Vasodilators have been used recendy for the treatment of primary pulmonary arterial hypertension. From the studies reported, it can be concluded that vasodilator therapy is effective for selected patients, namely, those with lower mean pulmonary arterial pressure and pulmonary arteriolar resistance. In these patients, vasodilator drugs might counteract the vasoconstriction of the pulmonary circulation that is considered a major factor responsible for the hypertensive state. Pulmonary hypertension
can complicate various forms of acute and chronic pulmonary disease. Recendy, hydralazine has been used in patients with chronic obstructive pulmonary disease (COPD), and the study has shown that this drug can produce a decrease in mean pulmonary arterial pressure when cardiac output was increased markedly, with litde change in pulmonary arterial wedge pressure, suggesting that hydralazine was capable of dilating the pulmonary vascular bed in patients with COPD. The experience of other investigators contrasts with the previously mentioned work. As a rule, no hemodynamic or clinical improvement and serious adverse reactions were observed; however, this study did not include patients with COPD.
In the present study, we attempted to better define the effect of hydralazine on patients with COPD and, in particular, in those with cor pulmonale. We evaluated the hemodynamic effects of short-term intravenous therapy with hydralazine in eight patients at rest and with exercise. In addition, in seven patients the changes in hemodynamics and blood gas exchange after seven days of oral therapy with hydralazine were recorded, both at rest and during exercise. Only two patients who had improvement in hemodynamics and blood gas exchange without adverse reactions were continued on oral therapy with hydralazine.
Materials and Methods
Eight patients with stable COPD due to chronic bronchitis, emphysema, or both were evaluated between January 1981 and January 1982. All were bom and raised at an altitude of2,240 meters and were permanent residents of Mexico City. Their diagnosis was based on clinical history, physical examination, and tests of pulmonary function (Table I). The patients were relatively uniform with respect to ventilatory characteristics. Based on pulmoriary function tests, six patients had very severe COPD, and two had severe pulmonary function impairment.
The major criterion for inclusion in this study was the demonstration of a cardiac index at rest below 5.5 L/min sq m (ie, absence of hyperdynamic hemodynamic profile) (normal values for Mexico City, 2.8 to 5.4 L/min/sq m). No patient was included if known to have had cardiac failure or a respiratory infection within ten weeks prior to the study, although all of them had a respiratory infection and recovered between four and eight months before the study. All patients had dyspnea and fatigue on minimal to moderate exertion. None of the patients had clinical or electrocardiographic evidence of systemic hypertension, valvular heart disease, coronary arterial disease, or primary myocardial disease. All had cor pulmonale, with the diagnosis made on the basis of either radiographic or electrocardiographic evidence of right ventricular enlargement.
In order to exclude pulmonary vasodilation due to bronchodila-tors, this therapy was suspended 12 hours prior to each of the hemodynamic studies. None of the patients had evidence of reversible bronchoconstriction (200 jig of albuterol salbutamol; Ventolin); however, all of the patients were treated with conventional therapy for at least two years before the study. This therapy included bronchodilators, antibiotic agents, diuretic drugs, and supplemental oxygen as each patients clinical status indicated. Supplemental oxygen therapy was discontinued six hours before and throughout each cardiac catheterization. None of the patients had been hemo-dynamically studied before. Our protocol was approved by the local committee for clinical investigation. All of the procedures were explained to the patients, and their consent was obtained.
Hemodynamic and Pulmonary Measurements
Our procedure for cardiac catheterization at rest and at exercise has been described elsewhere. In brief, cardiac output was measured by the thermodilution method, and pressures were obtained by a Swan-Ganz catheter. Standard formulas were used to calculate cardiac index, right ventricular work index, pulmonary arteriolar resistance, systemic resistance, and the left ventricular work index. Systolic, diastolic, and mean pressures were measured by averaging over at least three respiratory cycles. The stated results represent the average of three clustered measurements with less than 10-percent variation. Samples of blood were obtained from the pulmonary and brachial arteries over a one-minute period and were immediately analyzed using a gas analyzer (Instrumentation Laboratory; 127 bath, 213 electrometer) (normal values for Mexico City: arterial oxygen pressure [PaOj; 67 ±3 mm Hg; arterial carbon dioxide tension [PaC02], 33±3 mm Hg; and arterial pH, 7.33 to 7.43).
Measurements of pulmonary volume were made with the patients seated in a volume-displacement plethysmograph (J.H. Emerson). Total lung capacity (TLC) was measured by the method of Dubois et al. Recordings were made on an oscillographic photographic recorder (Electronics for Medicine VR-6). Pulmonary function results were compared to normal values reported by Comroe et al, Baldwin et al, and Morris et al and were expressed as a percentage of the predicted normal values. The mean forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%) and the ratio of the forced expiratory volume in one second over the forced vital capacity (FEV,/FVC) were not adjusted for the decreased air density at altitude. A person who at high altitude has expiratory flow below the predicted normal range at sea level clearly has airway obstruction.
Patients were familiarized with the exercise technique. After control measurements, supine exercise tests were performed. All pressures were recorded continuously except during collection of blood samples. Samples of blood and air were collected simultaneously, and cardiac output was measured during the flnal minute of exercise.
After obtaining baseline hemodynamic measurements at rest and during exercise, intravenous hydralazine (0.33 mg/kg of body weight) was infused into the pulmonary artery over three minutes. Pulmonary arterial and mean systemic arterial pressures were recorded continuously, except during the collection of samples of blood. Cardiac output was measured every five minutes.
The exercise test was performed in eight patients after a significant increase in cardiac output was observed. Only those patients who showed a beneficial effect on pulmonary and systemic hemodynamics and gas exchange in the intravenous trial were placed on oral therapy with hydralazine. During the intravenous trial of hydralazine, pulmonary hemodynamics worsened in patient 7 during rest and exercise (pulmonary arterial pressure increased from 30 to 43 mm Hg and pulmonary arteriolar resistance from 9 to 12 units/ sq m at rest; with exercise, pulmonary arterial pressure rose from 48 to 53 mm Hg), and it was decided not to continue with orally administered hydralazine.
After six hours of intravenous therapy with hydralazine, the drug was administered orally (50 mg every six hours) in seven out of the eight patients, and the hemodynamic measurements at rest and during exercise were repeated seven days later. Before each dose of hydralazine, pulse rates in the supine and standing positions and blood pressures were monitored. The last dose of hydralazine was always given one to two hours before cardiac catheterization.
Statistical analysis and the significance of results were calculated using standard methods for standard and paired f-tests. All of the results were expressed as the mean ± SE.
Table 1—Pulmonary Function in Eight Patients with COPD and Cor Pulmonale
|Case, Sex, Age (yr)t1,M,70||VC, L 1,600 (49)||RV, L 2,200 (147)||TLC, L 3,800 (76)||FEVi, L 0.55 (22)||FEF25-75%,L/min12 (8)|
|2,M,74||1,250 (38)||2,870 (152)||4,120 (76)||0.35 (15)||9(6)|
|3,M,74||2,850 (80)||3,180 (167)||6,000 (100)||0.75 (27)||12(8)|
|4,M,74||1,800 (84)||1,600 (122)||3,400 (70)||1.20 (50)||60(45)|
|5,M,66||1,850 (61)||3,900 (160)||4,700 (100)||0.35 (14)||19 (13)|
|6,M,77||2,350 (70)||3,130 (120)||5,480 (90)||0.90 (20)||15 (10)|
|7,M,57||2,100 (52)||1,650 (144)||3,500 (75)||0.81 (22)||42(17)|
|8,M,60||2,750 (80)||1,900 (135)||4,800 (100)||1.25 (48)||36(23)|
|Mean||2,068 (64)||2,553 (143)||4,475 (85)||0.77 (27)||26(16)|