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Comparison of Acute Hemodynamic Responses to Prostacyclin with Standard Vasodilators in Patients with Primary Pulmonary Hypertension
Comparison of Acute Hemodynamic Responses to Prostacyclln with Standard Vasodilators in Patients with Primary Pulmonary Hypertension* Harold I . Palevsky, M.D.; and Alfred P. Fishman, M.D.
,tlthough the benefit of long-term vasodilator therapy in patients with primary pulmonary hypertension (PPH) is still unsettled, efforts have been made to assess the role of evaluations of acute pulmonary vascular reactivity as a guide to long-term pharmacologic therapy. 1 Because of problems inherent in these studies and the lack of a specific pulmonary arterial vasodilator, many potential pulmonary vasodilator agents from different pharmacologic classes have been tried in these acute studies. 2 These acute drug studies can be lengthy and carry risk of substantial morbidity and even potential mortality. Recently, IV prostacyclin (PGIJ has become available and has been proposed as the optimal agent for evaluating pulmonary vascular reactivity. 3 We compared the acute effects of PGI 2 with that of standard vasodilator agents in 10 patients with PPH. The 10 patients had a mean age of 35.6 years (range 1~ 70 years); 7 were female, 3 were male. Their mean PA pressure was 65.2 mm Hg (range, 46-82 mm Hg), and their mean PVR was 1,630 dyne·s·cm-• (range, 705-2,695 years dyne·s·cm-•). Their mean cardiac output was 3.41 Umin (range, 2.00--5.15 Umin); their mean cardiac index was 1.89 Umin/m 2 (range, 1.16-2.77 Umin/m•). All patients were evaluated using a standard protocol to exclude identifiable etiologies of pulmonary hypertension. • Balloon flotation right heart catheterization was performed in the supine position. After establishment and recording of the baseline hemodynamic state, prostacyclin was administered IV in incremental doses up to a maximum infusion rate of 12 nglkglmin while hemodynamic parameters were recorded. Following termination of the prostacyclin infusion, the patient was observed until reestablishment of the baseline hemodynamic state. The standard vasodilators were then administered sequentially, each to the maximally tolerated dose, while hemodynamic parameters were recorded and each followed by the reestablishment of the baseline hemodynamic state before the administration of the next vasodilator agent. Patients were tested using an average of 5 vasodilator agents (range, 3--8 agents). In addition to PGI 2 , the agents tested included acetylcholine, nitroglycerin, isoproterenol, nifedipine, nitroprusside, phentolamine, and hydralazine. Changes in mean pulmonary artery (PA) pressure, pulmonary vascular resistance (PVR), and cardiac output (CO) were used to assess the responses to the vasodilator agents. Table 1 details the% changes (mean± SD) of the measured hemodynamic parameters in response to the various vasodilators administered. For each individual patient, the "maximal" vasodilator response was that agent with evoked
.t1
*From the Cardiovascular-Pulmonary Division, University of Pennsylvania School of Medicine, Philadelphia. Reprint requests: Dr: Palevsky, 975 Maloney Building, 3400 Spruce Street, PhilDdelphia 19104
Table 1-Vaodilotor ReBpOflles
Agent Prostacyclin Acetylcholine Nitroglycerin Isoproterenol Nifedipine Nitroprusside Phentolamine Hydralazine
No. %Change in Mean PA of Pressure Subjects
10 10 9 7 7 6 3
-5.7± 18.8 -6.1 ± 15.3 -2.4± 12.5 7.3±16.1 7.2± 14.4 5 .9 ±4.2 2.7±5.3
%Change in PVR
%Change in CO
-25.9±25.1 36.2±35.9 -11.1±24.6 9.6± 19.7 2 .3 ± 16.4 -3.8±16.2 -24.8±17.1 47.6± 16.3 -22.2±20.5 13.2±26.5 -9.7±16.9 20.9±22.5 -3.1±11.3 7.6± 14.9
11.0
-14.2
36.0
maximal decrements in both mean PA pressure and PVR. When the greatest decreases in mean PA pressure and PVR were brought about by different agents, the chosen maximal response was that agent which maintained or increased CO and reduced mean PA pressure while eliciting only minimal side effects. In 6 of the 10 patients, maximal vasodilator responses were achieved after administration of PGI 2 , in 2 patients after administration of isoproterenol, and in 1 patient each after the administration of nitroglycerin and nitroprusside. The responses of an individual patient to the various vasodilator agents was variable. The patterns of responses to an individual vasodilator agent also differed considerably among patients. However, no patient exhibited any substantial and beneficial vasodilator responsiveness without also exhibiting a favorable response to the administration ofPGI2 • One patient did have a 30% decrease in PVR and a 50% increase in CO in response to the administration of isoproterenol without any significant response to PGI2 administration. However, in this patient the isoproterenol infusion resulted in an increase in PA pressures and was accompanied by palpitations and chest pain. From this study we conclude that PGI2 appears promising as a screening agent for vasodilator responsiveness in patients with PPH, and may be of use in selecting which patients should go on to more extensive vasodilator studies. However, evaluation using multiple vasodilator agents seems necessary to determine the optimal vasodilator therapy for any individual patient. Long-term follow-up of treated and untreated patients who have exhibited both substantial and minimal responses to the acute administration of pulmonary vasodilator agents will be necessary to clarify the role of acute vasodilator studies in guiding the chronic therapy of patients with primary pulmonary hypertension. REFERENCES Reeves JT, Groves BM, Turkevich D . The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134:342-46 2 Palevsky HI, Fishman AP. Vasodilator therapy for primary pulmonary hypertension. Annu Rev Med 1985; 36:563-78 3 Long WA, Rubin LJ. Prostacyclin and PGE 1 treatment of pulmonary hypertension. Am Rev Respir Dis 1987; 136:773-76 4 Rich S, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107:216-23
CHEST I 93 I 3 I MARCH, 1988 I Supplement
179S
,tlthough the benefit of long-term vasodilator therapy in patients with primary pulmonary hypertension (PPH) is still unsettled, efforts have been made to assess the role of evaluations of acute pulmonary vascular reactivity as a guide to long-term pharmacologic therapy. 1 Because of problems inherent in these studies and the lack of a specific pulmonary arterial vasodilator, many potential pulmonary vasodilator agents from different pharmacologic classes have been tried in these acute studies. 2 These acute drug studies can be lengthy and carry risk of substantial morbidity and even potential mortality. Recently, IV prostacyclin (PGIJ has become available and has been proposed as the optimal agent for evaluating pulmonary vascular reactivity. 3 We compared the acute effects of PGI 2 with that of standard vasodilator agents in 10 patients with PPH. The 10 patients had a mean age of 35.6 years (range 1~ 70 years); 7 were female, 3 were male. Their mean PA pressure was 65.2 mm Hg (range, 46-82 mm Hg), and their mean PVR was 1,630 dyne·s·cm-• (range, 705-2,695 years dyne·s·cm-•). Their mean cardiac output was 3.41 Umin (range, 2.00--5.15 Umin); their mean cardiac index was 1.89 Umin/m 2 (range, 1.16-2.77 Umin/m•). All patients were evaluated using a standard protocol to exclude identifiable etiologies of pulmonary hypertension. • Balloon flotation right heart catheterization was performed in the supine position. After establishment and recording of the baseline hemodynamic state, prostacyclin was administered IV in incremental doses up to a maximum infusion rate of 12 nglkglmin while hemodynamic parameters were recorded. Following termination of the prostacyclin infusion, the patient was observed until reestablishment of the baseline hemodynamic state. The standard vasodilators were then administered sequentially, each to the maximally tolerated dose, while hemodynamic parameters were recorded and each followed by the reestablishment of the baseline hemodynamic state before the administration of the next vasodilator agent. Patients were tested using an average of 5 vasodilator agents (range, 3--8 agents). In addition to PGI 2 , the agents tested included acetylcholine, nitroglycerin, isoproterenol, nifedipine, nitroprusside, phentolamine, and hydralazine. Changes in mean pulmonary artery (PA) pressure, pulmonary vascular resistance (PVR), and cardiac output (CO) were used to assess the responses to the vasodilator agents. Table 1 details the% changes (mean± SD) of the measured hemodynamic parameters in response to the various vasodilators administered. For each individual patient, the "maximal" vasodilator response was that agent with evoked
.t1
*From the Cardiovascular-Pulmonary Division, University of Pennsylvania School of Medicine, Philadelphia. Reprint requests: Dr: Palevsky, 975 Maloney Building, 3400 Spruce Street, PhilDdelphia 19104
Table 1-Vaodilotor ReBpOflles
Agent Prostacyclin Acetylcholine Nitroglycerin Isoproterenol Nifedipine Nitroprusside Phentolamine Hydralazine
No. %Change in Mean PA of Pressure Subjects
10 10 9 7 7 6 3
-5.7± 18.8 -6.1 ± 15.3 -2.4± 12.5 7.3±16.1 7.2± 14.4 5 .9 ±4.2 2.7±5.3
%Change in PVR
%Change in CO
-25.9±25.1 36.2±35.9 -11.1±24.6 9.6± 19.7 2 .3 ± 16.4 -3.8±16.2 -24.8±17.1 47.6± 16.3 -22.2±20.5 13.2±26.5 -9.7±16.9 20.9±22.5 -3.1±11.3 7.6± 14.9
11.0
-14.2
36.0
maximal decrements in both mean PA pressure and PVR. When the greatest decreases in mean PA pressure and PVR were brought about by different agents, the chosen maximal response was that agent which maintained or increased CO and reduced mean PA pressure while eliciting only minimal side effects. In 6 of the 10 patients, maximal vasodilator responses were achieved after administration of PGI 2 , in 2 patients after administration of isoproterenol, and in 1 patient each after the administration of nitroglycerin and nitroprusside. The responses of an individual patient to the various vasodilator agents was variable. The patterns of responses to an individual vasodilator agent also differed considerably among patients. However, no patient exhibited any substantial and beneficial vasodilator responsiveness without also exhibiting a favorable response to the administration ofPGI2 • One patient did have a 30% decrease in PVR and a 50% increase in CO in response to the administration of isoproterenol without any significant response to PGI2 administration. However, in this patient the isoproterenol infusion resulted in an increase in PA pressures and was accompanied by palpitations and chest pain. From this study we conclude that PGI2 appears promising as a screening agent for vasodilator responsiveness in patients with PPH, and may be of use in selecting which patients should go on to more extensive vasodilator studies. However, evaluation using multiple vasodilator agents seems necessary to determine the optimal vasodilator therapy for any individual patient. Long-term follow-up of treated and untreated patients who have exhibited both substantial and minimal responses to the acute administration of pulmonary vasodilator agents will be necessary to clarify the role of acute vasodilator studies in guiding the chronic therapy of patients with primary pulmonary hypertension. REFERENCES Reeves JT, Groves BM, Turkevich D . The case for treatment of selected patients with primary pulmonary hypertension. Am Rev Respir Dis 1986; 134:342-46 2 Palevsky HI, Fishman AP. Vasodilator therapy for primary pulmonary hypertension. Annu Rev Med 1985; 36:563-78 3 Long WA, Rubin LJ. Prostacyclin and PGE 1 treatment of pulmonary hypertension. Am Rev Respir Dis 1987; 136:773-76 4 Rich S, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987; 107:216-23
CHEST I 93 I 3 I MARCH, 1988 I Supplement
179S