Pharmacokinetics of ketamine following a short intravenous infusion to isoflurane-anesthetized New Zealand White rabbits (Oryctolagus cuniculus)

ObjectiveTo describe the pharmacokinetics of ketamine following a short intravenous (IV) infusion to isoflurane-anesthetized rabbits.Study designProspective experimental study.AnimalsA total of six adult healthy female New Zealand White rabbits.MethodsAnesthesia was induced with isoflurane in oxygen. Following determination of isoflurane minimum alveolar concentration (MAC), the isoflurane concentration was reduced to 0.75 MAC and ketamine hydrochloride (5 mg kg^–1) was administered IV over 5 minutes. Blood samples were collected before and at 2, 5, 6, 7, 8, 9, 13, 17, 21, 35, 65, 125, 215 and 305 minutes after initiating the ketamine infusion. Samples were processed immediately and the plasma separated and stored at –80 °C until analyzed for ketamine and norketamine concentrations using liquid chromatography–mass spectrometry. Compartment models were fitted to the concentration–time data for ketamine and for ketamine plus norketamine using nonlinear mixed-effects (population) modeling.ResultsA three- and five-compartment model best fitted the plasma concentration–time data for ketamine and for ketamine plus norketamine, respectively. For the ketamine only model, the volume of distribution at steady state (Vss) was 3217 mL kg^–1, metabolic clearance was 88 mL minute^–1 kg^–1 and the terminal half-life was 59 minutes. For the model including both ketamine and norketamine, Vss were 3224 and 2073 mL kg^–1, total metabolic clearance was 107 and 52 mL minute^–1 kg^–1 and terminal half-lives were 52 and 55 minutes for the parent drug and its metabolite, respectively.Conclusions and clinical relevanceThis study characterized the pharmacokinetics of ketamine and norketamine in isoflurane-anesthetized New Zealand White rabbits following short IV infusion. The results obtained herein will be useful to determine ketamine infusion regimens in isoflurane-anesthetized rabbits.     

Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats

ObjectiveTo characterize the hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats.Study designProspective experimental study.AnimalsSix healthy adult female cats weighing 4.6 ± 0.8 kg.MethodsDexmedetomidine was administered intravenously using target-controlled infusions to maintain nine plasma concentrations between 0 and 20 ng mL^?1 in isoflurane-anesthetized cats. The isoflurane concentration was adjusted for each dexmedetomidine concentration to maintain the equivalent of 1.25 times the minimum alveolar concentration, based on a previous study. Heart rate, systemic and pulmonary arterial pressures, central venous pressure, pulmonary artery occlusion pressure, body temperature, and cardiac output were measured at each target plasma dexmedetomidine concentration. Additional variables were calculated. Arterial and mixed-venous blood samples were collected for blood gas, pH, and (on arterial blood only) electrolyte, glucose and lactate analysis. Plasma dexmedetomidine concentration was determined for each target. Pharmacodynamic models were fitted to the data.ResultsHeart rate, arterial pH, arterial bicarbonate concentration, mixed-venous PO₂, mixed-venous pH, mixed-venous hemoglobin oxygen saturation, cardiac index, stroke index, and venous admixture decreased following dexmedetomidine administration. Arterial blood pressure, central venous pressure, pulmonary arterial pressure, pulmonary arterial occlusion pressure, packed cell volume, PaO₂, PaCO₂, arterial hemoglobin concentration, mixed-venous PCO₂, mixed-venous hemoglobin concentration, ionized calcium concentration, glucose concentration, rate-pressure product, systemic and pulmonary vascular resistance indices, left ventricular stroke work index, arterial oxygen concentration, and oxygen extraction increased following dexmedetomidine administration. Most variables changed in a dexmedetomidine concentration-dependent manner.Conclusion and clinical relevanceThe use of dexmedetomidine as an anesthetic adjunct is expected to produce greater negative hemodynamic effects than a higher, equipotent concentration of isoflurane alone.     

Cardiovascular effects of increasing dosages of norepinephrine in healthy isoflurane-anesthetized New Zealand White rabbits

ObjectiveTo characterize the cardiovascular effects of increasing dosages of norepinephrine (NE) in healthy isoflurane-anesthetized rabbits.Study designProspective experimental study.AnimalsA total of nine female ovariohysterectomized New Zealand White rabbits weighing 3.4 ± 0.2 kg (mean ± standard deviation).MethodsRabbits were premedicated intramuscularly with buprenorphine (0.05 mg kg^–1) and midazolam (0.5 mg kg^–1). Anesthesia was induced with intravenous propofol and maintained with a 1.1 × minimum alveolar concentration of isoflurane for this species to induce hypotension. Rabbits were administered NE infusions at three doses: low, 0.1 μg kg^–1 minute^–1; medium, 0.5 μg kg^–1 minute^–1; and high doses, 1 μg kg^–1 minute^–1 for 10 minutes each in that order. Cardiovascular variables including heart rate (HR), cardiac output (CO) by lithium dilution technique and systolic (SAP), mean (MAP) and diastolic (DAP) invasive arterial blood pressures measured in the auricular artery were recorded at baseline, 10 minutes after the start of the infusion of each NE treatment and 10 minutes after NE was discontinued. A linear mixed model and a type III anova with Tukey’s post hoc comparison was performed (p < 0.05).ResultsSignificant increases in SAP (28% and 90%), MAP (27% and 90%) and DAP (33% and 97%) were measured with medium and high dose treatments, respectively (p < 0.001), with no changes in CO. HR decreased and stroke volume increased significantly with high dose treatment (by 17% and 15%, respectively; p < 0.05). No arrhythmias were noticed with NE treatments.Conclusions and clinical relevanceThe infusion of NE at 0.5–1.0 μg kg^–1 minute^–1 is a potentially effective treatment for hypotension in healthy isoflurane-anesthetized New Zealand White rabbits.     

Evaluation of alfaxalone total intravenous anesthesia in rabbits (Oryctolagus cuniculus) premedicated with dexmedetomidine or dexmedetomidine and buprenorphine

ObjectiveTo evaluate alfaxalone for total intravenous anesthesia (TIVA) in rabbits premedicated with dexmedetomidine or dexmedetomidine and buprenorphine.Study designCrossover study (part 1) with observational study (part 2).AnimalsA total of eight New Zealand White rabbits (Oryctolagus cuniculus), four female and four male, aged 12–16 weeks and weighing 2.8–3.5 kg in part 1. Separately, four additional rabbits in part 2.MethodsCrossover study design with eight rabbits per treatment. Rabbits were administered treatment D, dexmedetomidine (0.2 mg kg^–1), or treatment DB, dexmedetomidine (0.1 mg kg^–1) and buprenorphine (0.05 mg kg^–1) intramuscularly. Anesthesia was induced with alfaxalone intravenously until a supraglottic airway device was placed to deliver 100% oxygen. Anesthesia was maintained with alfaxalone (TIVA). Infusion rates were adjusted to achieve an absent pedal withdrawal reflex. Heart rate, respiratory rate, noninvasive blood pressure, end-tidal carbon dioxide partial pressure and peripheral hemoglobin oxygen saturation (SpO₂) were recorded every 5 minutes. Subsequently, four rabbits underwent ovariohysterectomy using treatment DB and alfaxalone TIVA.ResultsThe mean ± standard deviation alfaxalone infusion rate was 9.6 ± 2.6 and 4.5 ± 1.3 mg kg^–1 hour^–1 for treatments D and DB, respectively. In both treatments, blood pressure remained within acceptable range and SpO₂ was > 95%. Postinduction apnea and respiratory depression were observed in both treatments and managed with manual positive pressure ventilation. Four separate rabbits underwent successful ovariohysterectomy with treatment DB and alfaxalone TIVA. One rabbit required supplementation with inhalant anesthesia; three rabbits were successfully maintained using alfaxalone TIVA alone.Conclusions and clinical relevancePremedication with dexmedetomidine–buprenorphine combined with alfaxalone TIVA may be a viable alternative for performing abdominal surgery in the rabbit. The use of supplemental oxygen and ability to provide respiratory support are advised.     

Experimental evaluation of four airway devices in anaesthetized New Zealand White rabbits

Objective

To compare airway management during induction of anaesthesia, spontaneous ventilation (SV) and controlled mechanical ventilation (CMV), using an endotracheal tube (ETT), laryngeal mask (LM), rabbit-specific supraglottic airway device (v-gel) or facemask (FM).

Comparison of Doppler,oscillometric, auricular and carotid arterial blood pressure measurements in isoflurane anesthetized New Zealand white rabbits

ObjectiveTo assess agreement between carotid arterial pressure and auricular arterial, thoracic limb Doppler or thoracic limb oscillometric blood pressure measurements.Study designProspective experimental study.AnimalsSix adult New Zealand white rabbits.MethodsRabbits were anesthetized with isoflurane in oxygen at 1, 1.5 and 2 MAC on two separate occasions. Catheters in the auricular and the contralateral external carotid artery were connected to calibrated pressure transducers via non-compliant tubing. Inflatable cuffs of width equal to approximately 40% of the limb circumference were placed above the carpus on both thoracic limbs with a Doppler transducer placed distal to the cuff on one. Systolic (SAP) and mean (MAP) arterial blood pressure measurements were obtained at each dose, on each occasion. Agreement between measurement techniques was evaluated by repeated measures Bland Altman analysis with carotid pressure as the reference. Variation in bias over the measurement range was evaluated by regression analysis.ResultsCarotid MAP and SAP ranged from 20 to 65 mmHg and 37 to 103 mmHg respectively. Bias and 95% limits of agreement for auricular and oscillometric MAP were 7 (0–14) and ?5 (?21–11) mmHg, respectively, and for auricular, oscillometric and Doppler SAP were 23 (8–37), ?2 (?24–20) and 13 (?14–39) mmHg, respectively. Bias varied significantly over the measurement range (p < 0.001) for all three SAP techniques but not for MAP measurements.Conclusions and clinical relevanceLimits of agreement for all measurements were large but less so for MAP than SAP. Variation in bias with SAP should be considered when using these measurements clinically.     

Pharmacokinetics of florfenicol after intravenous and intramuscular administration in New Zealand White rabbits

The pharmacokinetic disposition and bioavailability of florfenicol (FF) were determined after single intravenous (i.v.) and intramuscular (i.m.) administrations of 25 mg/kg b.w. to ten healthy New Zealand White rabbits. Plasma FF concentrations were determined by high-performance liquid chromatography (HPLC). The plasma pharmacokinetic values for FF were best described by a one-compartment open model. The elimination half-life (t_1/2β) was different (p < 0.05) however, the area under curve (AUC) was similar (p > 0.05) after i.v. and i.m. administrations. FF was rapidly eliminated (t_1/2β 1.49 ± 0.23 h), slowly absorbed and high (F, 88.75 ± 0.22%) after i.m. injection. In addition, FF was widely distributed to the body tissues (V_ss 0.98 ± 0.05 L/kg) after i.v. injection. In this study the time that plasma concentration exceeded the concentration of 2 μg/mL was approximately 6 h. For bacteria with MIC of 2 μg/mL, frequent administration at this dose would be needed to maintain the concentration above the MIC. However, it is possible that rabbit pathogens may have MIC values less than 2 μg/mL which would allow for less frequent administration. Further studies are necessary to identify the range of MIC values for rabbit pathogens and to identify the most appropriate PK-PD parameter needed to predict an effective dose.     

Performance of New Zealand White and Californian male weaned rabbits in the subtropical environment of Egypt

The New Zealand White (NZW) was superior significantly ( P  < 0.05) to the Californian (Cal) breed in final body weight, final total body solids and preslaughter weight. In contrast, Cal showed greater plasma creatinine ( P  < 0.001) than the NZW. The differences in the other traits were not significant. NZW also showed higher dressing percentage and Cal showed higher mortality percentage. The Temperature-humidity Index (THI) values indicated absence of heat stress in the first period (mild period) and exposure to moderate (very close to severe) heat stress in the second one (hot period). The heat stress conditions caused significant ( P  < 0.001, 0.01 or 0.05) decreases in each of final body weight, daily body gain, daily feed intake, final total body solids, solids daily gain, plasma total protein, albumin, globulin, total lipids, glucose, thyroid hormone T3, sodium, potassium, calcium, magnesium and phosphorus and preslaughter weight. At the same time, significant ( P  < 0.001 or 0.01) increases occurred in each of water intake, water/feed ratio, total body water (mL/100 g body solids), blood urea-N, creatinine, respiration rate and rectal, skin and ear temperatures. The interaction of breed x period effects was significant ( P  < 0.01 or 0.05) on plasma creatinine and hind-limb cut. Estimations of 'adaptability' to the subtropical environment of Egypt were found to be 83.1% for NZW and 82.6% for Cal breeds.     

Sedative effects of an intramuscular or intranasal combination of sufentanil and midazolam in New Zealand White rabbits

ObjectiveTo evaluate the sedative effects of a combination of sufentanil and midazolam administered intramuscularly (IM) or intranasally (IN) prior to induction of anesthesia with propofol in New Zealand White rabbits.Study designProspective, randomized, crossover, experimental study.AnimalsA total of 11 adult New Zealand White rabbits.MethodsSufentanil (0.5 μg kg^–1) and midazolam (2 mg kg^–1) were administered to rabbits via IM or IN route. The righting reflex was assessed, and sedation was scored. Heart rate, respiratory rate (f_R) and temperature were recorded prior to treatment administration and after loss of the righting reflex.ResultsMeasured variables remained within normal physiologic ranges for all rabbits. The only statistically significant change was for f_R, which was significantly lower after sedation for both routes. The time to loss of righting reflex was 14.8 ± 6.5 and 12.5 ± 7.4 minutes and sedation scores were 6 (4–8) and 7 (6–8) for IM and IN routes, respectively, with no difference between treatments. No adverse effects were observed during the experimental period.Conclusions and clinical relevanceSufentanil combined with midazolam administered either IM or IN resulted in moderate to deep sedation in New Zealand White rabbits at the dose rates studied.     

24-hour Holter-monitoring in the perianaesthetic period in dogs premedicated with dexmedetomidine

Baseline and perianaesthetic 24-hour Holter recordings were carried out in six healthy beagles. After dexmedetomidine premedication anaesthesia was induced with propofol and maintained with propofol infusion or isoflurane for one hour. Dexmedetomidine alone was used as control. The recordings were analysed for ventricular premature complexes (VPC), atrioventricular (AV) blocks and mean heart rate/hour (HR). In most recordings, no ventricular arrhythmias were detected, the maximum frequency being two VPCs/24 h. VPCs were not seen during anaesthesia or during the recovery period. The development of second-degree AV-blocks varied from dog to dog. Most of the heart blocks were seen during the premedication period when bradycardia was most prominent. During the subsequent night, HR was similar between treatments and did not differ from that seen on the baseline recordings. In beagles treated with dexmedetomidine alone or combined with propofol or propofol/isoflurane, ventricular arrhythmias were not detected more frequently than those reported in healthy non-anaesthetised dogs.     

Effects of dopamine,norepinephrine or phenylephrine on the prevention of hypotension in isoflurane-anesthetized cats administered vatinoxan or vatinoxan and dexmedetomidine

ObjectiveTo determine the dose of phenylephrine, norepinephrine and dopamine necessary to maintain mean arterial pressure (MAP) within 70–80 mmHg during administration of isoflurane, isoflurane and vatinoxan and isoflurane, vatinoxan and dexmedetomidine at three plasma concentrations.Study designRandomized crossover experimental study.AnimalsA group of five adult healthy neutered male cats.MethodsInstrumentation occurred during anesthesia with isoflurane in oxygen. Isoflurane end-tidal concentration was set to 1.25 × minimum alveolar concentration (MAC). Phenylephrine, norepinephrine or dopamine was administered to maintain MAP 70–80 mmHg. A target-controlled infusion system was used to administer vatinoxan at a target plasma concentration of 1 μg mL^–1 and three dexmedetomidine concentrations (5, 10 and 20 ng mL^–1). Isoflurane concentration was altered to maintain an equivalent 1.25 MAC. Heart rate, arterial blood pressure, central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, body temperature, arterial and mixed venous blood gas, cardiac output and drug concentrations were measured at baseline (isoflurane alone), during vatinoxan administration, and during administration of vatinoxan and dexmedetomidine at the three target concentrations.ResultsMAP < 70 mmHg was observed with vatinoxan alone and in the dopamine treatment with dexmedetomidine concentrations ≤ 10 ng mL^–1. Norepinephrine and phenylephrine maintained MAP 70–80 mmHg during vatinoxan and dexmedetomidine ≤ 10 ng mL^–1. As the target dexmedetomidine concentration increased, the dose of norepinephrine and phenylephrine needed to maintain MAP 70–80 mmHg decreased; no treatment was necessary to maintain MAP > 70 mmHg at the 20 ng mL^–1 target dexmedetomidine concentration in most cats.Conclusions and clinical relevanceNorepinephrine and phenylephrine, but not dopamine, are effective to prevent hypotension in isoflurane-anesthetized cats administered dexmedetomidine and vatinoxan.     

Glaucoma in a New Zealand White Rabbit Fed High-cholesterol Diet

Goniodysgenesis, malformation of the filtration angle, was observed in a New Zealand white rabbit supplied with 100 g/day rabbit chow containing 0.2% cholesterol for 10 months. Histopathology revealed cupping of the optic disc, atrophy of the retina and hyalinization of the ciliary body in the bilateral eyeballs. These findings corresponded with histopathological features caused by glaucoma. On the basis of these findings, we diagnosed this lesion as glaucoma, and classified it as primary glaucoma because of the presence of developmental defects of the filtration angle. In this case, hypercholesterolemia-induced changes, such as aggregation of lipid-laden macrophages and cholesterin clefts in the sclera or choroid, might cause deterioration of the lesions in glaucoma.     

Disposition of ofloxacin in female New Zealand White rabbits

Limited information exists regarding the disposition of ofloxacin in rabbits. Pharmacokinetic information is necessary for the design of appropriate therapeutic regimens for the treatment of organisms (e.g. Pasteurella multocida ) commonly infecting this species. This study evaluated the pharmacokinetics of ofloxacin following intravenous (i.v.) and subcutaneous (s.c.) administration. Two groups of three female New Zealand White rabbits received a single dose of 20 or 40 mg/kg by the i.v. and s.c. routes. Samples were collected prior to drug administration, then 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h postdose. Ofloxacin concentrations in serum were determined using a validated HPLC assay. Mean maximum concentrations were 66.86 ± 10.83 mg/L and 14.1 ± 2.20 mg/L for the i.v. and s.c. administration of 20 mg/kg. The 40 mg/kg dose produced maximum concentrations of 154.96 ± 35.45 mg/L and 23.83 ± 4.01 mg/L for the i.v. and s.c. doses, respectively. The area under concentration–time curve increased proportionally with the dose, while the half-life was unaltered and ranged from 1.5–1.9 h. From these data, it appears that a 20 mg/kg dose administered every 8 h by the s.c. route would optimize the pharmacodynamic profile of ofloxacin and provide an appropriate regimen for the treatment of many susceptible organisms which commonly infect this species.     

Evaluation of the isoflurane‐sparing effects of fentanyl,lidocaine, ketamine,dexmedetomidine, or the combination lidocaine‐ketamine‐dexmedetomidine during ovariohysterectomy in dogs

ObjectiveTo evaluate the isoflurane‐sparing effects of an intravenous (IV) constant rate infusion (CRI) of fentanyl, lidocaine, ketamine, dexmedetomidine, or lidocaine‐ketamine‐dexmedetomidine (LKD) in dogs undergoing ovariohysterectomy.Study designRandomized, prospective, blinded, clinical study.AnimalsFifty four dogs.MethodsAnesthesia was induced with propofol and maintained with isoflurane with one of the following IV treatments: butorphanol/saline (butorphanol 0.4 mg kg^?1, saline 0.9% CRI, CONTROL/BUT); fentanyl (5 μg kg^?1, 10 μg kg^?1 hour^?1, FENT); ketamine (1 mg kg^?1, 40 μg kg^?1 minute^?1, KET), lidocaine (2 mg kg^?1, 100 μg kg^?1 minute^?1, LIDO); dexmedetomidine (1 μg kg^?1, 3 μg kg^?1 hour^?1, DEX); or a LKD combination. Positive pressure ventilation maintained eucapnia. An anesthetist unaware of treatment and end‐tidal isoflurane concentration (Fe′Iso) adjusted vaporizer settings to maintain surgical anesthetic depth. Cardiopulmonary variables and Fe′Iso concentrations were monitored. Data were analyzed using anova (p < 0.05).ResultsAt most time points, heart rate (HR) was lower in FENT than in other groups, except for DEX and LKD. Mean arterial blood pressure (MAP) was lower in FENT and CONTROL/BUT than in DEX. Overall mean ± SD Fe′Iso and % reduced isoflurane requirements were 1.01 ± 0.31/41.6% (range, 0.75 ± 0.31/56.6% to 1.12 ± 0.80/35.3%, FENT), 1.37 ± 0.19/20.8% (1.23 ± 0.14/28.9% to 1.51 ± 0.22/12.7%, KET), 1.34 ± 0.19/22.5% (1.24 ± 0.19/28.3% to 1.44 ± 0.21/16.8%, LIDO), 1.30 ± 0.28/24.8% (1.16 ± 0.18/32.9% to 1.43 ± 0.32/17.3%, DEX), 0.95 ± 0.19/54.9% (0.7 ± 0.16/59.5% to 1.12 ± 0.16/35.3%, LKD) and 1.73 ± 0.18/0.0% (1.64 ± 0.21 to 1.82 ± 0.14, CONTROL/BUT) during surgery. FENT and LKD significantly reduced Fe′Iso.Conclusions and clinical relevanceAt the doses administered, FENT and LKD had greater isoflurane‐sparing effect than LIDO, KET or CONTROL/BUT, but not at all times. Low HR during FENT may limit improvement in MAP expected with reduced Fe′Iso.