Ceftazidime pharmacokinetics in dogs after intravenous injection and delivered with the RxActuator Mini-Infuser infusion pump.

OBJECTIVE: To test the feasibility of an SC mini-infusion pump to deliver ceftazidime in dogs and produce plasma concentrations sufficient to reach a therapeutic target for 48 hours. SETTING: University research laboratory. ANIMALS: Six healthy Beagle dogs. INTERVENTIONS: Ceftazidime was administered by 2 routes to 6 healthy Beagle dogs. The first route was an IV bolus injection into a cephalic vein at a dose of 25 mg/kg. Blood samples were collected for 8 hours following injection. The second route was a SC infusion for 48 hours using the RxActuator Mini-Infuser wearable SC constant rate infusion pump. Blood samples were collected for 58 hours following application of the pump. All plasma samples were analyzed by high-pressure liquid chromatography and subject to pharmacokinetic analysis. MAIN RESULTS: After the IV bolus injection, there was rapid distribution and elimination. The elimination half-life was 0.95 hours, and the clearance was rapid at 0.176 ml/h/kg. After the 48-hour SC infusion, the half-life was slightly shorter, and the clearance was higher. The percent bioavailability from the SC infusion was approximately 72%. The SC infusion maintained plasma concentration near our target of 8 µg/ml for most of the dose interval but slightly lower after 24 hours. The concentrations below the target were attributed to slight drug loss, less than 100% bioavailability, and faster clearance from SC administration. CONCLUSIONS: This study demonstrated the successful application of the RxActuator Mini-Infuser wearable SC constant rate infusion pump for delivering an antimicrobial needed for serious, and sometimes resistant, infections in dogs.

Quantitative assessment of infusion pump-mediated haemolysis in feline packed red blood cell transfusions.

OBJECTIVES: Haemolysis caused by the use of peristaltic infusion pumps (PIPs) has been described in human and canine packed red blood cells (pRBCs). The aim of this study was to evaluate the effects of two different linear PIPs on the haemolysis of feline pRBC units stored for a long time. METHODS: Feline pRBC units stored with adenine, dextrose, mannitol and sodium chloride (SAGM) were manufactured. After 35-42 days of storage at 2-4°C, a line administration system with a 180 µm filter was attached to every pRBC bag, the system was drained by gravity alone (8 drops/min) and a 1.3 ml sample was collected (G). A NIKI V4 pump was then used at a flow rate of 25 ml/h, the flow was stopped when the infusion system was filled with blood coming from the infusion pump and another 1.3 ml sample was collected (NK). Finally, an Infusomat FmS pump was evaluated, collecting another 1.3 ml sample (IM). Packed cell volume (PCV) was measured in all samples by microhaematocrit centrifugation, total haemoglobin (HGB) was measured using a specific haemoglobin analyser and, after centrifugation, free HGB was determined by spectrophotometry. The percentage of haemolysis was calculated. Friedman's test was used to compare the samples. RESULTS: Fifteen feline pRBC units were evaluated. The average degree of haemolysis for sample G (gravity-assisted) was 1.12%. Comparison of the degree of gravity-assisted haemolysis with haemolysis in PIP NK (1.13%) and IM (1.14%) samples revealed no significant differences, with differences of only 0.01% and 0.02%, respectively. CONCLUSIONS AND RELEVANCE: The results of this study demonstrate that the use of two common PIPs in veterinary hospitals does not produce levels of haemolysis that are significantly different than that caused by gravity alone during transfusion of feline pRBCs at a rate of 25 ml/h.

Advances in Therapeutics and Delayed Drug Release.

Reducing the frequency of drug administration in the treatment of exotic pets is advantageous because it may decrease handling frequency and thus potential stress and injury risk for the animal, increase owner compliance with the prescribed treatment, and decrease need for general anesthesia in patients that cannot be handled safely. Increasing efficient drug plasma concentration using sustained-released delivery systems is an appealing solution. Potential candidates that could provide a promising solution have been investigated in exotic pets. In this article, the technologies that are the closest to being integrated in exotic pet medicine are reviewed: osmotic pumps, nanoparticles, and hydrogels.

Evaluation and optimisation of propofol pharmacokinetic parameters in cats for target-controlled infusion.

The aim of this study was to develop and evaluate a pharmacokinetic model-driven infusion of propofol in premedicated cats. In a first step, propofol (10 mg/kg) was administered intravenously over 60 seconds to induce anaesthesia for the elective neutering of seven healthy cats, premedicated intramuscularly with 0.3 mg/kg methadone, 0.01 mg/kg medetomidine and 2 mg/kg ketamine. Venous blood samples were collected over 240 minutes, and propofol concentrations were measured via a validated high-performance liquid chromatography assay. Selected pharmacokinetic parameters, determined by a three-compartment open linear model, were entered into a computer-controlled infusion pump (target-controlled infusion-1 (TCI-1)). In a second step, TCI-1 was used to induce and maintain general anaesthesia in nine cats undergoing neutering. Predicted and measured plasma concentrations of propofol were compared at specific time points. In a third step, the pharmacokinetic parameters were modified according to the results from the use of TCI-1 and were evaluated again in six cats. For this TCI-2 group, the median values of median performance error and median absolute performance error were -1.85 per cent and 29.67 per cent, respectively, indicating that it performed adequately. Neither hypotension nor respiratory depression was observed during TCI-1 and TCI-2. Mean anaesthesia time and time to extubation in the TCI-2 group were 73.90 (±20.29) and 8.04 (±5.46) minutes, respectively.

Development of a programmable piggyback syringe pump and four-times-a-day injection regimen for superovulation in non-lactating Holstein cows.

The objectives of the present study were to develop a programmable piggyback syringe pump for bovine superovulation and to evaluate the effects of a four-times-a-day injection regimen using the pump. Non-lactating Holstein cows were treated with a total of 30 armour units of porcine FSH by injection four times a day with the pump (study, n = 9) or injection twice a day manually (control, n = 9) for four consecutive days from D10 of the estrous cycle. The pump-driven program successfully induced superovulation in all cows tested. The numbers of small (3- < 5 mm in diameter) and large (≥ 10 mm in diameter) follicles were greater in the study group on D11-13 and D14, respectively. There were fewer unovulated follicles detected on D21 (7 days after estrus) in the study group than in the control group (1.2 ± 0.4 and 3.2 ± 0.6, respectively).

Stability of 1% voriconazole solution in a constant-rate infusion pump for topical ocular delivery to horses.

OBJECTIVE: To establish the effect of storage in a constant-rate infusion (CRI) pump on the sterility and stability of voriconazole 1% solution. PROCEDURE: Nine vials of voriconazole (Vfend(®) I.V.) 1% solution were prepared. Approximately half of each solution was used to prime a commercially available CRI pump with attached subpalpebral lavage system (CRI/SPL unit) with the remaining solution stored in the commercial glass vial. Three CRI/SPL units and their three corresponding vials were stored at one of three temperatures: 23 °C, 33 °C, and 40 °C. The CRI pumps ran for 7 days, and the vials were stored for 30 days. Fungal and aerobic bacterial cultures were performed on the first and last day of the storage period for each vessel. Samples were obtained at regular intervals for determination of voriconazole concentration using high-performance liquid chromatography. RESULTS: No bacterial or fungal contamination was identified in any solution at any time point. All solutions stored in the commercial glass vial remained stable throughout the study period. Multiple CRI/SPL units became blocked with crystallized voriconazole. There was a significant increase in voriconazole concentration after passage through the CRI/SPL units. CONCLUSIONS: Voriconazole 1% solution is not compatible for use in a CRI/SPL unit at temperatures between 23 and 40 °C. Voriconazole 1% solution is stable in the commercial glass vial when stored at controlled temperatures as high as 40 °C for up to 30 days.

Effect of syringe and aggregate filter administration on survival of transfused autologous fresh feline red blood cells.

OBJECTIVE: To assess the effect of transfusion using a syringe and microaggregate filter on short-term survival and circulating half-life of autologous feline RBCs. DESIGN: Prospective, internally controlled, observational study. SETTING: A University Teaching Hospital ANIMALS: Six apparently healthy, owned cats. INTERVENTIONS: Blood collection by jugular venipuncture. Transfusion with labeled, autologous, fresh RBCs. MEASUREMENTS AND MAIN RESULTS: Anticoagulated whole blood (35 mL/cat) was collected in 2 equal aliquots. RBCs were washed and labeled at 2 different biotin densities, before suspension in autologous plasma. Labeled RBCs were then transfused using 2 methods, gravity flow and pump delivery using a 20 mL syringe and 18 µm microaggregate filter. Whole blood samples were collected from each cat at 2-hour intervals for 12 hours following completion of the transfusions. Additional samples were collected at weekly intervals up to 6 weeks to assess circulating half-life of the transfused cells. Cell survival was assessed via flow cytometry. The proportion of transfused cells remaining in each of the 2 populations was measured. Biotinylated RBCs were readily detected in all cats over the 6-week sampling period. There was a significant decrease in both populations of labeled cells over the 6-week period (P < 0.01), as expected. There was no difference in probability that the RBCs would survive up to 12 hours immediately following transfusion, and no significant difference in survival between the 2 groups over 6 weeks. The average half-life of all labeled cells was approximately 23 days. CONCLUSIONS: We conclude that, in contrast to findings from dogs, transfusion of autologous feline RBCs using a syringe + aggregate filter method does not significantly impact short- or long-term survival of the transfused cells.

External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long-chain triglyceride emulsion propofol in beagle dogs.

This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PK-PD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.6-20.5), 1.9%/h, 7.3% (5.4-9.3), and -0.5% (-2.6 to 1.6), 8.7% (7.3-10.1), 2.5%/h, 6.0% (4.1-7.2) for microemulsion propofol, and -9.3% (-11.6 to -6.9), 20.1% (18.2-22.0), 5.1%/h, 7.6% (6.1-9.1) and 5.6% (4.1-7.1), 8.0% (6.9-9.3), 4.7%/h, 4.1% (3.1-5.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PK-PD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration.

Influence of transfusion technique on survival of autologous red blood cells in the dog.

OBJECTIVE: To determine the effect of 3 differing transfusion techniques on survival of autologous canine RBCs. DESIGN: Prospective, blinded study. SETTING: University Teaching Hospital. ANIMALS: Nine healthy dogs. INTERVENTIONS: Three distinct preparations of RBCs, each representing ~1% of red cell mass, were generated for each dog by biotinylation of RBCs at varying biotin densities. Labeled cells were transfused using 3 techniques (gravity, volumetric pump, syringe pump). Serial determinations of red cell survival were carried out by flow-cytometric analysis of RBCs collected at 7-day intervals for 49 days. In vitro analysis of the effect of transfusion methods on RBC integrity and osmotic fragility were carried out in 7/9 dogs. MEASUREMENTS AND MAIN RESULTS: RBCs administered via volumetric and syringe pumps exhibited a marked decrease in short-term probability of survival compared with RBCs delivered by gravity flow. At 24 hours, only 4/8 and 1/7 dogs had surviving cell populations delivered by volumetric and syringe pump, respectively, compared with 8/8 dogs which had surviving cell populations delivered by gravity flow. Circulating half-life of cells surviving at 24 hours after delivery by volumetric pump was not significantly different to that delivered by gravity flow. No significant effect on in vitro RBC integrity or osmotic fragility was detected in relation to transfusion technique. CONCLUSIONS: Delivery of autologous canine RBCs via mechanical delivery systems was associated with a high risk for early loss of transfused cells.

Chronic, constant-rate, gastric drug infusion in nontethered rhesus macaques (Macaca mulatta).

As part of a study of antipsychotic drug treatment in monkeys, we developed a technique to provide chronic, constant-rate, gastric drug infusion in nontethered rhesus macaques. This method allowed us to mimic the osmotic release oral delivery system currently used in humans for continuous enteral drug delivery. Rhesus macaques (n = 5) underwent gastric catheter placement by laparotomy. After the catheters were secured to the stomach, the remaining catheter length was exited through the lateral abdomen, tunneled subcutaneously along the back, and connected to a 2-mL osmotic pump enclosed in a subcutaneous pocket. Osmotic pumps were changed every 2 to 4 wk for 1 y and remained patent for the duration of the study. Four complications (including cutting of the catheter, incisional dehiscence at the pump site, and loss of 1 catheter into the abdominal cavity requiring catheter replacement) occurred among the 80 pump changes performed during the year-long study. At necropsy, histopathologic examination of the catheter implant sites revealed mild changes consistent with a foreign-body reaction. Our results indicate that the gastric catheter and osmotic pump system was well tolerated in rhesus macaques for as long as 12 mo after placement and suggest that this system will be an attractive option for use in studies that require chronic, constant-rate, gastric drug infusion in nontethered monkeys.

Efeitos da infusão contínua de propofol ou etomidato sobre variáveis intracranianas em cães / Effects of propofol or etomidate intravenous infusion on intracranial variables in dogs

Avaliaram-se os efeitos da infusão contínua de propofol ou de etomidato sobre as variáveis intracranianas em cães nomocapneicos. Foram utilizados 20 cães adultos distribuídos aleatoriamente em dois grupos: grupo propofol (GP) e grupo etomidato (GE). Para o GP, os animais foram induzidos à anestesia com propofol (10mg/kg) e, ato contínuo, iniciaram-se a infusão do fármaco (0,6mg/kg/min) e a ventilação controlada. No GE, o etomidato foi usado para indução (5mg/kg) e manutenção empregando-se a dose de 0,5mg/kg/min nos 10 minutos iniciais e, em seguida, de 0,2mg/kg/min. Após 30 minutos da implantação do cateter de fibra óptica do monitor de pressão intracraniana (PIC) na superfície do córtex cerebral direito, realizaram-se as primeiras mensurações (M1) da PIC, da pressão de perfusão cerebral (PPC), da temperatura intracraniana (TIC), de temperatura corpórea (TC), da pressão arterial média (PAM) e da frequência cardíaca (FC). As demais mensurações ocorreram em intervalos de 20 minutos (M2, M3 e M4). O propofol e o etomidato não ocasionaram alterações significativas nas variáveis estudadas com exceção da TC e TIC. Concluiu-se que a infusão contínua desses fármacos em cães mantém a perfusão cerebral e a autorregulação cerebral. Cães anestesiados com etomidato apresentam efeitos adversos intensos e redução gradativa da temperatura corpórea e intracraniana.

The effects of total intravenous infusion of propofol or etomidate on intracranial variables in normocapneic dogs were evaluated. Twenty adult mongrel dogs were randomly allotted to: propofol group (GP) or etomidate group (GE). In GP animals, the propofol was used for induction (10mg/kg), followed by immediate continuous infusion of the drug (0.6mg/kg/min) and controlled ventilation. In GE dogs, the etomidate was used for induction (5mg/kg), followed by a continuous rate infusion (CRI) at 0.5mg/kg/min during the first ten minutes and, right after, it was changed to 0.2mg/kg/min. The initial measurement (M1) was recorded 30 minutes after the implant of the fiber optic catheter and, after that, every 20 minutes (M2, M3, and M4). The studied parameters were intracranial pressure (ICP), cerebral perfusion pressure (CPP), intracranial temperature (ICT), body temperature (BT), mean arterial pressure (MAP), and heart rate (HR). The propofol and etomidate did not change the studied variables, except the ICT and BT. It was concluded that the continuous infusion of these drugs maintains the cerebral perfusion and autoregulation. Dogs anesthetized with etomidate have adverse effects and body and intracranial temperature decrease.

Intrauterine infusion of latency-associated peptide (LAP) during early porcine pregnancy affects conceptus elongation and placental size.

In the pig, transforming growth factor beta (TGFB), TGFB receptors (TGFBRs), and integrins are present during the peri-implantation period. Latency-associated peptide (LAP), a part of latent TGFB, can bind to integrin heterodimers via its Arg-Gly-Asp (RGD) sequence; therefore, ligand-receptor interactions between TGFB and TGFBRs, along with LAP and integrin heterodimers, may be functional in mediating events supporting conceptus elongation and attachment. With the use of surgically implantable osmotic pumps, we were able to maintain pregnancy with the aim of mechanistically altering in vivo receptor-ligand interactions involving TGFB with TGFBRs and LAP with integrins during porcine pregnancy. Day 9 pregnant gilts received intrauterine infusions of LAP-RGD, a recombinant mutant of LAP (LAP-RGE), or vehicle control and were ovariohysterectomized on Day 13 or 24 of pregnancy. We hypothesized that intrauterine infusion of LAP-RGD would decrease downstream signaling of TGFB while increasing LAP-integrin interactions and that net effect would enhance conceptus survival and attachment early in the peri-implantation period but possibly increase the chance of abnormal placentation later in pregnancy. Additionally, we hypothesized that infusion of LAP-RGE would disrupt TGFB signals but not alter integrin signaling, and thus the net result would be decreased conceptus survival and abnormal development. Unexpectedly, LAP-RGD intrauterine infusions resulted in a reduction of conceptus elongation, whereas infusions of LAP-RGE permitted implantation and placentation but resulted in larger fetal weight, allantois length, and allantoic fluid volume. Results suggest TGFB and integrins are contributing factors in the regulation of conceptus elongation and placental and fetal size.

Efeitos da aplicação intravenosa do cloridrato sobre a concentração alveolar mínima do sevofluorano em cães / Effects of the implementation of intravenous hydrochloride on the minimum alveolar concentration of sevoflurane in dogs

Foi realizado estudo experimental em cães para avaliar os efeitos da infusão contínua da lidocaína, nas doses de 50 e 200 /kg/min sobre a concentração alveolar mínima do sevofluorano, além dos efeitos cardiovasculares promovidos por essa associação. Foram realizadas 08 cadelas, adultas, castradas, hígidas, sem raça definida, com peso médio de 15,96 mais ou menos 2,10 kg. Os animais foram alocados aleatoriamente, em três grupos experimentais participando do grupo controle, onde a anestesia foi realizada com o sevofluorano (GC) e do grupo onde a infusão contínua de lidocaína foi associada ao anestésico geral inalatório, na dose de 50 miu/kg/min (GL50) ou 200 miu/kg/min (GL200). A indução foi realizada com o sevofluorano na concentração inicial de 8% no vaporizador calibrado, através de máscara facial e a intubação foi efetuada. Após o período de estabilização de 40 minutos, em uma concentração entre 2,4 e 3%, foi administrado um bôlus de salina na dose de 0,1 ml/kg, seguido de infusão contínua da mesma solução na dose de 200 miu/kg/min no GC, no GL50 e no GL200 foi administrado um bôlus de lidocaína na dose de 2 mg/kg, seguido de infusão contínua de 50 miu/kg/min e 200 miu/kg/min. A concentração de sevofluorano foi então, reduzida para 2,6% no GC, 2,4% no GL50 e 1,8% no GL200. O pinçamento de cauda foi realizado durante 60 segundos ou menos, caso a resposta fosse positiva. Se a resposta fosse negativa, a concentração era reduzida em 0,2%, sendo o procedimento repetido até que o animal apresentasse resposta positiva para a determinação da CAM. Os parâmetros avaliados antes de cada estímulo doloroso foram frequência cardíaca e respiratória, pressões arteriais, pressão parcial de dióxido de carbono ao final da expiração, saturação de oxigênio na hemoglobina, concentração de sevofluorano expirado, temperatura retal , ECG, hemogasometria e dosagem da lidocaína plasmática...

Surveillance of infections associated with intravenous catheters in dogs and cats in an intensive care unit.

Positive catheter-tip culture rates and risk factors associated with bacterial colonization of intravenous (i.v.) catheters were assessed in dogs and cats. Aerobic and anaerobic bacterial cultures were performed on 151 catheters, and 24.5% were positive. Of the positive cultures, 46.0% grew Enterobacter spp. The type of catheter used, blood sampling through the catheter, the type of i.v. infusate administered, the duration the catheter was in place, the catheter location, complications with the catheter, and the final outcome of the animal were not associated with an increased risk of a positive bacterial culture from the catheter tip.

New antimicrobials, systemic distribution, and local methods of antimicrobial delivery in horses.

The local delivery of antimicrobials is a valuable therapeutic tool with a low morbidity, is practical to use, and is well tolerated by horses. Clinically, its use has allowed equine practitioners to achieve better results when treating musculoskeletal infections, and it represents an extremely useful tool in the practitioner's armamentarium against these types of infections. The technique is indicated to combat orthopedic infections involving bones, joints, physes, tendon sheaths, and foot tissues. Optimal treatment must include other approaches, such as systemic antimicrobial therapy and surgical debridement and lavage, and monitoring of the clinical progression of the patient can help to determine the ideal protocol for each patient.

Treatment with continuous intrasynovial antimicrobial infusion for septic synovitis in horses: 31 cases (2000-2003).

OBJECTIVE-To determine clinical findings, complications, and outcome of septic synovitis in which continuous intrasynovial antimicrobial infusion (CIAI) was used for local antimicrobial delivery in horses. DESIGN-Retrospective case series. Animals-22 adult horses and 9 foals (horses<1 year of age). PROCEDURES-Records of horses with septic synovitis that had CIAI during treatment were reviewed. The association between clinical variables and whether horses performed their intended use following treatment was determined. RESULTS-42 synovial cavities were treated via CIAI. Twenty-nine cases were chronic (>7 days) in nature, 15 had been refractory to standard treatments, and 13 synovial infections had associated osteomyelitis. Mean duration from infection to initiation of CIAI was 19.7 days, and mean duration of CIAI was 6.1 days. Temporary discharge from the catheter site at the time of removal was evident in 8 horses. Dysfunction of the infusion system occurred in 2 horses and was corrected during the course of treatment. No long-term complications were reported. Thirty-nine (93%) synovial infections in 29 (94%) horses were resolved. Twenty adult horses and 8 foals were discharged from the hospital, and 19 of 24 horses with long-term follow-up performed their intended use. CONCLUSIONS AND CLINICAL RELEVANCE-CIAI was a useful adjunctive treatment for septic synovitis and allowed intrasynovial antimicrobial delivery into a variety of synovial cavities.