Stereoselective methadone disposition after administration of racemic methadone to anesthetized Shetland ponies assessed by capillary electrophoresis.

The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l-methadone and d-methadone and their major metabolites, l- and d-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection from liquid/liquid extracts prepared at alkaline pH. In both trials, the d-methadone concentrations were lower than those of l-methadone and the d-EDDP levels were lower than those of L-EDDP. For the case of a single intravenous bolus injection, the plasma concentration versus time profile of methadone enantiomers was analyzed with a two-compartment pharmacokinetic model. l-methadone showed a slower elimination rate constant, a lower body clearance, and a smaller steady-state volume of distribution than d-methadone. d-methadone and d-EDDP were eliminated faster than their respective l-enantiomers. This is the first study that outlines that the disposition of racemic methadone administered to anesthetized equines is enantioselective.

Combined caudal retrocostal and lateral ultrasound-guided approach for transversus abdominis plane injection: A descriptive pilot study in pig cadavers.

Transversus abdominis plane (TAP) block is a regional anesthetic technique used to desensitize the abdominal wall in several species. This study aimed to describe the anatomical characteristics of the abdominal wall and to identify a feasible approach for an US-guided TAP injection that would result in adequate staining of the relevant nerves in the abdominal wall in pig cadavers. Fresh cadavers from five Landrace pigs (age, 12 weeks; body weight, 35.5 ± 1.6 kg) were used. One pig (n = 1) was anatomically dissected, and four pigs (n = 4; i.e., 8 hemiabdomens) were used for TAP injections and evaluation of dye spread. The volume of 0.3 mL/kg/injection point of methylene blue was injected bilaterally. In the caudal retrocostal approach, the injection was performed ventral to the most caudal part of the costal arch. In the lateral approach, the injection was performed between the last rib and iliac crest. A needle was inserted in plane for the caudal retrocostal and the lateral approach caudocranially and craniocaudally, respectively. Successful staining was defined as presence of dye on the nerve for a length of >1 cm in its entire circumference. The TAP was found between different muscle layers in the described anatomical regions. In the caudal retrocostal approach the TAP was found between the external abdominal oblique and transversus abdominis muscle bellies. In the lateral approach the TAP was found between the internal abdominal oblique and transversus abdominis muscles. The approach combining lateral and caudal retrocostal injections at the studied volume stained a median of 5 (3-6) target nerves from the fourth-last thoracic nerve to L2 (six nerves). Combined caudal retrocostal and lateral TAP injections of 0.3 mL/kg/injection point, resulted in staining of target nerve branches which supply the periumbilical and caudal abdominal wall in pig cadavers.

Pharmacokinetics and pharmacodynamics of l-methadone in isoflurane-anaesthetized and mechanically ventilated ponies.

OBJECTIVE: To evaluate the pharmacokinetics and selected pharmacodynamic effects of a commercially available l-methadone/fenpipramide combination administered to isoflurane anaesthetized ponies. STUDY DESIGN: Prospective single-group interventional study. ANIMALS: A group of six healthy adult research ponies (four mares, two geldings). METHODS: Ponies were sedated with intravenous (IV) detomidine (0.02 mg kg-1) and butorphanol (0.01 mg kg-1) for an unrelated study. Additional IV detomidine (0.004 mg kg-1) was administered 85 minutes later, followed by induction of anaesthesia using IV diazepam (0.05 mg kg-1) and ketamine (2.2 mg kg-1). Anaesthesia was maintained with isoflurane in oxygen. Baseline readings were taken after 15 minutes of stable isoflurane anaesthesia. l-Methadone (0.25 mg kg-1) with fenpipramide (0.0125 mg kg-1) was then administered IV. Selected cardiorespiratory variables were recorded every 10 minutes and compared to baseline using the Wilcoxon signed-rank test. Adverse events were recorded. Arterial plasma samples for analysis of plasma concentrations and pharmacokinetics of l-methadone were collected throughout anaesthesia at predetermined time points. Data are shown as mean ± standard deviation or median and interquartile range (p < 0.05). RESULTS: Plasma concentrations of l-methadone showed a rapid initial distribution phase followed by a slower elimination phase which is best described with a two-compartment model. The terminal half-life was 44.3 ± 18.0 minutes, volume of distribution 0.43 ± 0.12 L kg-1 and plasma clearance 7.77 ± 1.98 mL minute-1 kg-1. Mean arterial blood pressure increased from 85 (±16) at baseline to 100 (±26) 10 minutes after l-methadone/fenpipramide administration (p = 0.031). Heart rate remained constant. In two ponies fasciculations occurred at different time points after l-methadone administration. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of a l-methadone/fenpipramide combination to isoflurane anaesthetized ponies led to a transient increase in blood pressure without concurrent increases in heart rate. Pharmacokinetics of l-methadone were similar to those reported for conscious horses administered racemic methadone.

Ultrasound-Guided Transversus Abdominis Plane Block in Shetland Ponies: A Description of a Three-Point Injection Technique and Evaluation of Potential Analgesic Effects.

Colic surgery is one of the most painful procedures carried out in horses. Common strategies to alleviate immediate postsurgical abdominal pain include the administration of potent systemic analgesics; however, these may cause unwanted adverse effects such as cardiovascular depression, ileus, and ataxia. The administration of local anesthetics at the incision site in form of an ultrasound-guided subcostal transversus abdominis plane (TAP) block may therefore be preferred to provide adequate analgesia without significant side effects. To date, no technique for a TAP block in horses undergoing median celiotomy has been described. The objective of the study was to develop a TAP block technique, which will lead to the desensitization of the ventrolateral abdominal wall and adjacent skin area of experimental Shetland Ponies using bupivacaine 0.125%. This is a prospective, blinded, self-controlled trial. A cadaver study was performed to determine the ideal injection points and the volume required to stain the nerves responsible for the sensation of the ventrolateral abdominal wall and skin in Shetland pony cadavers (i.e., T9-L 2). Subsequently, using the ideal injectate volume and the landmarks obtained in the first phase of the study, six Shetland ponies received a bilateral TAP injection, either with a local anesthetic solution (bupivacaine 0.125%) or with saline in a randomized, crossover, blinded fashion. Effectiveness was determined over a 4 hour postinjection time, by using a pinprick technique. Significant differences were found to the responses of the pinprick evaluation between the bupivacaine- and saline-treated sides after 30 minutes of TAP block injection. Reported "learned behavior" could have affected the results of the pinprick testing. The TAP block technique reported in this study using bupivacaine 0.125% appeared effective in desensitizing the lower abdomen of ponies for up to 2 hours. Further research is required to apply this technique in horses undergoing celiotomy. Potentially larger volumes and/or higher concentrations of bupivacaine may be necessary to provide longer duration of action of the block.

Canine mammary tumour cells exposure to sevoflurane: effects on cell proliferation and neuroepithelial transforming gene 1 expression.

OBJECTIVE: The influence of perioperative factors, such as anaesthetic and analgesic techniques, on metastatic spread following surgery for primary cancer removal is of growing interest. The present study investigated the effects of sevoflurane on canine mammary tumour cell proliferation (MTT colorimetric assay) and on the expression of neuroepithelial transforming gene 1 (NET1). STUDY DESIGN: Prospective controlled in vitro trial. STUDY MATERIAL: Primary (CIPp) and metastatic canine tubular adenocarcinoma (CIPm) cells. METHODS: To perform MTT tests, cell lines were seeded at a density of 3000 cells per well and incubated with sevoflurane (1, 2.5 or 4 mM) or only with the culture medium (control). Sevoflurane was added to the cell cultures every hour to avoid changes in drug concentration. MTT assays were performed after 6 hours of exposure obtaining absolute values of absorbance. The RNA isolated from the lysates of the same cell lines underwent quantitative polymerase chain reaction to evaluate NET1 gene expression changes compared with controls. One- or two-way analysis of variance was used as appropriate (p < 0.05). RESULTS: A significant increase in cell proliferation compared with controls was observed in CIPp treated with lower sevoflurane concentrations, whereas a significant decrease in cell proliferation was found in CIPm treated with all the sevoflurane concentrations. All CIPp treatments did not induce changes in gene expression compared with controls, whereas a significant increase in gene expression was observed in CIPm between controls and the higher sevoflurane concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Sevoflurane treatments modified the cell proliferation rate in both cell lines showing an increase or decrease when applied to CIPp or CIPm, respectively. Expression of the NET1 gene increased after treatment with sevoflurane 4 mM in metastatic cells. The role of sevoflurane on cancer recurrence should be further investigated.

Enantioselective capillary electrophoresis for pharmacokinetic analysis of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equines anesthetized with ketamine and isoflurane.

An enantioselective assay for the determination of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equine plasma based on capillary electrophoresis with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection is described. The assay is based on liquid/liquid extraction of the analytes at alkaline pH from 0.1 mL plasma followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3 phosphate buffer containing 0.16% (w/v) of highly sulfated γ-cyclodextrin. The developed assay is precise (intra- and interday RSD < 4% and < 7%, respectively), is capable to determine enantiomer levels of methadone and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in plasma down to 2.5 ng/mL, and was successfully applied to monitor enantiomer drug and metabolite levels in plasma of a pony that was anesthetized with racemic ketamine and isoflurane and received a bolus of racemic methadone and a bolus followed by constant rate infusion of racemic methadone. The data suggest that the assay is well suited for pharmacokinetic purposes.

Influence of anesthetic variables on short-term and overall survival rates in cats undergoing renal transplantation surgery.

OBJECTIVE: To identify factors associated with short-term (30-day) and overall survival rates in cats that underwent renal transplantation surgery (RTS). DESIGN: Retrospective cohort study. ANIMALS: 94 cats that underwent RTS from 1998 through 2010. PROCEDURES: Data obtained from the medical records pertinent to RTS included cat signalment; anesthetic agents, techniques, and timings; supportive treatment; perioperative physiologic findings; and surgery and warm ischemia times. Associations with short-term and overall survival rates were investigated. RESULTS: Median survival time was 653 days (range, 2 to 4,580 days). Prolonged anesthesia (median, 300 minutes; range, 225 to 445 minutes) reduced overall survival rate but did not influence short-term survival rate. No associations were identified between survival rates and anesthetic agent used, amount and type of fluid administered IV, physiologic abnormalities, and blood product administration. All cats that received µ-opioid receptor antagonists at anesthetic recovery to reverse the effects of µ-opioid receptor agonists survived for at least 30 days. High Hct at the end of anesthesia was also associated with an increase in short-term survival rate. Two cats had an intraoperative hemoglobin oxygen saturation < 90%, and both died within 7 days after surgery. Cats > 12 years old had a lower overall survival rate than did younger cats. CONCLUSIONS AND CLINICAL RELEVANCE: Minimization of total anesthesia time, reversal of µ-opioid receptor agonists at the end of anesthesia, and prevention of intraoperative decreases in blood oxygen saturation and postoperative decreases in Hct appeared to help maximize postsurgical survival time in cats undergoing RTS.

Trending ability and limitations of transpulmonary thermodilution and pulse contour cardiac output measurement in cats as a model for pediatric patients.

The present study evaluated transpulmonary thermodilution (TPTD) and pulse contour cardiac output (PCCO) both measured by the PiCCO Plus™ monitor (Pulsion Medical Systems, Munich, Germany) against pulmonary artery thermodilution (PATD) in cats as a hemodynamic model for small children. A wide range of cardiac outputs (CO) was simultaneously measured. Accuracy and trending abilities were critically evaluated. Three cats were studied under isoflurane anesthesia and 160 CO measurements were performed with 3 mL ice-cold 5 % dextrose with PATD and TPTD. The results were compared with the PCCO measurement before the bolus measurement. Cardiac output was manipulated from 32 to 224 mL/kg/min by dobutamine, dopamine, phenylephrine, medetomidine and increased concentrations of isoflurane. Bland-Altman analysis, concordance and polar plot analysis were performed to assess accuracy and trending ability. TPTD was measuring constantly higher than PATD with a mean bias of 73 mL/kg/min and limits of agreement of 34-112 mL/kg/min, a concordance rate of 94 % and a mean polar angle of -5° with radial limits of agreement (RLOA) of 33°. Concordance rate of the PCCO versus PATD was 82 % with a mean polar angle of -10° and RLOA of 46° and versus TPTD 90 % with a mean polar angle of -6° and RLOA of 46°. Both tested methods constantly overestimated simultaneous PATD measurements. The small size, low flows and the relative short catheter not reaching the abdominal aorta may explain that. However TPTD tracked changes accurately opposed to a poor trending ability of the PCCO measurement.

Effects of acepromazine or methadone on midazolam-induced behavioral reactions in dogs.

This study evaluated whether acepromazine or methadone reduced behavioral parameters, overall excitement, and activity associated with midazolam administration to healthy dogs. Dogs received midazolam (M) alone [M: 0.25 mg/kg body weight (BW)] or with methadone (MM) (MM: 0.75 mg/kg BW) or acepromazine (MA) (MA: 0.03 mg/kg BW) or saline (S) solution alone, all intramuscularly. Two blinded observers evaluated behavioral parameters using video recordings 30 min before and after injection of drugs. Accelerometery was used to evaluate "total activity counts" (TAC) at baseline and post-treatment. Post-treatment excitement scores were significantly higher in M and MA compared to baseline, M and MM compared to S, and M compared to MA. Behavioral parameters showed significantly higher proportions of "pacing" post-treatment in all groups receiving midazolam, and "restlessness," "chewing/licking," and "sniffing" in M. No significant differences were found for TAC at baseline and post-treatment. Midazolam-induced paradoxical behavioral changes (excitation, panting, pacing, restlessness, licking/chewing, and vocalization) were not prevented by acepromazine or methadone in healthy dogs.

Effets de l'acépromazine ou de la méthadone sur les réactions comportementales induites par le midazolam chez les chiens. Cette étude a évalué si l'acépromazine ou la méthadone réduisait les paramètres comportementaux, le niveau d'excitation général et l'activité associée à l'administration de midazolam chez des chiens en santé. Les chiens ont reçu le midazolam (M) seul (M : 0,25 mg/kg poids corporel [PC]) ou avec de la méthadone (MM) (MM : 0,75 mg/kg PC) ou de l'acépromazine (MA) (MA : 0,03 mg/kg PC) ou une solution saline (S) seule, tous administrés par voie intramusculaire. Deux observateurs à l'aveugle ont évalué les paramètres comportementaux à l'aide d'enregistrements vidéo 30 minutes avant et après l'injection des médicaments. Un accéléromètre a été utilisé pour évaluer les «numérations de l'activité totale¼ (NAT) comme données de référence et après le traitement. Les notes d'excitation après le traitement étaient significativement supérieures pour M et MA comparativement aux données de référence, M et MM comparativement à S et M comparativement à MA. Les paramètres comportementaux ont montré des proportions significativement supérieures de «va-et-vient¼ après le traitement dans tous les groupes qui avaient reçu midazolam et une «agitation¼, de «mastication et léchage¼ et de «reniflement¼ dans M. Aucune différence significative n'a été constatée pour NAT aux données de référence et après le traitement. Les changements comportementaux paradoxes induits par le midazolam (excitation, halètement, va-et-vient, agitation, lèchage et mastication et vocalisation) n'ont pas été prévenus par l'acépromazine ni la méthadone chez les chiens en santé.(Traduit par Isabelle Vallières).