Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats

Zonca, A., Ravasio, G., Gallo, M., Montesissa, C., Carli, S., Villa, R., Cagnardi, P. Pharmacokinetics of ketamine and propofol combination administered as ketofol via continuous infusion in cats. J. vet. Pharmacol. Therap.  35 , 580–587. The pharmacokinetics of the extemporaneous combination of low doses of ketamine and propofol, known as ‘ketofol’, frequently used for emergency procedures in humans to achieve safe sedation and analgesia was studied in cats. The study was performed to assess propofol, ketamine and norketamine kinetics in six female cats that received ketamine and propofol (1:1 ratio) as a loading dose (2 mg/kg each, IV) followed by a continuous infusion (10 mg/kg/h each, IV, 25 min of length). Blood samples were collected during the infusion period and up to 24 h afterwards. Drug quantification was achieved by HPLC analysis using UV‐visible detection for ketamine and fluorimetric detection for propofol. The pharmacokinetic parameters were deduced by a two‐compartment bolus plus infusion model for propofol and ketamine and a monocompartmental model for norketamine. Additional data were derived by a noncompartmental analysis. Propofol and ketamine were quantifiable in most animals until 24 and 8 h after the end of infusion, respectively. Propofol showed a long elimination half‐life (t_1/2λ2 7.55 ± 9.86 h), whereas ketamine was characterized by shorter half‐life (t_1/2λ2 4 ± 3.4 h) owing to its rapid biotransformation into norketamine. The clinical significance of propofol’s long elimination half‐life and low clearance is negligible when the drug is administered as short‐term and low‐dosage infusion. The concurrent administration of ketamine and propofol in cats did not produce adverse effects although it was not possible to exclude interference in the metabolism.     

Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fuscata fuscata). [corrected

ObjectiveTo describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model.Study designProspective experimental trial.AnimalsFour male macaques (5-6 years old, 8.0-11.2 kg).MethodsThe macaque was restrained and 8 mg kg^?1 of propofol was administrated intravenously at 6 mg kg^?1 minute^?1. Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI.ResultsMacaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5) minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute^?1 and 72-144 beats minute^?1, respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V₁ = 10.4 L, V₂=8.38 L, V₃=72.7 L, CL₁= 0.442 L minute^?1, CL₂= 1.14 L minute^?1, CL₃= 0.313 L minute^?1, (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively).ConclusionsIntravenous administration of propofol (8 mg kg^?1) at 6 mg kg^?1 minute^?1 to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours.Clinical relevanceThe developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.     

Real time monitoring of propofol blood concentration in ponies anaesthetized with propofol and ketamine

This study examined the pharmacokinetics of propofol by infusion in ponies using an analyser for the rapid measurement of propofol concentrations. The analyser (Pelorus 1000; Sphere Medical Ltd., Cambridge, UK) has a measurement cycle of approximately five minutes. Ten Welsh‐cross ponies (weighing 135–300 kg) undergoing minor procedures were studied after premedication with acepromazine 0.03 mg/kg and detomidine 0.015 mg/kg. Anaesthesia was induced with ketamine 2 mg/kg and diazepam 0.03 mg/kg, and maintained with an infusion of propofol at an initial rate of 0.16 mg/kg/min for the first thirty minutes, after a bolus of 0.3 mg/kg; and ketamine by infusion (20–40 μg/kg/min). Blood samples (<2 mL) were collected prior to, during and after the infusion, and on assuming standing position. Anaesthesia was uneventful; with the duration of infusion 31–89 min. Blood propofol concentrations during the infusion ranged between 1.52 and 7.65 μg/mL; pseudo‐steady state concentrations 3.64–6.78 μg/mL, and concentrations on assuming standing position 0.75–1.40 μg/mL. Propofol clearance and volume of distribution were 31.4 (SD 6.1) mL/min/kg and 220.7 (132.0) mL/kg, respectively. The propofol analyser allows titration of propofol to a given concentration; and may be useful for anaesthesia in animals where kinetics are unknown; in disease states; and where intercurrent therapies affect propofol disposition.     

The minimum infusion rate (MIR) of propofol for total intravenous anesthesia after premedication with xylazine in horses

To investigate an adequate infusion rate of propofol for total intravenous anesthesia (TIVA) in horses, the minimum infusion rate (MIR) comparable to the minimum alveolar anesthetic concentration (MAC) of inhalation anesthetic was determined under constant ventilation condition by intermittent positive pressure ventilation (IPPV). In addition, arterial propofol concentration was measured to determine the concentration corresponding to the MIR (concentration preventing reaction to stimulus in 50% of population, Cp(50)). Further, 95% effective dose (ED(95)) was estimated as infusion rate for acquiring adequate anesthetic depth. Anesthetic depth was judged by the gross purposeful movement response to painful stimulus. MIR and Cp(50) were 0.10 +/- 0.02 mg/kg/min and 5.3 +/- 1.4 microg/ml, respectively. ED(95) was estimated as 0.14 mg/kg/min (1.4MIR).     

Evaluation of total intravenous anesthesia with propofol or ketamine-medetomidine-propofol combination in horses

Objective-To compare the anesthetic and cardiorespiratory effects of total IV anesthesia with propofol (P-TIVA) or a ketamine-medetomidine-propofol combination (KMP-TIVA) in horses. Design-Randomized experimental trial. Animals-12 horses. Procedure-Horses received medetomidine (0.005 mg/kg [0.002 mg/lb], IV). Anesthesia was induced with midazolam (0.04 mg/kg [0.018 mg/lb], IV) and ketamine (2.5 mg/kg [1.14 mg/lb], IV). All horses received a loading dose of propofol (0.5 mg/kg [0.23 mg/lb], IV), and 6 horses underwent P-TIVA (propofol infusion). Six horses underwent KMP-TIVA (ketamine [1 mg/kg/h {0.45 mg/lb/h}] and medetomidine [0.00125 mg/kg/h {0.0006 mg/lb/h}] infusion; the rate of propofol infusion was adjusted to maintain anesthesia). Arterial blood pressure and heart rate were monitored. Qualities of anesthetic induction, transition to TIVA, and maintenance of and recovery from anesthesia were evaluated. Results-Administration of KMP IV provided satisfactory anesthesia in horses. Compared with the P-TIVA group, the propofol infusion rate was significantly less in horses undergoing KMP-TIVA (0.14 +/- 0.02 mg/kg/min [0.064 +/- 0.009 mg/lb/min] vs 0.22 +/- 0.03 mg/kg/min [0.1 +/- 0.014 mg/lb/min]). In the KMP-TIVA and P-TIVA groups, anesthesia time was 115 +/- 17 minutes and 112 +/- 11 minutes, respectively, and heart rate and arterial blood pressure were maintained within acceptable limits. There was no significant difference in time to standing after cessation of anesthesia between groups. Recovery from KMP-TIVA and P-TIVA was considered good and satisfactory, respectively. Conclusions and Clinical Relevance-In horses, KMP-TIVA and P-TIVA provided clinically useful anesthesia; the ketamine-medetomidine infusion provided a sparing effect on propofol requirement for maintaining anesthesia.     

Disposition of propofol after medetomidine premedication in beagle dogs

Propofol by infusion was administered to 6 adult beagle dogs on 2 separate occasions. The dogs received either no premedication or 20 μg/kg im medetomidine 15 min before induction of anaesthesia, with propofol given at 7 mg/kg/min to permit tracheal intubation. After tracheal intubation the infusion rate was maintained for 120 min at 0.4 mg/kg/min in the non-premedicated, and 0.2 mg/kg/min in the premedicated dogs. The latter group received atipamezole 50 μg/kg im immediately at the end of the infusion. After induction of anaesthesia, a 7F balloon catheter designed for thermal dilution measurement of cardiac output was inserted via the right jugular vein. Blood propofol concentrations were measured by HPLC with fluorescence detection and kinetic variables calculated using non-compartmental moment analysis. The induction dose of propofol was 7.00 (sem 0.55) mg/kg in non-premedicated compared with 3.09 (0.25) mg/kg in premedicated dogs. There were differences in systemic clearance and mean residence time (MRT_iv); 47.5 (6.2) ml/kg/min vs 29.0 (4.4) ml/kg/min (non-premedicated vs premedicated) and 132.3 (5.2) min vs 152.4 (3.1) min (P < 0.02 and P < 0.001, respectively). Cardiorespiratory effects were similar in the 2 groups although heart rate was lower in the premedicated dogs. Venous admixture was high (20–45%) but similar in the 2 groups.     

Anaesthetic and cardiorespiratory effects of propofol at 10% for induction and 1% for maintenance of anaesthesia in horses

Reasons for performing study: Studies have demonstrated the clinical usefulness of propofol for anaesthesia in horses but the use of a concentrated solution requires further investigation. Objectives: To determine the anaesthetic and cardiorespiratory responses to a bolus injection of 10% propofol solution in mature horses. Methods: Three randomised crossover experimental trials were completed. Trial 1: 6 horses were selected randomly to receive 10% propofol (2, 4 or 8 mg/kg bwt i.v.). Trial 2: 6 horses received 1.1 mg/kg bwt i.v. xylazine before being assigned at random to receive one of 5 different doses (1–5 mg/kg bwt) of 10% propofol. Trial 3: 6 horses were sedated with xylazine (0.5 mg/kg bwt, i.v.) and assigned randomly to receive 10% propofol (3, 4 or 5 mg/kg bwt, i.v.); anaesthesia was maintained for 60 min using an infusion of 1% propofol (0.2‐0.4 mg/kg bwt/min). Cardiorespiratory data, the quality of anaesthesia, and times for induction, maintenance and recovery from anaesthesia and the number of attempts to stand were recorded. Results: Trial 1 was terminated after 2 horses had received each dose of 10% propofol. The quality of induction, anaesthesia and recovery from anaesthesia was judged to be unsatisfactory. Trial 2: 3 horses administered 1 mg/kg bwt and one administered 2 mg/kg bwt were not considered to be anaesthetised. Horses administered 3–5 mg/kg bwt i.v. propofol were anaesthetised for periods ranging from approximately 10–25 min. The PaO₂ was significantly decreased in horses administered 3–5 mg/kg bwt i.v. propofol. Trial 3: The quality of induction and recovery from anaesthesia were judged to be acceptable in all horses. Heart rate and rhythm, and arterial blood pressure were unchanged or decreased slightly during propofol infusion period. Conclusions: Anaesthesia can be induced with a 10% propofol solution and maintained with a 1% propofol solution in horses administered xylazine as preanaesthetic medication. Hypoventilation and hypoxaemia may occur following administration to mature horses. Potential relevance: Adequate preanaesthetic sedation and oxygen supplementation are required in horses anaesthetised with propofol.     

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.     

Total intravenous anaesthesia in the horse with propofol

The use of propofol, solubilised in a non-ionic emulsifying agent, for the induction and maintenance of anaesthesia in experimental ponies was assessed. Pilot studies revealed that premedication with xylazine (0.5 mg/kg bodyweight [bwt]) intravenously (iv) followed by propofol (2.0 mg/kg bwt) iv provided a satisfactory smooth induction. Two infusion rates (0.15 mg/kg bwt/min and 0.2 mg/kg bwt/min) were compared for maintenance of anaesthesia. An infusion rate of 0.2 mg/kg/min produced adequate anaesthesia in these ponies. Cardiovascular changes included a decrease in arterial pressure and cardiac output during maintenance. Respiratory depression was manifested by a decrease in rate and an increase in arterial carbon dioxide tension. Recovery after 1 h anaesthesia was rapid and smooth. In conclusion, induction and maintenance of anaesthesia with propofol in premedicated ponies proved a satisfactory technique.     

Pharmacokinetics of tramadol following intravenous and oral administration in male rhesus macaques (Macaca mulatta)

Recently, tramadol and its active metabolite, O‐desmethyltramadol (M1), have been studied as analgesic agents in various traditional veterinary species (e.g., dogs, cats, etc.). This study explores the pharmacokinetics of tramadol and M1 after intravenous (IV) and oral (PO) administration in rhesus macaques (Macaca mulatta), a nontraditional veterinary species. Rhesus macaques are Old World monkeys that are commonly used in biomedical research. Effects of tramadol administration to monkeys are unknown, and research veterinarians may avoid inclusion of this drug into pain management programs due to this limited knowledge. Four healthy, socially housed, adult male rhesus macaques (Macaca mulatta) were used in this study. Blood samples were collected prior to, and up to 10 h post‐tramadol administration. Serum tramadol and M1 were analyzed using liquid chromatography–mass spectrometry. Noncompartmental pharmacokinetic analysis was performed. Tramadol clearance was 24.5 (23.4–32.7) mL/min/kg. Terminal half‐life of tramadol was 111 (106–127) min IV and 133 (84.9–198) min PO. Bioavailability of tramadol was poor [3.47% (2.14–5.96%)]. Maximum serum concentration of M1 was 2.28 (1.88–2.73) ng/mL IV and 11.2 (9.37–14.9) ng/mL PO. Sedation and pruritus were observed after IV administration.     

Pharmacokinetic properties of toceranib phosphate (Palladia™, SU11654), a novel tyrosine kinase inhibitor,in laboratory dogs and dogs with mast cell tumors

Yancey, M. F., Merritt, D. A., Lesman, S. P., Boucher, J. F., Michels, G. M. Pharmacokinetic properties of toceranib phosphate (Palladia?, SU11654), a novel tyrosine kinase inhibitor, in laboratory dogs and dogs with mast cell tumors. J. vet. Pharmacol. Therap. 33 , 162–171. Toceranib phosphate (Palladia?, SU11654), an oral tyrosine‐kinase inhibitor, is under investigation for the treatment of mast cell tumors in dogs. The pharmacokinetics of toceranib phosphate has been characterized in dogs. Means of the following pharmacokinetic parameters were estimated following a 1.0 mg/kg i.v. dose to laboratory beagles: plasma clearance of 1.45 L/kg/h, volume of distribution of 29.7 L/kg, and terminal half‐life of 17.7 h. Following single oral doses of 3.25 mg/kg administered to laboratory beagles, mean C_max estimates ranged from 68.6 ng/mL to 112 ng/mL with t_max ranging from 5.3 h and 9.3 h postdose. Terminal half‐life was estimated at 31 h. Oral bioavailability was 76.9%. There were no statistically significant (P > 0.05) differences with any pharmacokinetic parameter due to fed/fasted state or with time during 13 weeks of every‐other‐day dosing at 3.25 mg/kg. Toceranib concentrations were proportional with dose over the range of 2.0 to 6.0 mg/kg. The pharmacokinetics of toceranib in client‐owned dogs of a variety of pure and mixed breeds with mast cell tumors was similar to that in healthy laboratory dogs. In summary, toceranib phosphate exhibited moderate clearance, a high volume of distribution, and a moderate elimination half‐life. After a single oral dose at 3.25 mg/kg, the concentration vs. time curve showed broad, sustained exposure with measurable concentrations for more than 48 h. These pharmacokinetic parameters support every‐other‐day administration of toceranib phosphate at an initial dose of 3.25 mg/kg for the treatment of mast cell tumors in dogs.     

Effect of variable-dose propofol alone and in combination with two fixed doses of ketamine for total intravenous anesthesia in cats

OBJECTIVE: To determine the minimum infusion rate (MIR50) for propofol alone and in combination with ketamine required to attenuate reflexes commonly used in the assessment of anesthetic depth in cats. ANIMALS: 6 cats. PROCEDURE: Propofol infusion started at 0.05 to 0.1 mg/kg/min for propofol alone or 0.025 mg/kg/min for propofol and ketamine (low-dose ILD] constant rate infusion [CRI] of 23 microg/kg/min or high-dose [HD] CRI of 46 microg/kg/min), and after 15 minutes, responses of different reflexes were tested. Following a response, the propofol dose was increased by 0.05 mg/kg/min for propofol alone or 0.025 mg/kg/min for propofol and ketamine, and after 15 minutes, reflexes were retested. RESULTS: The MIR50 for propofol alone required to attenuate blinking in response to touching the medial canthus or eyelashes; swallowing in response to placement of a finger or laryngoscope in the pharynx; and to toe pinch, tetanus, and tail-clamp stimuli were determined. Addition of LD ketamine to propofol significantly decreased MIR50, compared with propofol alone, for medial canthus, eyelash, finger, toe pinch, and tetanus stimuli but did not change those for laryngoscope or tail-clamp stimuli. Addition of HD ketamine to propofol significantly decreased MIR50, compared with propofol alone, for medial canthus, eyelash, toe pinch, tetanus, and tail-clamp stimuli but did not change finger or laryngoscope responses. CONCLUSIONS AND CLINICAL RELEVANCE: Propofol alone or combined with ketamine may be used for total IV anesthesia in healthy cats at the infusion rates determined in this study for attenuation of specific reflex activity.     

Cardiovascular Effects of a Continuous Two-Hour Propofol Infusion in Dogs Comparison With Isoflurane Anesthesia

The cardiovascular effects during 2 hours of anesthesia with either a continuous propofol infusion or isoflurane were compared in the same six healthy dogs. Dogs were randomly assigned to be anesthetized with either propofol (5 mg/kg, IV administered over 30 seconds, immediately followed by a propofol infusion beginning at 0.4 mg/kg/min), or isoflurane (2.0% end-tidal concentration). The propofol infusion was adjusted to maintain a light plane of anesthesia. Dogs anesthetized with propofol had higher values for systemic arterial pressure due to higher systemic vascular resistance. Dogs anesthetized with isoflurane had higher values for heart rate and mean pulmonary artery pressure. Cardiac index was not different between the two groups. Apnea and cyanosis were observed during induction of anesthesia with propofol. At the end of anesthesia the mean time to extubation for dogs anesthetized with either propofol or isoflurane was 13.5 min and 12.7 min, respectively. A continuous infusion of propofol (0.44 mg/kg/min) provided a light plane of anesthesia. Ventilatory support during continuous propofol infusion is recommended.     

Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals

Hewson, J., Johnson, R., Arroyo, L. G., Diaz‐Mendez, A., Ruiz‐López, J. A., Gu, Y., del Castillo, J. R. E. Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals. J. vet. Pharmacol. Therap.  36 , 68–77. Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg IV q6h for 12 doses; n = 10) or by infusion (loading dose of 40 mg/kg IV followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n = 5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 μg/mL and minimum drug concentration (C_min) was 0.78 μg/mL at 6‐h postadministration (immediately before each next dose), whereas infusion resulted in a steady‐state concentration of 16.10 μg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P = 0.051) in the infusion group (5.02 μg/mL) compared to the bolus group (0.78 μg/mL). Drug concentration in CSF at 72 h was not different between groups (P = 0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.     

Pharmacokinetics of buprenorphine following intravenous and intramuscular administration in male rhesus macaques (Macaca mulatta)

This study reports the pharmacokinetics of buprenorphine in conscious rhesus macaques (Macaca mulatta) after intravenous (i.v.) and intramuscular (i.m.) administration. Four healthy, opioid‐naïve, socially housed, adult male macaques were used. Buprenorphine (0.03 mg/kg) was administered intravenously as a bolus or intramuscularly on separate occasions. Blood samples were collected prior to, and up to 24 h, postadministration. Serum buprenorphine concentrations were analyzed with liquid chromatography–mass spectrometry. Noncompartmental pharmacokinetic analysis was performed with commercially available software. Mean residence time in the i.v. study as compared to the i.m. study was 177 (159–189) vs. 185 (174–214) min, respectively [median (range)]. In the i.v. study, concentration back‐extrapolated to time zero was found to be 33.0 (16.8–57.0) ng/mL [median (range)]. On the other hand, the maximum serum concentration found in the i.m. study was 11.8 (6.30–14.8) ng/mL [median (range)]. Rhesus macaques maintained concentrations >0.10 ng/mL for over 24 h in the i.v. study and over 12 h in the i.m. study. Bioavailability was found to be 68.1 (59.3–71.2)% [median (range)]. No significant adverse effects were observed in the monkeys at the 0.03 mg/kg dose of buprenorphine during either study.     

Pharmacokinetics and effects on clinical and physiological parameters following a single bolus dose of propofol in common marmosets (Callithrix jacchus)

The objectives of this study were (a) to establish a population pharmacokinetic model and (b) to investigate the clinical and physiological effects of a single bolus dose of propofol in common marmosets. In Study 1, pharmacokinetic analysis was performed in six marmosets under sevoflurane anaesthesia. 8 mg/kg of propofol was administrated at a rate of 4 mg kg^?1 min^?1. Blood samples were collected 2, 5, 15, 30, 60, 90, 120 or 180 min after starting propofol administration. Plasma concentration was measured, and population pharmacokinetic modelling was performed. A two‐compartment model was selected as the final model. The population pharmacokinetic parameters were as follows: V₁ = 1.14 L, V₂ = 77.6 L, CL₁ = 0.00182 L/min, CL₂ = 0.0461 L/min. In Study 2, clinical and physiological parameters were assessed and recorded every 2 min after 12 mg/kg of propofol was administrated at a rate of 4 mg kg^?1 min^?1. Immobilization was sustained for 5 min following propofol administration without apparent bradycardia. While combination of propofol and sevoflurane caused apnoea in Study 1, apnoea was not observed following single administration of propofol in Study 2. These data provide bases for further investigation on intravenous anaesthesia using propofol in common marmosets.     

Pharmacokinetic and pharmacodynamic evaluation of propofol administered to cats in a novel,aqueous, nano‐droplet formulation or as an oil‐in‐water macroemulsion1

This study evaluated pharmacokinetic and pharmacologic properties of a novel, non‐lipid microemulsion, 1% w/v formulation of propofol to a conventional macroemulsion formulation of propofol (Rapinovet^®) in cats. The study utilized a two‐period crossover design with two treatments and 10 female, intact, purpose bred domestic shorthair cats. Cats were fitted with telemetry transmitters for direct measurement of arterial blood pressure, pulse rate, electrocardiogram (ECG, lead II), and body temperature. At least 7 days separated treatments. Orotracheal intubation was the clinical endpoint utilized to evaluate adequate depth of anesthesia. Blood samples were drawn from jugular vascular access ports before propofol treatment; 3, 5, 15, 25, 35, 45, and 60 min and then 2, 3, 6, 8, 12, 18, and 24 h after administration of propofol into a cephalic vein. Whole blood samples were assayed for propofol concentrations using a gas chromatography/mass spectrometry method validated for feline blood at a limit of quantification of 5 ng/mL. Pulse rate, ECG, heart rhythm, respiratory rate, systolic, diastolic and mean arterial blood pressures, SpO₂, and body temperature were monitored continuously during each anesthetic episode. Time to lateral recumbency, orotracheal intubation, and extubation, time to sternal recumbency during recovery, times to adverse events, and doses of propofol required for induction to anesthesia were documented. Cats required 6.96 ± 0.90 mg propofol/kg from the novel microemulsion formulation of propofol and 7.07 ± 1.55 mg propofol/kg from Rapinovet^® to achieve anesthesia adequate to allow orotracheal intubation (P > 0.05). Areas under the dose‐normalized propofol concentration by time curves (AUC_0‐LOQ) and maximum propofol concentrations (C_max) were equal for the novel microemulsion formulation of propofol and Rapinovet^® (P > 0.05). Effects of anesthesia induction doses on cardiorespiratory values were comparable between treatments, and consistent with known effects of propofol anesthesia. Results provide evidence that the novel microemulsion formulation of propofol and Rapinovet^® macroemulsion produced comparable pharmacodynamic, physiological, and pharmacokinetic responses in cats. The unique composition of the microemulsion formulation, and the presence of an antimicrobial preservative minimize the potential for bacterial contamination and prolong shelf life.     

The pharmacokinetics of dexmedetomidine administered as a constant rate infusion in horses

Dexmedetomidine, the most selective α₂‐adrenoceptor agonist in clinical use, is increasingly being used in both conscious and anaesthetized horses; however, the pharmacokinetics and sedative effects of this drug administered alone as an infusion are not previously described in horses. Seven horses received an infusion of 8 μg dexmedetomidine/kg/h for 150 min, venous blood samples were collected, and dexmedetomidine concentrations were assayed using liquid chromatography‐mass spectrometry (LC/MS) and analyzed using noncompartmental pharmacokinetic analysis. Sedation was scored as the distance from the lower lip of the horse to the ground measured in centimetre. The harmonic mean (SD) plasma elimination half‐life (Lambda z half‐life) for dexmedetomidine was 20.9 (5.1) min, clearance (Cl) was 0.3 (0.20) L/min/kg, and volume of distribution at steady‐state (Vd_ss) was 13.7 (7.9) L/kg. There was a considerable individual variation in the concentration of dexmedetomidine vs. time profile. The level of sedation covaried with the plasma concentration of dexmedetomidine. This implies that for clinical use of dexmedetomidine constant rate infusion in conscious horses, infusion rates can be easily adjusted to effect, and this is preferable to an infusion at a predetermined value.     

Evaluation of cardiovascular effects of total intravenous anesthesia with propofol or a combination of ketamine-medetomidine-propofol in horses

OBJECTIVE: To evaluate the cardiovascular effects of total IV anesthesia with propofol (P-TIVA) or ketamine-medetomidine-propofol (KMP-TIVA) in horses. ANIMALS: 5 Thoroughbreds. PROCEDURES: Horses were anesthetized twice for 4 hours, once with P-TIVA and once with KMP-TIVA. Horses were medicated with medetomidine (0.005 mg/kg, IV) and anesthetized with ketamine (2.5 mg/kg, IV) and midazolam (0.04 mg/kg, IV). After receiving a loading dose of propofol (0.5 mg/kg, IV), anesthesia was maintained with a constant rate infusion of propofol (0.22 mg/kg/min) for P-TIVA or with a constant rate infusion of propofol (0.14 mg/kg/min), ketamine (1 mg/kg/h), and medetomidine (0.00125 mg/kg/h) for KMP-TIVA. Ventilation was artificially controlled throughout anesthesia. Cardiovascular measurements were determined before medication and every 30 minutes during anesthesia, and recovery from anesthesia was scored. RESULTS: Cardiovascular function was maintained within acceptable limits during P-TIVA and KMP-TIVA. Heart rate ranged from 30 to 40 beats/min, and mean arterial blood pressure was > 90 mm Hg in all horses during anesthesia. Heart rate was lower in horses anesthetized with KMP-TIVA, compared with P-TIVA. Cardiac index decreased significantly, reaching minimum values (65% of baseline values) at 90 minutes during KMP-TIVA, whereas cardiac index was maintained between 80% and 90% of baseline values during P-TIVA. Stroke volume and systemic vascular resistance were similarly maintained during both methods of anesthesia. With P-TIVA, some spontaneous limb movements occurred, whereas with KMP-TIVA, no movements were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiovascular measurements remained within acceptable values in artificially ventilated horses during P-TIVA or KMP-TIVA. Decreased cardiac output associated with KMP-TIVA was primarily the result of decreases in heart rate.     

Comparison of the cardiopulmonary effects of anesthesia maintained by continuous infusion of ketamine and propofol with anesthesia maintained by inhalation of sevoflurane in goats undergoing magnetic resonance imaging

OBJECTIVE: To compare the cardiopulmonary effects of anesthesia maintained by continuous infusion of ketamine and propofol with anesthesia maintained by inhalation of sevoflurane in goats undergoing magnetic resonance imaging. ANIMALS: 8 Saanen goats. PROCEDURES: Goats were anesthetized twice (1-month interval) following sedation with midazolam (0.4 mg/kg, IV). Anesthesia was induced via IV administration of ketamine (3 mg/kg) and propofol (1 mg/kg) and maintained with an IV infusion of ketamine (0.03 mg/kg/min) and propofol (0.3 mg/kg/min) and 100% inspired oxygen (K-P treatment) or induced via IV administration of propofol (4 mg/kg) and maintained via inhalation of sevoflurane in oxygen (end-expired concentration, 2.3%; 1X minimum alveolar concentration; SEVO treatment). Cardiopulmonary and blood gas variables were assessed at intervals after induction of anesthesia. RESULTS: Mean +/- SD end-expired sevoflurane was 2.24 +/- 0.2%; ketamine and propofol were infused at rates of 0.03 +/- 0.002 mg/kg/min and 0.29 +/- 0.02 mg/kg/min, respectively. Overall, administration of ketamine and propofol for total IV anesthesia was associated with a degree of immobility and effects on cardiopulmonary parameters that were comparable to those associated with anesthesia maintained by inhalation of sevoflurane. Compared with the K-P treatment group, mean and diastolic blood pressure values in the SEVO treatment group were significantly lower at most or all time points after induction of anesthesia. After both treatments, recovery from anesthesia was good or excellent. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that ketamine-propofol total IV anesthesia in goats breathing 100% oxygen is practical and safe for performance of magnetic resonance imaging procedures.