Pharmacokinetics of midazolam in sevoflurane-anesthetized cats.

OBJECTIVE: To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats. STUDY DESIGN: Prospective pharmacokinetic study. ANIMALS: A group of six healthy adult, female domestic cats. METHODS: Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg-1) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (fR), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO2) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling. RESULTS: The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg-1, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute-1 kg-1, respectively. No significant changes in HR, MAP, fR or Pe'CO2 were observed following midazolam administration. CONCLUSION AND CLINICAL RELEVANCE: In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables.

Prolonged Anesthetic Recovery after Continuous Infusion of Midazolam in 2 Domestic Cats (Felis catus).

Two healthy research cats involved in a randomized, blinded prospective pharmacodynamics study evaluating midazolam continuous-rate infusion as a means to decrease sevoflurane concentrations experienced unexpectedly prolonged recoveries. Midazolam loading doses, infusion rates, and the targeted plasma midazolam concentrations at steady-state were determined by pharmacokinetic modeling based on the results of a preliminary pharmacokinetic study using a single dose of midazolam. In the pharmacodynamics study, cats remained oversedated after recovery from anesthesia, and plasma concentrations of midazolam and its primary metabolite (1-hydroxymidazolam) remained elevated. The use of flumazenil was unsuccessful in timely treatment of oversedation. Administration of intravenous lipid emulsion was used in one of the cats to facilitate recovery and appeared to be effective in both reducing the depth of midazolam-induced oversedation and significantly reducing the plasma concentration of 1-hydroxymidazolam. The effects after the administration of both treatment modalities on clinical signs and plasma drug concentrations in cats are discussed. The observations suggest that cats may eliminate 1-hydroxymidazolam more slowly than expected; consequently dose adjustments may be required when continuous infusion of midazolam is intended. In addition, intravenous lipid emulsion may facilitate recovery from midazolam oversedation, particularly in cases unresponsive to traditional treatment modalities. However, further investigations are warranted to delineate the efficacy of this modality in the treatment of midazolam oversedation.

Anesthetic effects and body weight changes associated with ketamine-xylazine-lidocaine administered to CD-1 mice.

Anesthesia for mice is commonly performed through the injection of parenteral agents via the intraperitoneal (IP) route. Variability in anesthetic sensitivities has been noted in mice resulting in inconsistencies in anesthetic depth and/or mortality. Anesthetic protocols that improve consistency and safety are needed. The objectives of this study were to assess the effects of intraperitoneal (IP) ketamine (95 mg/kg) and xylazine (7 mg/kg) alone or combined with lidocaine at 4, 8, or 16 mg/kg on time to loss (LRR) and return (RRR) of righting reflex, duration of immobilization and loss of pedal withdrawal response (PWR), body weight and histopathology in CD-1 mice. In a prospective, randomized trial, 36 male CD-1 mice, 4-6 weeks of age were randomly assigned to 5 groups: saline (SA, n = 4); ketamine-xylazine (KX, n = 8); ketamine-xylazine-lidocaine 4 mg/kg (KXL4, n = 8); ketamine-xylazine-lidocaine 8 mg/kg (KXL8, n = 8); ketamine-xylazine-lidocaine 16 mg/kg (KXL16, n = 8). Two mice in each group were euthanized at day 2 post-injection and the remaining mice were euthanized at day 11 post-injection. After IP injection, LRR and RRR, duration of immobilization and loss of PWR, body weight and histopathology were evaluated. LRR occurred sooner in mice receiving KXL16 compared with KX, with median (range) times of 78 (62-104) and 107 (91-298) seconds, respectively. Loss of PWR occurred in 1, 5, 4, 6 mice for groups KX, KXL4, KXL8, and KXL16 respectively. Median (range) duration of absent PWR was longer in mice receiving KXL16 at 13 (0-30) minutes, compared to KX at 0 (0-9) minutes. Duration of immobilization and RRR were not different between groups. Weight loss occurred 2 days following anesthesia but was not different between groups. Weight gain was significantly greater in all lidocaine groups 11 days post-injection compared to KX. No mortality or histopathologic abnormalities were observed in any group. Lidocaine administered with ketamine and xylazine shortens the onset of anesthesia in mice and improves anesthetic depth without prolonging recovery time.

Determination of RBC Survival in C57BL/6 and C57BL/6-Tg(UBC-GFP) Mice.

Although several methods for determining erythrocyte lifespan are used in research studies that involve mice, all involve the alteration of RBC to allow for its tracking over time, which may affect overall RBC survival. The aims of this study were to determine 1) whether sex affects RBC survival; 2) whether RBC survival differs between the biotin method and an alternative method that uses GFP; and 3) whether repeat exposure of mice to biotin results in an antibiotin antibody response or decreased RBC survival. The results suggest no difference in the RBC half-life between male and female C57BL/6 mice (22.9 ± 1.2 and 22.4 ± 0.9 d, respectively). In addition, RBC half-life did not differ between the biotin- and GFP-based methods (20.5 ± 2.1 d and 22.7 ± 2.1 d, respectively). Finally, retransfusion of mice 90 d after an initial transfusion with biotin-labeled RBC did not induce detectable antibiotin antibodies nor alter the half-life of transfused biotin-labeled RBC (initial transfusion, 22.0 ± 1.2 d; subsequent transfusion, 23.4 ± 1.4 d, respectively).