Management of Acute Decompensated Congestive Heart Failure
Dogs with dilated cardiomyopathy or mitral regurgitation often present with acute onset of coughing, dyspnea, restlessness, orthopnea, and weakness subsequent to the development of severe pulmonary edema and/or low cardiac output. The immediate priorities in these patients are resolution of the pulmonary edema, maintenance of adequate tissue perfusion pressure, and adequate delivery of blood flow to vital tissues. These goals must be achieved quickly, therefore it is important that the practitioner use drugs with proven hemodynamic benefits and a rapid onset of action.
As left atrial and pulmonary capillary pressures increase and the lymphatics’ capacity to remove fluid is overwhelmed, the interstitial space and alveoli become flooded. Because these flooded alveoli lack ventilation and represent areas of functional shunting, oxygen administration must be combined with agents that effectively lower pulmonary venous pressure. Oxygen can easily be administered to compromised patients by provision of an oxygen-enriched environment (i.e., oxygen cage) or by use of nasal insufflation, achieving maximal inspired oxygen concentrations of 40% to 90%, respectively.
Reduction of Pulmonary Venous Pressure
Rapid reduction of pulmonary venous pressure is most readily achieved through use of a combination of intravenous (IV) drugs that lower the circulating plasma volume and redistribute the intravascular volume. Intravenous furosemide (2 to 8 mg/kg) should be administered to dogs with severe pulmonary edema to promote natriuresis and diuresis quickly. These large doses may be repeated (initially every 1 to 2 hours) until the respiratory rate and dyspnea start to decline. After stabilization, the dose should be reduced (2 to 4 mg/kg every 8 to 12 hours), because excessive administration may lead to profound dehydration, electrolyte depletion, renal failure, low cardiac output, and circulatory collapse.
Drugs that decrease preload (to combat congestion) and afterload (to decrease myocardial work) are administered concurrently with furosemide. Intravenous sodium nitroprusside is a potent, ultrarapid, balanced vasodilator that seems to reduce pulmonary venous pressure quickly and effectively. When used in animals with congestive heart failure, nitroprusside decreases right atrial and pulmonary capillary wedge pressures and systemic vascular resistance and increases cardiac output. Although hypotension and tachycardia are reported side effects, the reduction in systemic vascular resistance (SVR) is theoretically associated with an increase in cardiac output (CO) that serves to maintain systemic arterial blood pressure (BP = SVR. x CO). Nausea, vomiting, and cyanide toxicity during prolonged administration are other reported side effects. Because of its short half-life, nitroprusside, mixed with 5% dextrose, must be administered by constant-rate infusion (CRI). After institution of an initial dose of 1 µg/kg/min, the rate is slowly titrated upward while the blood pressure is monitored. An infusion rate of 2 to 5 µg/kg/min usually is sufficient to decrease afterload, although rarely doses as high as 10 µg/kg/min may be required. If significant hypotension is encountered after administration of nitroprusside, slowing the infusion rate generally is effective at raising the blood pressure to acceptable levels.
Sodium nitroprusside Nitroprusside is an intravenous preparation with potent arteriolar and venous vasodilative properties mediated by the formation of nitric oxide and subsequently the second messenger cyclic guanosine monophosphate (cGMP). To some degree, the combination of nitroprusside and dobutamine can be considered short-term “cardiac life support,” used primarily during an attempt to rescue dogs with severe, life-threatening pulmonary edema subsequent to dilated cardiomyopathy. This drug combination’s ability to reduce afterload quickly appears to be beneficial also in patients with chronic degenerative valvular disease and pulmonary edema, although management of these cases often can be accomplished less intensively.
Unfortunately, the beneficial hemodynamic profile of nitroprusside is accompanied by a difficult administration protocol that requires intensive monitoring. Because nitroprusside produces an almost immediate and often profound reduction in systemic vascular resistance, continuous blood pressure monitoring throughout administration is recommended. The drug is light sensitive, is given by constant-rate infusion (typically 2 to 5 µg/kg/min), and should not be infused with another agent, which necessitates placement of a second intravenous catheter for administration of dobutamine. These stringent requirements may provide cause for more frequent use of intravenous bipyridines to combat life-threatening heart failure, at least until studies are able to elucidate whether either method produces better results.
If nitroprusside is unavailable, balanced vasodilatation may be attempted through administration of an arterial vasodilator (hydralazine, 0.5 to 2 mg/kg given orally) in combination with a venodilator (nitroglycerin ointment, ¼ to ¾ -inch applied cutaneously every 8 to 12 hours; or isosorbide dinitrate, 0.5 to 2 mg/kg given orally every 8 hours). Although easier to administer, this therapy seems to be less effective at quickly reducing pulmonary venous pressure compared with nitroprusside.
Potent afterload reduction in patients with severe mitral insufficiency and large regurgitant volumes serves to decrease the left ventricular to left atrial pressure gradient and hence the volume of insufficiency. Nitroprusside, or possibly hydralazine, can effectively decrease the volume of mitral regurgitation and lower left atrial pressure in cases of severe congestive heart failure subsequent to rupture of the chordae tendineae or the onset of atrial fibrillation. Despite this obvious theoretical advantage, a recent human study showed that mitral regurgitation worsened in four of nine patients with mitral valve prolapse during nitroprusside infusion. This finding highlights the point that adjustments in the therapeutic regimen may be required and should be based on patient response rather than physiologic principles.
Augmentation of Systolic Performance
Preload reducing agents, such as furosemide, cannot enhance systolic function and in fact at high doses serve only to decrease cardiac output. Therefore the use of a rapid-acting, intravenous inotropic agent is vital to the management of acute decompensated congestive heart failure in dogs with dilated cardiomyopathy. Although there is debate over whether dogs with mitral valve insufficiency have systolic dysfunction, acutely positive inotropic agents may serve to decrease the regurgitant orifice area and hence the volume of insufficiency.
The short-acting, positive inotropic agents most commonly used to manage decompensated heart failure increase cyclic adenosine monophosphate (cAMP). Dobutamine and dopamine are sympathomimetic agents that bind to beta, receptors, thereby stimulating adenylyl cyclase activity and production of cAMP. The bipyridines amrinone and milrinone increase cyclic adenosine monophosphate by preventing its degradation by phosphodiesterase. Both drug classes are capable of rapidly augmenting systolic function during constant-rate intravenous infusions. By increasing cytosolic cAMP, these agents enhance (1) calcium entry into the cell, promoting ventricular contraction; (2) diastolic calcium uptake by the sarcoplasmic reticulum, promoting ventricular relaxation; and (3) peripheral vasodilatation, reducing after-load. It should be remembered that the sympathomimetics also have alpha-agonistic properties that promote vasoconstriction. Unfortunately, both the sympathomimetics and the bipyridines may promote tachycardia and undesirable ventricular arrhythmias. Therefore careful electrocardiographs (ECG) monitoring is required during administration of these drugs, and significant or worsening ventricular arrhythmias may warrant discontinuation of the infusion and institution of antiarrhythmic therapy.
Sympathomimetics The sympathomimetics enhance cardiac contractility by complexing with myocardial beta receptors. After substrate binding to an unoccupied beta receptor, a coupled G-protein stimulates the enzyme cyclase to produce cAMP. This second-messenger “effector” system acts by means of protein kinase A to phosphorylate intracellular proteins, including the L-type calcium channel, phospholamban, and troponin I, thereby enhancing ventricular contraction and relaxation. Despite the sympathomimetics’ ability to increase cardiac contractility approximately 100% above baseline, not all drugs in this class are suitable for the management of heart failure. The specificity for beta receptor binding depends on the specific agent and dose administered. Sympathomimetics inappropriate for the management of heart failure include the pure beta agonist isoproterenol and the naturally occurring catecholamines norepinephrine and epinephrine. These agents tend to promote tachycardia, arrhythmias, and untoward alterations in systemic vascular resistance
Dobutamine and dopamine are more appropriate sympathomimetics for the management of heart failure. Although both drugs can enhance cardiac contractility, several drawbacks discourage long-term use: (1) they must be given intravenously, because successful oral administration is precluded by extensive first-pass hepatic metabolism; (2) because of their extremely short half-lives (approximately 1 to 2 minutes), they must be administered by constant-rate infusion; (3) almost any positive inotropic response tends to increase myocardial work and thus the propensity for ventricular arrhythmias; and (4) after 24 to 48 hours of constant-rate infusion, their positive inotropic response is limited by beta receptor downregulation and uncoupling. The tendency for long-term sympathomimetic administration to increase mortality, as documented in humans, appears to relegate these agents to short-term management of acute, life-threatening heart failure.
Dobutamine Dobutamine is a synthetic analog of dopamine that displays predominately betaj receptor binding (beta1 > beta2 > alpha). Dobutamine is able to increase cardiac contractility and thus cardiac output without causing a profound, concomitant increase in the heart rate. The mechanism underlying the lack of a positive chronotropic response is not well understood, but this characteristic tends to make dobutamine the most appropriate agent for short-term treatment of heart failure. It appears that complexing with vasodilative beta receptors and vasoconstrictive alpha receptors, combined with an increase in cardiac output, maintains arterial blood pressure at near baseline values. If the systolic blood pressure is normal to elevated, dobutamine infusion (slow titration up to 5 to 15 µg/kg/min in 5% dextrose) can be combined with the potent vasodilator nitroprusside in an attempt to decrease internal cardiac work and further enhance forward blood flow. Continuous ECG and blood pressure monitoring is recommended during this treatment regimen, and exacerbation of tachycardia or ventricular arrhythmias may necessitate discontinuation of dobutamine.
Dopamine A precursor of norepinephrine, dopamine can bind myocardial beta receptors in addition to peripherally located dopaminergic, beta2, and alpha receptors. Within the renal, mesenteric, coronary, and cerebral vascular beds, these dopaminergic DA2 receptors are able to promote vasodilata-tion at low infusion rates of dopamine (1 to 2 µg/kg/min). However, at higher infusion rates (10 to 20 µg/kg/min), these vasodilative properties are over-ridden by an undesirable, alpha-mediated vasoconstrictive response. Also, high doses are accompanied by increases in the heart rate, the likelihood of arrhythmogenesis, the release of norepinephrine, and the myocardial oxygen demand. Dopamine (slow titration up to 1 to 10 µg/kg/min) may be used in situations similar to those in which dobutamine is appropriate (e.g., profound myocardial failure) and may further enhance renal blood flow. For the authors, an increased propensity for the development of tachycardia relegates dopamine to the role of second-choice drug. As with dobutamine, careful ECG and blood pressure monitoring is indicated during dopamine administration.
Bipyridines Similar to the sympathomimetics, the bipyridines promote an increase in cardiac contractility by increasing cytosolic cyclic adenosine monophosphate levels. However, rather than directly enhancing the production of cAMP, they increase circulating levels by inhibiting phosphodiesterase III, the enzyme responsible for cyclic adenosine monophosphate inactivation. Unlike the sympathomimetics, the bipyridines do not rely on beta-adrenergic receptors and therefore are less affected by downregulation and uncoupling. Furthermore, because phosphodiesterase inhibitors increase vascular smooth muscle cyclic adenosine monophosphate without displaying affinity for alpha receptors, they are also vasodilators. Because of the bipyridines’ combination of positive inotropic and vasodilative properties, the term inodilators has come into use for these agents. Because they increase cytosolic calcium and myocardial work, they inherently carry the caveats of tachycardia and ventricular arrhythmias. In fact, the 28% increase in all-cause mortality identified in humans randomized to oral milrinone versus placebo has severely limited further attempts to evaluate agents that act via cAMP-dependent mechanisms.
Milrinone The phosphodiesterase inhibitor milrinone is substantially more potent than amrinone and is available in an intravenous preparation. Because of its combined positive inotropic and vasodilative properties, milrinone may be used as a substitute for the dobutamine/nitroprusside combination in the management of acute life-threatening heart failure. Despite milrinone’s ability to increase measures of fractional shortening after oral administration in dogs, this formulation is no longer available for prescription.”
There are no published reports regarding the hemodynamic effects of intravenous milrinone administered to dogs with acute myocardial failure. When administered to normal dogs at an infusion rate of 1 to 10 µg/kg/min, milrinone increased cardiac contractility 50% to 140%. Whether similar doses are efficacious in dogs with heart failure is uncertain, and dosing recommendations currently are difficult to propose. Because CRI milrinone requires 10 to 30 minutes to reach maximal peak effects in normal dogs, it may be prudent to administer a loading dose, followed by constant-rate infusion. Theoretical administration guidelines after the bolus would be to titrate the infusion rate upward slowly while monitoring the systemic blood pressure and a continuous electrocardiogram. Efficacy may be monitored clinically (e.g., reduction in the respiratory rate, alleviation of orthopnea) or echocardiographically with periodic measures of systolic function.
Amrinone The effects of amrinone are almost identical to those of milrinone except that it does not appear to be as potent. Although there are no reports of its large-scale use in the management of acute decompensated congestive heart failure, treatment recommendations have been extrapolated from studies of normal dogs. Constant-rate infusions of 10 to 100 µg/kg/min appear to be capable of increasing cardiac contractility by 10% to 80% in awake, normal dogs. Anesthetized dogs showed a 15% increase in the heart rate at an infusion rate of 30 µg/kg/min and a 20% increase at 100 µg/kg/min. This tachycardia may have been induced either directly, through cyclic adenosine monophosphate stimulation, or indirecdy, in response to a decrease in blood pressure. The 30 µg/kg/min infusion rate was associated with a 10% decrease in blood pressure, whereas the 100 µg/kg/min rate reduced blood pressure by 30%.I After institution of a CRI, amrinone requires approximately 45 minutes to reach peak effect. Therefore, similar to milrinone, it appears most appropriate to administer a slow IV bolus of 1 to 3 mg/kg, followed by a slowly up-titrated CRI of 10 to 100 µg/kg/min. Continuous ECG monitoring should be instituted to allow evaluation for excessive tachycardia or arrhythmogenesis, and the systemic blood pressure should be monitored to avoid hypotension.
Management of Acute Heart Failure Secondary to Diastolic Dysfunction
Cats with hypertrophic cardiomyopathy (HCM) often present with signs of respiratory distress subsequent to the development of pulmonary edema or pleural effusion. Impaired ventricular relaxation produces elevated atrial and venous pressures, with eventual fluid exudation into the alveoli or pleural space. The treatment goals for cats with HCM and heart failure focus on relieving congestion through preload reduction rather than augmenting systolic function or decreasing afterload.