Low-dose desoxycorticosterone pivalate treatment of hypoadrenocorticism in dogs: A randomized controlled clinical trial.

BACKGROUND: Desoxycorticosterone pivalate (DOCP) is a commonly used mineralocorticoid replacement for dogs with primary hypoadrenocorticism (HA), but manufacturer-recommended dosing protocols can be cost-prohibitive. Recent reports also have raised concerns that label dose protocols could be excessive. OBJECTIVE: To investigate the relative efficacy and adverse effects of 2 DOCP dosages in dogs with primary glucocorticoid and mineralocorticoid deficient HA. ANIMALS: Thirty-seven dogs, including 19 test population dogs and 18 controls. METHODS: Randomized controlled double-blinded clinical trial. Dogs with newly diagnosed primary HA were assigned to standard (2.2 mg/kg q30d, control population) or low-dose (1.1 mg/kg q30d, test population) DOCP treatment. Clinical and laboratory variables were assessed 10 to 14 days and approximately 30 days after each DOCP treatment for 90 days. RESULTS: Mean serum sodium to potassium ratios at reevaluations were ≥32 in both populations throughout the study. No dog developed electrolyte abnormalities warranting medical treatment, although hypokalemia occurred on at least 1 occasion in 9 controls and 6 test population dogs. Urine specific gravities (median, interquartile range) were lower in control dogs (1.022, 1.016-1.029) as compared to test population dogs (1.033, 1.023-1.039; P = .006). Plasma renin activity was overly suppressed on 84 of 104 (80.8%) assessments in control dogs whereas increased renin activity occurred on 23 of 112 (20.5%) assessments in test population dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Low-dose DOCP protocols appear to be safe and effective for treatment of HA in most dogs. Standard-dose protocols are more likely to result in biochemical evidence of overtreatment.

Comparison of noninvasive pulse transit time estimates as markers of blood pressure using invasive pulse transit time measurements as a reference.

Pulse transit time (PTT) measured as the time delay between invasive proximal and distal blood pressure (BP) or flow waveforms (invasive PTT [I-PTT]) tightly correlates with BP PTT estimated as the time delay between noninvasive proximal and distal arterial waveforms could therefore permit cuff-less BP monitoring. A popular noninvasive PTT estimate for this application is the time delay between ECG and photoplethysmography (PPG) waveforms (pulse arrival time [PAT]). Another estimate is the time delay between proximal and distal PPG waveforms (PPG-PTT). PAT and PPG-PTT were assessed as markers of BP over a wide physiologic range using I-PTT as a reference. Waveforms for determining I-PTT, PAT, and PPG-PTT through central arteries were measured from swine during baseline conditions and infusions of various hemodynamic drugs. Diastolic, mean, and systolic BP varied widely in each subject (group average (mean ± SE) standard deviation between 25 ± 2 and 36 ± 2 mmHg). I-PTT correlated well with all BP levels (group average R(2) values between 0.86 ± 0.03 and 0.91 ± 0.03). PPG-PTT also correlated well with all BP levels (group average R(2) values between 0.81 ± 0.03 and 0.85 ± 0.02), and its R(2) values were not significantly different from those of I-PTT PAT correlated best with systolic BP (group average R(2) value of 0.70 ± 0.04), but its R(2) values for all BP levels were significantly lower than those of I-PTT (P < 0.005) and PPG-PTT (P < 0.02). The pre-ejection period component of PAT was responsible for its inferior correlation with BP In sum, PPG-PTT was not different from I-PTT and superior to the popular PAT as a marker of BP.

Pharmacologic evaluation of ammonium tetrathiomolybdate after intravenous and oral administration to healthy dogs.

OBJECTIVE: To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations. ANIMALS: 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females). PROCEDURES: Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis. RESULTS: For IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 4.9 ± 0.6 µg/mL, 30.7 ± 5.4 µg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 3.0 ± 3.5 hours, 0.2 ± 0.4 µg/mL, 6.5 ± 8.0 µg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs). CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Cardioversion of atrial fibrillation in a dog with structural heart disease using an esophageal-right atrial lead configuration.

Atrial fibrillation is a common arrhythmia in dogs with structural cardiac disease and can result in significant clinical signs. Several methods of electrical cardioversion of atrial fibrillation have been described. Biphasic transthoracic cardioversion of atrial fibrillation in dogs with naturally occurring heart disease has been described in veterinary medicine and has been shown to be highly successful. In humans and research animals intracardiac and transesophageal cardioversion of atrial fibrillation has been described as an alternative to transthoracic cardioversion. While transesophageal cardioversion is very successful in humans and research animals, this technique has not been previously described in a clinical patient with naturally occurring heart disease in veterinary medicine. This report describes the use of transesophageal cardioversion in a dog with atrial fibrillation and structural cardiac disease. Cardioversion was unsuccessful using two electrodes positioned within the esophagus. Cardioversion of atrial fibrillation to normal sinus rhythm was successfully achieved and maintained using one electrode positioned within the esophagus and one electrode positioned within the right atrium using a synchronized monophasic shock of 50 J.

Improved pulse wave velocity estimation using an arterial tube-load model.

Pulse wave velocity (PWV) is the most important index of arterial stiffness. It is conventionally estimated by noninvasively measuring central and peripheral blood pressure (BP) and/or velocity (BV) waveforms and then detecting the foot-to-foot time delay between the waveforms wherein wave reflection is presumed absent. We developed techniques for improved estimation of PWV from the same waveforms. The techniques effectively estimate PWV from the entire waveforms, rather than just their feet, by mathematically eliminating the reflected wave via an arterial tube-load model. In this way, the techniques may be more robust to artifact while revealing the true PWV in absence of wave reflection. We applied the techniques to estimate aortic PWV from simultaneously and sequentially measured central and peripheral BP waveforms and simultaneously measured central BV and peripheral BP waveforms from 17 anesthetized animals during diverse interventions that perturbed BP widely. Since BP is the major acute determinant of aortic PWV, especially under anesthesia wherein vasomotor tone changes are minimal, we evaluated the techniques in terms of the ability of their PWV estimates to track the acute BP changes in each subject. Overall, the PWV estimates of the techniques tracked the BP changes better than those of the conventional technique (e.g., diastolic BP root-mean-squared errors of 3.4 versus 5.2 mmHg for the simultaneous BP waveforms and 7.0 versus 12.2 mmHg for the BV and BP waveforms (p <; 0.02)). With further testing, the arterial tube-load model-based PWV estimation techniques may afford more accurate arterial stiffness monitoring in hypertensive and other patients.

Emax monitoring by aortic pressure waveform analysis.

Emax- the maximal left ventricular elastance- is perhaps the best available scalar index of contractility. However, the conventional method for its measurement involves obtaining multiple ventricular pressure-volume loops at different loading conditions and is thus impractical. We previously proposed a more practical technique for tracking Emax from just a single beat of an aortic pressure waveform based on a lumped parameter model of the left ventricle and arteries. Here, we tested the technique against the conventional Emax measurement method in animals during inotropic interventions. Our results show that the estimated Emax changes corresponded fairly well to the reference changes, with a correlation coefficient of 0.793. With further development and testing, the technique could ultimately permit continuous and less invasive monitoring of Emax.

Novel cutaneous use of implantable loop recorders in two dogs with unexplained episodes of collapse.

Determining the cause of episodes of collapse can be difficult. Even in patients with frequent collapsing episodes due to cardiac causes, diagnostic surface electrocardiogram and 24 hr ambulatory electrocardiographic (Holter) monitoring are sometimes inconclusive. Event monitors with multiple leads can be challenging to use in veterinary medicine over long periods of time due to lead dislodgment. Implantable leadless loop recorders (ILRs) are useful, but owners are sometimes unwilling to have an ILR implanted due to the associated risks and/or costs. In this case report, the authors describe the use of cutaneously placed ILRs in two dogs with unexplained episodes of collapse/exercise intolerance. Data recorded provided clinically useful information. Cutaneously placed ILRs can be used effectively in veterinary medicine to evaluate patients with unexplained episodes of collapse.

Caudal vena cava kinking in dogs with ascites.

A 9-year-old dog with spontaneous ascites was found to have hepatic vein distension and a tortuous vena cava on abdominal ultrasound. In right lateral recumbency, the caudal vena cava crossed the diaphragm and became kinked before entering into the right atrium. Following this observation, we performed an experimental study in a normal dog to determine whether kinking of the caudal vena cava could be the result and not the cause of ascites. Ascites was induced using warm saline injected through a needle inserted into the abdominal cavity. Venograms were collected from different body positions, under four conditions: before and after a total of one, two and 3 liters of saline had been injected. Caudal vena cava kinking was observed in the experimental dog after 2 liters of fluid had been injected. Vena cava obstruction may cause ascites, but we found that sometimes caudal vena cava kinking can be the result and not the cause of the peritoneal effusion.

Pulse arrival time is not an adequate surrogate for pulse transit time as a marker of blood pressure.

Pulse transit time (PTT) is a proven, simple to measure, marker of blood pressure (BP) that could potentially permit continuous, noninvasive, and cuff-less BP monitoring (after an initial calibration). However, pulse arrival time (PAT), which is equal to the sum of PTT and the pre-ejection period, is gaining popularity for BP tracking, because it is even simpler to measure. The aim of this study was to evaluate the hypothesis that PAT is an adequate surrogate for PTT as a marker of BP. PAT and PTT were estimated through the aorta using high-fidelity invasive arterial waveforms obtained from six dogs during wide BP changes induced by multiple interventions. These time delays and their reciprocals were evaluated in terms of their ability to predict diastolic, mean, and systolic BP (DBP, MBP, and SBP) per animal. The root mean squared error (RMSE) between the BP parameter predicted via the time delay and the measured BP parameter was specifically used as the evaluation metric. Taking the reciprocals of the time delays tended to reduce the RMSE values. The DBP, MBP, and SBP RMSE values for 1/PAT were 9.8 ± 5.2, 10.4 ± 5.6, and 11.9 ± 6.1 mmHg, whereas the corresponding values for 1/PTT were 5.3 ± 1.2, 4.8 ± 1.0, and 7.5 ± 2.2 mmHg (P < 0.05). Thus tracking BP via PAT was not only markedly worse than via PTT but also unable to meet the FDA BP error limits. In contrast to previous studies, our results quantitatively indicate that PAT is not an adequate surrogate for PTT in terms of detecting challenging BP changes.

Pulse arrival time is not an adequate surrogate for pulse transit time in terms of tracking diastolic pressure.

We compared pulse arrival time (PAT) and pulse transit time (PTT) in terms of their ability to track diastolic pressure (DP). We performed the comparison using high fidelity, invasive arterial waveforms recorded from six dogs during multiple interventions. On average, DP ranged from 40 to 106 mmHg and therefore varied widely. PAT and PTT were able to predict DP with average root-mean-squared-errors of 9.8 ± 5.8 mmHg and 5.7 ± 2.0 mmHg (p = 0.02). Thus, even though PAT is simpler to measure, we can only recommend using PTT for tracking DP.

Calculation of forward and backward arterial waves by analysis of two pressure waveforms.

We developed a technique to calculate forward and backward arterial waves from proximal and distal pressure waveforms. First, the relationship between the waveforms is represented with an arterial tube model. Then, the model parameters are estimated via least-squares fitting. Finally, the forward and backward waves are calculated using the parameter estimates. Thus, unlike most techniques, the arterial waves are determined without a more difficult flow measurement or an experimental perturbation. We applied the technique to central aortic and femoral artery pressure waveforms from anesthetized dogs during drug infusions, volume changes, and cardiac pacing. The calculated waves predicted an abdominal aortic pressure waveform measurement more accurately (2.4 mmHg error) than the analyzed waveforms (5.3 mmHg average error); reliably predicted relative changes in a femoral artery flow measurement (14.7% error); and changed as expected with selective vasoactive drugs. The ratio of the backward- to forward-wave magnitudes was 0.37 ± 0.05 during baseline. This index increased by ∼50% with phenylephrine and norepinephrine, decreased by ∼60% with dobutamine and nitroglycerin, and changed little otherwise. The time delay between the waves in the central aorta was 175 ± 14 ms during baseline. This delay varied by ±âˆ¼25% and was inversely related to mean pressure.

Effect of semen in urine specimens on urine protein concentration determined by means of dipstick analysis.

OBJECTIVE: To determine the effect of semen in urine specimens on urine protein concentration measured by means of dipstick analysis. SAMPLE POPULATION: 14 urine samples from 3 adult castrated male dogs and 14 semen samples from 7 adult sexually intact male dogs. PROCEDURES: Serial dilutions of the whole ejaculate or spermatozoa-free seminal fluid in urine were created, and unaltered and diluted urine samples were analyzed by means of a commercially available dipstick; pH and specific gravity of the samples were also measured. Spermatozoa and WBC counts of the semen samples and protein concentration of the seminal fluid were determined. RESULTS: Protein concentrations determined by means of dipstick analysis of urine samples to which whole ejaculate (dilutions of 1:1, 1:2, 1:16, 1:64, and 1:256) or seminal fluid (dilutions of 1:1, 1:2, 1:16, and 1:64) had been added were significantly higher than concentrations in unaltered urine samples. All 13 samples to which whole ejaculate was added at a dilution of 1:2 and 10 of 12 samples to which seminal fluid was added at a dilution of 1:2 were positive for blood on dipstick analysis. There was no significant linear correlation between spermatozoa or WBC count of the semen sample and protein concentration of the spermatozoa-free seminal fluid. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that regardless of whether spermatozoa were present, semen contamination could result in false-positive results for protein and blood during dipstick analysis of urine samples from sexually intact male dogs.

Iron sufficient to cause hepatic fibrosis and ascites does not cause cardiac arrhythmias in the gerbil.

Chronic iron overload associated with hereditary hemochromatosis or repeated red cell transfusions is known to cause cardiac failure. Cardiac arrhythmias have been incidentally noted in patients with iron overload, but they are often dismissed as being related to comorbid conditions. Studies with anesthetized iron-loaded gerbils using short recordings suggest a role for iron in the development of arrhythmias. Our goal was to characterize iron-induced arrhythmias in the chronically instrumented, untethered, telemetered gerbil. Electrocardiograms were recorded for 10 s every 30 min for approximately 6 months in iron-loaded (n=23) and control (n=8) gerbils. All gerbils in both groups showed evidence of frequent sinus arrhythmia. There was no difference in heart rate, electrocardiographic parameters, or number of arrhythmias per minute between groups. Gerbils rarely showed significant arrhythmias. Body weight and heart weight were not significantly different between groups, whereas liver weight increased with increasing iron dose in the treated group. Cardiac and hepatic iron concentrations were significantly increased in iron-loaded gerbils. Eight of 14 gerbils loaded to 6.2 g/kg body weight developed ascites. We conclude that an iron load sufficient to cause clinical liver disease does not cause cardiac arrhythmias in the gerbil model of iron overload.

An adaptive transfer function for deriving the aortic pressure waveform from a peripheral artery pressure waveform.

We developed a new technique to mathematically transform a peripheral artery pressure (PAP) waveform distorted by wave reflections into the physiologically more relevant aortic pressure (AP) waveform. First, a transfer function relating PAP to AP is defined in terms of the unknown parameters of a parallel tube model of pressure and flow in the arterial tree. The parameters are then estimated from the measured PAP waveform along with a one-time measurement of the wave propagation delay time between the aorta and peripheral artery measurement site (which may be accomplished noninvasively) by exploiting preknowledge of aortic flow. Finally, the transfer function with its estimated parameters is applied to the measured waveform so as to derive the AP waveform. Thus, in contrast to the conventional generalized transfer function, the transfer function is able to adapt to the intersubject and temporal variability of the arterial tree. To demonstrate the feasibility of this adaptive transfer function technique, we performed experiments in 6 healthy dogs in which PAP and reference AP waveforms were simultaneously recorded during 12 different hemodynamic interventions. The AP waveforms derived by the technique showed agreement with the measured AP waveforms (overall total waveform, systolic pressure, and pulse pressure root mean square errors of 3.7, 4.3, and 3.4 mmHg, respectively) statistically superior to the unprocessed PAP waveforms (corresponding errors of 8.6, 17.1, and 20.3 mmHg) and the AP waveforms derived by two previously proposed transfer functions developed with a subset of the same canine data (corresponding errors of, on average, 5.0, 6.3, and 6.7 mmHg).

Cardiac output and left atrial pressure monitoring by right ventricular pressure waveform analysis for potential implantable device application.

A well-tested and safe implantable device is now available for long-term ambulatory monitoring of the right ventricular pressure (RVP) waveform of congestive heart failure patients. However, cardiac output (CO) and left atrial pressure (LAP) are more useful for assessing cardiac function and managing volume status. We developed a new technique to estimate relative CO change and LAP by long time interval analysis of the RVP waveform. To demonstrate feasibility, we performed four chronic canine experiments in which the RVP waveform and accurate reference measurements were simultaneously recorded during common hemodynamic interventions. The overall root-mean-squared-errors of the estimated relative CO change and LAP were 16.0% and 2.0 mmHg. For comparison, the corresponding errors for the previously proposed intra-beat RVP waveform analysis techniques were 21% and 160% higher. With further successful testing, the new technique may potentially be employed with an established implantable device for chronic monitoring of essential hemodynamic variables.

Continuous left ventricular ejection fraction monitoring by aortic pressure waveform analysis.

We developed a technique to monitor left ventricular ejection fraction (EF) by model-based analysis of the aortic pressure waveform. First, the aortic pressure waveform is represented with a lumped parameter circulatory model. Then, the model is fitted to each beat of the waveform to estimate its lumped parameters to within a constant scale factor equal to the arterial compliance (C (a)). Finally, the proportional parameter estimates are utilized to compute beat-to-beat absolute EF by cancelation of the C (a) scale factor. In this way, in contrast to conventional imaging, EF may be continuously monitored without any ventricular geometry assumptions. Moreover, with the proportional parameter estimates, relative changes in beat-to-beat left ventricular end-diastolic volume (EDV), cardiac output (CO), and maximum left ventricular elastance (E (max)) may also be monitored. To evaluate the technique, we measured aortic pressure waveforms, reference EF and EDV via standard echocardiography, and other cardiovascular variables from six dogs during various pharmacological influences and total intravascular volume changes. Our results showed overall EF and calibrated EDV root-mean-squared-errors of 5.6% and 4.1 mL, and reliable estimation of relative E (max) and beat-to-beat CO changes. These results demonstrate, perhaps for the first time, the feasibility of estimating EF from only a blood pressure waveform.

Continuous cardiac output and left atrial pressure monitoring by long time interval analysis of the pulmonary artery pressure waveform: proof of concept in dogs.

We developed a technique to continuously (i.e., automatically) monitor cardiac output (CO) and left atrial pressure (LAP) by mathematical analysis of the pulmonary artery pressure (PAP) waveform. The technique is unique to the few previous related techniques in that it jointly estimates the two hemodynamic variables and analyzes the PAP waveform over time scales greater than a cardiac cycle wherein wave reflections and inertial effects cease to be major factors. First, a 6-min PAP waveform segment is analyzed so as to determine the pure exponential decay and equilibrium pressure that would eventually result if cardiac activity suddenly ceased (i.e., after the confounding wave reflections and inertial effects vanish). Then, the time constant of this exponential decay is computed and assumed to be proportional to the average pulmonary arterial resistance according to a Windkessel model, while the equilibrium pressure is regarded as average LAP. Finally, average proportional CO is determined similar to invoking Ohm's law and readily calibrated with one thermodilution measurement. To evaluate the technique, we performed experiments in five dogs in which the PAP waveform and accurate, but highly invasive, aortic flow probe CO and LAP catheter measurements were simultaneously recorded during common hemodynamic interventions. Our results showed overall calibrated CO and absolute LAP root-mean-squared errors of 15.2% and 1.7 mmHg, respectively. For comparison, the root-mean-squared error of classic end-diastolic PAP estimates of LAP was 4.7 mmHg. On future successful human testing, the technique may potentially be employed for continuous hemodynamic monitoring in critically ill patients with pulmonary artery catheters.

Quantification of forward and backward arterial waves by model-based analysis of aortic and femoral artery pressure waveforms.

We developed a technique to quantify forward and backward arterial waves by model-based analysis of aortic and femoral artery pressure waveforms. Thus, in contrast to conventional techniques, our technique does not require a more difficult arterial flow measurement. We validated the forward and backward waves through a set of canine experiments by showing that the waves accurately predicted a third arterial pressure waveform measurement and changed in the expected manner to interventions of known effect. We also calculated the waves during nine different hemodynamic conditions. Our results showed that the relative magnitude of the backward wave was smallest during nitroglycerin and dobutamine and largest during phenylephrine and hemorrhage, while the time delay between the two waves was smallest during atrial pacing and about the same during the remaining eight conditions.

Towards automating the pulmonary artery catheter: a canine validation study.

We have recently introduced a unique technique to automatically estimate both cardiac output (CO) and left atrial pressure (LAP) by pulmonary artery pressure (PAP) waveform analysis. In this contribution, we review the technique and present its evaluation with respect to gold standard, but highly invasive, reference aortic flow probe CO and direct LAP catheter measurements from two dogs during various pharmacological interventions. We report that the technique achieved an overall CO error of 15.3% and an overall LAP error of 17.1% over a wide hemodynamic range. For comparison, the overall LAP error of classic end-diastolic PAP estimates was about three times as large. With further successful testing, the technique may ultimately be employed so as to effectively automate the pulmonary artery catheter.