Furosemide continuous rate infusion diluted with 5% dextrose in water or hypertonic saline in normal adult dogs: a pilot study

Objective

The goal of this study was to investigate the short-term safety and diuretic efficacy of furosemide constant rate infusion (CRI) diluted with 5% dextrose in water (D5W) compared to dilution with 2.4% hypertonic saline in healthy dogs.

Pharmacodynamic assessment of diuretic efficacy and braking in a furosemide continuous infusion model

Introduction

Diuretic failure is a potential life-ending event but is unpredictable and poorly understood. The objectives of this study were to evaluate pharmacodynamic markers of furosemide-induced diuresis and to investigate mechanisms of diuretic braking in dogs receiving constant rate infusion (CRI) of furosemide.

Effect of sampling time on urinary electrolytes following oral furosemide administration in dogs with myxomatous mitral valve disease

Introduction/ObjectivesUrine chemistry has received growing attention to estimate the diuretic response in dogs with cardiac disease.The aim of the study was to evaluate the impact of time elapsed between the oral furosemide administration and sample collection on urine chemistry in dogs with myxomatous mitral valve disease (MMVD) receiving diuretic therapy in American College of Veterinary Internal Medicine (ACVIM) stage C.Materials and methodsSeventy-three dogs with MMVD ACVIM stage C and 106 healthy dogs were prospectively included. Dogs with MMVD were divided, based on the time of sampling, in morning group (MMVD-MG) of one to 6 h and an evening group (MMVD-EG) over 6 h from oral furosemide administration. Analogously, healthy dogs sampled between 9 a.m. and 1 p.m. and between 2 and 7 p.m. were divided in a morning group (H-MG) and an evening group (H-EG), respectively. Urine chemistry, including fractional excretion of electrolytes, was evaluated and compared among groups.ResultsHigher excretion of sodium and chloride and higher urine sodium to urine potassium ratio (uNa⁺:uK⁺) were detected in MMVD-MG than MMVD-EG (P = 0.021, P = 0.038, and P = 0.016, respectively). Natriuresis, chloriuresis, and uNa⁺:uK+ were higher in MMVD-MG than H-MG, while no differences were found in the comparison between H-MG and H-EG and between MMVD-EG and H-EG.ConclusionsUrinary electrolyte excretion is significantly increased within 6 h from furosemide administration in MMVD ACVIM stage C dogs. Time of sampling from furosemide administration significantly affects urine chemistry in MMVD dogs and should be considered in clinical practice and the research field.     

Effects of carvedilol treatment in dogs with chronic mitral valvular disease

BACKGROUND: Stimulation of the sympathetic nervous system occurs during the development of heart failure in dogs with chronic mitral valvular disease (CMVD). HYPOTHESIS: The use of beta-blockers to modulate the activation of the sympathetic nervous system would be useful in dogs with CMVD. ANIMALS: Group A included 13 dogs who received the conventional treatment (digoxin, benazepril, a reduced sodium diet, and codeine, and a diuretic when indicated), and group B included 12 dogs who received the protocol above plus carvedilol (0.3 mg/kg q12h). METHODS: Blinded, placebo, controlled study. RESULTS: The main echodopplercardiographic variables, heart rate, biochemical data, functional classification (FC) (New York Heart Association) and quality of life score (functional evaluation of cardiac health questionnaire) were assessed at baseline (TO) and after 3 months (T1). Only group B showed improvement in score of quality of life (13.8 +/- 8.8 versus 6.0 +/- 6.3; P < .001), in FC (2.4 - 0.9 versus 1.8 +/- 0.7; P = .032) and a reduction in systolic blood pressure (151.2 +/- 18.3 versus 124.5 +/- 23.4; P = .021). Two deaths from group A and 1 from B were related to CMVD. CONCLUSION: The studied dose of carvedilol in this group did not improve the sympathetic activation and echocardiographic variables over 3 months of chronic oral treatment. However, the results suggested a beneficial effect on the quality of life score, functional classification, and a reduction on systolic blood pressure.     

Time-action profiles of insulin detemir in normal and diabetic dogs

Insulin detemir is the first member of a new class of long-acting soluble insulin analogues capable of maintaining the basal level of insulin in humans. In this preliminary study, we investigated the time-action profiles of insulin detemir in normal and diabetic dogs since the use of insulin detemir in canines has yet to be determined. Eight animals were used in our study (three normal and five insulin dependent diabetic dogs). Time-action profiles of insulin detemir were monitored in normal dogs using an artificial pancreas apparatus under euglycemic condition. Blood sampling was performed at 2 h intervals post feeding, with insulin administration, in insulin dependent diabetic dogs. Time-action profiles of insulin detemir, in normal dogs, demonstrated that insulin detemir is a long-lasting preparation similar to what has been observed in humans. A pronounced peak was detected at 8–10 h while the glucose-lowering effect lasted for over 24 h after insulin injection, thus illustrating its longer prolonged peak activity time. Furthermore, intensive glycemic control was achieved with insulin detemir in insulin dependent diabetic dogs, using a lower dosage than NPH insulin and insulin glargine therapeutic doses. Our results indicate that insulin detemir has a greater effect than either NPH insulin or insulin glargine in canines, requiring a lower dose than either insulin preparation. However, using insulin detemir also carries a higher risk of inducing hypoglycemia as compared to either NPH insulin or insulin glargine.     

Furosemide continuous rate infusion in the horse: evaluation of enhanced efficacy and reduced side effects

Continuous rate infusion (CRI) of furosemide in humans is considered superior to intermittent administration (IA). This study examined whether furosemide CRI, compared with IA, would increase diuretic efficacy with decreased fluid and electrolyte fluctuations and activation of the renin-angiotensin-aldosterone system (RAAS) in the horse. Five mares were used in a crossover-design study. During a 24-hour period, each horse received a total of 3 mg/kg furosemide by either CRI (0.12 mg/kg/h preceded by a loading dose of 0.12 mg/kg IV) or IA (1 mg/kg IV q8h). There was not a statistically significant difference in urine volume over 24 hours between methods; however, urine volume was significantly greater after CRI compared with IA during the first 8 hours ([median 25th percentile, 75th percentile]: 9.6 L [8.9, 14.4] for CRI versus 5.9 L [5.3, 6.0] for IA). CRI produced a more uniform urine flow, decreased fluctuations in plasma volume, and suppressed renal concentrating ability throughout the infusion period. Potassium, Ca, and Cl excretion was greater during CRI than IA (1,133 mmol [1.110, 1,229] versus 764 mmol [709, 904], 102.7 mmol [96.0, 117.2] versus 73.3 mmol [65.0, 73.5], and 1,776 mmol [1,657, 2.378] versus 1,596 mmol [1,457, 1,767], respectively). Elimination half-lives of furosemide were 1.35 and 0.47 hours for CRI and IA, respectively. The area under the excretion rate curve was 1,285.7 and 184.2 mL x mg/mL for CRI and IA, respectively. Furosemide CRI (0.12 mg/kg/h) for 8 hours, preceded by a loading dose (0.12 mg/kg), is recommended when profound diuresis is needed acutely in horses.     

Use of rocuronium administered by continuous infusion in dogs

OBJECTIVE: A clinical trial to determine whether continuous infusion administration technique was suitable for maintaining neuromuscular blockade with rocuronium bromide in dogs. ANIMALS: Twenty-two dogs, 10 males and 12 females, median age 2 years 4 months, median weight 32 kg undergoing elective surgical procedures under general anaesthesia: ASA classification I or II. MATERIALS AND METHODS: After induction of anaesthesia, neuromuscular function was evaluated using train-of-four (TOF) stimulation of the dorsal buccal branch of the facial nerve. A bolus dose of 0.5 mg kg(-1) rocuronium was administered intravenously and an infusion of 0.2 mg kg(-1) hour(-1) was started immediately. Neuromuscular blockade was assessed visually by counting the number of twitches observed during TOF stimulation repeated at 10-second intervals. RESULTS: The bolus dose of rocuronium abolished the response to TOF stimulation in 21 of the 22 dogs. The median onset time of neuromuscular blockade (complete loss of all four twitches) was 82 seconds (range 38-184 seconds). Median infusion duration was 76 minutes (range 20.3-146 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: This protocol of rocuronium administration was considered to be effective in dogs. Constant infusion of rocuronium is easily applicable to clinical practice and further work is required on infusion titration.     

Evaluation of serum cystatin-C in dogs with visceral leishmaniasis

Serum Cystatin C (sCys-C) is one of the most important serum markers of renal function assessment in dogs. The purpose of this study was to determine the sCys-C concentration in dogs with visceral leishmaniasis (VL). In the study, 16 dogs with VL and 10 clinical healty dogs (control) were used. Mean sCys-C concentration of the infected dogs was significantly higher than that of the control group (p < 0.05). Mean serum creatinine concentration was lower and mean blood urea nitrogen, albumin and globulin concentrations were higher in dogs with VL; however, these changes were not statistically significant. Mean total protein and phosphorus concentrations were found to be higher in dogs with VL than healthy dogs (p < 0.05). No significant correlation had been determined between sCys-C and other variables. Visceral leishmaniasis in dogs has increased sCys-C concentration indicating a possible renal impairment; however, further studies are needed to be performed together with renal biopsies in the investigation sCys-C in dogs with VL.     

Estimated plasma bupivacaine concentration after single dose and eight-hour continuous intra-articular infusion of bupivacaine in normal dogs

Objective— To estimate maximum plasma concentration (C_max) and time to maximum plasma (t_max) bupivacaine concentration after intra‐articular administration of bupivacaine for single injection (SI) and injection followed by continuous infusion (CI) in normal dogs. Study Design— Cross‐over design with a 2‐week washout period. Animals— Healthy Coon Hound dogs (n=8). Methods— Using gas chromatography/mass spectrometry, canine plasma bupivacaine concentration was measured before and after SI (1.5 mg/kg) and CI (1.5 mg/kg and 0.3 mg/kg/h). Software was used to establish plasma concentration–time curves and estimate C_max, T_max and other pharmacokinetic variables for comparison of SI and CI. Results— Bupivacaine plasma concentration after SI and CI best fit a 3 exponential model. For SI, mean maximum concentration (C_max, 1.33±0.954 μg/mL) occurred at 11.37±4.546 minutes. For CI, mean C_max (1.13±0.509 μg/mL) occurred at 10.37±4.109 minutes. The area under the concentration–time curve was smaller for SI (143.59±118.390 μg/mL × min) than for CI (626.502±423.653 μg/mL × min, P=.02) and half‐life was shorter for SI (61.33±77.706 minutes) than for CI (245.363±104.415 minutes, P=.01). The highest plasma bupivacaine concentration for any dog was 3.2 μg/mL for SI and 2.3 μg/mL for CI. Conclusion— Intra‐articular bupivacaine administration results in delayed absorption from the stifle into the systemic circulation with mean C_max below that considered toxic and no systemic drug accumulation. Clinical Relevance— Intra‐articular bupivacaine can be administered with small risk of reaching toxic plasma concentrations in dogs, though toxic concentrations may be approached. Caution should be exercised with multimodal bupivacaine administration because plasma drug concentration may rise higher than with single intra‐articular injection.     

Comparison of primary mitral valve disease in German Shepherd dogs and in small breeds

The case records of 58 German Shepherds (GS group) affected by mitral valve prolapse (MVP) and/or mitral valve regurgitation (MR), and 49 dogs weighing < 15 kg (D group), affected by chronic valvular disease (CVD) were reviewed. The dogs of the GS group were presented more often without a detectable heart murmur (p < 0.01), and less frequently with a high intensity heart murmur (p < 0.01). Atrial fibrillation (AF) was more common in the GS group (p < 0.001). MVP associated with mitral valve thickening was more common in the D group (p < 0.001). Fractional shortening (FS) was lower (p < 0.0001) and end-systolic volume index (ESV-I) was increased (p < 0.0001) in the GS group, whereas end-diastolic volume index (EDV-I) did not differ between the 2 groups. Prevalence and severity of pulmonary hypertension were similar in the 2 groups. Dogs with mitral valve disease weighing more than 20 kg had a 5.8 higher chance of developing decreased FS, increased ESV-I, AF and ventricular arrhythmias. In the GS group, the decreased FS and increased ESV-I were not associated with the presence of AF or ventricular arrhythmias (p > 0.05). It appears that GS may be affected both by mitral valve prolapse and mitral insufficiency. It also appears that a comparatively large proportion of GS shows no major mitral valve thickening or MVP, but still presents with significant mitral regurgitation, possibly suggesting a different cause for the important incompetence observed in most cases.     

Comparison of time-action profiles of insulin Glargine and NPH insulin in normal and diabetic dogs

Intermediate insulin injections are commonly used for glycemic control in insulin dependent diabetic dogs acting as a replacement for natural insulin. Neutral Protamin Hagedorn (NPH) insulin and insulin glargine are two types of injectable insulin preparations commonly used in humans. In our study, we investigated the time-action profiles of both aforementioned insulin preparations in normal dogs in order to determine whether co-administration of NPH and glargine would be of benefit to insulin dependent diabetic dogs as it is for humans suffering from insulin dependent diabetes. Time-action profiles of NPH insulin and insulin glargine in normal dogs demonstrated a clear difference between both insulin preparations confirming that NPH insulin is an intermediate-acting preparation whereas insulin glargine is a long-lasting preparation. In addition, co-administration of NPH insulin and insulin glargine resulted in tight glycemic control as compared to NPH insulin alone in insulin dependent diabetic dogs. However, co-administration result in hypoglycemia at the dosages tested.     

Placental transfer of etomidate in pregnant ewes after an intravenous bolus dose and continuous infusion

Etomidate (ETO) is a short-acting intravenous (IV) anaesthetic characterised by cardiopulmonary stability and favourable pharmacokinetics. Although ETO has been used satisfactorily in obstetrical anaesthesia, little is known about placental transfer and the drug's pharmacokinetics in the fetus. Placental transfer in pregnant ewes has been evaluated following the administration of an IV bolus of 1mg/kg ETO; and after a 1-h infusion of 100 microg/kg min(-1) ETO preceded by an IV bolus of 1mg/kg. In ewes, ETO concentration and AUC were higher than those found in fetuses. After the ETO bolus dose, the fetus:ewe AUC ratio was 0.45+/-0.32, and the mean residence time (MRT) was 20+/-7 min for dams and 22+/-3 min for the fetuses. After ETO infusion, the AUC ratio was 0.37+/-0.08, and MRT was 46+/-12 min for ewes and 46+/-22 min for fetuses. Although ETO crosses the placenta very rapidly and reaches the fetus in high amounts, a certain placental barrier effect limits its transfer. There is no evidence of cumulative effects of the drug in the fetus as fetal ETO elimination was as rapid as in the dam.     

Effects of dexamethasone infusion on the plasma cortisol response to cosyntropin (synthetic ACTH) injection in normal dogs

Graded dosages of cosyntropin (synthetic corticotropin) were injected into groups of normal dogs on consecutive days. On the first day, cosyntropin was administered alone and, on the second, dogs were infused with dexamethasone three hours before cosyntropin injection. Adrenocortical function was assessed by sequential measurement of plasma cortisol (hydrocortisone) concentration. While no response differences were noted to the various amounts of cosyntropin injected with or without dexamethasone pretreatment, the magnitude of adrenocortical response was significantly greater in dogs infused with dexamethasone. It is concluded that dexamethasone pretreatment renders the canine adrenal cortex more responsive to a subsequent injection of cosyntropin. The combined dexamethasone infusion-cosyntropin injection test produces consistent adrenocortical responses in normal dogs, and has potential value in evaluation of adrenopathic dogs.     

Echocardiography and conventional Doppler examination in clinically healthy adult Cavalier King Charles Spaniels: Effect of body weight,age, and gender,and establishment of reference intervals

ObjectivesThe objectives of this study were (1) to assess the potential effect of body weight (BW), age, and gender on the most commonly used echocardiographic and conventional Doppler variables in a large population of healthy Cavalier King Charles Spaniels (CKCS), and (2) to establish the corresponding reference intervals (RI).Animals134 healthy adult CKCS.MethodsUltrasound examinations were performed by trained observers in awake dogs. M-mode variables included left ventricular (LV) end-diastolic and end-systolic diameters, LV free wall and interventricular septal thicknesses at end-diastole and end-systole, and LV fractional shortening (FS%). The left atrium (LA) and aortic (Ao) diameters were measured using a 2D method, and the LA/Ao was calculated. Pulsed-wave Doppler variables included peak systolic aortic and pulmonary flow velocities, mitral E and A waves, and E/A ratio. Effects of BW, age, and gender on these 15 variables were tested using a general linear model, and RIs were determined by applying the statistical procedures recommended by the Clinical and Laboratory Standards Institute.ResultsA significant BW effect was observed for all variables, except LA/Ao, FS%, and mitral E/A ratio. A significant but negligible effect of gender and age was also observed for 5/15 and 4/15 of the tested variables, respectively. Only the BW effect on M-mode variables was considered as clinically relevant and the corresponding regression-based RIs were calculated.ConclusionsBody weight should be taken into account when interpreting echocardiographic values in CKCS, except for LA/Ao, FS%, and mitral E/A ratio.     

Allometric scaling of M-mode cardiac measurements in normal adult dogs

Indices for M-mode measurements in dogs usually have been based on the assumption that a linear relationship exists between these measurements and body weight (BW) or body surface area (BSA). The relationships between the geometry of 3-dimensional objects do not support this assumption. The purposes of this study were to retrospectively examine M-mode data from a large number of dogs of varying sizes and breeds that were examined by a large number of ultrasonographers, to use the allometric equation to determine the appropriate BW exponent required to predict these cardiac dimensions, and to determine normal mean values and prediction intervals for common M-mode variables. Linear regression analyses of data from 494 dogs (2.2-95 kg) revealed a good correlation between M-mode measurements and BW after logarithmic transformation of the data (r2 = .55-.88). Most variables were most closely related to an index of body length, BW(1/3), although the exponent that best predicted diastolic and systolic left ventricular wall thicknesses was closer to 0.25. No variable indexed well to BW or BSA. With these data, appropriate mean values and prediction intervals were calculated for normal dogs, allowing veterinarians to correctly and appropriately index M-mode values. The equations developed from this study appear to be applicable to adult dogs of most breeds.     

Comparison between continuous rate infusion and target-controlled infusion of propofol in dogs: a randomized clinical trial

ObjectiveTo compare a propofol continuous rate infusion (CRI) with a target-controlled infusion (TCI) in dogs.Study designRandomized prospective double-blinded clinical study.AnimalsA total of 38 healthy client-owned dogs.MethodsDogs premedicated intramuscularly with acepromazine (0.03 mg kg^–1) and an opioid (pethidine 3 mg kg^–1, morphine 0.2 mg kg^–1 or methadone 0.2 mg kg^–1) were allocated to P-CRI group (propofol 4 mg kg^–1 intravenously followed by CRI at 0.2 mg kg^–1 minute^–1), or P-TCI group [propofol predicted plasma concentration (Cp) of 3.5 μg mL^–1 for induction and maintenance of anaesthesia via TCI]. Plane of anaesthesia, heart rate, respiratory rate, invasive blood pressure, oxygen haemoglobin saturation, end-tidal carbon dioxide and body temperature were monitored by an anaesthetist blinded to the group. Numerical data were analysed by unpaired t test or Mann–Whitney U test, one-way analysis of variance and Dunnett’s post hoc test. Categorical data were analysed with Fisher’s exact test. Significance was set for p < 0.005.ResultsOverall, propofol induced a significant incidence of relative hypotension (mean arterial pressure 20% below baseline, 45%), apnoea (71%) and haemoglobin desaturation (65%) at induction of anaesthesia, with a higher incidence of hypotension and apnoea in the P-CRI than P-TCI group (68% versus 21%, p = 0.008; 84% versus 58%, p = 0.0151, respectively). Propofol Cp was significantly higher at intubation in the P-CRI than P-TCI group (4.83 versus 3.5 μg mL^–1, p < 0.0001), but decreased during infusion, while Cp remained steady in the P-TCI group. Total propofol administered was similar between groups.Conclusions and clinical relevanceBoth techniques provided a smooth induction of anaesthesia but caused a high incidence of side effects. Titration of anaesthesia with TCI caused fewer fluctuations in Cp and lower risk of hypotension compared with CRI.     

Total bilirubin is an independent predictor of death in dogs with degenerative valvular disease and dilated cardiomyopathy

IntroductionThere is little published regarding the association between canine cardiovascular disease and the hepatic system. The objective of the study was to evaluate the relationship between hepatic parameters, survival, and disease stages of dogs with either dilated cardiomyopathy (DCM) or degenerative valvular disease (DVD).Animals, materials, and methodsRetrospective study analyzing hepatic parameters in dogs with DVD or DCM in American College of Veterinary Internal Medicine stage B or C and healthy control dogs. Associations between liver parameters, type and stage of disease, and survival were investigated.ResultsNinety-nine dogs were included in the study: 61 DVD, 22 DCM, and 16 controls. Differences in liver parameter concentrations between DCM, DVD, and disease stages were found. Univariate analysis identified alanine aminotransferase (P < 0.001), aspartate aminotransferase (P = 0.02), and total bilirubin (P = 0.005) as predictors of mortality. In the multivariate analysis, total bilirubin remained an independent predictor of mortality.ConclusionsThe observed differences between DCM, DVD, and disease stages are likely consistent with disease-specific hemodynamics and progression of disease. This and the role of total bilirubin as an independent predictor for mortality indicate that in dogs with DVD and DCM the cardiovascular–hepatic interaction might be of relevance for disease progression and outcome, as reported for humans with cardiac disease. Further studies into the role of hepatic function in canine cardiac disease are required.     

Pharmacokinetics of fentanyl after single intravenous injection and constant rate infusion in dogs

OBJECTIVE: To determine the plasma concentration and define the pharmacokinetic characteristics of fentanyl (10 microg kg(-1)) administered as a single intravenous (IV) injection followed by: (a) no further drug; or (b) a constant rate infusion (CRI) of fentanyl 10 microg kg(-1) hour(-1) lasting 1, 3 or 4 hours in dogs. Animals Fourteen healthy adult beagles (seven males and seven females). EXPERIMENTAL DESIGN: Randomized cross-over design. MATERIALS AND METHODS: Dogs were randomly assigned to four treatment groups. Drugs were administered to each dog in a randomized cross-over design with at least a 14-day washout interval between experiments. All dogs received an IV loading dose of fentanyl (10 microg kg(-1)). One group received no further fentanyl. In others, the loading dose was followed by a CRI of fentanyl (10 microg kg(-1) hour(-1)) for 1, 3 or 4 hours. Blood samples were collected and plasma fentanyl concentrations determined using high-performance liquid chromatography-mass spectrometry. Plasma pharmacokinetic estimates were obtained by plotting plasma concentrations versus time data and by fitting the change in concentration to a pharmacokinetic model, using a purpose-built program written by the Graduate School of Pharmaceutical Sciences (Kyoto University) in Visual Basic (VBA) on Excel (Microsoft Corporation). RESULTS: Plasma fentanyl concentration decreased rapidly after single IV injection: the plasma concentration-time curve best fitted a two-compartment model. Pharmacokinetic variables for IV injection were characterized by a short distribution half-time (t1/2alpha was 4.5 minutes), a relatively long elimination half time (t1/2beta was 45.7 minutes), a large volume of distribution (approximately 5 L kg(-1)) and high total body clearance (77.9 mL minute(-1) kg(-1)). Stable plasma fentanyl levels were obtained in all CRI groups although pharmacokinetic variables were influenced by the duration of administration. CONCLUSIONS AND CLINICAL RELEVANCE: While this study clarified the pharmacokinetic features of rapid IV fentanyl injection and CRI in dogs, the plasma concentration achieving analgesia was not and so further research is needed. Further studies on the effects of other sedatives and/or anaesthetics on fentanyl's disposition are also required as the drug is commonly used with other agents.