The effect of ketamine on the MACBAR of sevoflurane in dogs

ObjectiveTo determine the effect of intravenous ketamine on the minimum alveolar concentration of sevoflurane needed to block autonomic response (MAC_BAR) to a noxious stimulus in dogs.Study designRandomized, crossover, prospective design.AnimalsEight, healthy, adult male, mixed-breed dogs, weighing 11.2–16.1 kg.MethodsDogs were anesthetized with sevoflurane on two occasions, 1 week apart, and baseline MAC_BAR (B-MAC_BAR) was determined on each occasion. MAC_BAR was defined as the mean of the end-tidal sevoflurane concentrations that prevented and allowed an increase (≥15%) in heart rate or invasive mean arterial pressure in response to a noxious electrical stimulus (50 V, 50 Hz, 10 ms). Dogs then randomly received either a low-dose (LDS) or high-dose series (HDS) of ketamine, and treatment MAC_BAR (T-MAC_BAR) was determined. The LDS had an initial loading dose (LD) of 0.5 mg kg^?1 and constant rate infusion (CRI) at 6.25 μg kg^?1 minute^?1, followed, after T-MAC_BAR determination, by a second LD (1 mg kg^?1) and CRI (12.5 μg kg^?1 minute^?1). The HDS had an initial LD (2 mg kg^?1) and CRI (25 μg kg^?1 minute^?1) followed by a second LD (3 mg kg^?1) and CRI (50 μg kg^?1 minute^?1). Data were analyzed with a mixed-model anova and are presented as LSM ± SEM.ResultsThe B-MAC_BAR was not significantly different between treatments. Ketamine at 12.5, 25, and 50 μg kg^?1 minute^?1 decreased sevoflurane MAC_BAR, and the maximal decrease (22%) occurred at 12.5 μg kg^?1 minute^?1. The percentage change in MAC_BAR was not correlated with either the log plasma ketamine or norketamine concentration.Conclusions and clinical relevanceKetamine at clinically relevant doses of 12.5, 25, and 50 μg kg^?1 minute^?1 decreased sevoflurane MAC_BAR, although the reduction was neither dose-dependent nor linear.     

Effects of clomipramine hydrochloride on dominance-related aggression in dogs.

OBJECTIVE: To compare effects of the serotonergic drug clomipramine hydrochloride with those of placebo for treatment of dominance-related aggression in dogs. DESIGN: Randomized, placebo-controlled, double-blind clinical trial. ANIMALS: 28 neutered dogs > 1 year old with dominance-related aggression. PROCEDURE: Dogs displaying > or = 3 aggressive episodes/wk toward > or = 1 human family member in response to identifiable behavioral triggers were included in the study. Owners were instructed not to change patterns of interaction with their dogs during the study. After 2 weeks of baseline observations, dogs were treated for 6 weeks with clomipramine (1.5 mg/kg [0.7 mg/lb] of body weight, q 12 h; n = 15) or placebo (13). Responses to triggers were assigned the following aggression scores: no response, 0; growl or lip curl, 1; snap or bite, 2. Mean scores for responses to triggers were obtained during the 2-week pretreatment period (baseline) and during the first and second weeks, third and fourth weeks, and fifth and sixth weeks of treatment. At the end of the study, owners assigned a score designed to evaluate their overall perceived change in aggressiveness; this was referred to as the global score. RESULTS: Mean aggression scores decreased at the fifth and sixth week of treatment in both groups, compared with baseline scores. However, mean scores between groups were not different. Global scores, assigned by the owner, generally reflected changes in mean aggression scores. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with placebo, clomipramine administered to dogs at the dosage recommended for treatment of separation anxiety did not reduce aggressiveness toward human family members.     

The pharmacokinetics of ketamine administered intravenously in calves and the modifying effect of premedication with xylazine hydrochloride

Ketamine hydrochloride was administered intravenously to unpremedicated and xylazine-treated calves. The plasma concentrations of ketamine and norketamine were measured at several time intervals after drug administration and the data were fitted to a two-compartment open model. In unpremedicated female calves the distribution and elimination half-lives averaged 6.9 and 60.5 min, respectively. The volume of the central compartment was 1.21 1/kg and the peripheral compartment was 4.04 1/kg. Total body clearance of ketamine averaged 40.4 ml/ min/kg. Premedication with xylazine, whilst not affecting the half-lives signifi-candy, reduced volumes of distribution and the clearance rate of the drug by approximately 50%. The results for the male calves which were premedicated were intermediate between the two groups of female calves.     

Pharmacokinetics of ketamine and its metabolite, norketamine, after intravenous administration of a bolus of ketamine to isoflurane-anesthetized dogs

OBJECTIVE: To determine the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized dogs. Animals-6 dogs. PROCEDURE: The minimum alveolar concentration (MAC) of isoflurane was determined in each dog. Isoflurane concentration was then set at 0.75 times the individual's MAC, and ketamine (3 mg/kg) was administered IV. Blood samples were collected at various times following ketamine administration. Blood was immediately centrifuged, and the plasma separated and frozen until analyzed. Ketamine and norketamine concentrations were measured in the plasma samples by use of liquid chromatography-mass spectrometry. Ketamine concentration-time data were fitted to compartment models. Norketamine concentration-time data were examined by use of noncompartmental analysis. RESULTS: The MAC of isoflurane was 1.43 +/- 0.18% (mean +/- SD). A 2-compartment model best described the disposition of ketamine. The apparent volume of distribution of the central compartment, the apparent volume of distribution at steady state, and the clearance were 371.3 +/- 162 mL/kg, 4,060.3 +/- 2,405.7 mL/kg, and 58.2 +/- 17.3 mL/min/kg, respectively. Norketamine rapidly appeared in plasma following ketamine administration and had a terminal half-life of 63.6 +/- 23.9 minutes. A large variability in plasma concentrations, and therefore pharmacokinetic parameters, was observed among dogs for ketamine and norketamine. CONCLUSIONS AND CLINICAL RELEVANCE: In isofluraneanesthetized dogs, a high variability in the disposition of ketamine appears to exist among individuals. The disposition of ketamine may be difficult to predict in clinical patients.     

Cardiopulmonary effects of a ketamine hydrochloride/acepromazine combination in healthy cats.

The effect of a ketamine hydrochloride/acepromazine combination on the cardiopulmonary function of 11 healthy cats was studied. Test parameters included cardiac output, measured by thermodilution, heart rate, respiratory rate, arterial blood pressure (systolic, diastolic and mean) and arterial blood gas analysis. Values for systemic vascular resistance, cardiac index and stroke volume were calculated. The cardiac output, cardiac index, stroke volume, arterial blood pressure and arterial blood pH decreased significantly (p less than 0.006). The arterial CO2 increased significantly (p less than 0.006). All changes occurred during the five to 45 minute postinduction time period. The heart rate, respiratory rate, arterial O2 and systemic vascular resistance were not significantly altered. The anesthetic regime maintained an adequate plane of surgical anesthesia for 30-45 minutes.     

Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs

Brown, S.A., Jacobson, J.D., Hartsfield, S.M. Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs. J. vet. Pharmacol. Therap. 16 , 419–425. Midazolam, a water-soluble benzodiazepine tranquilizer, has been considered by some veterinary anaesthesiologists to be suitable as a combination anaesthetic agent when administered concurrently with ketamine because of its water solubility and miscibility with ketamine. However, the pharmacokinetics of midazolam have not been extensively described in the dog. Twelve clinically healthy mixed breed dogs (22.2–33.4 kg) were divided into two groups at random and were administered ketamine (10 mg/kg) and midazolam (0.5 mg/kg) either as an intravenous bolus over 30 s (group 1) or as an i.v. infusion in 0.9% NaCl (2 ml/kg) over 15 min. Blood samples were obtained immediately before the drugs were injected and periodically for 6 h afterwards. Serum concentrations were determined using gas chromatography with electron-capture detection. Serum concentrations were best described using a two-compartment open model and indicated a t_½α of 1.8 min and t_½β.p of 27.8 min after i.v. bolus, and t_½α f 1–35 min and t_½β of 31.6 min after i.v. infusion. The calculated pharmacokinetic coefficient B was significantly smaller after i.v. infusion (429 ± 244 ng/ml) than after i.v. bolus (888 ± 130 ng/ml, P = 0.004). Furthermore, AUC was significantly smaller after i.v. infusion (29 800 ±6120 ng/h/ml) than after i.v. bolus (42 500 ± 8460 ng/h/ml, P < 0.05), resulting in a larger Cl_B after i.v. infusion (17.4 ± 4.00 ml/min/kg than after i.v. bolus (12.1 ± 2.24 ml/min/kg, P < 0.05). No other pharmacokinetic value was significantly affected by rate of intravenous administration.     

Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs

OBJECTIVE: To characterize the shape of the relationship between plasma ketamine concentration and minimum alveolar concentration (MAC) of isoflurane in dogs. STUDY DESIGN: Retrospective analysis of previous data. ANIMALS: Four healthy adult dogs. METHODS: The MAC of isoflurane was determined at five to six different plasma ketamine concentrations. Arterial blood samples were collected at the time of MAC determination for measurement of plasma ketamine concentration. Plasma concentration/effect data from each dog were fitted to a sigmoid inhibitory maximum effect model in which MAC(c)= MAC(0) - (MAC(0)-MAC(min)) x C(gamma)/EC(50)(gamma)+C(gamma), where C is the plasma ketamine concentration, MAC(c) is the MAC of isoflurane at plasma ketamine concentration C, MAC(0) is the MAC of isoflurane without ketamine, MAC(min) is the lowest MAC predicted during ketamine administration, EC(50) is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and gamma is a sigmoidicity factor. Nonlinear regression was used to estimate MAC(min), EC(50), and gamma. RESULTS: Mean +/- SEM MAC(min), EC(50) and gamma were estimated to be 0.11 +/- 0.01%, 2945 +/- 710 ng mL(-1) and 3.01 +/- 0.84, respectively. Mean +/- SEM maximal MAC reduction predicted by the model was 92.20 +/- 1.05%. CONCLUSIONS: The relationship between plasma ketamine concentration and its effect on isoflurane MAC has a classical sigmoid shape. Maximal MAC reduction predicted by the model is less than 100%, implying that high plasma ketamine concentrations may not totally abolish gross purposeful movement in response to noxious stimulation in the absence of inhalant anesthetics. CLINICAL RELEVANCE: The parameter estimates reported in this study will allow clinicians to predict the expected isoflurane MAC reduction from various plasma ketamine concentrations in an average dog.     

Effect of lenperone hydrochloride on gastroesophageal sphincter pressure in healthy dogs.

Treatment of healthy dogs with the butyrophenone derivative, lenperone hydrochloride, at two different doses significantly decreased gastroesophageal sphincter pressure (GESP). No dose-related effect was identified. Individual variation in the response to lenperone hydrochloride was noted which was consistent on a day-to-day basis. Lenperone hydrochloride is unsuitable for chemical restraint of dogs undergoing esophageal manometry because it decreases GESP and because the magnitude of the decrease varies considerably between dogs.     

Studies on the distribution and metabolism of ketamine in sheep

A comparison of the distribution and metabolism of intravenous and intra-cerebroventricular ketamine hydrochloride in sheep showed that following intravenous administration there was a rapid biexponential decline in plasma ketamine, metabolism was rapid and both the demethylation and subsequent oxidation metabolites were detected. In the urine the second metabolite appeared to be the major one together with a third unidentified metabolite. In the CSF both ketamine and the first metabolite appeared to follow the plasma concentrations, but the entry of the second metabolite seemed to show a much slower pattern. Following injection of ketamine into the lateral cerebral ventricles the levels of ketamine in the CSF declined rapidly and the plasma concentration of ketamine showed a similar pattern to that seen following intravenous injection, indicating a rapid transfer to the blood. The levels of the metabolites found in the CSF suggest that their production does not take place in the CSF and that they penetrate back from the plasma. The findings of rapid metabolism following both routes of injection suggests that metabolism plays a major part in the termination of the effects of ketamine in the sheep, and that plasma levels of ketamine are of more importance than CSF levels in the maintenance of anaesthesia.     

The effects of medetomidine hydrochloride on the electroretinogram of normal dogs

Purpose  To determine the effects of a standardized intravenous dose of an α-2 agonist (Domitor^®, Orion Pharma, distributed by Pfizer Animal Health, Exton, PA) on the electroretinogram (ERG) response in normal dogs.
Methods  Twenty-five normal dogs were used to collect ERG responses including a- and b-wave implicit times (IT) and amplitudes (AMP) before and after administration of medetomidine. Dogs were dark adapted for 20 min and ERGs were obtained using the HMsERG (RetVetCorp Inc., Columbia, MO). The QuickRetCheck protocol (Narfström) was employed to provide the following flash intensities: 10 mcd s/m², 3 cd s/m², and 10 cd s/m². ERGs were repeated after 375 µg/m² of medetomidine intravenously. Statistical analysis of the difference between the responses before and after medetomidine at all flash intensities was performed using a mixed effects model for anova .
Results  The P value for the effect of medetomidine on each of the ERG responses was < 0.01. The estimates of the effect of medetomidine were (+)1.35 ms, (–)23 µV, (+)3.16 ms, and (–)47 µV for the a-wave IT, a-wave AMP, b-wave IT, and the b-wave AMP, respectively.
Conclusions  Medetomidine significantly prolongs the implicit time and lowers the amplitude response of both the a- and b-waves in normal dogs at all flash intensities examined. Clinically, however, medetomidine only minimally affects the retinal responses and is a viable choice for use in dog ERGs.     

An evaluation of the influence of medetomidine hydrochloride and atipamezole hydrochloride on the arrhythmogenic dose of epinephrine in dogs during halothane anesthesia.

Alterations in the arrhythmogenic dose of epinephrine (ADE) were determined following administration of medetomidine hydrochloride (750 micrograms/M2) and a saline placebo, or medetomidine hydrochloride (750 micrograms/M2), followed by specific medetomidine reversal agent, atipamezole hydrochloride (50 micrograms/kg) 20 min later, in halothane-anesthetized dogs (n = 6). ADE determinations were made prior to the administration of either treatment, 20 min and 4 h following medetomidine/saline or medetomidine/atipamezole administration. Epinephrine was infused for 3 min at increasing dose rates (2.5 and 5.0 micrograms/kg/min) until the arrhythmia criterion (4 or more intermittent or continuous premature ventricular contractions) was reached. The interinfusion interval was 20 min. There were no significant differences in the amount of epinephrine required to reach the arrhythmia criterion following the administration of either treatment. In addition, the ADE at each determination was not different between treatment groups. In this study, the administration of medetomidine to halothane-anesthetized dogs did not alter their arrhythmogenic response to infused epinephrine.