Over rime, many patients become refractory to standard medical therapy as disease progression continues or if a concurrent systemic disease process develops that exerts detrimental effects on the cardiovascular system (e.g., hyperadrenocorticism, hypothyroidism, renal failure, systemic Hypertension, neoplasia, anemia, pneumonia, or pulmonary thromboembolism). Infrequent causes of an acute bout of decompensation include the development of hemodynamically important arrhythmias, sudden rupture of chordae tendineae, or splitting of the left atrial wall subsequent to severe mitral insufficiency and elevated left atrial pressure. For these reasons, any patient that continues to show clinical signs of congestion or low cardiac output despite appropriate medical therapy should be closely re-evaluated. After determining whether the owner is administering the prescribed drugs at the appropriate intervals, the practitioner should obtain an ECG, thoracic radiographs, complete blood count, biochemical profile, and blood pressure measurement. Echocardiography often is warranted to characterize the severity of valvular insufficiency, the extent of chamber enlargement, and the degree of systolic dysfunction.
If an underlying disease process is identified, it should be managed appropriately before institution of therapy with new cardiac drugs. Attempts should be made to suppress significant ventricular arrhythmias; agents capable of slowing conduction through the atrioventricular node (e.g., calcium channel Mockers or beta blockers) may be required to help control the ventricular response rate in the face of atrial fibrillation. Potent afterload reduction with nitroprusside or hydralazine often is required to combat the effects of ruptured chordae tendineae. Left atrial tears are difficult to manage.
If no underlying disease process is identified, several strategies may be used to manage these refractory patients. Afterload reduction using arterial vasodilators, preload reduction using additional diuretics or venodilators, or additional neurohormonal blockade using beta blockers or spironolactone may be warranted. The route of diuretic administration may be modified, or positive inotropic agents periodically may be given intravenously. The inherent risks and complications of treatment are greatest in patients with refractory heart failure, and referral to a specialist is wiser than embarking on an unconventional treatment protocol.
Vasodilators promote smooth muscle relaxation of the arterioles (arterial vasodilators), veins (venodilators), or arteries and veins (balanced vasodilators). Although these drug classes promote a similar therapeutic end-point, vasodilatation, a variety of mechanisms are involved in achieving their effect.
Heart failure is associated with activation of the sympathetic nervous system and renin-angiotensin system. In the face of decreased cardiac output, these systems promote arteriolar vasoconstriction to maintain adequate perfusion pressure and venoconstriction to enhance venous return to the heart. Unfortunately, the arteriolar vasoconstriction further increases the workload of the failing heart; more energy must be expended to overcome high systemic vascular resistance, and less energy is available to expel blood into the aorta. Stroke volume (and hence cardiac output (CO]) decreases, but systemic vascular resistance (SVR) continues to increase in an effort to maintain blood pressure (BP = CO x SVR). The increase in preload promoted by venoconstriction also proves detrimental because the diseased heart, operating on the plateau of the Frank-Starling curve, is unable to further hypertrophy or increase its contractility. Ventricular end-diastolic pressures begin to rise, leading to the eventual formation of edema.
Based on these hemodynamic sequelae, it seemed apparent that a reduction in afterload and/or preload ultimately would reduce mortality. Interestingly, the first V-HeFT study found that prazosin, the agent most capable of reducing blood pressure, was unable to reduce mortality compared with placebo. The combination of hydralazine and isosorbide dinitrate reduced mortality, but in the V-HeFT II trial, enalapril was more effective than the combined vasodilators at preventing death. This beneficial effect was seen despite the inability of the angiotensin-converting enzyme inhibitor to reduce blood pressure. Obviously blood pressure and systemic vascular resistance are not synonymous, but these findings have detracted from the use of potent after-load reducers in the routine management of heart failure. Venodilators may still be effective at reducing the development of edema, but the problem of drug tolerance has limited their use to animals with refractory heart failure.
Amlodipine Amlodipine is a second-generation, dihydropyridine (DHP) calcium channel blocker that primarily produces arteriolar vasodilatation and is used in the treatment of systemic hypertension. Unlike the non-DHPs diltiazem and verapamil, amlodipine has little effect on conduction through the atrioventricular node, and its negative inotropic properties appear to be offset by a reduction in afterload. Although amlodipine was unable to reduce mortality in an evaluation of 1153 patients with left ventricular dysfunction and severe heart failure (P = 0.07), it did reduce the mortality rate by 31 % (P = 0.04) in the subgroup of patients with nonischemic DCM. Despite this mortality benefit, 14 of the 209 patients with dilated cardiomyopathy assigned to amlodipine developed pulmonary edema (compared with 2 of 212 patients assigned to placebo). The mechanism involved in this development was uncertain. An interesting application of amlodipine therapy may be for severe mitral valve insufficiency. A reduction in systemic vascular resistance (and hence the systolic left ventricular to left atrial pressure gradient) may serve to decrease the volume of mitral valve insufficiency. Potential benefits of amlodipine are its 30-hour half-life and peak effect in 4 to 7 days after institution of therapy to dogs. This slow onset of action may give the baroreceptors time to reset, thereby avoiding sympathetic activation and reflex tachycardia. The effective dose of amlodipine seems to vary; a common strategy is to institute therapy at a low dose (0.05 mg/kg given orally once daily), followed by slow titration up to 0.2 mg/kg until a reduction in blood pressure is achieved. Because of the drug’s long half-life, the authors typically monitor blood pressure weekly, using uptitration until the target blood pressure is attained.
Hydralazine Hydralazine is a direct-acting arterial vasodilator that promotes vasodilatation through an unknown mechanism. It was studied in the 1980s for the management of CDVD in dogs and was found to produce substantial decreases in mean arterial blood pressure, total systemic resistance index, and pulmonary capillary wedge pressure. Since that time, hydralazine appears to have been pushed aside by the angiotensin-converting enzyme inhibitors in the management of uncomplicated heart failure. This trend likely resulted from the commonly encountered side effects of hydralazine (i.e, symptomatic hypotension, anorexia, vomiting, and diarrhea), the presence of elevated aldosterone levels seen after hydralazine therapy compared with captopril, and the significant results of the V-HeFT II trial.
Hydralazine is still used in the acute management of decompensated heart failure when nitroprusside is unavailable (or impractical to use) because of its rapid onset of action. Similar to amlodipine, the reduction in systemic vascular resistance may reduce the volume of mitral insufficiency and promote an increase in the forward stroke volume. In contrast to amlodipine, the peak vasodilative effect of hydralazine occurs within 3 hours and subsides within 12 hours. Unfortunately, this same characteristic may result in reflex tachycardia and further stimulation of the sympathetic nervous system and RAS. A study by Haggstrom et al. identified significant increases in heart rate and plasma aldosterone and angiotensin II concentrations, as well as evidence of fluid retention, in Cavalier King Charles spaniels with mitral insufficiency that were treated with hydralazine monotherapy for 3 weeks. These findings suggest that angiotensin-converting enzyme inhibitors should be used concurrently with hydralazine if chronic afterload reduction is warranted.
For the management of fulminant congestive heart failure, hydralazine may be administered at a dosage of 2 mg/kg given orally twice daily to dogs with a systolic blood pressure above 100 mm Hg. The authors recommend blood pressure monitoring, with the twin goals of avoiding hypotension and monitoring therapeutic efficacy. Ideally the increase in effective cardiac output will counterbalance the hydralazine-mediated reduction in systemic vascular resistance, preventing the development of symptomatic hypotension.
Nitrates The nitrates, which include nitroglycerin, isosorbide dinitrate and isosorbide mononitrate, and nitroprusside, are a class of vasodilators that promote the formation of nitric oxide. Although nitroprusside administered intravenously is a potent balanced vasodilator, topical and oral administration of nitroglycerin and oral administration of isosorbide dinitrate and isosorbide mononitrate appear to promote primarily venodilatation. The premise behind venodilatation is to promote redistribution of the circulating blood volume from the heart and pulmonary vasculature to the systemic venous circulation. This reduction in preload should decrease ventricular enddiastolic, atrial, and pulmonary capillary pressures, shifting the Frank-Starling curve to the left and alleviating pulmonary edema. Currendy the efficacy of nitrates in the management of chronic heart failure is uncertain and may be limited by nitrate tolerance, the phenomenon in which continued drug exposure reduces the agent’s effectiveness.
Nitrogfycerin A 2% topical formulation of nitroglycerin combined with furosemide and oxygen (with or without hydralazine) is frequendy used in the management of acute heart failure. Anecdotal recommendations have called for application of nitroglycerin cream to a clipped or hairless region (V2 to 2 inches every 6 to 8 hours for dogs; tA-inch every 6 to 8 hours for cats) to promote continuous transdermal absorption and venodilatation. Studies evaluating the absorption of cutaneously applied nitroglycerin, the optimal site for topical administration, and the efficacy of this therapy for dogs or cats with heart failure have not been reported. There is a report that nitroglycerin applied to the auricular pinna promotes splenic vasodilatation in normal anesthetized dogs, but by no means should nitroglycerin replace furosemide as the primary agent for reducing preload and alleviating pulmonary edema.
Isosorbide dinitrate and isosorbide mononitrate Isosorbide dinitrate and its major metabolite, mononitrate, are orally administered venodilators that may help reduce preload and hence pulmonary edema. Similar to nitroglycerin, the orally administered nitrates have not been extensively studied in naturally occurring heart failure. However, Adin et al. were unable to document circulatory redistribution after a single dose of isosorbide mononitrate in normal dogs or in those with heart failure. Whether nitrates can regress cardiac remodeling in naturally occurring heart failure remains to be investigated.
Although their efficacy is unknown, isosorbide dinitrate (0.5 to 2 mg/kg given orally twice daily) and isosorbide mononitrate (0.25 to 2 mg/kg given orally twice daily) occasionally are used in the management of refractory heart failure or in combination with hydralazine or amlodipine for patients unable to tolerate angiotensin-converting enzyme inhibitors. Whether dosing-free intervals are required to combat the development of nitrate tolerance for dogs and cats is unknown.
Triple Diuretic Therapy
Although twice-daily administration of a loop diuretic appears to be the regimen most frequently used to manage congestive heart failure, there are physiologic benefits to altering the dosing frequency or combining agents from different classes. Although not a true component of diuretic resistance, the activity of the nephron in the absence of therapeutic diuretic concentrations must be kept in mind. The loop diuretics currently available are not long-acting formulations. Therefore the original diuretic effects have dissipated well before the administration of a second daily dose. During this time, when it is not inhibited, the Na+/K+/2Cl- pump promotes avid sodium resorption, possibly to a degree that negates any previous natriuretic effect. This highlights the point that, in cases of worsening heart failure, three times daily dosing of furosemide may be more beneficial than merely increasing the twice daily dose. In cases of right-sided heart failure, in which oral drug absorption may be impaired, changing the type of administration to the subcutaneous or intramuscular route may prove beneficial. Administration of a diuretic by means of a constant-rate infusion may prove the most beneficial during emergency treatment of heart failure, although frequent, moderate doses likely achieve a similar end-point.
No matter the dosing interval or the route of administration, the segments of the nephron distal to the loop of Henle are capable of producing diuretic resistance. Increased solute exposure to the distal nephron promotes hypertrophy and increased resorptive capacity of the early distal tubule, the connecting tubule, and the cortical collecting duct. Although the exact mechanisms are unclear, aldosterone has been implicated as promoting this process. Strategies to combat diuretic resistance associated with long-standing administration of a loop diuretic include (1) addition of a thiazide diuretic to encourage diuresis in the hypertrophied region and/or (2) addition of an aldosterone antagonist to target the proposed hypertrophic mechanism. This synergistic nephron blockade, using multiple agents with activity in different regions of the nephron, may allow a reduction in the dose of furosemide required to control the patient’s congestive signs. In the authors’ experience, furosemide and spironolactone, combined with conservative doses of hydrochlorothiazide, have palliated the congestive signs of many heart failure patients. However, this more aggressive diuretic management predisposes the patient to the development of electrolyte abnormalities and a reduction in cardiac output and the glomerular filtration rate unless care is taken to avoid overzealous volume contraction. Outpatients should be carefully and periodically evaluated through biochemical profiles to make sure that adverse effects are avoided.
Additional factors that can contribute to diuretic resistance include (1) poor cardiac output, which impairs delivery of the diuretic to its site of action; (2) prominent activation of the renin-angiotensin system; and (3) hypokalemia, which may impair the efficacy of the diuretic. If concern exists about diuretic resistance, care should be taken to optimize the angiotensin-converting enzyme inhibitor dose, to correct electrolyte imbalances, and to combat low-output conditions.
Dietary Sodium Restriction
Historically, sodium restriction has been recommended for patients with cardiovascular disease to decrease the delivery of sodium to and its resorption in the distal tubule. This recommendation was in place well before any of the current understanding of the renin-angiotensin system developed, and it therefore may need to be reevaluated.
It currendy is recognized that reduced sodium concentrations at the macula densa serve as a stimulus for renin release and subsequent production of angiotensin. A study of Cavalier King Charles spaniels with mild asymptomatic mitral valve insufficiency showed that a low-sodium diet (17 mg/kg/day) was associated with higher plasma renin activity and aldosterone concentrations than a control diet (96 mg/kg/day). In light of the concern that activation of neurohormonal pathways promotes the progressive nature of cardiovascular disease, the authors currendy do not use sodium restriction in asymptomatic patients. Whether symptomatic patients receive clinical benefit from sodium restriction is uncertain, but one study found that dogs with mitral valve insufficiency that were fed a low-sodium diet (24 mg/kg/day) had significandy smaller left atrial and left ventricular dimensions than they did when fed a moderate-sodium diet (42 mg/kg/day). Only a small number of dogs with dilated cardiomyopathy were enrolled in the study, but no significant differences in their echocardiographic parameters were seen between the two diets. Despite angiotensin-converting enzyme inhibitor therapy, greater than 70% of the dogs enrolled in the study had increased baseline concentrations of atrial natriuretic peptide and increased plasma renin activity and aldosterone concentrations; however, the dietary modifications were not associated with significant alterations from baseline.
Whether exclusively feeding a low-sodium diet to patients with heart failure is feasible often hinges on the palatability of the diet and the willingness of the owner to abandon treats and table scraps. Although uncertain of its clinical benefit or potential detriment, the authors often recommend a low- to moderate-sodium diet for patients with refractory heart failure. As evidenced by the study by Mallery et al., anorexia is a large contributing factor (68%) in the decision for euthanasia; therefore caution, education, and a willingness to abandon the regimen must accompany the prescription of a potentially less palatable, sodium-restricted diet.