Although it is well known that the pulmonary circulation is altered in patients with pulmonary arterial or venous hypertension, the resultant hemodynamic behavior has not been systematically studied. We undertook to do so in a group of patients with pulmonary hypertension of diverse etiology. We measured pulmonary arterial (PAP) and occlusive wedge pressures and cardiac output at rest (i.e., standing) and during progressive upright treadmill exercise in 51 patients. Forty-two had chronic, stable, cardiac failure secondary to ischemic, myopathic or valvular heart disease and were grouped according to whether their mean PAP was less than (normotensive) or greater than (hypertensive) 19 mm Hg, and nine had pulmonary vascular disease of diverse etiology and were considered separately. In the majority of patients, we found that irrespective of whether the hypertension was arterial or venous in origin or etiology: (1) the mean PAP-flow relationship was linear; (2) pulmonary capillary wedge pressure was greater than or equal to the average closure pressure of the pulmonary vascular bed and could therefore be used as the downstream pressure in calculating pulmonary vascular resistance; and (3) pulmonary vascular resistance declined with exercise. Notable exceptions to the third observation were patients with valvular heart disease or a resting pulmonary vascular resistance -5 greater than 800 dyne-sec-cm Circulation 72, No. 6, 1270No. 6, -1278No. 6, , 1985 THE HEMODYNAMIC behavior of a vascular bed can be characterized by the relationship between blood flow and the pressure gradient. In the absence of external forces, the pressure gradient is simply the difference between the upstream or arterial and the downstream or venous pressure. However, because most of the pulmonary vasculature is contained within the parenchyma of the lung, it is subjected to extravascular pressures that result in a critical closure pressure. 1 2 It is not certain whether this pressure normally exceeds the venous pressure and therefore the calculation of the true pressure gradient of the pulmonary circulation remains uncertain. In the isolated lung preparation, in

A number of uncontrolled studies have indicated that oral administration of amrinone, a phosphodiesterase inhibitor with potent positive inotropic effects in experimental preparations, may be beneficial in patients with chronic congestive heart failure. The present multicenter trial was designed to prospectively evaluate clinical response and change in exercise tolerance during 12 weeks of amrinone therapy in a double-blind, placebo-controlled protocol. Ninety-nine patients with NYHA functional class 3 or 4 congestive heart failure on digitalis and diuretics, of whom 31 were also receiving captopril, were enrolled. After baseline clinical assessment and determination of exercise tolerance, radionuclide left ventricular ejection fraction, and roentgenographic cardiothoracic ratio, patients were randomly assigned to receive amrinone or placebo, beginning at 1.5 mg/kg tid and increasing to a maximum dosage of 200 mg tid. After 12 weeks of therapy or at the last blinded evaluation in patients who did not complete this protocol, there were no significant differences from baseline values between treatment with amrinone or placebo with regard to symptoms, NYHA functional class, left ventricular ejection fraction, cardiothoracic ratio, frequency and severity of ventricular ectopy, or mortality. Exercise tolerance improved significantly from baseline by 37 + 10% (mean 163 sec) in patients on amrinone and 35 ± 11 % (mean 149 sec) in patients on placebo, but there was no significant difference between treatments. Adverse reactions were significantly more frequent and more severe on amrinone, occurring in 83% of patients and necessitating withdrawal in 34%. Downward adjustment of amrinone dosage because of side effects was responsible for a significantly lower mean total daily dose of 355 vs 505 mg for placebo (p < .001). These findings indicate that oral administration of amrinone is not clinically effective in patients with chronic congestive heart failure, in part because of frequent adverse effects. Circulation 71, No. 5, 96-971, 1985. IN THE LAST DECADE there has been growing interest in new approaches to drug treatment of refractory congestive heart failure. Early investigations centered on drugs that altered the loading conditions of the left ventricle. More recently, agents possessing positive inotropic activity with chemical structures and mechanisms of action different from those of digitalis glycosides or catecholamines have been investigated. ' Amrinone, a bipyridine derivative,2 was the first of these to undergo extensive clinical evaluation. Shortterm therapy with amrinone administered intravenous-*Participating centers and investigators are listed in an appendix to

Milrinone is a new bipyridine inotrope that has shown promise in initial clinical testing when administered intravenously or orally. The present multicenter study was designed to evaluate the clinical effectiveness and safety of sustained (48 hour) intravenous infusions of different doses of milrinone, as would be used clinically, in a controlled fashion using invasive hemodynamic monitoring. Entry was limited to adult patients with chronic heart failure of functional class III or IV, with a cardiac index less than or equal to 2.5 liters/min per m2 or a pulmonary capillary wedge pressure greater than or equal to 15 mm Hg, or both. After stable baseline hemodynamic recordings were obtained, milrinone was given as loading (microgram/kg per 10 min) and maintenance infusions (microgram/kg per min) to 189 patients in one of four loading/maintenance dosage regimens: 37.5/0.375 (low dose, n = 26), 50/0.50 (intermediate dose, n = 95), 75/0.75 (high dose, n = 15) and 50/0.25 (lowest dose, n = 53). The lowest dose was shown to be ineffective for maintenance therapy. Effective individual patient responses were defined as greater than or equal to 20% increase in cardiac index or decrease in pulmonary capillary wedge pressure, or both. During early therapy (less than or equal to 3 hour), 99% of patients showed an effective maximal response, and 90% an effective mean response. An effective mean response was observed during days 1 and 2 in 80% of patients, with a positive dose-response trend (69% response, low dose; 80%, intermediate dose; 93%, high dose; day 1). Each loading regimen was effective, with maximal mean response occurring at 15 minutes. Cardiac index initially increased by an average of 24 to 42% for all patients in the three groups, whereas pulmonary capillary wedge pressure decreased by 24 to 33%. Initial decreases in systemic vascular resistance averaged 15 to 31%. Initial changes in heart rate (+4 to +13%) and mean arterial pressure (-2 to -13%) were modest. Significant mean hemodynamic responses were maintained over the 48 hours. Increases in cardiac index for days 1 and 2 averaged 38 and 39% for those completing constant low dose drug, 34 and 37% for intermediate dose and 73 and 44% for high dose. Decreases in pulmonary capillary wedge pressure for all patients averaged 18 to 32% on days 1 and 2, with little dose response. Heart rate changes were modest and variable, averaging -9 to 9%.(ABSTRACT TRUNCATED AT 400 WORDS)

The maximal oxygen uptake and anaerobic threshold can be determined in patients with pulmonary vascular disease from noninvasive gas exchange measurements during progressive exercise. Maximal O2 utilization correlates directly with the maximal level of cardiac output and is inversely proportional to the pulmonary vascular resistance and the level of pulmonary arterial pressure. The accuracy of predicting the hemodynamic profile from noninvasive gas exchange measurements will obviously improve as more such patients are evaluated. Therefore, the determination of VO2 max has the potential of becoming a practical screening technique for detecting and predicting the severity of pulmonary vascular disease.

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