The effect of induction with propofol or ketamine and diazepam on quality of anaesthetic recovery in dogs.

OBJECTIVE: To evaluate the quality of recovery in dogs undergoing elective orthopaedic surgery induced with either propofol or a combination of ketamine and diazepam. MATERIALS AND METHODS: Sixty client-owned dogs undergoing single-limb elective orthopaedic procedures were enrolled. Dogs were randomly assigned to receive induction with propofol (4 mg/kg) (group P) or ketamine (5 mg/kg) with diazepam (0.25 mg/kg) (group KD) to which all scorers were blinded. The recovery monitoring period lasted for 1 hour following extubation. The recovery period was video-recorded for blinded scoring at a later time. Scoring for quality of recovery was carried out using three different systems (lower numbers=better quality): a simple descriptive scale (1 to 5), a visual analogue scale (0 to 10 cm) and a numeric rating scale (0 to 10). Videos were reviewed by three ACVAA board-certified anaesthesiologist raters. RESULTS: Five dogs were deemed to be ineligible. The mean (±SD) duration of anaesthesia was 260.4 ±57.84 minutes in group KD and 261.1 ±51.83 minutes in group P. There was no difference between groups for time to extubation, head lift or sternal recumbency. The number of dogs having a recovery that was scored overall as bad (mean simple descriptive scale > 4, mean visual analogue scale or numeric rating scale > 5) was not different between groups. Dogs in group KD had significantly lower scores than group P dogs (simple descriptive scale P=0.01, numeric rating scale P=0.03, visual analogue scale P=0.03). CLINICAL SIGNIFICANCE: Induction with ketamine and diazepam resulted in a smoother recovery from anaesthesia than induction with propofol.

Comparison of the pharmacokinetics of two formulations of hydroxyethyl starch in healthy horses.

A lower molecular weight and molar substitution formulation (130/0.4) of hydroxyethyl starch solution has been shown to have a more sustained effect on COP and similar hemodynamic effects as a higher molecular weight and molar substitution formulation (600/0.75) in healthy horses. In humans, these pharmacodynamic characteristics are coupled with more rapid clearance and decreased adverse coagulation effects and accumulation. The objective of this study was to determine and compare the pharmacokinetics of these two formulations in horses. Eight healthy horses were given a 10 mL/kg bolus of each formulation (600/0.75 and 130/0.4) of hydroxyethyl starch solution in a randomized crossover design. Blood was collected, and plasma was harvested for plasma levels over 24 h. Pharmacokinetic parameters for each horse were estimated from a noncompartmental analysis. Treatment with 600/0.75 resulted in a higher initial plasma concentration (C0 ), systemic half-life (t1/2 ), and overall drug exposure (AUC0-inf ) in addition to decreased elimination rate (ß), volume of distribution (Vd), and clearance (CL), compared to treatment with 130/0.4 (P < 0.001). The pharmacokinetic findings combined with previous pharmacodynamics findings suggest that 130/0.4 can provide similar benefits to 600/0.75 with a lower risk of accumulation in the circulation.

Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease.

Cardiovascular, colloid osmotic pressure, and hemostatic effects of 2 formulations of hydroxyethyl starch in healthy horses.

BACKGROUND: Lower molecular weight and molar substitution formulations of hydroxyethyl starch (HES) solutions might maximize cardiovascular function and colloid osmotic pressure (COP) and minimize adverse effects on coagulation. HYPOTHESIS/OBJECTIVES: To compare effects of 1 low and 1 high molecular weight and molar substitution HES solution on cardiovascular variables, COP, and hemostasis in normal horses. ANIMALS: Eight healthy adult horses. METHODS: Randomized, crossover designed study: 10 mL/kg bolus of 6% HES (600/0.75) (hetastarch) (HS), 6% HES (130/0.4) tetrastarch (TS), and 0.9% NaCl (NS). Variables recorded included central venous pressure (CVP), noninvasive arterial blood pressure, packed cell volume (PCV), COP, and automated platelet analysis (CT). RESULTS: Central venous pressure was increased for 8 hours after all treatment (baseline = 8.4 ± 3.8; 8 hours = 10.3 ± 3.5 cm H2 O; P < .001). HS and TS produced an increase in systolic arterial pressure (HS = 109.1 ± 11.9; TS = 109.5 ± 10.9 mmHg) and mean arterial pressure (HS = 80.4 ± 13.0; TS = 82.3 ± 10.1 mmHg) compared to NS (SAP = 103.2 ± 13.2 [P = .023]; MAP = 74.2 ± 11.4 mmHg [P = .048]). PCV decreased transiently with HS (baseline = 37.1 ± 4.4%; 1.5 hours = 31.6 ± 3.9%) and TS (baseline = 38.4 ± 3.9%; 1.5 hours = 32.2 ± 3.3%), but not NS (P = .007). COP was greater with HS (1 hour; 24.0 ± 2.1 mmHg) and TS (8 hours; 25.9 ± 2.1 mmHg) than NS (1 hour = 20.8 ± 2.6; 8 hours = 22.9 ± 3.1 mmHg; P < .001). CT was greater at 8 (HS = 178.6 ± 36.9; TS = 121.9 ± 33.3; NS = 108.3 ± 23.6 seconds) and 24 hours (HS = 174.2 ± 41.7; TS = 100.8 ± 26.0; NS = 118.7 ± 38.7 seconds; P < .001) in horses receiving HS than TS or NS. CONCLUSION AND CLINICAL IMPORTANCE: Both TS and HS resulted in more effective volume expansion and arterial pressure support than NS. TS produced a more sustained effect on COP with shorter duration of adverse effects on platelet function than HS.

Therapeutic plasma concentrations of epsilon aminocaproic acid and tranexamic acid in horses.

BACKGROUND: Antifibrinolytic drugs such as epsilon aminocaproic acid (EACA) and tranexamic acid (TEA) are used to treat various bleeding disorders in horses. Although horses are hypofibrinolytic compared to humans, dosing schemes have been derived from pharmacokinetic studies targeting plasma concentrations in humans. HYPOTHESIS/OBJECTIVES: We hypothesized therapeutic plasma concentrations of antifibrinolytic drugs in horses would be significantly lower than in humans. Our objective was to use thromboleastography (TEG) and an in vitro model of hyperfibrinolysis to predict therapeutic concentrations of EACA and TEA in horses and humans. ANIMALS: Citrated plasma collected from 24 random source clinically healthy research horses. Commercial pooled human citrated plasma with normal coagulation parameters was purchased. METHODS: Minimum tissue plasminogen activator (tPA) concentration to induce complete fibrinolysis within 10 minutes was determined using serial dilutions of tPA in equine plasma. Results used to create an in vitro hyperfibrinolysis model with equine and human citrated plasma, and the minimum concentrations of EACA and TEA required to completely inhibit fibrinolysis for 30 minutes (estimated therapeutic concentrations) determined using serial dilutions of the drugs. RESULTS: Estimated therapeutic concentrations of EACA and TEA were significantly lower in horses (5.82; 95% CI 3.77-7.86 µg/mL and 0.512; 95% CI 0.277-0.748 µg/mL) than in humans (113.2; 95% CI 95.8-130.6 µg/mL and 11.4; 95% CI 8.62-14.1 µg/mL). CONCLUSIONS AND CLINICAL IMPORTANCE: Current dosing schemes for EACA and TEA in horses may be as much as 20× higher than necessary, potentially increasing cost of treatment and risk of adverse effects.

Assessment of coagulation and potential biochemical markers for hypercoagulability in canine hyperadrenocorticism.

BACKGROUND: Anecdotal accounts and limited research suggest that dogs with spontaneous hyperadrenocorticism (HAC) are at risk of developing thromboembolic complications. Detailed description of coagulation status and identification of subsets of dogs at greatest risk would impact therapeutic recommendations for these patients. HYPOTHESIS: A subset of dogs with HAC will have a hypercoagulable tendency as identified by increased procoagulant activity, decreased fibrinolysis, or both. Objective 1: To document the existence of this hypercoagulable tendency in HAC dogs using assays of individual coagulation factors, fibrinolytic activity, and systemic coagulation. Objective 2: To evaluate clinical and biochemical markers in HAC dogs to identify a subset of HAC patients at increased risk of this hypercoagulable tendency. ANIMALS: Seventeen dogs newly diagnosed with HAC. METHODS: Prospective study. Medical history, physical examination findings, routine diagnostic tests, and comprehensive coagulation testing were performed at the time of HAC diagnosis. Coagulation parameters were assessed individually and as panels for each dog. Historical and clinical variables were correlated with coagulation parameters to identify risk factors. RESULTS: The majority (88.2%) of HAC dogs exhibited a hypercoagulable tendency. Abnormalities in 1 coagulation assay did not predict abnormalities in others. Duration of clinical signs of HAC did not predict hypercoagulability. Comorbid conditions or abnormal clinicopathologic parameters that predicted hypercoagulability were not identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Although HAC dogs may demonstrate a hypercoagulable tendency individually and as a group, comorbid conditions or biochemical variables that would predict more severe coagulation abnormalities were not identified.

Sonoclot® evaluation of single- and multiple-dose subcutaneous unfractionated heparin therapy in healthy adult dogs.

BACKGROUND: Heparin therapy is difficult to monitor due to variation in animal response. While laboratory measurements of activated partial thromboplasin time (aPTT) and Anti-Xa activity (AXA) accurately describe heparin effect, their availability is limited. HYPOTHESIS: Sonoclot analysis would be as sensitive as AXA and aPTT to monitor effects of unfractionated heparin (UFH) in healthy adult dogs. ANIMALS: Six adult mixed-breed dogs. METHODS: A prospective study design was employed. On day 1, baseline samples were collected (CBC, PT, aPTT, and Sonoclot), and UFH (300 U/kg SC) was administered to 6 dogs following an IV loading dose of 50 U/kg. Sonoclot and aPTT were performed hourly for 12 hours. AXA was assayed at hours 3, 6, 9, and 12. UFH (300 U/kg q8 h SC) was administered at 12 hours, and subsequently (q8 h) for 2 additional days. On day 4, a final dose of UFH was administered, and a sampling protocol identical to day 1 was performed. RESULTS: Sonoclot activated clotting time (ACT) and clot rate (CR) correlated with AXA (R = 0.69, R = 0.65, respectively, P < .001), although to a lesser degree than aPTT (R = 0.75, P < .001). Linear regression using ACT and CR as covariates indicated a stronger correlation with AXA (R = 0.73, P < .001). ACT values strongly correlated with aPTT (R = 0.87, P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of UFH to healthy dogs results in progressive changes in Sonoclot values. AXA was correlated with a combination of ACT and CR and with aPTT. Sonoclot may play a role in monitoring UFH therapy; however, prospective studies evaluating its utility in clinical cases are warranted.

Bilateral renal ischemia as a model of acute kidney injury in cats.

The objective of this study was to evaluate the effect of 1h, bilateral, warm ischemia-reperfusion kidney injury as a model of acute kidney injury in the cat. Four adult healthy cats underwent 60 min of bilateral, in vivo renal warm ischemia; three cats were sham operated controls. Kidney function was evaluated with creatinine and BUN concentration, urine protein: creatinine, and glomerular filtration rate. Post-reperfusion endothelin and renin was measured by ELISA and RT-qPCR. Blood pressure (BP), platelet count, and platelet aggregation were monitored. Renal biopsy specimens were evaluated histopathologically. There was significant reduction in renal function characterized by severe azotemia and proximal tubular brush border loss. Changes in renin or endothelin gene expression or serum concentration were not detected. No changes were detected in BP. Platelet count and hematocrit decreased markedly after ischemia and reperfusion. Sixty minutes bilateral renal ischemia is an effective model for acute renal injury.

Pharmacokinetic assessment of ketanserin in the horse.

The purpose of this study was to determine the pharmacokinetics (PK) of the 5-HT(2A) receptor antagonist ketanserin in healthy adult horses, and to develop a computational model that could be used to optimize dosing. Plasma concentrations of ketanserin were determined using liquid chromatography with mass spectrometry after single and multiple intravenous administration in the horse. A two-compartment linear pharmacokinetic model described the plasma concentration-time profile of ketanserin after single and multiple doses in healthy horses; the terminal half-life was 11.5 h; steady-state volume of distribution was 10.5 L/kg; AUC was 115 ng · h/mL; and clearance was 0.87 L/h/kg. Model simulations followed by the examination in three healthy horses suggest 0.3 mg/kg q.8 h exhibited linear PK and produced consistent systemic blood concentrations of ketanserin above 3 ng/mL.

An evaluation of the Abaxis VSPro for the measurement of equine plasma fibrinogen concentrations.

REASONS FOR PERFORMING STUDY: Accurate measurement of plasma fibrinogen concentrations is an important tool for assessment of horses with inflammatory diseases. OBJECTIVES: To determine the precision and accuracy of a benchtop instrument using both fresh and frozen equine plasma by comparing the plasma fibrinogen concentration measured by a benchtop instrument to 2 separate laboratory standard methods (ACL 100 and STA Compact) for fibrinogen measurement. METHODS: Accuracy and precision of the VSPro was evaluated using both human fibrinogen standards and samples from horses. Fifty frozen samples from horses with gastrointestinal disease had the fibrinogen concentration measured using the ACL 1000 and the VSPro. Fifty fresh samples were collected from hospitalised horses and fibrinogen concentration was measured using the STA Compact coagulation machine and the VSPro. Correlations for measurements were performed, as well as Bland-Altman analysis. RESULTS: Coefficients of variability for the VSPro ranged from 7% to 15%. The VSPro fibrinogen values were well correlated to both the ACL 1000 (r = 0.94, P<0.001) and the STA Compact measurements (r = 0.926, P<0.001). Bland-Altman analysis showed a mean bias of -0.83 g/l (95% confidence interval -2.03-0.324 g/l) for the ACL 1000 and a mean bias of -0.024 g/l (95% confidence interval -1.434-1.386 g/l) for the STA Compact. CONCLUSIONS: The VSPro appears to have adequate accuracy and precision for clinical measurement of plasma fibrinogen concentrations. POTENTIAL RELEVANCE: The VSPro provides a measurement of equine plasma fibrinogen concentration using a benchtop instrument with a rapid test time that has comparable accuracy to the fibrinogen concentration obtained from reference laboratories.

Thrombelastography in horses with acute gastrointestinal disease.

BACKGROUND: Coagulopathies in horses with gastrointestinal disease are frequently identified and associated with morbidity and fatality. OBJECTIVE: Determine if thrombelastography (TEG) identifies abnormalities associated with lesion type, presence of systemic inflammatory response syndrome (SIRS), morbidity, and fatality more consistently than traditional coagulation testing. ANIMALS: One-hundred and one horses examined for gastrointestinal disease and 20 healthy horses. METHODS: TEG, tissue factor (TF)-TEG, and traditional coagulation panels parameters and percentages of horses with coagulopathies were compared for lesion type, presence of SIRS, complications, and survival. RESULTS: Changes in individual parameters and increased incidence of coagulopathies were associated with fatality (R, P= .007; k-value [K], P= .004; clot lysis [CL]30, P= .037; CL60, P= .050; angle [Ang], P= .0003; maximum amplitude [MA], P= .006; lysis [Ly]30, P= .042; Ly60, P= .027; CI, P= .0004; ≥ 2 TEG coagulopathies, P= .013; ≥ 3 TEG coagulopathies, P= .038; TF-R, P= .037; TF-K, P= .004; TF-CL30, P < .0001; TF-CL60, P < .0001; TF-Ang, P= .005; TF-Ly30, P= .0002; TF-Ly60, P < .0001; TF-CI, P= .043; ≥ 1 TF-TEG coagulopathies, P= .003; ≥ 2 TF-TEG coagulopathies, P= .0004; prothrombin tme [PT], P < .0001; activated partial throboplastin time [aPTT], P= .021), inflammatory lesions (MA, P= .013; TF-CL30, P= .033; TF-CL60, P= .010; TF-Ly60, P= .011; ≥ 1 TF-TEG coagulopathy, P= .036; ≥ 2 TF-TEG coagulopathy, P= .0007; PT, P= .0005; fibrinogen, P= .019), SIRS (MA, P= .004; TF-CL30, P= .019; TF-CL60, P= .013; TF-Ly30, P= .020; TF-Ly60, P= .010; PT, P < .0001; aPTT, P= .032; disseminated intravascular coagulation, P= .005), and complications (ileus: aPTT, P= .020; diarrhea: TF-CL30, P= .040; TF-Ly30, P= .041; thrombophlebitis: ≥ 1 TF-TEG coagulopathy, P= .018; laminitis: MA, P= .004; CL60, P= .045; CI, P= .036; TF-MA, P= .019; TF-TEG CI, P= .019). Abnormalities in TEG and TF-TEG parameters were indicative of hypocoagulation and hypofibrinolysis. CONCLUSIONS AND CLINICAL IMPORTANCE: TEG identifies changes in coagulation and fibrinolysis associated with lesion type, SIRS, morbidity, and fatality in horses with gastrointestinal disease.

Effects of clopidogrel and aspirin on platelet aggregation, thromboxane production, and serotonin secretion in horses.

BACKGROUND: Critically ill horses are susceptible to thrombotic disease, which might be related to increased platelet reactivity and activation. OBJECTIVES: To compare the effect of oral clopidogrel and aspirin (ASA) on equine platelet function. ANIMALS: Six healthy adult horses. METHODS: Horses received clopidogrel (2 mg/kg p.o. q24h) or ASA (5 mg/kg p.o. q24h) for 5 days in a prospective randomized cross-over design. Platelet aggregation responses to adenosine diphosphate (ADP) and collagen via optical aggregometry, and platelet secretion of serotonin (5HT) and production of thromboxane B(2) (TXB(2) ) by ELISA were evaluated. In horses receiving clopidogrel, high-performance liquid chromatography analysis for clopidogrel and its carboxylic-acid metabolite SR 26334 was performed. RESULTS: SR 26334 was identified in all clopidogrel-treated horses, although the parent compound was not detected. Clopidogrel resulted in decreases in ADP-induced platelet aggregation persisting for 120 hours after the final dose. ADP-induced platelet aggregation decreased from a baseline of 70.2 ± 14.7% to a minimum of 15.9 ± 7.7% 24 hours after the final dose (P < .001). Collagen-induced aggregation decreased from a baseline of 93 ± 9.5% to a minimum of 70.8 ± 16.9% 48 hours after the final dose (P < .001). ASA did not decrease platelet aggregation with either agonist. ASA decreased serum TXB(2) from a baseline value of 1310 ± 1045 to 128 ± 64 pg/mL within 24 hours (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Clopidogrel effectively decreases ADP-induced platelet aggregation in horses, and could have therapeutic applications for equine diseases associated with platelet activation.