Combined therapy with digoxin and nitroprusside in heart failure complicating acute myocardial infarction.

The hemodynamic effects of digoxin plus nitroprusside were compared with those of nitroprusside alone in 11 patients with congestive heart failure complicating acute myocardlal infarction. Hemodynamic measurements were made using a Swan-Ganz thermodilution catheter and a bedside thermodilution cardiac output computer. Patients received increasing doses of nitroprusside until mean arterial pressure decreased to 70 mm Hg or pulmonary arterial wedge pressure decreased to 16 mm Hg. The infusion rate of nitroprusside was then held constant for 120 minutes. After 30 minutes of constant nitroprusside infusion, 0.5 mg of digoxin was given intravenously. Hemodynamic measurements were obtained before treatment with nitroprusside and immediately before and 30, 60 and 90 minutes after the administration of digoxin.Nitroprusside produced a significant decrease in pulmonary arterial wedge pressure (24 to 16 mm Hg), mean arterial pressure (92 to 85 mm Hg and systemic vascular resistance (1,816 to 1,480 dynes sec cm^?5) and a significant increase in cardiac index (2.19 to 2.51 liters/min per m²). Ninety minutes after the administration of digoxin, cardiac index was further increased (2.51 to 28.2 liters/min per m², P = 0.03) and systemic vascular resistance was tower (1,480 to 1,320 dynes sec cm^?5, P = 0.03). Pulmonary arterial wedge pressure was not further decreased by the addition of digoxin. Thus, the addition of digoxin further increases cardiac output in patients with congestive heart failure complicating myocardial infarction who are receiving nitroprusside but does not produce any further decrease in pulmonary arterial wedge pressure.     

Effect of isosorbide dinitrate on response to submaximal and maximal exercise in patients with congestive heart failure.

Isosorbide dinitrate is an effective vasodilator that improves resting left ventricular performance in patients with congestive heart failure, but little is known of the effect of the drug on the response to exercise. Bicycle exercise to symptomatic maximum was performed by 18 patients with class II to IV congestive heart failure before and 90 minutes after administration of isosorbide dinitrate, 40 mg orally. Although resting pulmonary wedge pressure and systemic vascular resistance were significantly reduced after isosorbide dinitrate, exercise duration was not altered and maximal oxygen consumption was not significantly changed (13.6 +/- 1.3 [SEM] standard error of the mean versus 13.8 +/- 1.2 ml/kg per min). At peak exercise pulmonary wedge pressure of 37.1 +/- 1.7 mm Hg, cardiac index of 4.19 +/- 0.35 liters/min per m2, and systemic vascular resistance of 14.7 +/- 1.3 units were not significantly different after nitrate administration. However, at submaximal loads, pulmonary wedge pressure was reduced from 33.6 +/- 1.7 to 27.9 +/- 1.8 mm Hg (P less than 0.01), and systemic resistance from 16.5 +/- 1.5 to 13.7 +/- 1.0 units (P less than 0.01) after administration of isosorbide dinitrate. Thus, short-term administration of nitrates does not improve maximal exercise capacity or left ventricular performance at maximal exercise in patients with congestive heart failure, but it does appear to improve pump function at submaximal work loads and may therefore enable patients to perform limited exercise more comfortably.     

Hemodynamic effects of oral ephedrine given alone or combined with nitroprusside infusion in patients with severe left ventricular failure

Potent vasodilator or inotropic agents alone may be of limited value in some patients with severe congestive heart failure because of their exaggerated peripheral vascular effects. Nitroprusside and potent inotropic agents in combination are hemodynamically more effective than either alone. Although oral vasodilators can mimic nitroprusside, there is a need for potent oral inotropic agents. Ephedrine is an oral sympathomimetic inotropic drug. The hemodynamic effects of ephedrine alone (50 mg orally), nitroprusside alone and the two agents combined were studied in 11 patients with severe congestive heart failure. Heart rate increased from 89.9 ± 5.2 (standard error of the mean) to 98.2 ± 5.0 beats/min after ephedrine (P < 0.001) and to 96.4 ± 4.7 beats/min with ephedrine plus nitroprusside (P < 0.02); it was unchanged with nitroprusside alone. Mean systemic arterial pressure increased from 83.7 ± 2.1 to 89.2 ± 2.7 mm Hg after ephedrine (P < 0.02) and decreased to 73.4 ± 2.4 mm Hg with nitroprusside added (P < 0.01). Left ventricular filling pressure was unchanged after ephedrine but decreased from 30.9 ± 2.3 to 20.6 ± 2.1 mm Hg during nitroprusside infusion (P < 0.01). Control cardiac output averaged 3.94 ± 0.30 liters/min and increased by 1.25 ± 0.31 liters/min with nitroprusside, by 1.09 ± 0.30 liters/min after ephedrine and by 2.20 ± 0.34 liters/min with the two combined. Although the increases in cardiac output with each agent alone were significant and similar, the increase with the two combined was significantly greater than with either alone. The data suggest that ephedrine is an orally effective inotropic agent especially when combined with a vasodilator. Further evaluation of ephedrine in congestive heart failure is warranted.     

"Optimal" left ventricular filling pressure during nitroprusside infusion for congestive heart failure

On the basis of preload manipulations, an optimal left ventricular filling pressure of 14 to 18 mm Hg has been suggested for patients with left ventricular failure. Since afterload reduction results in increased cardiac output in heart failure, the hypothesis that left ventricular filling pressure could be reduced to normal by nitroprusside without compromising cardiac output was tested in 15 patients with acutely decompensated chronic congestive heart failure. Cardiac index was measured after each 4 to 6 mm Hg decrease in pulmonary wedge pressure until the latter fell below 14 mm Hg (Group I, nine patients) or until systolic arterial pressure reached 90 mm Hg during nitroprusside infusion (Group II, six patients). In Group I, pulmonary wedge pressure fell in significant decrements (p < 0.001) from 28 ± 4 (SD) to 24 ± 3, 17 ± 2, and 11 ± 2 mm Hg during nitroprusside infusion. Cardiac index rose in significant increments (p < 0.05) from 2.5 ± 0.8 to 2.8 ± 0.6, 3.3 ± 0.7, and 3.7 ± 1.1 liter/minute/m² with each increase in nitroprusside dosage. Mean arterial pressure fell during nitroprusside infusion from 97 ± 16 to 70 ± 8 mm Hg (p < 0.001) without any change in heart rate. In Group II, directionally identical changes in hemodynamics were observed during nitroprusside infusion; the highest cardiac index occurred at the lowest pulmonary wedge pressure attained, and no side effects were observed despite the fall in systolic arterial pressure to 90 mm Hg. Thus, reduction of left ventricular filling pressure to within the normal range by nitroprusside infusion in patients with chronic left ventricular failure can raise cardiac output beyond levels observed at left ventricular filling pressures of 14 to 18 mm Hg. Normalization of filling pressure may improve subendocardial coronary perfusion, and invasive monitoring of filling pressure during nitroprusside infusion may not be routinely required.     

Hemodynamic effects of nitroglycerin ointment in congestive heart failure

The hemodynamic effects of nitroglycerin absorbed transcutaneously from an ointment base were determined in 10 patients with chronic congestive heart failure (9 with ischemic heart disease and 1 with cardiomyopathy). The response was characterized by a decrease in pulmonary capillary wedge pressure from an average of 30 to 19 mm Hg, and an increase in cardiac index from 1.7 to 2.2 liters/min per m², with concomitant decreases in systemic and pulmonary vascular resistance and an increase in venous capacitance. Mean arterial pressure decreased from 85 to 80 mm Hg, and heart rate remained unchanged. The hemodynamic effects persisted for 3 to 6 hours. These results indicate that nitroglycerin ointment is a hemodynamically potent vasodilating agent with potential value in the therapy of congestive heart failure.     

Acute hemodynamic effects of combined therapy with digoxin and nifedipine in patients with chronic heart failure

The acute hemodynamic effects of combining administration of digoxin (DIG) (0.01 mg/kg intravenously) with nifedipine (NFP) (10 mg sublingually) were compared with those of DIG and NFP considered alone in 12 patients with chronic congestive heart failure due to coronary artery disease (CAD, seven patients) or primary congestive cardiomyopathy (CCM, five patients); four patients also had mitral regurgitation (MR). NFP significantly reduced systolic and diastolic blood pressure (BP), systemic vascular resistance (SVR) from 1925 ± 400 (mean ± SD) to 1333 ± 256 dyne · sec · cm^?5 after 30 minutes (p < 0.00001), and left ventricular filling pressure (LVFP) from 19 ± 7.5 to 15.6 ± 4.2 mm Hg (p < 0.005). The cardiac index (CI) increased from 2.16 ± 0.47 to 2.81 ± 0.63 L/min/m² (p < 0.00001). DIG induced a significant reduction in LVFP from 18.1 ± 7.7 to 14.3 ± 5.4 mm Hg after 90 minutes (p < 0.005) and a slight increase in stroke volume index; no significant change in BP, Cl, and SVR was seen. The combination of DIG and NFP produced a significant increase in Cl from control value of 2.2 ± 0.48 to 2.95 ± 0.44 L/min/m² (p < 0.00001), and a significant reduction in LVFP from 18.1 ± 7.7 to 13 ± 4.7 mm Hg (p < 0.00001), and in SVR. Simultaneous administration of DIG and NFP resulted in an augmentation in cardiac performance greater than that achieved with either agent considered alone. The combination produced a greater output increase and a greater LVFP reduction, indicating a shift upwards and to the left to a more improved left ventricular function curve. No significant difference was seen between the hemodynamic response to the three drug regimens in patients with CAD versus patients with CCM. NFP produced a greater improvement in cardiac performance in patients with MR when compared with those without MR.     

Hemodynamic responsiveness to short- and long-acting vasodilators in left ventricular failure

Vasodilators acutely reduce afterload and improve hemodynamics in congestive heart failure. Intravenous nitroprusside reduces left ventricular filling pressure and increases cardiac output while modestly reducing blood pressure and not changing heart rate in patients with heart failure in whom this response is characteristic. Comparably reduced blood pressure during nitroprusside infusion in normal subjects or hypertensive patients without failure results in a decrease in cardiac output and tachycardia. Long-acting vasodilators are also effective in patients with congestive heart failure. Nitrates, predominant venodllators, decrease left ventricular filling pressure as much as nitroprusside does, but increase cardiac output less. Hydralazine, an arterial dilator, increases cardiac output similarly to nitroprusside but decreases filling pressure less. Combining hydralazine with nitrates results in hemodynamic effects almost identical to those of nitroprusside. The quinazoline derivatives, trlmazosin and prazosin, are also effective vasodilators, which act on both arteries and veins in patients with congestive heart failure. The hemodynamic response to vasodilators is influenced by the underlying hemodynamic status, as the change in cardiac output is directly related to base line ventricular filling pressure as well as systemic vascular resistance, and inversely related to the base line cardiac output. Response to vasodilators does not appear to be altered by age, diabetes, acute myocardial infarction or the cause of congestive myocardiopathy.     

Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure.

Patients with severe left ventricular failure generally have both reduced cardiac output and increased pulmonary and systemic venous pressures. A study was therefore made of the use of combined vasodilator therapy with nonparenterally administered nitrates, which act primarily on venous capacitance vessels and thus reduce preload, and orally administered hydralazine, which acts on arteriolar resistance vessels and thus reduces afterload. Twelve patients with chronic refractory heart failure were given these drugs individually and in combination during continuous hemodynamic monitoring. Heart rate and arterial pressure did not change significantly. Nitrates significantly reduced filling pressures of both ventricles without affecting cardiac index. Hydralazine did not alter filling pressures but dramatically increased cardiac index. The hemodynamic effects of each drug were additive during combined therapy, resulting in a 36 percent (28 to 18 mm Hg) mean decrease in left ventricular filling pressure and a 58 percent (2.1 to 3.3 liters/min per m(2)) mean increase in cardiac index. The seven patients who have continued to receive combined therapy for 3 to 10 months have shown sustained clinical improvement.     

Afterload reduction with phentolamine in patients with acute pulmonary edema

Phentolamine in amounts of 10 to 40 μg/kg/min was infused intravenously for the emergency treatment of acute pulmonary edema due to left ventricular failure. Fourteen patients with arteriosclerotic heart disease, ranging in age from 52 to 87 years, had clinical and roentgenographic signs of pulmonary edema. The pulmonary artery wedge pressure was increased to an average of 24 mm Hg and the cardiac index was decreased to 1.9 liters/min/m² or less prior to the administration of phentolamine. A reduction in the pulmonary artery wedge pressure to 14 mm Hg and an increase in the cardiac index to 2.5 liters/min/m² was observed in response to this alpha adrenergic blocking agent. Reduction in peripheral resistance with phentolamine was associated with reversal of pulmonary edema.     

Enhanced left ventricular performance with phentolamine in acute myocardial infarction

The hemodynamic effects of phentolamine (Regitine) were evaluated in nine patients with increased left ventricular filling pressure and clinical left ventricular failure (Group A) and five patients with normal left ventricular filling pressure and an uncomplicated course (Group B) within 48 hours of an acute myocardial infarction. Decreased afterload was noted in both groups after administration of phentolamine. Improved left ventricular performance was noted only in Group A and was manifested by a decrease in left ventricular filling pressure (from 23.9 to 13.6 mm Hg), increase in cardiac index (from 2.1 to 2.9 liters/min per m²), increase in stroke volume index (from 22.5 to 29.3 cc/beat per m²), and little change in heart rate (from 94.2 to 99.8 beats/min). In contrast, a decrease in stroke volume index (32 to 26 cc/beat per m²) and a greater increase in heart rate (77 to 94 beats/min) were noted in Group B. Reduction of preload, which accompanies a reduction in afterload with administration of phentolamine, may have caused a greater decrease in end-diastolic volume in Group B, resulting in the reduced stroke volume index and compensatory increase in heart rate. Our findings suggest that afterload reduction induced by administration of phentolamine enhances depressed left ventricular function in patients with increased left ventricular filling pressure after myocardial infarction. Careful monitoring to prevent complications is required.     

Sustained salutary effects of oral controlled-release nitroglycerin on ventricular function in congestive heart failure.

The hemodynamic effects of a controlled-release preparation of original nitroglycerin (ONTG), 6.5 mg to 19.5 mg, were determined during a four hour period in 10 patients with left ventricular failure. After ONTG ingestion left ventricular filling pressure (LVFP) diminished in 20 min (23 to 17 mm Hg, p < 0.01), declined maximally within one hour (15 mm Hg, p < 0.001) and remained decreased (p < 0.02) throughout the four hours. For the entire group no significant alterations (p > 0.05) occurred in systolic blood pressure, heart rate, cardiac index (CI) and peripheral vascular resistance (PVR). However, two subgroups were identified relative to ONTG hemodynamic response. In the four patients in whom LVFP declined but remained substantially elevated (29 to 23 mm Hg, p < 0.05), CI rose (1.7 to 2.1 l/min/m², p < 0.01) while PVR fell (2074 to 1571 dyne · s · cm^-5, p < 0.02). In contrast, in the six patients with LVFP reductions to 12 mm Hg or less (18 to 10 mm Hg, p < 0.005), CI was unchanged (2.2, p > 0.05) without alteration of PVR (1799, p > 0.05). This investigation provides objective evidence of the salutary hemodynamic effects of ONTG and confirms adequate gastrointestinal absorption with attainment of pharmacologically active blood levels. Moreover, oral sustained-release nitroglycerin is shown to possess long-acting peripheral vasodilator actions of considerable value in the treatment of congestive heart failure.     

Variability of hemodynamic responses to acute digitalization in chronic cardiac failure due to cardiomyopathy and coronary artery disease

Eight patients with chronic congestive heart failure (four with cardiomyopathy and four with ischemic heart disease) underwent hemodynamic studies during acute administration of digoxin, given intravenously in two 0.5 mg doses 2 hours apart. Observations were made before administration of digitalis (control period) and serially thereafter for 4 hours after the first dose. Resting mean cardiac index and pulmonary arterial wedge pressure were as follows: 2.0 liters/min per m² and 23 mm Hg (control period); 2.1 and 24 (at 1 hour); 2.0 and 23 (at 2 hours); 2.7 and 19 (at 3 hours); and 2.3 and 20 (at 4 hours). Exercise responses of mean cardiac index and pulmonary arterial wedge pressure in five patients were: 3.1 liters/min per m² and 36 mm Hg (control period); 3.2 and 33 (at 1 hour); 3.2 and 28 (at 2 hours); 3.1 and 27 (at 3 hours); and 3.4 and 31 (at 4 hours). The pulmonary arterial wedge pressure remained elevated during exercise in all cases. Arrhythmias were seen in five patients after administration of 0.5 mg of digoxin. Hemodynamic improvement at 4 hours involving both reduced filling pressure and increased blood flow was observed in only two patients at rest and in one additional patient during exercise. Acute deterioration of cardiac function (elevated pulmonary arterial wedge pressure or decreased cardiac index) occurred 30 minutes after administration of digoxin in four patients, concomitantly with increased systemic resistance. In six patients, a peak hemodynamic effect appeared 1 to 1 $\text{1}\text{2}$ hours after administration of digoxin, with partial or total loss of initial benefit by 2 and 4 hours.In previously performed studies observations have seldom exceeded 1 hour; the results of this 4 hour study suggest that, in patients with cardiomyopathy or coronary artery disease and chronic congestive heart failure, acute digitalization does not necessarily lead to consistent, marked or lasting hemodynamic improvement. Thus, current concepts of the use of digitalis in such patients may require revision.     

Comparison of hemodynamic actions of pirbuterol and dobutamine on cardiac function in severe congestive heart failure

There is considerable interest in the development of beneficial oral inotropic agents for sustained ambulatory management of patients with severe chronic congestive heart failure. Therefore, the hemodynamic actions of the oral beta adrenergic receptor agonist pirbuterol and of intravenous dobutamine were compared in nine patients with severe heart failure. Both agents produced similar effects on ventricular pump function: The cardiac index was markedly increased from 1.8 to 2.6 liters/min per m² (p < 0.005) by dobutamine and from 1.8 to 2.9 liters/min per m² (p < 0.001) by pirbuterol; stroke index was increased from 24 to 32 ml/beat per m² (p < 0.02) by dobutamine and from 23 to 35 ml/beat per m² (p < 0.001) by pirbuterol; the stroke work index was increased from 19 to 27 g-m/m² (p < 0.005) by dobutamine and from 20 to 28 g-m/m² (p < 0.005) by pirbuterol. However, although dobutamine did not change mean blood pressure or left ventricular filling pressure (p < 0.05), pirbuterol modestly decreased mean blood pressure from 83 to 75 mm Hg (p < 0.02) and moderately decreased left ventricular filling pressure from 23 to 18 mm Hg (p < 0.005). Dobutamine reduced total systemic vascular resistance 22 percent from 2,049 to 1,582 dynes s cm^?5 (p < 0.001), whereas pirbuterol reduced this index 42 percent (p < 0.05 versus dobutamine) from 2,068 to 1,150 dynes s cm^?5. Neither agent altered heart rate or the heart rate-systolic blood pressure product (p < 0.05).Thus, oral pirbuterol has dobutamine-like beneficial hemodynamic effects on left ventricular pump function but causes a greater decrease in total systemic vascular resistance consistent with the combined inotropic and peripheral vasodilator actions of this oral beta adrenergic receptor agonist. These salutary hemodynamic responses suggest that oral pirbuterol may be useful for the prolonged treatment of severe chronic congestive heart failure.     

Long-term outpatient vasodilator therapy of congestive heart failure. Consideration of agents at rest and during exercise.

Increased left ventricular filling pressure and reduced cardiac output are two major hemodynamic deficits in pump failure. In patients with chronic heart failure, consequences of these hemodynamic deficits and diminished cardiac reserve are manifested initially during stress and eventually at rest. The purpose of therapeutic interventions include reduction of ventricular filling pressure increase in cardiac output and improvement in cardiac reserve. To achieve these goals, the hemodynamic effects of predominantly venodilators (nitrates), predominantly arteriolar dilators (hydralazine) and the combination of nitrates and hydralazine were evaluated in patients with chronic heart failure at rest: left ventricular filling pressure (mm Hg) control 28, nitrates 17, hydralazine 25, nitrates plus hydralazine 18; cardiac output (liters/min/m2) control 2.1, nitrates 2.1, hydralazine 3.2, nitrates plus hydralazine 3.3; mean blood pressure (mm Hg) control 87, nitrates 85, hydralazine 83, nitrates plus hydralazine 85. These data suggest improved left ventricular performance with a combination of nitrates and hydralazine. Exercise hemodynamics improved in some patients, suggesting that such vasodilator therapy may be beneficial in chronic heart failure.     

Comparative effects of lidocaine and procainamide on acutely impaired hemodynamics

Controversy exists regarding the relative safety of intravenously administered lidocaine and procainamide to patients with acutely impaired hemodynamics. Accordingly, their effects were studied in 15 such patients, 14 with acute myocardial infarction and one with cardiomyopathy and severe congestive heart failure. All had elevated levels of pulmonary capillary wedge pressure (>15 mm Hg) and/or low cardiac index (<2.5 liters/min/m²). Patients were given lidocaine, a 100 mg bolus followed by a 3 mg/min infusion and, after at least a 30 minute recovery period, procainamide, a 100 mg bolus over 2 minutes followed by a 20 mg/min infusion for 20 to 25 minutes. Hemodynamic measurements were compared early and late in the infusion of each drug. Small, clinically insignificant differences were observed in the hemodynamic responses to the drugs, and no clinically significant deterioration occurred with either. Conventional therapeutic doses of intravenous procainamide can be administered by this regimen, to patients with acute myocardial infarction complicated by cardiac failure or low cardiac output, without producing deleterious hemodynamic effects.     

Hemodynamic effects of intravenous prenalterol in severe heart failure

Nine patients with chronic severe low output heart failure (radionuclide left ventricular ejection fraction 17 ± 5 percent [mean ± standard deviation], left ventricular filling pressure 26 ± 6 mm Hg, cardiac index 1.9 ± 0.4 liters/min per m², left ventricular stroke work index 18 ± 6 g-m/m²) from various causes were treated with intravenous prenalterol (a new catecholamine-like inotropic agent) in doses of 1, 4 and 8 mg. Significant hemodynamic improvement occurred as measured by increased left ventricular ejection fraction (to 26 ± 4 percent), decreased left ventricular filling pressure (to 21 ± 8 mm Hg) and increased cardiac index (to 2.4 ± 0.6 liters/min per m²) and left ventricular stroke work index (to 25 ± 8 g-m/m²). Significant increases in heart rate (from 87 ± 18 to 91 ± 18 beats/min) and mean systemic arterial pressure (from 87 ± 8 to 92 ± 7 mm Hg) also occurred. Peak hemodynamic response occurred at various doses. Significant adverse effects associated with prenalterol consisted of increased ventricular ectopic beats in two patients and asymptomatic ventricular tachycardia in two patients. Thus, intravenous prenalterol produces hemodynamic improvement in patients with a chronic severe low output state but may be associated with increased ventricular ectopic activity.     

Differences in hemodynamic effects of nitroprusside and prazosin in severe chronic congestive heart failure: evidence for a direct negative chronotropic effect of prazosin.

To compare the hemodynamic effects of prazosin and nitroprusside in patients with severe congestive heart failure, nine patients with heart failure refractory to conventional therapy received oral prazosin and intravenous nitroprusside administered so as to produce a similar decrease in left ventricular filling pressure in each patient. By this comparison, both drugs produced similar decreases in mean right atrial pressure, mean pulmonary arterial pressure and systemic and pulmonary vascular resistance. However, with nitroprusside, cardiac index increased more (+0.97 versus +0.73 liters/min per m2, P less than 0.01) and mean arterial pressure decreased less (-13.7 versus -18.3 mm Hg, P less than 0.05) than with prazosin. Both drugs produced similar changes in stroke volume index (+11.7 cc/beat per m2 with nitroprusside and +12.5 with prazosin) and stroke work index (+8.1 g-m/m2 with nitroprusside and +6.6 with prazosin). Therefore, the differences in the hemodynamic responses observed with the two agents were due to the significantly greater decrease in heart rate with prazosin (-8 beats/min) than with nitroprusside (-2 beats/min, P less than 0.05). These clinical data support experimental evidence suggesting that there is a significant negative chronotropic action of prazosin independent of its peripheral vascular effects.     

Quantitative differences in the hemodynamic effects of captopril and nitroprusside in severe chronic heart failure

The hemodynamic effects of oral captopril and intravenous nitroprusside were compared in 15 patients with severe chronic congestive heart failure. At doses of both drugs titrated so as to produce similar decreases in systemic vascular resistance in each patient, nitroprusside produced substantially greater increases in cardiac index (+0.67 versus +0.31 liters/min/m2, p less than 0.01) but smaller decreases in mean arterial pressure (-18.4 versus -11.0 mm Hg, p less than 0.01) than did captopril. This finding was due to a significant decrease in heart rate with captopril (-7 beats/min, p less than 0.01) which was not seen with nitroprusside, since changes in stroke volume index with both drugs were similar. Nitroprusside produced a decrease in pulmonary arteriolar resistance quantitatively similar to the decrease in systemic vascular resistance, but the decrease in pulmonary arteriolar resistance with captopril was not significant. Despite similar decreases in systemic resistance, captopril produced a greater decrease in left ventricular filling pressure (-10.2 versus -6.9 mm Hg, p less than 0.01) but a smaller decrease in mean right atrial pressure (-3.1 versus -5.3 mm Hg, p less than 0.01) than did nitroprusside. Thus, captopril has actions independent of its systemic vasodilator effects which account for the quantitative differences observed in its hemodynamic responses compared with those of nitroprusside in patients with severe chronic heart failure. These differences support experimental evidence that angiotensin, in addition to its direct systemic arterial vasoconstrictor actions, exerts positive chronotropic effects and alters ventricular compliance but has minimal direct effects on the limb venous circulation and on the pulmonary vasculature.     

Long-term amrinone therapy in patients with severe heart failure: Drug-dependent hemodynamic benefits despite progression of the disease

Six patients with severe congestive heart failure refractory to conventional therapy, including vasodilators, were treated with oral amrinone for a mean duration of 41 weeks (range 20 to 72 weeks). At initiation of therapy, the cardiac index increased from 1.74 ± 0.31 to 2.62 ± 0.52 (mean ± SD) liters/min/m² (p < 0.01) and pulmonary capillary wedge pressure decreased from 26.5 ± 3.5 to 19.5 ± 5.4 mm Hg (p < 0.05). Symptoms were alleviated and exercise capacity increased from 5.9 ± 3.9 to 11.5 ± 4.5 minutes (p < 0.05). During long-term therapy, exercise capacity remained constants in three patients whereas it decreased in three others. All patients demonstrated an increase in heart size. Withdrawal of amrinone therapy precipitated severe symptoms at rest and hemodynamic deterioration in all patients. The cardiac index decreased from 1.87 ± 0.49 to 1.32 ± 0.30 liter/min/m² (p < 0.05) and pulmonary capillary wedge pressure rose from 20.6 ± 2.9 to 28.8 ± 5.6 mm Hg (p < 0.05). These changes were reversed by reinstitution of therapy. Thus, amrinone-dependent hemodynamic benefits were demonstrated during long-term therapy without tachyphylaxis. In addition, progression of the underlying cardiac disease was observed in every patient.     

Isosorbide dinitrate for the relief of severe heart failure after myocardial infarction.

Severe congestive heart failure secondary to myocardial infarction remains a difficult management problem. Although intravenous vasodilators and mechanical assist devices have been reported to improve the depressed hemodynamic function, these interventions are limited to the intensive care unit and cannot be used for long-term management. This study evaluates the hemodynamic and symptomatic response to sublingual administration to isosorbide dinitrate (5 to 10 mg) in seven consecutive patients with severe congestive heart failure after anterior wall myocardial infarction. Serial measurements of mean right atrial and pulmonary arterial end-diastolic pressure, mean blood pressure, heart rate and cardiac output were obtained during the control period and during the 4 hours after administration of isosorbide dinitrate. The peak response occurred approximately 30 minutes after drug administration with an 83 percent reduction in mean right atrial pressure (from 6 to 1 mm Hg, P less than 0.02), a 36 percent reduction in pulmonary arterial end-diastolic pressure (from 25 to 16 mm Hg, P less than 0.0001) and a 6 percent reduction in mean blood pressure (from 94 to 88 mm Hg (P less than 0.05). There were small but statistically not significant increases in cardiac index (from 2.3 to 2.6 liters/min per m2 and stroke work index (from 26 to 32 gm/beat per m2). The total systemic vascular resistance was reduced by 5 percent from 1,605 to 1,518 dynes sec cm-5 (P less than 0.10). The baseline heart rate of 105 beats/min was not significantly changed. The reduction in pulmonary arterial end-diastolic pressure became statistically significant (P less than 0.05) between 15 and 30 minutes after administration of isosorbide dinitrate and remained significant for 3 to 4 hours. This reduction of pulmonary arterial end-diastolic pressure to less than 22 mm Hg was associated with relief of the patients' pulmonary symptoms. The response to nitroglycerin (0.4 mg) was similar in magnitude but of much shorter duration (approximately 15 minutes for nitroglycerin versus 4 hours for isosorbide dinitrate in patients with and without congestive heart failure. The slope (calculated by dividing the change in cardiac index or stroke work index by the change in pulmonary arterial end-diastolic pressure) was significantly (P less than 0.05) depressed in the patients with congestive heart failure. These data demonstrate that the symptomatic pulmonary venous hypertension can be effectively relieved by isosorbide dinitrate without further compromising left ventricular function.