The effect of intravenous administration of variable-dose midazolam after fixed-dose ketamine in healthy awake cats

The effects of intravenous administration of variable-dose midazolam and ketamine (3 mg/kg) were studied in twelve healthy unmedicated cats from time of administration until full recovery. A range of midazolam doses (0.0, 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg) was chosen, so that beneficial and/or detrimental effects could be documented and the therapeutic window for further study determined. One minute after administration of ketamine, all cats had assumed a lateral position, mostly with head up. Muscle tone was increased (100%), apneustic breathing pattern evident in 92% of cats, chewing without stimulation of the oropharyngeal area was observed in most cats (97%), but most cats did not salivate (87%). At 2.5 min after completion of ketamine injection and 1 min after administration of saline, a similar picture was observed, except that salivation was evident. All cats chewed or swallowed in response to a finger or laryngoscope placed in the oropharyngeal area and, while most cats were not aware of a noxious stimulus to the tail, some cats were aware of a noxious stimulus to the paw. Recovery from ketamine alone was rapid and smooth with cats rolling into sternal recumbency and then cautiously walking with ataxia. Recovery to walking without incoordination was also rapid (< 2 h) and no abnormal behavioural patterns were observed during recovery. Administration of midazolam after ketamine, had beneficial effects and the therapeutic window for midazolam was found to lie between 0.05 mg/kg and 0.5 mg/kg. Administration of any dose of midazolam after ketamine caused a greater proportion of cats to assume a laterally recumbent position with head down compared with ketamine alone, however, the time period of recumbency was only significantly longer with a midazolam dose of 2.0 mg/kg or above. Doses of midazolam of 0.5 mg/kg or above decreased muscle rigidity but did not affect salivation or respiratory pattern observed in cats which received ketamine alone. A significantly greater proportion of cats which received ketamine and midazolam 0.5 mg/kg or above did not swallow in response to a finger or a laryngoscope placed in the mouth compared with that which received ketamine alone. The length of time in which cats did not swallow was only significantly longer at midazolam doses of 1.0 mg/kg and above. At midazolam doses of 0.5 mg/kg or above, the proportion of cats without a nociceptive response to a tail or paw clamp was significantly greater than cats which received ketamine alone. The time period without nociceptive response, however, was not influenced by midazolam administration. The time taken for cats which received ketamine and midazolam 0.05 mg/kg or 0.5 mg/kg to assume sternal position, walk with ataxia, walk without ataxia, behave normally when approached or restrained and recover normal arousal state was not significantly different from cats which received ketamine alone. Ketamine and midazolam 5.0 mg/kg significantly prolonged all recovery times compared with ketamine alone. Unfortunately, a greater proportion of cats which received ketamine and midazolam 0.5 or 5.0 mg/kg exhibited detrimental behavioural effects. These were more likely to be adverse and included restlessness, vocalization and difficulty approaching and restraining cats. In this study, an     

The effect of intravenous administration of variable-dose flumazenil after fixed-dose ketamine and midazolam in healthy cats

The effects of intravenous administration of variable-dose flumazenil (0, 0.001, 0.005, 0.01, and 0.1 mg/kg) after ketamine (3 mg/kg) and midazolam (0.0 and 0.5 mg/kg) were studied in 18 healthy unmedicated cats from time of administration until full recovery. End-points were chosen to determine whether flumazenil shortened the recovery period and/or modified behaviors previously identified and attributed to midazolam. Overall, flumazenil administration had little effect on recovery or behaviors. One minute after flumazenil administration, all cats were recumbent but a greater proportion of cats which received the highest dose assumed sternal recumbency with head up than any other group. Although not significant, those cats that received the highest flumazenil dose also had shorter mean times for each of the initial recovery stages (lateral recumbency with head up, sternal recumbency with head up and walking with ataxia) than any of the other treatment groups that received midazolam. For complete recovery, flumazenil did decrease the proportion of the cats that was sedated, but did not shorten the time to walking without ataxia. Based on this study, the administration of flumazenil in veterinary practice, at the doses studied, to shorten and/or improve the recovery from ketamine and midazolam in healthy cats cannot be recommended.     

The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam

The onset of action and behavioural effects following intravenous (i.v.) and intramuscular (i.m.) administration of 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg of midazolam were studied for 2 h in 20 awake, healthy cats. All cats, except one that received 0.05 mg/kg i.m., showed effects of the drug, whereas no effects were observed in cats administered only the vehicle in which midazolam was dissolved. The onset of action was rapid following both i.v. and i.m. administration, some cats became ataxic, while others assumed positions of sternal or lateral recumbency. Even after administration of the highest dose (5.0 mg/kg), anaesthesia was not induced, with swallowing reflexes and conscious perception of a clamp placed on the tail still present in all cats. An abnormal arousal state was observed in many cats after administration of midazolam. During the first hour, restlessness was more commonly observed, while from 1 to 2 h, sedation was more prominent in cats that received the highest dose. Ataxia occurred in all but one cat, was short-lived in cats that received the lower doses, but still present at 2 h in all cats that received 2.0 and 5.0 mg/kg. Midazolam caused some of the cats to behave differently when approached and restrained compared with behavioural patterns identified prior to administration of the drug. The cats were more likely to behave abnormally following i.v. administration rather than i.m. administration and, for the most part, abnormal behaviour was equally distributed between the two extremes; cats being easier to approach and restrain and cats being more difficult to approach and restrain. Food consumption increased significantly, during the 2 h period, following all i.m. doses and all but the highest (5.0 mg/kg) i.v. dose, with most of the food being consumed in the first hour after administration.     

The pharmacokinetics of intravenous fenoldopam in healthy,awake cats

Fenoldopam is a selective dopamine‐1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well‐tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client‐owned cats aged 2–6 years old received a 120‐min constant rate infusion of fenoldopam at 0.8 μg/kg/min followed by a 20‐min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half‐life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 μg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended.     

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.     

The pharmacokinetics of midazolam after intravenous,intramuscular, and rectal administration in healthy dogs

Intravenous benzodiazepines are utilized as first‐line drugs to treat prolonged epileptic seizures in dogs and alternative routes of administration are required when venous access is limited. This study compared the pharmacokinetics of midazolam after intravenous (IV), intramuscular (IM), and rectal (PR) administration. Six healthy dogs were administered 0.2 mg/kg midazolam IV, IM, or PR in a randomized, 3‐way crossover design with a 3‐day washout between study periods. Blood samples were collected at baseline and at predetermined intervals until 480 min after administration. Plasma midazolam concentrations were measured by high‐pressure liquid chromatography with UV detection. Rectal administration resulted in erratic systemic availability with undetectable to low plasma concentrations. Arithmetic mean values ± SD for midazolam peak plasma concentrations were 0.86 ± 0.36 μg/mL (C₀) and 0.20 ± 0.06 μg/mL (C_max), following IV and IM administration, respectively. Time to peak concentration (T_max) after IM administration was 7.8 ± 2.4 min with a bioavailability of 50 ± 16%. Findings suggest that IM midazolam might be useful in treating seizures in dogs when venous access is unavailable, but higher doses may be needed to account for intermediate bioavailability. Rectal administration is likely of limited efficacy for treating seizures in dogs.     

Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration

BackgroundIsavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.ObjectivesTo determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.AnimalsEight healthy, adult research cats.MethodsFour cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra‐high performance liquid chromatography‐tandem mass spectrometry. Data were analyzed using a 2‐compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y² weighting for IV administration. Predicted 24 and 48‐hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.ResultsBoth PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half‐life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.Conclusions and Clinical ImportanceIsavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long‐term isavuconazole use are needed.     

Cardiovascular effects of propofol alone and in combination with ketamine for total intravenous anesthesia in healthy cats

This study was designed to compare the cardiovascular effects of equipotent maintenance of anesthetic doses (determined in a previous study) of propofol and propofol/ketamine, administered with and without noxious stimulation. Six healthy adult cats were anesthetized with propofol (loading dose 6.6 mg kg^?1, infusion 0.22 mg kg^?1 minute^?1), and instrumented to allow determination of blood gas and acid–base balance and measurement of blood pressures and cardiac output. The propofol infusion was continued for a further 60 minutes after which measurements were taken prior to and during application of a noxious stimulus. The propofol infusion was decreased to 0.14 mg kg^?1 minute^?1, and ketamine (loading dose 2 mg kg^?1, infusion 23 µg kg minute^?1) was administered. After a further 60 minutes, measurements were again taken prior to and during application of a noxious stimulus. The data were analyzed, using several Repeated Measures anova (first, ketamine/propofol and noxious stimulation were each treated as within‐subject factors; secondly, the levels of these two factors were combined into a single within‐subject factor). Mean arterial pressure, CVP, PAOP, SI, CI, SVRI, PVRI, oxygen delivery index, oxygen consumption index, oxygen utilization ratio, PvO₂, pHa, PaCO₂, bicarbonate concentration, and BD values collected during propofol administration were not changed by addition of ketamine and reduction of propofol concentration or by application of a noxious stimulus under propofol alone. Application of a noxious stimulus under propofol alone did, however, significantly increase HR and PaO₂, and these responses were not blunted by the addition of ketamine. Compared with propofol, administration of ketamine and reduction of propofol concentration significantly increased PAP and venous admixture, and significantly decreased PaO₂. Although application of a noxious stimulus to cats under propofol alone did not significantly change CVP, SI, CI, PVRI, oxygen delivery index, and oxygen consumption index, significant differences were found in these variables between propofol and propofol/ketamine. In conclusion, propofol alone provided cardiopulmonary stability; addition of ketamine did not improve hemodynamics but did decrease oxygenation.     

Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats

Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (±16.54)%. The clearance of RDZ following IV administration was 0.82 (±0.07) ml/kg/min. The terminal half-life was 9.80 (±0.35) and 10.50 (±0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats.     

Echocardiographic reference values in healthy cats sedated with ketamine hydrochloride

An M-mode echocardiographic examination was performed in a consistent manner in 30 clinically healthy cats under light ketamine hydrochloride sedation. There was a significant linear relationship between increasing body size and increasing cardiac dimensions for several echocardiographic values. Positive correlation existed between body weight and body surface area with aortic root, left ventricular caudal wall thickness (LVCW), interventricular septal thickness (IVS), IVS/LVCW, and mean velocity of circumferential fiber shortening (Vcf); there was a negative correlation between body weight and body surface area with left ventricular ejection time (LVET). Body surface area also correlated positively with percentage of ventricular minor axis dimensional change (% delta D). Positive correlations were recorded between left ventricular end-diastolic dimension (LVEDD) and left ventricular endsystolic dimension (LVESD), LVESD and LVET, LVCW and IVS, LVET (calculated by LVCW motion) and LVET (calculated by aortic valve motion), % delta D and Vcf, heart rate and Vcf, and Vcf (calculated using aortic valve motion to compute LVET) and Vcf (using LVCW motion to compute LVET). There were negative correlations between LVEDD and % delta D, LVEDD and Vcf, LVESD and Vcf, LVET and Vcf, LVET and heart rate, LVET and % delta D. Significant differences were recorded between means of echocardiographic reference values generated in this and other studies, except for LVESD.     

The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs

The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high‐performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio‐respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Cl_area, Vd_area and T_1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Cl_area/F, Vd_area/F and T_1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.     

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.     

The effects of diazepam or midazolam on the dose of propofol required to induce anaesthesia in cats

ObjectivesAssess effects of benzodiazepine administration on the propofol dose required to induce anaesthesia in healthy cats, investigate differences between midazolam and diazepam, and determine an optimal benzodiazepine dose for co-induction.Study designProspective, randomised, blinded, placebo-controlled clinical trial.AnimalsNinety client-owned cats (ASA I and II) with a median (interquartile range) body mass of 4.0 (3.4–4.9) kg.MethodsAll cats received 0.01 mg kg⁻¹ acepromazine and 0.2 mg kg⁻¹ methadone intravenously (IV). Fifteen minutes later, sedation was scored on a scale of 1–5, with 5 indicating greatest sedation. Propofol, 2 mg kg⁻¹, administered IV, was followed by either midazolam or diazepam at 0.2, 0.3, 0.4 or 0.5 mg kg⁻¹ or saline 0.1 mL kg⁻¹. Further propofol was administered until endotracheal intubation was possible. Patient signalment, sedation score, propofol dosage and adverse reactions were recorded.ResultsMidazolam and diazepam (all doses) significantly reduced the propofol dose required compared with saline (p < 0.001). There was no difference between midazolam and diazepam in propofol dose reduction (p = 0.488). All individual doses of midazolam reduced propofol requirement compared with saline (0.2 mg kg⁻¹, p = 0.028; 0.3 mg kg⁻¹, p = 0.006; 0.4 mg kg⁻¹, p < 0.001; 0.5 mg kg⁻¹, p = 0.009). Diazepam 0.2 mg kg⁻¹ did not reduce the propofol dose compared with saline (p = 0.087), but the remaining doses did (0.3 mg kg⁻¹, p = 0.001; 0.4 mg kg⁻¹, p = 0.032; 0.5 mg kg⁻¹, p = 0.041). Cats with sedation scores of 3 required less propofol than cats with scores of 2 (p = 0.008). There was no difference between groups in adverse events.Conclusions and clinical relevanceMidazolam (0.2–0.5 mg kg⁻¹) and diazepam (0.3–0.5 mg kg⁻¹) administered IV after 2 mg kg⁻¹ propofol significantly reduced the propofol dose required for tracheal intubation.     

Acute insulin response to intravenous arginine in nonobese healthy cats

The purpose of this study was to document and characterize insulin response to intravenous administration of arginine, a nonglucose secretagogue, and compare it to insulin response during intravenous glucose tolerance tests (IVGTTs) in clinically healthy nonobese cats. In addition, we examined the influence of plasma glucose level on insulin response to arginine in cats. Five dosages of 10% L-arginine hydrochloride (0.015, 0.025, 0.05, 0.1, and 0.2 g/kg of body weight) were administered to 5 cats. All doses of arginine elicited an abrupt insulin response that peaked at 2-4 minutes and returned to basal concentrations within 30 minutes. Mean insulin peak response (IPR) and mean area under the curve of plasma insulin concentration evaluated for the initial 10 minutes after administration (AUC10) increased with each progressive increase in arginine dosage. An asymptotic maximal response estimated by mean insulin AUC10 reached plateau at 0.1-0.2 g arginine/kg. Arginine at 0.2 g/kg induced hypersalivation in 2 of 4 cats. No adverse effects were evident at lower doses. Mean insulin AUC10 produced by equimolar amount of glucose (0.086 g/kg) was only 42% of that seen in response to 0.1 g arginine/kg, and mean IPR was much lower (18 +/- 7 versus 61 +/- 17 microU/mL). Mild hyperglycemia (211 +/- 6 mg/dL) induced by variable infusion rate of glucose resulted in a significant (P < .05) potentiation of insulin response to arginine; mean insulin AUC10 increased 287 +/- 26 to 551 +/- 167 microU/mL/10 minutes. These findings indicate that the arginine challenge is a more meaningful tool than is the IVGTT for evaluating the insulin secretory capacity in cats.     

Effects of ketamine or midazolam continuous rate infusions on alfaxalone total intravenous anaesthesia requirements and recovery quality in healthy dogs: a randomized clinical trial

ObjectiveTo determine the alfaxalone dose reduction during total intravenous anaesthesia (TIVA) when combined with ketamine or midazolam constant rate infusions and to assess recovery quality in healthy dogs.Study designProspective, blinded clinical study.AnimalsA group of 33 healthy, client-owned dogs subjected to dental procedures.MethodsAfter premedication with intramuscular acepromazine 0.05 mg kg^-1 and methadone 0.3 mg kg^-1, anaesthetic induction started with intravenous alfaxalone 0.5 mg kg^-1 followed by either lactated Ringer’s solution (0.04 mL kg^-1, group A), ketamine (2 mg kg^-1, group AK) or midazolam (0.2 mg kg^-1, group AM) and completed with alfaxalone until endotracheal intubation was achieved. Anaesthesia was maintained with alfaxalone (6 mg kg^-1 hour^-1), adjusted (±20%) every 5 minutes to maintain a suitable level of anaesthesia. Ketamine (0.6 mg kg^-1 hour^-1) or midazolam (0.4 mg kg^-1 hour^-1) were employed for anaesthetic maintenance in groups AK and AM, respectively. Physiological variables were monitored during anaesthesia. Times from alfaxalone discontinuation to extubation, sternal recumbency and standing position were calculated. Recovery quality and incidence of adverse events were recorded. Groups were compared using parametric analysis of variance and nonparametric (Kruskal-Wallis, Chi-square, Fisher’s exact) tests as appropriate, p < 0.05.ResultsMidazolam significantly reduced alfaxalone induction and maintenance doses (46%; p = 0.034 and 32%, p = 0.012, respectively), whereas ketamine only reduced the alfaxalone induction dose (30%; p = 0.010). Recovery quality was unacceptable in nine dogs in group A, three dogs in group AK and three dogs in group AM.Conclusions and clinical relevanceMidazolam, but not ketamine, reduced the alfaxalone infusion rate, and both co-adjuvant drugs reduced the alfaxalone induction dose. Alfaxalone TIVA allowed anaesthetic maintenance for dental procedures in dogs, but the quality of anaesthetic recovery remained unacceptable irrespective of its combination with ketamine or midazolam.     

Pharmacokinetics of midazolam in sevoflurane-anesthetized cats

ObjectiveTo estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.Study designProspective pharmacokinetic study.AnimalsA group of six healthy adult, female domestic cats.MethodsAnesthesia 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 (f_R), 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.ResultsThe 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, f_R or Pe′CO₂ were observed following midazolam administration.Conclusion and clinical relevanceIn 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.     

Sedative-hypnotic effects of midazolam in goats after intravenous and intramuscular administration

Objective To examine the effect of dose and route of administration on the sedative‐hypnotic effects of midazolam. Design Prospective randomized controlled study Animals Six indigenous, African bred goats. Methods Pilot studies indicated that the optimum dose of midazolam for producing sedation was 0.6 mg kg^?1 for intramuscular (IM) injection, while the optimum intravenous (IV) doses causing hypnosis without, and with loss of palpebral reflexes were 0.6 mg kg^?1 and 1.2 mg kg^?1, respectively. These doses and routes of administration were compared with a saline placebo in a randomized block design in the main experiment, and the sedative‐hypnotic effects evaluated according to pre‐determined scales. Results Intramuscular midazolam produced sedation with or without sternal recumbency in all animals with the peak effect occurring 20 minutes after administration. The scores for IM sedation with midazolam were significantly different (p < 0.05) from placebo. Intravenous midazolam at 0.6 mg kg^?1 resulted in hypnosis, and at 1.2 mg kg^?1 increased reflex suppression was observed. The maximum scores for hypnosis at both doses were obtained 5 minutes after IV injection. The mean (± SD) duration of lateral recumbency was 10.8 (± 3.8) minutes after IV midazolam (0.6 mg kg^?1) compared to 20 (± 5.2) minutes after midazolam at 1.2 mg kg^?1. Compared to baseline, the heart rate increased significantly (p < 0.05) after high dose IV midazolam. Conclusion Intramuscular midazolam (0.6 mg kg^?1) produced maximum sedation 20 minutes after injection. Intravenous injection produced maximum hypnosis within 5 minutes. Increasing the IV dose from 0.6 to 1.2 mg kg^?1 resulted in increased reflex suppression and duration of hypnosis. Clinical relevance For a profound effect with rapid onset midazolam should be given IV in doses between 0.6 and 1.2 mg kg^?1.     

Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats

OBJECTIVE: To describe the pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide (MEGX), after i.v. administration of a single bolus of lidocaine in cats that were awake in phase 1 and anesthetized with isoflurane in phase 2 of the study. ANIMALS: 8 healthy adult cats. PROCEDURE: During phase 1, cats were administered lidocaine (2 mg/kg, i.v.) as a bolus injection (time 0). During phase 2, cats were anesthetized with isoflurane and maintained at 0.75 times the minimum alveolar concentration of isoflurane for each specific cat. After a 15-minute equilibration period, lidocaine (2 mg/kg, i.v.) was administered as a bolus injection to each cat (time 0). In both phases, plasma concentrations of lidocaine and MEGX were measured at various time points by use of liquid chromatography-mass spectrometry. RESULTS: Anesthesia with isoflurane significantly decreased the volume of the central compartment, clearance, and elimination half-life of lidocaine and significantly increased the extrapolated plasma drug concentration at time 0, compared with values for awake cats. Pharmacokinetics of MEGX were also changed by isoflurane-induced anesthesia because the maximum observed plasma concentration (C(max)), area under the concentration-time curve extrapolated to infinity, and time to C(max) were significantly higher in anesthetized cats, compared with values for awake cats. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics of lidocaine and MEGX were substantially altered in cats anesthetized by use of isoflurane. When pharmacokinetic variables are used to determine loading and infusion doses in awake or anesthetized cats, they should be measured in cats that are awake or anesthetized, respectively.