at a dose of 0.1 mg kg-1 resulted in plasma concentrations compatible with antinociceptive activity for at least 48 hours. The observed severe and undesirable effects of colon constipation and increased locomotor activity definitely preclude clinical use of sustained-release buprenorphine at this dose.

Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration.

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.

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

OBJECTIVE: To evaluate medetomidine as a continuous rate infusion (CRI) in horses in which anaesthesia is maintained with isoflurane and CRIs of ketamine and lidocaine. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Forty horses undergoing elective surgery. METHODS: After 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. RESULTS: FE'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 RELEVANCE: A 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.

Evaluation of the isoflurane-sparing effects of lidocaine infusion during umbilical surgery in calves.

OBJECTIVE: To evaluate the isoflurane-sparing effects of lidocaine administered by constant rate infusion (CRI) during umbilical surgery in calves. STUDY DESIGN: Randomized 'blinded' prospective clinical study. ANIMALS: Thirty calves (mean 4.7 ± SD 2.5 weeks old) undergoing umbilical surgery. METHODS: After premedication with xylazine (0.1 mg kg(-1) , IM), anaesthesia was induced with ketamine (4 mg kg(-1) , IV) and maintained with isoflurane in O(2) administered through a circle breathing system. The calves were assigned randomly to receive a bolus of 2 mg kg(-1) lidocaine IV after induction of anaesthesia, followed by CRI of 50 µg kg(-1) minute(-1) (group L, n=15) or a bolus and CRI of 0.9% sodium chloride (NaCl, group S, n=15). End-tidal isoflurane was adjusted to achieve adequate depth of anaesthesia. Heart rate, direct arterial blood pressure and body temperature were measured intraoperatively. Groups were compared by t- tests, anova or Mann-Whitney rank sum test as appropriate. RESULTS: The end-tidal concentration of isoflurane (median, IQR) was significantly lower in group L [1.0% (0.94-1.1)] compared to group S [1.2% (1.1-1.5)], indicating a 16.7% reduction in anaesthetic requirement during lidocaine CRI. Cardiopulmonary parameters and recovery times did not differ significantly between groups. CONCLUSION AND CLINICAL RELEVANCE: Lidocaine CRI may be used as a supplement to inhalation anaesthesia during umbilical surgery in calves in countries where such a protocol would be within the legal requirements for veterinary use in food animals. This study did not show any measurable benefit to the calves other than a reduction in isoflurane requirement.

Effect of ketamine on the limb withdrawal reflex evoked by transcutaneous electrical stimulation in ponies anaesthetised with isoflurane.

The purpose of this study was to evaluate the anti-nociceptive activity of ketamine and isoflurane in horses using a limb withdrawal reflex (WR) model. Single and repeated stimulations were applied to the digital nerve of the left forelimb in ponies anaesthetised with isoflurane before, during and after intravenous administration of racemic ketamine. Surface electromyographic activity was recorded from the deltoid muscle. Higher stimulation intensity was required to evoke a reflex during ketamine administration. Furthermore, the amplitudes of response to stimulations were significantly and dose-dependently depressed and a flattening of the stimulus-response curves was observed. The reflex activity recovered partially once the ketamine infusion finished. The results demonstrated that the limb WR can be used to quantify the temporal effect of ketamine on the sensory-motor processing in ponies anaesthetised with isoflurane.

Stereoselective pharmacokinetics of ketamine and norketamine after constant rate infusion of a subanesthetic dose of racemic ketamine or S-ketamine in Shetland ponies.

OBJECTIVE: To evaluate pharmacokinetics of ketamine and norketamine enantiomers after constant rate infusion (CRI) of a subanesthetic dose of racemic ketamine or S-ketamine in ponies. ANIMALS: Five 6-year-old Shetland pony geldings that weighed between 101 and 152 kg. PROCEDURES: In a crossover study, each pony received a CRI of racemic ketamine (loading dose, 0.6 mg/kg; CRI, 0.02 mg/kg/min) and S-ketamine (loading dose, 0.3 mg/kg; CRI, 0.01 mg/kg/min), with a 1-month interval between treatments. Arterial blood samples were collected before and at 5, 15, 30, 45, and 60 minutes during drug administration and at 5, 10, 30, and 60 minutes after discontinuing the CRI. Plasma ketamine and norketamine enantiomers were quantified by use of capillary electrophoresis. Individual R-ketamine and S-ketamine concentration-versus-time curves were analyzed by use of a monocompartmental model. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating the area under the concentration-versus-time curve (AUC), maximum concentration (Cmax), and time until Cmax. RESULTS: Plasma concentrations of S-ketamine decreased and biodegradation products increased more rapidly after S-ketamine CRI, compared with results after racemic ketamine CRI. The R-norketamine was eliminated faster than was the S-norketamine. Significant differences between treatments were found for the AUC of S-ketamine and within the racemic ketamine CRI for the AUC and Cmax of norketamine isomers. CONCLUSIONS AND CLINICAL RELEVANCE: CRI of S-ketamine may be preferable over CRI of racemic ketamine in standing equids because the S-enantiomer was eliminated faster when infused alone instead of as part of a racemic mixture.

Determination of the minimum alveolar concentration of isoflurane in Shetland ponies using constant current or constant voltage electrical stimulation.

OBJECTIVE: To determine the minimum alveolar concentration (MAC) of isoflurane in Shetland ponies using a sequence of three different supramaximal noxious stimulations at each tested concentration of isoflurane rather than a single stimulation. STUDY DESIGN: Prospective, experimental trial. ANIMALS: Seven 4-year-old, gelding Shetland ponies. METHODS: The MAC of isoflurane was determined for each pony. Three different modes of electrical stimulation were applied consecutively (2 minute intervals): two using constant voltage (90 V) on the gingiva via needle- (CVneedle) or surface-electrodes (CVsurface) and one using constant current (CC; 40 mA) via surface electrodes applied to the skin over the digital nerve. The ability to clearly interpret the responses as positive, the latency of the evoked responses and the inter-electrode resistance were recorded for each stimulus. RESULTS: Individual isoflurane MAC (%) values ranged from 0.60 to 1.17 with a mean (+/-SD) of 0.97 (+/-0.17). The responses were more clearly interpreted with CC, but did not reach statistical significance. The CVsurface mode produced responses with a longer delay. The CVneedle mode was accompanied by variable inter-electrode resistances resulting in uncontrolled stimulus intensity. At 0.9 MAC, the third stimulation induced more positive responses than the first stimulation, independent of the mode of stimulation used. CONCLUSIONS: The MAC of isoflurane in the Shetland ponies was lower than expected with considerable variability among individuals. Constant current surface electrode stimulations were the most repeatable. A summation over the sequence of three supramaximal stimulations was observed around 0.9 MAC. CLINICAL RELEVANCE: The possibility that Shetland ponies require less isoflurane than horses needs further investigation. Constant current surface-electrode stimulations were the most repeatable. Repetitive supramaximal stimuli may have evoked movements at isoflurane concentrations that provide immobility when single supramaximal stimulation was applied.

Clinical evaluation of ketamine and lidocaine intravenous infusions to reduce isoflurane requirements in horses under general anaesthesia.

OBJECTIVE: To compare isoflurane alone or in combination with systemic ketamine and lidocaine for general anaesthesia in horses. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Forty horses (ASA I-III) undergoing elective surgery. METHODS: Horses were assigned to receive isoflurane anaesthesia alone (ISO) or with ketamine and lidocaine (LKI). After receiving romifidine, diazepam, and ketamine, the isoflurane end-tidal concentration was set at 1.3% and subsequently adjusted by the anaesthetist (unaware of treatments) to maintain a light plane of surgical anaesthesia. Animals in the LKI group received lidocaine (1.5 mg kg(-1) over 10 minutes, followed by 40 microg kg(-1) minute(-1)) and ketamine (60 microg kg(-1) minute(-1)), both reduced to 65% of the initial dose after 50 minutes, and stopped 15 minutes before the end of anaesthesia. Standard clinical cardiovascular and respiratory parameters were monitored. Recovery quality was scored from one (very good) to five (very poor). Differences between ISO and LKI groups were analysed with a two-sample t-test for parametric data or a Fischer's exact test for proportions (p < 0.05 for significance). Results are mean +/- SD. RESULTS: Heart rate was lower (p = 0.001) for LKI (29 +/- 4) than for ISO (34 +/- 6). End-tidal concentrations of isoflurane (ISO: 1.57% +/- 0.22; LKI: 0.97% +/- 0.33), the number of horses requiring thiopental (ISO: 10; LKI: 2) or dobutamine (ISO:8; LKI:3), and dobutamine infusion rates (ISO:0.26 +/- 0.09; LKI:0.18 +/- 0.06 microg kg(-1) minute(-1)) were significantly lower in LKI compared to the ISO group (p < 0.001). No other significant differences were found, including recovery scores. CONCLUSIONS AND CLINICAL RELEVANCE: These results support the use of lidocaine and ketamine to improve anaesthetic and cardiovascular stability during isoflurane anaesthesia lasting up to 2 hours in mechanically ventilated horses, with comparable quality of recovery.

Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration in Shetland ponies sedated with xylazine.

The pharmacokinetics of ketamine and norketamine enantiomers after administration of intravenous (IV) racemic ketamine (R-/S-ketamine; 2.2 mg/kg) or S-ketamine (1.1 mg/kg) to five ponies sedated with IV xylazine (1.1mg/kg) were compared. The time intervals to assume sternal and standing positions were recorded. Arterial blood samples were collected before and 1, 2, 4, 6, 8 and 13 min after ketamine administration. Arterial blood gases were evaluated 5 min after ketamine injection. Plasma concentrations of ketamine and norketamine enantiomers were determined by capillary electrophoresis and were evaluated by non-linear least square regression analysis applying a monocompartmental model. The first-order elimination rate constant was significantly higher and elimination half-life and mean residence time were lower for S-ketamine after S-ketamine compared to R-/S-ketamine administration. The maximum concentration of S-norketamine was higher after S-ketamine administration. Time to standing position was significantly diminished after S-ketamine compared to R-/S-ketamine. Blood gases showed low-degree hypoxaemia and hypercarbia.

Accidental entrapment of an endo-bronchial blocker tip by a surgical stapler during selective ventilation for lung lobectomy in a dog.

OBJECTIVE: To describe the use of an endobronchial blocker (EBB) and to perform selective ventilation during pulmonary lobe resection via thoracotomy in a dog and report its accidental stapling in the resection site. STUDY DESIGN: Clinical case report. ANIMAL: One female dog with a suspected abscess or neoplasia of the right caudal pulmonary lobe. METHODS: One-lung ventilation was performed using a wire-guided EBB to seal the contaminated parenchyma and facilitate surgical access. The affected lung parenchyma was resected and the resection site was closed with staples. RESULTS: Lobar resection was performed successfully, but the loop of the EBB guide wire was inadvertently entrapped in the staple line of the lobectomy. Staples were removed to release the wire loop, and the resulting air leak caused loss of ventilation control until the parenchyma was re-sealed. CONCLUSIONS: We recommend removing the wire guide associate with the EBB after successful lung separation to avoid accidents that could have life-threatening consequences if not recognized. CLINICAL RELEVANCE: One-lung ventilation is useful to isolate healthy parenchyma from diseased parenchyma during lobectomy. Anesthesiologists and surgeons need to be aware of the potential complications associated with use of EBB.

Experimental stenting of the posterior mitral leaflet to correct prolapse in mitral valve insufficiency.

OBJECTIVE: This study investigated the use of a new concept of mitral valve reconstruction using a novel device to stent the posterior mitral leaflet in combination with semicircular annuloplasty. Modern mitral valve repair is an accepted modality and a routine procedure for treatment of degenerative mitral valve insufficiency. One of the most common mechanisms of mitral valve insufficiency is leaflet prolapse. In the majority of cases the posterior leaflet is dysfunctional and therapeutic reconstruction of the PII flail leaflet segment involves quadrangular resection which is usually combined to mitral annulo-plasty with a ring. A new time-saving concept of mitral valve reconstruction by stenting the posterior mitral leaflet in combination with semicircular annuloplasty is presented. METHODS: The new mitral valve reconstruction device (Shelhigh MitroFast, Shelhigh, Inc., Union, NJ, USA) was implanted in four adult sheep. It is constructed as an annuloplasty ring in combination with a posterior leaflet stent. The device has the shape of a closed posterior leaflet and forms a "buttress" against which the anterior leaflet can coapt. RESULTS: Every implantation of a MitroFast device could be performed in less than 30 minutes. After implantation of the device, all animals could be successfully weaned from CPB. Invasively measured left atrial pressure was below 12 mm Hg in all animals. After chest closure, transoesophageal echocardiography revealed a competent mitral valve in all animals, without any inflow restriction in three animals, and suspected mild stenosis in one animal. CONCLUSIONS: In this experimental model, implantation of the newly designed annuloplasty ring with stenting the posterior mitral leaflet avoids extensive and time-consuming reconstructive surgery on a flail posterior leaflet. Implantation of the device resulted in favorable short-term hemodynamic effects. Implantation technique of the device is simple, the potential for minimal invasive implantation of a conceptual similar device will be further investigated.