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Selection of vasodilator, inotropic or combined therapy for the management of heart failure
Selection of Vasodilator, lnotropic or Combined Therapy for the Management of Heart Failure
JAY N. COHN, M.D. JOSEPH A. FRANCIOSA, M.D. Minneapolis. Minnesota
Vasodiiator and inotropic drugs work through independent mechanisms in augmenting left ventricular pump function in patients with heart failure. The seiectlon between these two classes of pharmacologic agents for an individual patient may be based on the control blood pressure as well as the underlying disease. Although vasodilator drugs are easiest and safest to employ in pattents wtth normal or high arterial pressure levels, even In relatively hypotensive subjects (systolic arterial pressure less than 105 mm Hg), a salutary hemodynamic effect can be achieved without an undue decrease in pressure. inotropic drugs may be safest to administer to patients without coronary artery disease, but the oxygen-consuming effect of these drugs need not necessarily have an adverse effect on patients with ischemic heart disease. Combined vasodiiator and inotropic drug therapy is the most potent pharmacologic means of restoring pump function in patients with severe heart failure. The long-term use of vasodiiator and inotropic drugs in the treatment of heart failure is dependent on the availability of agents that will produce a sustained hemodynamic effect. Hydraiazine, nltrates and prazosin have been employed atone or in combination and provkte a promising approach to vasodiiator treatment of heart falture. Better and more selective oral inotropic agents are needed to allow this therapeutic modality to be employed optimally. The recently demonstrated efficacy of vasodilator drugs in the treatment of left ventricular failure [l-5] has provided physicians with two pharmacologic means of augmenting cardiac output: inotropic drugs, which are available in a number of parenteral but fewer oral forms, and vasodilators, which are available for both parenteral and oral administration. The management of pump failure, therefore, now requires a choice between administering an inotropic or a vasodilator drug, or a decision to use the two agents together. The variety of drugs available in these two classes of compounds has greatly expanded the therapeutic armamentarium for severe heart failure. However, these new advances in therapeutics also represent a challenge to the physician, who must understand the pathophysiology of heart failure and the pharmacodynamics of the drugs in order to apply this new, selective therapy rationally. We shall, therefore, consider the physiology of the disease and the hemodynamic effects of the drugs in order to arrive at a basis for selecting inotropic, vasodilator or combined therapy for the treatment of severe heart fail-
From ths Universityof MinnesotaMedicalSchool, Minneapolis,Minnesota.Requests for reprints shouldbe addressedto Dr. JayN. C&n, University of MinnesotaHospital, Box 488. Minneapolis, Minnesota55455.
ure.
Mechanisms of inotropic and Vasodilator Effects. Ample evidence indicates that inotropic and vasodilator drugs work through independent mechanisms in augmenting stroke volume. The inotropic drugs, partitularly
the sympathomimetic
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enteral management of sudden pump failure, increase the velocity and force of ventricular contraction [6]. This action is apparent in isolated muscle preparations, in intact animal studies and by measuring indices of contractility in man. Careful measurement of ventricular dimensions during an inotropic intervention with infusion of dopamine in awake dogs reveals a constant or slightly reduced end-diastolic volume, an increased velocity of wall movement during systole and a reduction in endsystolic volume [ 71. Vasodilator drugs, on the other hand, exert no effect on myocardial contractility in isolated preparations [8]. In the intact circulation, drugs that relax arteriolar resistance reduce left ventricular outflow resistance (aortic impedance) and left ventricular end-systolic volume [7]. The increase in stroke volume may be at least partially counteracted, however, by a simultaneous reduction in end-diastolic volume or preload. Since the decrease, if any, in end-diastolic volume during an inotropic intervention usually is less than that during a vasodilator intervention, an increase in stroke volume cannot be the major factor in reducing end-diastolic volume. Therefore, an important factor in determining changes in end-diastolic volume in response to a vasodilator drug is the effect of the drug on venous capacitance vessels [8]. A reduction in ventricular and diastolic volume usually is attributed to a shift of volume from the central to peripheral capacitance vessels because of venodilation. However, a role for pulmonary venous dilation that would increase the capacitance of the pulmonary circulation also is a possible contributing factor. Simultaneous administration of vasodilator and inotropic drugs results in an augmentation of left ventricular function greater than that achieved with either agent alone. This augmentation was shown in the awake dog by a further increase in left ventricular ejection fraction because of a decrease in end-systolic volume to levels lower than could be achieved by either drug given independently [7]. These changes in ventricular dimensions when the normal heart is exposed to a varying outflow resistance are inconsistent with previous suggestions that the heart adjusts its stroke work from an unchanged end-diastolic volume when outflow resistance is altered. This concept of homeometric autoregulation, introduced by Sarnoff et al. [9], does not appear to pertain during acute pharmacologic interventions in awake subjects. Hemodynamic Effects of lnotropic and Vasodilator Drugs in Heart Failure. All inotropic drugs exert some peripheral vascular actions that make it difficult to assess the effects of a pure inotropic intervention. Even if such an agent were available, however, it would be impossible to isolate the inotropic effects of the drug from the reflex circulatory effects which may occur
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when the drug is administered to a patient with heart failure. Thus, any increase in stroke volume generated by a more forceful ventricular contraction would lead to a change in arterial pressure that would likely lead to reflex adjustment in the peripheral circulation resulting in a decrease in systemic vascular resistance. It would then be difficult to separate the secondary response to change in resistance from the primary response to the inotropic intervention. The response to inotropic drugs with prominent peripheral vascular effects is often dominated by the peripheral vascular actions. Norepinephrine, a potent inotropic drug with a marked vasoconstrictor effect, increases blood pressure through vasoconstriction and results in such reflex vagal stimulation that the inotropic effect of the drug may be overlooked in the intact animal [lo]. Isoproterenol, on the other hand, exerts such potent peripheral vasodilation that aortic diastolic pressure decreases and heart rate increases prominently. Indeed, much of the increase in cardiac output previously attributed to the inotropic effect of isoproterenol could well be due to the peripheral vasodilation induced by the drug. Dopamine was introduced as an inotropic drug with lesser peripheral vascular and chronotropic properties [ 111. It has gained widespread use in the treatment of pump failure because it induces less vasoconstriction than norepinephrine and less tachycardia than isoproterenol. Peripheral vascular actions are present, however, and as the dose is increased alpha adrenergic vasoconstriction begins to predominate over the socalled dopaminergic vasodilation [ 121. The presently available pharmacologic agent which comes closest to providing a specific inotropic effect is dobutamine, a dopamine derivative [ 131. Dobutamine lacks dopamine’s direct vasodilator effect on the renal vasculature and also lacks the predominant vasoconstrictor (alpha adrenergic) effect of dopamine observed with higher doses of the drug. Furthermore, dobutamine has been shown not to increase heart rate even when given in doses that produce a prominent increase in myocardial contractility [ 141. The absence of net peripheral vascular effects of dobutamine appear to be related to a unique balance of alpha and beta peripheral vascular actions that tend to cancel each other out [ 151. The absence of a heart rate response despite the inotropic effect of the drug raises interesting speculations about the possible dissociation of inotropic from chronotropic properties of beta agonists [ 161. lnotropic drugs such as dobutamine increase stroke volume by generating more forceful muscle shortening, whereas vasodilator drugs like sodium nitroprusside increase stroke volume by reducing outflow resistance and passively allowing greater muscle shortening. We thought it would be of some interest to compare directly
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the potency of dobutamine and nitroprusside in augmenting left ventricular pump function in patients with severe left ventricular failure. Therefore, we studied the effect of both drugs infused sequentially in 12 patients [ 171. Dobutamine in a dose of 10 pg/kg/min produced an increase in systolic and mean arterial pressure with an unchanged heart rate. Cardiac output increased prominently and there was a decrease in pulmonary wedge pressure, and in systemic and pulmonary vascular resistance (Figure 1). Infusion of sodium nitroprusside in the same patients produced a similar augmentation in left ventricular performance but with certain distinct differences (Figure 2). The cardiac output increased to a similar extent during infusion of the vasodilator drug, but the arterial pressure was slightly reduced during nitroprusside infusion and the heart rate slowed slightly. Pulmonary wedge pressure was decreased to a greater extent than with the dobutamine infusion, but the systemic and pulmonary vascular resistance were similarly reduced. Since both drugs produced similar decrements in vascular resistance, it was appropriate to question whether these drugs are similarly potent vasodilators. In order to assess the direct vascular effects of the drug, the two agents were infused sequentially into the brachial artery of patients with heart failure while forearm blood flow was monitored using a Whitney mercuryin-rubber resistance gauge and venous occlusion plethysmography. During infusion of sodium nitroprusside in very small doses representing less than 5 per cent of the systemic infusion rate of the drug, forearm blood flow was markedly augmented confirming the potent direct peripheral vasodilator effect of nitroprusside. In contrast, when dobutamine was infused into the brachial artery little if any direct vascular effect of the drug could be identified until the infusion rate reached the point at which systemic hemodynamic effects of the dobutamine could be recognized. These studies, therefore, provide strong evidence that the decrease in peripheral vascular resistance during dobutamine infusion is not a manifestation of a direct vasodilator effect of the drug but rather a manifestation of a reflex decrease in systemic vascular resistance as the cardiac output is augmented by the inotropic agent. In contrast, the decrease in systemic vascular resistance during nitroprusside infusion could represent largely a direct vasodilator effect of this agent. Thus, dobutamine and nitroprusside produce comparable augmentation in left ventricular function in the setting of heart failure, but they do it through an entirely different mechanism. The inotropic drug increases force of ventricular contraction and augments stroke volume leading to a secondary decrease in systemic vascular resistance; the vasodilator drug primarily reduces
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10 Figure 1. Hemodynamic response to dobutamine infusion in 12 patients with severe heart failure. Note marked increase in cardiac output with only slight increase in systolic arterial pressure and decrease in pulmonary wedge pressure (PWP). Systemic vascular resistance (S VR) and pulmonary vascular resistance (PVR) decrease.
systemic resistance and through a mechanical reduction in outflow resistance allows the stroke volume and cardiac output to increase. Since the agents act through independent mechanisms, it is not surprising that their hemodynamic effects are additive when the drugs are infused together. The combination of dobutamine or dopamine with nitroprusside is the most potent pharmacologic means
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Figure 2. Hemodynamic response to nitroprusside in 12 patients with severe heart failure. Note that hemodynamic response is similar to that of &butamine except that arterial pressure decreases slightly.
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Figure 3. t?esponse to nitroprusside (NP), dobutamine (DOB) and isoproterenol (ISO) in a 55 year old man with severe cardiomyopathy. Blood pressure (BP) and heart rate (M) changed little during all interventions. However, extremely low cardiac output (CO) was unsatisfactorily augmented by either nitroprusside or dobutamine, 10 pglkglmin. The combination of the two restored output to a normal level. lsoproterenol was less effective even though the heart rate increased further. prolonged therapy with nitroprusside and dobutamine led to gradual improvement. Administration of the drugs was discontinued after three days, and the patient was weaned onto oral therapy that maintained the herno@namic improvement and allowed him to return home.
available for restoring cardiac output to adequate levels in the setting of severe pump failure (Figure 3). The hemodynamic response to all vasodilator agents is, of course, not the same. The drugs all share a net dilating effect on arterial resistance vessels, an effect that accounts for their ability to increase left ventricular ejection fraction. But their direct action on the venous bed, the pulmonary circulation, the myocardium, reflex sympathetic stimulation and regional vascular beds varies widely among different agents. Metabolic Effects of lnotropic and Vasodilator Drugs. The different hemodynamic effects of these two classes of agents would be expected to be reflected in a difference in myocardial metabolic response. During sodium nitroprusside infusion an increase in systolic blood pressure, an increase in velocity of fiber shortening and a slight but insignificant increase in heart rate would be expected to augment myocardial oxygen consumption [ 181. A reduction in ventricular volume might tend to
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moderate the oxygen-consuming effect of the drug somewhat. In contrast, during infusion of nitroprusside the systolic pressure is reduced, the heart rate is unchanged or decreases slightly and the velocity of fiber shortening is not significantly altered. Consequently, myocardial oxygen consumption should decrease, particularly when there is a simultaneous reduction in ventricular volume [ 191. The differing metabolic effects of these two compounds have been demonstrated in dogs with induced myocardial infarction. In a series of dogs in which the left circumflex coronary artery was embolized with mercury to produce a syndrome of pump failure, infusion of dobutamine and infusion of nitroprusside produced similar augmentation in left ventricular function [20]. The dobutamine infusion was accompanied by a 23 per cent increase in myocardial oxygen consumption, whereas the nitroprusside infusion was accompanied by an 11 per cent reduction in myocardial oxygen consumption. Therefore, the prediction of changes in oxygen consumption based on hemodynamic determinants of myocardial oxygen consumption appeared to be quite reliable in these experimental studies. If one wished to calculate in the patient with heart failure the oxygen cost of increasing cardiac output, it is clear that vasodilator therapy provides a more economical use of oxygen than does inotropic therapy. These studies on global myocardial function and metabolism do not, however, provide necessary information on the response of regionally ischemic myocardium in patients with. coronary artery disease. Preliminary studies in both experimental animals and man indicate that nitroprusside may, in at least some situations, improve the metabolism and function of ischemic myocardium [21,22]. Of course, if the drug is given in a dose to reduce arterial pressure to critical levels or if heart rate is increased, then ischemia may be aggravated. lnotropic drugs are generally thought to be likely to aggravate ischemia because of their tendency to increase myocardial oxygen consumption. Nonetheless, recent studies in experimental dogs suggest that dobutamine could actually protect against ischemia [231. Selection of Patients for lnotropic and Vasodilator Therapy. Left ventricular failure is characterized by a high left ventricular filling pressure and a reduced stroke volume and cardiac output. The arterial pressure may be low, normal or high depending on the state of the peripheral vascular resistance. The goal of therapy is to increase cardiac output and to reduce left ventricular filling pressure while keeping arterial pressure above intolerable hypotensive levels. A general approach to management, therefore, is to use vasodilator drugs when the control arterial pressure is well within the normal range or even elevated, but to preferentially
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choose inotropic drugs when the arterial pressure is at borderline levels. Care must be taken, however, to document that the low blood pressure is a true hypotensive state and not the result of a cuff artifact, which causes a low or unobtainable auscultatory pressure because of reduced forearm flow [ 241. Despite this concern about the use of dilators when arterial pressure is already low, it is often possible to titrate a vasodilator drug to achieve a considerable increase in cardiac output with no significant alteration or with even an increase in arterial pressure. This response can be understood if one recognizes that arterial pressure represents the product of output and resistance. Since stroke volume and cardiac output increase as the resistance is reduced in patients with heart failure, little change in arterial pressure may occur. A high resistance-low output state may thus be transformed into a lower resistance-higher output state at substantially similar arterial pressures. Although it is generally assumed that patients with low arterial pressures are not ideal candidates for vasodilator drugs, the response in these patients is frequently salutary. In reviewing our experience with sodium nitroprusside infusion in patients with heart failure, we identified 16 patients with a control arterial systolic pressure of less than 105 mm Hg who were given an infusion of nitroprusside in an attempt to improve left ventricular function. These 16 patients were matched with 16 nonhypotensive patients who had similar control pulmonary wedge pressure and cardiac output, and who were also given a nitroprusside infusion in an attempt to augment left ventricular function. As shown in Figure 4 the hemodynamic response was similar in these two groups of patients. Cardiac output was similarly augmented and left ventricular filling pressure similarly reduced. Arterial pressure decreased in both groups but the decrease in the initially normotensive group was greater and during the peak effect of the nitroprusside infusion, the average blood pressure in the hypotensive group was still within tolerable limits. Indeed, the diastolic arterial pressure in this group was now very similar to the diastolic pressure in the initially normotensive group. It is clear that vasodilator therapy need not necessarily be withheld from the patient with borderline blood pressure and left ventricular failure. Nonetheless, even a slight decrease in arterial pressure during the nitroprusside infusion in such patients may be a cause for concern, particularly in patients who have underlying coronary artery disease. In these subjects the use of an inotropic agent either alone or in combination with the vasodilator is entirely rational. Not only should the arterial pressure be a determinant of the selection of inotropic versus vasodilator drugs, but the underlying disease process also should be kept
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Figure 4. Hemodynamic response to infusion of sod& nitroprusside (NP) in 32 patients with severe heart failure, 16 with arterial systolic pressure (AP) greater than 105 mm Hg (open symbols, broken lines) and 16 subjects matched for similar cardiac output (CO) and pulmonary wedge pressure (PWP) but with arterial pressure less than 105 mm Hs_(closed symbols, solid lines). The decrease in PWP and increase in CO were similar in the two groups and the hemodynamic improvement in the hypotensive group was achieved with only a slight decrease in arteM pressure. C = pre-NP control period.
in mind. Since inotropic drugs augment myocardial oxygen consumption they should be employed with caution in patients with ischemia in whom further augmentation of oxygen consumption could have a deleterious effect. lnotropic drugs often are not well tolerated by patients with severe coronary artery disease; in this group of patients, it is often preferable to initiate therapy with a vasodilator drug in hopes that pump function can be improved with little if any decrease in aortic pressure. In contrast, the young person with apparently normal coronary arteries but severe myocardial dysfunction seems to be an ideal candidate for the use of inotropic drugs. In the setting of severe pump failure accompanying acute myocardial infarction, the urgent goal is to increase cardiac output and restore peripheral circulation. Concern for the preservation of ischemic myocardium may of necessity be secondary in such persons. The combination of inotropic and vasodilator drugs in this particular patient population is extremely potent and, usually, effective in restoring an adequate cardiac output and left ventricular filling pressure. This combination therapy has gradually supplanted mechanical assistance for the management of pump failure in the
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FIgare 5. Comparative effects of 50 mg oral ephedrine (f and intravenous infusion of sodium nitroprusside (N) on ler ventricular function in six patients with heart failure. Ephedrine increased cardiac output to the same extent as nitroprusside but did not reduce pulmonary wedge pressure. The combination produceda greater output increase than either agent alone. Cs = pre-drug control period.
setting of acute myocardial infarction. Although this pharmacologic approach has reduced the dependence in the coronary care unit on intraaortic balloon pumping it is not at all certain at this time whether the pharmacologic therapy has the potential for a beneficial effect on myocardial metabolism. The ease of pharmacologic therapy as opposed to mechanical assistance makes it particularly attractive, but studies of the myocardial metabolic effects of these interventions are needed before one can rationally choose between pharmacologic and mechanical treatment. Selecting among the various vasodilator and inotropic drugs for the immediate management of left ventricular failure presents a number of options. Sodium nitroprusside is the most potent and reliable vasodilator drug for this purpose, and it has generally become the drug of choice. Titration to the required dose generally requires an automated infusion system and close monitoring of circulatory function. When an infusion of nitroprusside is continued for more than a few days, blood thiocyanate levels should be measured to avoid thiocyanate toxicity. Fortunately, patients usually can be weaned from intravenous nitroprusside therapy to effective nonparenteral vasodilator therapy before toxicity becomes a problem. Other drugs, such as phentolamine, trimethaphan, nitroglycerin and hydralazine, are available for parenteral administration when an alternative to nitroprusside is sought. lnotropic drugs present a greater problem. Digitalis preparations tend to be quite ineffective in the immediate management of pump failure. Cardiac output is generally not increased very much, and left ventricular filling pressure decreases only slightly if at all [25]. Immediate support of the failing heart, therefore, re-
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quires administration of an inotropic agent that exerts its effect through beta adrenergic receptors in the myocardium. Although dobutamine and dopamine produce an inotropic effect with little perturbation of the peripheral circulation, some patients exhibit little hemodynamic response to these drugs. When arterial pressure is low and augmentation of myocardial contractility is urgently needed, norepinephrine appears to be a more reliable agent. Indeed, one can utilize norepinephrine for its myocardial stimulation and simultaneously administer nitroprusside to counteract the peripheral vasoconstrictor effect of the drug. This combination provides unique control of both the heart and peripheral circulation, since the two drugs can be titrated independently. lsoproterenol has lost favor as an inotropic drug because it may produce undesirable tachycardia and because its peripheral vasodilator effect involves predominantly the skeletal muscle bed [26]. Therefore, the regional distribution of blood flow induced by isoproterenol would be expected to be quite different from that produced by the combination of nitroprusside with dobutamine, dopamine or norepinephrine, even if the cardiac output were similar. Long-Term Therapy with lnotropic and Vasodilator Drugs. In the last few years a number of oral vasodilator drug regimens have been explored for efficacy in the treatment of left ventricular failure. The regimens that come closest to simulating the hemodynamic effects of intravenous sodium nitroprusside are the combination of nitrate with hydralazine [27,28] or the new vasodilator prazosin [29]. For the most part, only the immediate effects of these drugs have been studied. Carefully controlled long-term studies must be designed to demonstrate whether these agents maintain their effectiveness during chronic administration. When it comes to oral inotropic therapy, the physician has been left with few options. Digitalis has of course been a mainstay for the long-term management of heart failure. Unfortunately, however, most of the patients who are currently being considered for more aggressive therapy are symptomatic while receiving adequate doses of a digitalis preparation. It is clear, therefore, that optimal hemodynamic management of left ventricular pump failure requires a more potent nonparenteral inotropic drug. Dobutamine, like most sympathomimetic drugs, is absorbed from mucous membranes, but it is not absorbed intact after oral administration. A sublingual or rectal form of the drug would likely be effective but would probably not provide a constant blood level of the drug. Ephedrine is a sympathomimetic agent that is absorbed after oral administration and has a fairly long duration of action. Its direct myocardial stimulation
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probably results from release of norepinephrine from tissue stores [30], but it also exerts a direct peripheral vasodilating effect [31]. We have recently explored the hemodynamic effects of oral administration of ephedrine in patients with heart failure [32]. The response to ephedrine alone was studied in comparison to the response to nitroprusside and then the effect of combining the drugs was evaluated. The purpose was to determine whether this oral inotropic agent would act similar to dobutamine in augmenting the systemic hemodynamic effect of the vasodilator drug. As shown in Figure 5, ephedrine increased cardiac output but did not reduce pulmonary artery wedge pressure. In contrast, nitroprusside infusion increased cardiac output while reducing wedge pressure. The combination of ephedrine and nitroprusside produced a greater improvement in left ventricular function, similar to the augmentation when dobutamine is added to nitroprusside. Arterial pressure increased slightly after oral administration of ephedrine, and heart rate was slightly increased (Figure 6). The addition of nitroprusside reduced arterial pressure and, paradoxically, also slowed the ephedrine-induced tachycardia. These preliminary studies indicate the potential for oral inotropic drugs, especially when combined with vasodilators in the management of severe heart failure. Ephedrine is probably not an ideal agent, because tachyphylaxis to the drug is likely to develop and, as with isoproterenol, the peripheral distribution of the increased cardiac output may not be physiologically ideal. Other inotropic agents have been explored but none have yet been approved for clinical use. Esproquin, an isoquinoline derivative, exerts a prolonged dose-dependent inotropic effect in normal subjects and in patients with heart failure [33,34]. Tazolol is a sympathomimetic-like drug that also has inotropic properties when administered orally [35]. It is likely that new orally effective agents that exert inotropic properties with favorable effects on the distribution of peripheral blood flow and little effect on heart rate will be developed, tested and marketed in the next few years. Inotropics, Vasodilators and the Therapy of Heart Failure. Heart failure is the most common precedent to cardiovascular mortality. Prognosis, once the diagnosis of congestive heart failure has been made, is poor [36]. But the physiologic mechanism of the natural progression of heart failure remains obscure. Cardiac dilation seems to develop and progresses without necessarily an acute event. The clinical syndrome has the characteristics of a positive feedback system ]371. Until recent years therapy was devoted to restoring contractility with digitalis and relieving congestion with diuretics. We now know that digitalis has limited ino-
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6. Changes in mean arterial pressure (MAP) and heart fate (I-R) during infusion of nitropmsside and after oral administration of ephedrine. Ephedrine alone increased pressure and heart rate slightly, but when nitroprusside was infused simultaneously the heart rate and arterial pressure effects were counteracted. Figure
tropic potential and that vasodilators may produce a considerably greater improvement in cardiac performance comparable to that achieved by the most potent inotropic interventions. How, then, can this new insight into cardiovascular regulation be integrated into an over-all management plan for heart failure? In the setting of severe, intractable pump failure the use of potent inotropic and vasodilator drugs has considerably altered inhospital management. Most patients who reach this point of decompensation, however, have such severe and irreversible myocardial damage that long term prognosis is extremely poor. Although many such patients have been restored to stability and have returned home, their life style is usually very limited and their survival short-term. To have an impact on the morbidity and mortality from heart failure, effective interventions may need to be instituted at an early stage of the disease, perhaps before symptoms become obvious to the patient. If the impact of such an approach on the natural history of the disease were to be tested, a large scale controlled trial would need to be mounted and a therapeutic regimen employed. Whether such an early intervention trial should test an inotropic drug, a vasodilator drug, a diuretic or all three is, at the present, not known. We are, perhaps, on the threshold of a new understanding of congestive heart failure. These new insights have resulted from application of hemodynamic technics to the study of therapeutic responses in patients with heart failure. More rational and effective management of the patient with heart disease should follow.
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37.
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Massie B, Chatterjee K, Werner J, et al.: Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol40: 794, 1977. Miller RR, Awan NA, Maxwell KS, et al.: Sustained reduction of cardiac impedance and preload in congestive heart failure with the antihypertensive vasodilator prazosin. N Engl J Med 297: 303, 1977. Burn JH, Rand MJ: The action of sympathomimetic amines in animals treated with reserpine. J Physiol 144: 314, 1956. Cohn JN: Comparative cardiovascular effects of tyramine, ephedrine and norepinephrine in man. Circ Res 16: 174, 1965. Franciosa JA, Cohn JN: Ephedrine-nitroprusside combination in congestive heart failure. Am J Cardiol 41: 419, 1978. Kotelanskl B, Groszrnann RJ, Cohn JN: Positive inotropic effect of oral NC7197 in normal subjects. Clin Pharmacol Ther 14: 427, 1973. Sriussadaporn S, Cohn JN: lnotropic properties of an isoquinoline derivative (NC7197) in man. Am Heart J 85: 374, 1973. Buckley HT, Strosberg AM, Harrison DC: Circulatory effects of tazolol In experimental myocardial infarction. Am J Cardio135: 619, 1975. McKee PA, Castelli WP, McNamara PM, et al.: The natural history of congestive heart failue. The Framingham study. N Engl J Med 285: 1441, 1971. Burch GE, Welch JJ. Black WC: Value of prolonged bed rest in management of cardiomegaly . JAMA 183: 8 1, 1963.
JAY N. COHN, M.D. JOSEPH A. FRANCIOSA, M.D. Minneapolis. Minnesota
Vasodiiator and inotropic drugs work through independent mechanisms in augmenting left ventricular pump function in patients with heart failure. The seiectlon between these two classes of pharmacologic agents for an individual patient may be based on the control blood pressure as well as the underlying disease. Although vasodilator drugs are easiest and safest to employ in pattents wtth normal or high arterial pressure levels, even In relatively hypotensive subjects (systolic arterial pressure less than 105 mm Hg), a salutary hemodynamic effect can be achieved without an undue decrease in pressure. inotropic drugs may be safest to administer to patients without coronary artery disease, but the oxygen-consuming effect of these drugs need not necessarily have an adverse effect on patients with ischemic heart disease. Combined vasodiiator and inotropic drug therapy is the most potent pharmacologic means of restoring pump function in patients with severe heart failure. The long-term use of vasodiiator and inotropic drugs in the treatment of heart failure is dependent on the availability of agents that will produce a sustained hemodynamic effect. Hydraiazine, nltrates and prazosin have been employed atone or in combination and provkte a promising approach to vasodiiator treatment of heart falture. Better and more selective oral inotropic agents are needed to allow this therapeutic modality to be employed optimally. The recently demonstrated efficacy of vasodilator drugs in the treatment of left ventricular failure [l-5] has provided physicians with two pharmacologic means of augmenting cardiac output: inotropic drugs, which are available in a number of parenteral but fewer oral forms, and vasodilators, which are available for both parenteral and oral administration. The management of pump failure, therefore, now requires a choice between administering an inotropic or a vasodilator drug, or a decision to use the two agents together. The variety of drugs available in these two classes of compounds has greatly expanded the therapeutic armamentarium for severe heart failure. However, these new advances in therapeutics also represent a challenge to the physician, who must understand the pathophysiology of heart failure and the pharmacodynamics of the drugs in order to apply this new, selective therapy rationally. We shall, therefore, consider the physiology of the disease and the hemodynamic effects of the drugs in order to arrive at a basis for selecting inotropic, vasodilator or combined therapy for the treatment of severe heart fail-
From ths Universityof MinnesotaMedicalSchool, Minneapolis,Minnesota.Requests for reprints shouldbe addressedto Dr. JayN. C&n, University of MinnesotaHospital, Box 488. Minneapolis, Minnesota55455.
ure.
Mechanisms of inotropic and Vasodilator Effects. Ample evidence indicates that inotropic and vasodilator drugs work through independent mechanisms in augmenting stroke volume. The inotropic drugs, partitularly
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enteral management of sudden pump failure, increase the velocity and force of ventricular contraction [6]. This action is apparent in isolated muscle preparations, in intact animal studies and by measuring indices of contractility in man. Careful measurement of ventricular dimensions during an inotropic intervention with infusion of dopamine in awake dogs reveals a constant or slightly reduced end-diastolic volume, an increased velocity of wall movement during systole and a reduction in endsystolic volume [ 71. Vasodilator drugs, on the other hand, exert no effect on myocardial contractility in isolated preparations [8]. In the intact circulation, drugs that relax arteriolar resistance reduce left ventricular outflow resistance (aortic impedance) and left ventricular end-systolic volume [7]. The increase in stroke volume may be at least partially counteracted, however, by a simultaneous reduction in end-diastolic volume or preload. Since the decrease, if any, in end-diastolic volume during an inotropic intervention usually is less than that during a vasodilator intervention, an increase in stroke volume cannot be the major factor in reducing end-diastolic volume. Therefore, an important factor in determining changes in end-diastolic volume in response to a vasodilator drug is the effect of the drug on venous capacitance vessels [8]. A reduction in ventricular and diastolic volume usually is attributed to a shift of volume from the central to peripheral capacitance vessels because of venodilation. However, a role for pulmonary venous dilation that would increase the capacitance of the pulmonary circulation also is a possible contributing factor. Simultaneous administration of vasodilator and inotropic drugs results in an augmentation of left ventricular function greater than that achieved with either agent alone. This augmentation was shown in the awake dog by a further increase in left ventricular ejection fraction because of a decrease in end-systolic volume to levels lower than could be achieved by either drug given independently [7]. These changes in ventricular dimensions when the normal heart is exposed to a varying outflow resistance are inconsistent with previous suggestions that the heart adjusts its stroke work from an unchanged end-diastolic volume when outflow resistance is altered. This concept of homeometric autoregulation, introduced by Sarnoff et al. [9], does not appear to pertain during acute pharmacologic interventions in awake subjects. Hemodynamic Effects of lnotropic and Vasodilator Drugs in Heart Failure. All inotropic drugs exert some peripheral vascular actions that make it difficult to assess the effects of a pure inotropic intervention. Even if such an agent were available, however, it would be impossible to isolate the inotropic effects of the drug from the reflex circulatory effects which may occur
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when the drug is administered to a patient with heart failure. Thus, any increase in stroke volume generated by a more forceful ventricular contraction would lead to a change in arterial pressure that would likely lead to reflex adjustment in the peripheral circulation resulting in a decrease in systemic vascular resistance. It would then be difficult to separate the secondary response to change in resistance from the primary response to the inotropic intervention. The response to inotropic drugs with prominent peripheral vascular effects is often dominated by the peripheral vascular actions. Norepinephrine, a potent inotropic drug with a marked vasoconstrictor effect, increases blood pressure through vasoconstriction and results in such reflex vagal stimulation that the inotropic effect of the drug may be overlooked in the intact animal [lo]. Isoproterenol, on the other hand, exerts such potent peripheral vasodilation that aortic diastolic pressure decreases and heart rate increases prominently. Indeed, much of the increase in cardiac output previously attributed to the inotropic effect of isoproterenol could well be due to the peripheral vasodilation induced by the drug. Dopamine was introduced as an inotropic drug with lesser peripheral vascular and chronotropic properties [ 111. It has gained widespread use in the treatment of pump failure because it induces less vasoconstriction than norepinephrine and less tachycardia than isoproterenol. Peripheral vascular actions are present, however, and as the dose is increased alpha adrenergic vasoconstriction begins to predominate over the socalled dopaminergic vasodilation [ 121. The presently available pharmacologic agent which comes closest to providing a specific inotropic effect is dobutamine, a dopamine derivative [ 131. Dobutamine lacks dopamine’s direct vasodilator effect on the renal vasculature and also lacks the predominant vasoconstrictor (alpha adrenergic) effect of dopamine observed with higher doses of the drug. Furthermore, dobutamine has been shown not to increase heart rate even when given in doses that produce a prominent increase in myocardial contractility [ 141. The absence of net peripheral vascular effects of dobutamine appear to be related to a unique balance of alpha and beta peripheral vascular actions that tend to cancel each other out [ 151. The absence of a heart rate response despite the inotropic effect of the drug raises interesting speculations about the possible dissociation of inotropic from chronotropic properties of beta agonists [ 161. lnotropic drugs such as dobutamine increase stroke volume by generating more forceful muscle shortening, whereas vasodilator drugs like sodium nitroprusside increase stroke volume by reducing outflow resistance and passively allowing greater muscle shortening. We thought it would be of some interest to compare directly
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the potency of dobutamine and nitroprusside in augmenting left ventricular pump function in patients with severe left ventricular failure. Therefore, we studied the effect of both drugs infused sequentially in 12 patients [ 171. Dobutamine in a dose of 10 pg/kg/min produced an increase in systolic and mean arterial pressure with an unchanged heart rate. Cardiac output increased prominently and there was a decrease in pulmonary wedge pressure, and in systemic and pulmonary vascular resistance (Figure 1). Infusion of sodium nitroprusside in the same patients produced a similar augmentation in left ventricular performance but with certain distinct differences (Figure 2). The cardiac output increased to a similar extent during infusion of the vasodilator drug, but the arterial pressure was slightly reduced during nitroprusside infusion and the heart rate slowed slightly. Pulmonary wedge pressure was decreased to a greater extent than with the dobutamine infusion, but the systemic and pulmonary vascular resistance were similarly reduced. Since both drugs produced similar decrements in vascular resistance, it was appropriate to question whether these drugs are similarly potent vasodilators. In order to assess the direct vascular effects of the drug, the two agents were infused sequentially into the brachial artery of patients with heart failure while forearm blood flow was monitored using a Whitney mercuryin-rubber resistance gauge and venous occlusion plethysmography. During infusion of sodium nitroprusside in very small doses representing less than 5 per cent of the systemic infusion rate of the drug, forearm blood flow was markedly augmented confirming the potent direct peripheral vasodilator effect of nitroprusside. In contrast, when dobutamine was infused into the brachial artery little if any direct vascular effect of the drug could be identified until the infusion rate reached the point at which systemic hemodynamic effects of the dobutamine could be recognized. These studies, therefore, provide strong evidence that the decrease in peripheral vascular resistance during dobutamine infusion is not a manifestation of a direct vasodilator effect of the drug but rather a manifestation of a reflex decrease in systemic vascular resistance as the cardiac output is augmented by the inotropic agent. In contrast, the decrease in systemic vascular resistance during nitroprusside infusion could represent largely a direct vasodilator effect of this agent. Thus, dobutamine and nitroprusside produce comparable augmentation in left ventricular function in the setting of heart failure, but they do it through an entirely different mechanism. The inotropic drug increases force of ventricular contraction and augments stroke volume leading to a secondary decrease in systemic vascular resistance; the vasodilator drug primarily reduces
Arterial Pressure
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10 Figure 1. Hemodynamic response to dobutamine infusion in 12 patients with severe heart failure. Note marked increase in cardiac output with only slight increase in systolic arterial pressure and decrease in pulmonary wedge pressure (PWP). Systemic vascular resistance (S VR) and pulmonary vascular resistance (PVR) decrease.
systemic resistance and through a mechanical reduction in outflow resistance allows the stroke volume and cardiac output to increase. Since the agents act through independent mechanisms, it is not surprising that their hemodynamic effects are additive when the drugs are infused together. The combination of dobutamine or dopamine with nitroprusside is the most potent pharmacologic means
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Figure 2. Hemodynamic response to nitroprusside in 12 patients with severe heart failure. Note that hemodynamic response is similar to that of &butamine except that arterial pressure decreases slightly.
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Figure 3. t?esponse to nitroprusside (NP), dobutamine (DOB) and isoproterenol (ISO) in a 55 year old man with severe cardiomyopathy. Blood pressure (BP) and heart rate (M) changed little during all interventions. However, extremely low cardiac output (CO) was unsatisfactorily augmented by either nitroprusside or dobutamine, 10 pglkglmin. The combination of the two restored output to a normal level. lsoproterenol was less effective even though the heart rate increased further. prolonged therapy with nitroprusside and dobutamine led to gradual improvement. Administration of the drugs was discontinued after three days, and the patient was weaned onto oral therapy that maintained the herno@namic improvement and allowed him to return home.
available for restoring cardiac output to adequate levels in the setting of severe pump failure (Figure 3). The hemodynamic response to all vasodilator agents is, of course, not the same. The drugs all share a net dilating effect on arterial resistance vessels, an effect that accounts for their ability to increase left ventricular ejection fraction. But their direct action on the venous bed, the pulmonary circulation, the myocardium, reflex sympathetic stimulation and regional vascular beds varies widely among different agents. Metabolic Effects of lnotropic and Vasodilator Drugs. The different hemodynamic effects of these two classes of agents would be expected to be reflected in a difference in myocardial metabolic response. During sodium nitroprusside infusion an increase in systolic blood pressure, an increase in velocity of fiber shortening and a slight but insignificant increase in heart rate would be expected to augment myocardial oxygen consumption [ 181. A reduction in ventricular volume might tend to
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moderate the oxygen-consuming effect of the drug somewhat. In contrast, during infusion of nitroprusside the systolic pressure is reduced, the heart rate is unchanged or decreases slightly and the velocity of fiber shortening is not significantly altered. Consequently, myocardial oxygen consumption should decrease, particularly when there is a simultaneous reduction in ventricular volume [ 191. The differing metabolic effects of these two compounds have been demonstrated in dogs with induced myocardial infarction. In a series of dogs in which the left circumflex coronary artery was embolized with mercury to produce a syndrome of pump failure, infusion of dobutamine and infusion of nitroprusside produced similar augmentation in left ventricular function [20]. The dobutamine infusion was accompanied by a 23 per cent increase in myocardial oxygen consumption, whereas the nitroprusside infusion was accompanied by an 11 per cent reduction in myocardial oxygen consumption. Therefore, the prediction of changes in oxygen consumption based on hemodynamic determinants of myocardial oxygen consumption appeared to be quite reliable in these experimental studies. If one wished to calculate in the patient with heart failure the oxygen cost of increasing cardiac output, it is clear that vasodilator therapy provides a more economical use of oxygen than does inotropic therapy. These studies on global myocardial function and metabolism do not, however, provide necessary information on the response of regionally ischemic myocardium in patients with. coronary artery disease. Preliminary studies in both experimental animals and man indicate that nitroprusside may, in at least some situations, improve the metabolism and function of ischemic myocardium [21,22]. Of course, if the drug is given in a dose to reduce arterial pressure to critical levels or if heart rate is increased, then ischemia may be aggravated. lnotropic drugs are generally thought to be likely to aggravate ischemia because of their tendency to increase myocardial oxygen consumption. Nonetheless, recent studies in experimental dogs suggest that dobutamine could actually protect against ischemia [231. Selection of Patients for lnotropic and Vasodilator Therapy. Left ventricular failure is characterized by a high left ventricular filling pressure and a reduced stroke volume and cardiac output. The arterial pressure may be low, normal or high depending on the state of the peripheral vascular resistance. The goal of therapy is to increase cardiac output and to reduce left ventricular filling pressure while keeping arterial pressure above intolerable hypotensive levels. A general approach to management, therefore, is to use vasodilator drugs when the control arterial pressure is well within the normal range or even elevated, but to preferentially
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choose inotropic drugs when the arterial pressure is at borderline levels. Care must be taken, however, to document that the low blood pressure is a true hypotensive state and not the result of a cuff artifact, which causes a low or unobtainable auscultatory pressure because of reduced forearm flow [ 241. Despite this concern about the use of dilators when arterial pressure is already low, it is often possible to titrate a vasodilator drug to achieve a considerable increase in cardiac output with no significant alteration or with even an increase in arterial pressure. This response can be understood if one recognizes that arterial pressure represents the product of output and resistance. Since stroke volume and cardiac output increase as the resistance is reduced in patients with heart failure, little change in arterial pressure may occur. A high resistance-low output state may thus be transformed into a lower resistance-higher output state at substantially similar arterial pressures. Although it is generally assumed that patients with low arterial pressures are not ideal candidates for vasodilator drugs, the response in these patients is frequently salutary. In reviewing our experience with sodium nitroprusside infusion in patients with heart failure, we identified 16 patients with a control arterial systolic pressure of less than 105 mm Hg who were given an infusion of nitroprusside in an attempt to improve left ventricular function. These 16 patients were matched with 16 nonhypotensive patients who had similar control pulmonary wedge pressure and cardiac output, and who were also given a nitroprusside infusion in an attempt to augment left ventricular function. As shown in Figure 4 the hemodynamic response was similar in these two groups of patients. Cardiac output was similarly augmented and left ventricular filling pressure similarly reduced. Arterial pressure decreased in both groups but the decrease in the initially normotensive group was greater and during the peak effect of the nitroprusside infusion, the average blood pressure in the hypotensive group was still within tolerable limits. Indeed, the diastolic arterial pressure in this group was now very similar to the diastolic pressure in the initially normotensive group. It is clear that vasodilator therapy need not necessarily be withheld from the patient with borderline blood pressure and left ventricular failure. Nonetheless, even a slight decrease in arterial pressure during the nitroprusside infusion in such patients may be a cause for concern, particularly in patients who have underlying coronary artery disease. In these subjects the use of an inotropic agent either alone or in combination with the vasodilator is entirely rational. Not only should the arterial pressure be a determinant of the selection of inotropic versus vasodilator drugs, but the underlying disease process also should be kept
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Figure 4. Hemodynamic response to infusion of sod& nitroprusside (NP) in 32 patients with severe heart failure, 16 with arterial systolic pressure (AP) greater than 105 mm Hg (open symbols, broken lines) and 16 subjects matched for similar cardiac output (CO) and pulmonary wedge pressure (PWP) but with arterial pressure less than 105 mm Hs_(closed symbols, solid lines). The decrease in PWP and increase in CO were similar in the two groups and the hemodynamic improvement in the hypotensive group was achieved with only a slight decrease in arteM pressure. C = pre-NP control period.
in mind. Since inotropic drugs augment myocardial oxygen consumption they should be employed with caution in patients with ischemia in whom further augmentation of oxygen consumption could have a deleterious effect. lnotropic drugs often are not well tolerated by patients with severe coronary artery disease; in this group of patients, it is often preferable to initiate therapy with a vasodilator drug in hopes that pump function can be improved with little if any decrease in aortic pressure. In contrast, the young person with apparently normal coronary arteries but severe myocardial dysfunction seems to be an ideal candidate for the use of inotropic drugs. In the setting of severe pump failure accompanying acute myocardial infarction, the urgent goal is to increase cardiac output and restore peripheral circulation. Concern for the preservation of ischemic myocardium may of necessity be secondary in such persons. The combination of inotropic and vasodilator drugs in this particular patient population is extremely potent and, usually, effective in restoring an adequate cardiac output and left ventricular filling pressure. This combination therapy has gradually supplanted mechanical assistance for the management of pump failure in the
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FIgare 5. Comparative effects of 50 mg oral ephedrine (f and intravenous infusion of sodium nitroprusside (N) on ler ventricular function in six patients with heart failure. Ephedrine increased cardiac output to the same extent as nitroprusside but did not reduce pulmonary wedge pressure. The combination produceda greater output increase than either agent alone. Cs = pre-drug control period.
setting of acute myocardial infarction. Although this pharmacologic approach has reduced the dependence in the coronary care unit on intraaortic balloon pumping it is not at all certain at this time whether the pharmacologic therapy has the potential for a beneficial effect on myocardial metabolism. The ease of pharmacologic therapy as opposed to mechanical assistance makes it particularly attractive, but studies of the myocardial metabolic effects of these interventions are needed before one can rationally choose between pharmacologic and mechanical treatment. Selecting among the various vasodilator and inotropic drugs for the immediate management of left ventricular failure presents a number of options. Sodium nitroprusside is the most potent and reliable vasodilator drug for this purpose, and it has generally become the drug of choice. Titration to the required dose generally requires an automated infusion system and close monitoring of circulatory function. When an infusion of nitroprusside is continued for more than a few days, blood thiocyanate levels should be measured to avoid thiocyanate toxicity. Fortunately, patients usually can be weaned from intravenous nitroprusside therapy to effective nonparenteral vasodilator therapy before toxicity becomes a problem. Other drugs, such as phentolamine, trimethaphan, nitroglycerin and hydralazine, are available for parenteral administration when an alternative to nitroprusside is sought. lnotropic drugs present a greater problem. Digitalis preparations tend to be quite ineffective in the immediate management of pump failure. Cardiac output is generally not increased very much, and left ventricular filling pressure decreases only slightly if at all [25]. Immediate support of the failing heart, therefore, re-
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quires administration of an inotropic agent that exerts its effect through beta adrenergic receptors in the myocardium. Although dobutamine and dopamine produce an inotropic effect with little perturbation of the peripheral circulation, some patients exhibit little hemodynamic response to these drugs. When arterial pressure is low and augmentation of myocardial contractility is urgently needed, norepinephrine appears to be a more reliable agent. Indeed, one can utilize norepinephrine for its myocardial stimulation and simultaneously administer nitroprusside to counteract the peripheral vasoconstrictor effect of the drug. This combination provides unique control of both the heart and peripheral circulation, since the two drugs can be titrated independently. lsoproterenol has lost favor as an inotropic drug because it may produce undesirable tachycardia and because its peripheral vasodilator effect involves predominantly the skeletal muscle bed [26]. Therefore, the regional distribution of blood flow induced by isoproterenol would be expected to be quite different from that produced by the combination of nitroprusside with dobutamine, dopamine or norepinephrine, even if the cardiac output were similar. Long-Term Therapy with lnotropic and Vasodilator Drugs. In the last few years a number of oral vasodilator drug regimens have been explored for efficacy in the treatment of left ventricular failure. The regimens that come closest to simulating the hemodynamic effects of intravenous sodium nitroprusside are the combination of nitrate with hydralazine [27,28] or the new vasodilator prazosin [29]. For the most part, only the immediate effects of these drugs have been studied. Carefully controlled long-term studies must be designed to demonstrate whether these agents maintain their effectiveness during chronic administration. When it comes to oral inotropic therapy, the physician has been left with few options. Digitalis has of course been a mainstay for the long-term management of heart failure. Unfortunately, however, most of the patients who are currently being considered for more aggressive therapy are symptomatic while receiving adequate doses of a digitalis preparation. It is clear, therefore, that optimal hemodynamic management of left ventricular pump failure requires a more potent nonparenteral inotropic drug. Dobutamine, like most sympathomimetic drugs, is absorbed from mucous membranes, but it is not absorbed intact after oral administration. A sublingual or rectal form of the drug would likely be effective but would probably not provide a constant blood level of the drug. Ephedrine is a sympathomimetic agent that is absorbed after oral administration and has a fairly long duration of action. Its direct myocardial stimulation
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probably results from release of norepinephrine from tissue stores [30], but it also exerts a direct peripheral vasodilating effect [31]. We have recently explored the hemodynamic effects of oral administration of ephedrine in patients with heart failure [32]. The response to ephedrine alone was studied in comparison to the response to nitroprusside and then the effect of combining the drugs was evaluated. The purpose was to determine whether this oral inotropic agent would act similar to dobutamine in augmenting the systemic hemodynamic effect of the vasodilator drug. As shown in Figure 5, ephedrine increased cardiac output but did not reduce pulmonary artery wedge pressure. In contrast, nitroprusside infusion increased cardiac output while reducing wedge pressure. The combination of ephedrine and nitroprusside produced a greater improvement in left ventricular function, similar to the augmentation when dobutamine is added to nitroprusside. Arterial pressure increased slightly after oral administration of ephedrine, and heart rate was slightly increased (Figure 6). The addition of nitroprusside reduced arterial pressure and, paradoxically, also slowed the ephedrine-induced tachycardia. These preliminary studies indicate the potential for oral inotropic drugs, especially when combined with vasodilators in the management of severe heart failure. Ephedrine is probably not an ideal agent, because tachyphylaxis to the drug is likely to develop and, as with isoproterenol, the peripheral distribution of the increased cardiac output may not be physiologically ideal. Other inotropic agents have been explored but none have yet been approved for clinical use. Esproquin, an isoquinoline derivative, exerts a prolonged dose-dependent inotropic effect in normal subjects and in patients with heart failure [33,34]. Tazolol is a sympathomimetic-like drug that also has inotropic properties when administered orally [35]. It is likely that new orally effective agents that exert inotropic properties with favorable effects on the distribution of peripheral blood flow and little effect on heart rate will be developed, tested and marketed in the next few years. Inotropics, Vasodilators and the Therapy of Heart Failure. Heart failure is the most common precedent to cardiovascular mortality. Prognosis, once the diagnosis of congestive heart failure has been made, is poor [36]. But the physiologic mechanism of the natural progression of heart failure remains obscure. Cardiac dilation seems to develop and progresses without necessarily an acute event. The clinical syndrome has the characteristics of a positive feedback system ]371. Until recent years therapy was devoted to restoring contractility with digitalis and relieving congestion with diuretics. We now know that digitalis has limited ino-
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6. Changes in mean arterial pressure (MAP) and heart fate (I-R) during infusion of nitropmsside and after oral administration of ephedrine. Ephedrine alone increased pressure and heart rate slightly, but when nitroprusside was infused simultaneously the heart rate and arterial pressure effects were counteracted. Figure
tropic potential and that vasodilators may produce a considerably greater improvement in cardiac performance comparable to that achieved by the most potent inotropic interventions. How, then, can this new insight into cardiovascular regulation be integrated into an over-all management plan for heart failure? In the setting of severe, intractable pump failure the use of potent inotropic and vasodilator drugs has considerably altered inhospital management. Most patients who reach this point of decompensation, however, have such severe and irreversible myocardial damage that long term prognosis is extremely poor. Although many such patients have been restored to stability and have returned home, their life style is usually very limited and their survival short-term. To have an impact on the morbidity and mortality from heart failure, effective interventions may need to be instituted at an early stage of the disease, perhaps before symptoms become obvious to the patient. If the impact of such an approach on the natural history of the disease were to be tested, a large scale controlled trial would need to be mounted and a therapeutic regimen employed. Whether such an early intervention trial should test an inotropic drug, a vasodilator drug, a diuretic or all three is, at the present, not known. We are, perhaps, on the threshold of a new understanding of congestive heart failure. These new insights have resulted from application of hemodynamic technics to the study of therapeutic responses in patients with heart failure. More rational and effective management of the patient with heart disease should follow.
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