Vasodilator therapy for pulmonary hypertensive disorders.

Vasodilator Therapy for Pulmonary Hypertensive Disorders T he successful application of vasodilator agents to the treatment ofsystemic hypertension has stimulated physicians to attempt similar treatment of pulmonary hypertensive disorders. Early reports of success initiated a phase of great optimism. All types of vasodilator drugs have been tried, and newer ones which are close at hand will be tried in the future. Reports of therapeutic failures and unwanted side effects with vasodilator therapy soon swung the therapeutic pendulum toward extreme pessimism. As so often happens in medicine, the swaying is steadied by studies that further define the application of pharmacologic agents to set right the pathologic distortions caused by cardiopulmonary diseases. The via media has not yet been marked out. The report by Lupi-Herrera and colleagues in this issue (see page 156) is another indication that not all patients with pulmonary hypertension from chronic obstructive pulmonary disease (COPD) are helped by hydralazine, a widely used systemic vasodilator. In their report, hydralazine initially improved arterial and venous oxygen saturations, and decreased systemic vascular resistance, but did not affect pulmonary vascular resistance. Indeed, in one week, even these small benefits were lost. On the other hand, Rubin and Peter’ reported that in addition to short-term therapy with antibiotics, steroids, oxygen, bronchodilators and chest physiotherapy, some patients, during a stable period with COPD and pulmonary hypertension, respond well to hydralazine, at least during the 48 hours they were monitored. Pulmonary vascular resistance decreased and cardiac output increased both at rest and during exercise. Here, the pulmonary arterial pressures and systemic arterial 02 saturations were higher in the earlier study, but the patients were younger, had higher mixed venous oxygen saturation, and lived near sea level rather than at 2.4 km. Moreover, the effect ofhydralazine on patients with unexplained or primary pulmonary hypertension is in. completely understood.23 Rubin and Peter’ found this drug to be effective in reducing pulmonary vascular resistance and improving symptoms, but Packer and co-workers4 found no beneficial effect in primary pulmonary hypertension or in hypertension secondary to pulmonary embolus, sarcoidosis or interstitial fibrosis. Indeed, many adverse responses were encountered. Some of the differences seem to be accounted for by the studies of Lupi-Herrera and co-workers2 in patients with primary pulmonary hypertension. In their patients with lower pulmonary arterial pressure, lower pulmonary vascular resistance and pulmonary-to-systemic vascular resistance ratio, hydralazine was helpful. The pulmonary and systemic vascular resistances decreased, cardiac output increased, but pulmonary arterial pressure and the ratio of pulmonary-to-systemic resistance were unchanged. Moreover, in their patients with much higher pulmonary arterial pressures, hydralazine dilated the systemic vascular bed, but did not affect the pulmonary vascular bed or cardiac output. On the other hand, the beneficial effects reported by Rubin and Peter’ were in patients with pulmonary arterial pressure quite high enough to augur poor results, and at least halfthe patients studied by Packer and co-workers4 had pressures that were 45 mm Hg or less. Which patients are likely to be helped with chronic vasodilator therapy? The elements needed for relief of dyspnea and improved exercise tolerance include pulmonary hypertension induced, in large measure, by active vasoconstriction rather than from irreversible vascular damage or parenchymal fibrosis, adequate ventricular function to propel blood quickly and more efficiently, and a vasodilator drug that induces more pulmonary than systemic vasodilation. Attention must also be directed toward the imprecision of the clinical measurements available to assess these parameters. Prediction of success on the basis of current hemodynamic reckoning is often wide of the mark. Estimation of the extent to which active vasoconstriction contributes to the increased pulmonary arterial pressure at a given cardiac output is often chancy. The relation of pressure to blood flow, a reflection of vascular resistance, is complex.5 In the normal lung, the curve is skewed to the pressure axis at the lower flows, and to the flow axis at physiologic or higher flows. Thus, as flow increases, calculated vascular resistance decreases sharply, then more gradually becomes asymptotic. Equally difficult is attempting to learn the effects ofa drug on the pressure-flow curve of a diseased lung on the basis of one point on the curve