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Paradoxical pulmonary vasoconstriction induced by nitroglycerin in idiopathic pulmonary hypertension
490
JACC Vol. 6, No.2 August 1985:490-2
Paradoxical Pulmonary Vasoconstriction Induced by Nitroglycerin in Idiopathic Pulmonary Hypertension BRIAN HOlT, MD, GABRIEL GREGORATOS, MD, FACC, RALPH SHABETAI, MD, FACC San Diego, California
Administration of intravenous nitroglycerin in a patient with idiopathic pulmonary hypertension resulted in an increase in pulmonary artery pressure associated with a decrease in blood How that is best explained by an
increase in pulmonary vascular resistance. This observation highlights the need for hemodynamic monitoring when potent vasodilators are used in this disorder. (J Am Coil CardioI1985;6:490-2)
Interest in the use of systemic vasodilators in pulmonary hypertension has been spurred by a number of reports demonstrating significant beneficial hemodynamic effects (1-7). Although these agents have been effective in some patients, success has been limited, and reports of adverse effects including death have appeared (8-12). A major limiting factor has been the reduction of systemic vascular resistance and the resultant systemic arterial hypotension. In addition, a decrease in pulmonary vascular resistance may be accompanied by an increase in pulmonary blood flow that prevents a decrease in pulmonary artery pressure. Nitroglycerin, a preferential venodilator, has recently been shown to be highly effective in patients with pulmonary hypertension (13). We describe here a previously unreported adverse hemodynamic effect of intravenous nitroglycerin in a patient with idiopathic pulmonary hypertension.
fusion reduced both pulmonary and systemic vascular resistances, but pulmonary artery pressure did not decrease. Treatment with hydralazine, 50 mg every 6 hours, resulted in no significant change in symptoms over a 1 year period of follow-up. In 1982, a second cardiac catheterization (Table 1) revealed worsening of pUlmonary hypertension. Infusions of phentolamine and verapamil did not decrease pulmonary vascular resistance. Accordingly, hydralazine was discontinued and the patient was discharged without drug treatment. Further deterioration prompted a third catheterization. The blood pressure was 110no mm Hg, the pulse 74 beats/min and the venous pressure 8 cm H20. A left parasternal impulse was noted. The second heart sound was split narrowly with an increased pulmonary component. A grade 2/6 systolic ejection munnur that did not change with respiration was heard at the left sternal border. Cardiac catheterization and effect of nitroglycerin. The current cardiac catheterization study revealed that the patient's pulmonary hypertension had not increased since 1982 (Table 1). The cardiac output measured by thennodilution was consistent with the measured arteriovenous oxygen difference. As expected, the pulmonary vascular resistance was greatly elevated. The systemic vascular resistance was slightly elevated, and the ratio between the two resistances was 0.82. One minute after administration of 200 f,Lg of nitroglycerin by Swan-Ganz catheter, pulmonary artery pressure increased and aortic pressure decreased (Fig. 1). The cardiac output measured by thennodilution decreased 23% from 4.2 to 3.2 liters/min and the arteriovenous oxygen difference widened from 5.0 to 5.4 vol %, a 7% reduction of cardiac output assuming a constant oxygen consumption. These changes were accompanied by an increase in pulmonary vascular, total pulmonary and systemic vascular resistances calculated from standard fonnulas. Ten minutes after nitroglycerin infusion, intravascular pressures
Case Report Clinical features. A 15 year old Hispanic girl with idiopathic pulmonary hypertension was admitted to University of California-San Diego Medical Center in February 1984 for cardiac catheterization. She was well until 1980 when she developed hoarseness, exertional fatigue and dyspnea. Technetium lung scan showed no evidence of emboli and disclosed the characteristic fint> mottled appearance of pulmonary hypertension. In 1OSl, cardiac catheterization (Table 1) revealed moderate pulmonary hypertension, no shunts and nonnal cardiac output. Phentolamine and tolazoline in-
From the University of California Medical Center, San Diego, California. Manuscript received November 20, 1984; revised manuscript received February 20, 1985, accepted March 14, 1985. Address for requests: Brian Hoit, MD, University of California Medical Center, 225 Dickinson Street, H8IlA, Sail Diego, California 92103. © 1985 by the American College of Cardiology
0735-1097/85/$3.30
HOlT ET AL. PULMONARY HYPERTENSION
lACC Vol. 6, No.2 August 1985:490-2
491
Table 1. Results of Sequential Cardiac Catheterization Studies 2/8/S4
1J4/S2 6/26/S1
(no medication) PAP (mm Hg) PAP mean (mm Hg) PAWP mean (mm Hg) RAP mean (mm Hg) ArtP (mm Hg) ArtP mean (mm Hg) CO (liters/min) HR (beats/min) Art O2 saturation (%) PA O2 saturation (%) av02 diff (vol %) PVR (dynes's'cm ') TPR (dynes·s'cm ') SVR (dynes's'cm ') Rp/Rs
70/35 50
5
(hydralazine. 50 mg every 6 hours) 103/49 69 6
100/62 78 4.54
120/65 S5 4.36
4.R 793 SRI 1.339 0.59
4.7 1,156 1.266 1,486 0.78
I Minute
Control 100/50 70 9 4 100165
7R 4.22 75 96.7 66.5 5.0 1.156 1.327 1.402 0.82
After NTG
10 Minutes After NTG
115/65 80
110/55 75
4 S5/60 74 3.26 93 '!6 64.6 5.4 1.742 1,963 1.717 1.01
5 110/68 80 3.51 76
1,504 1,709 1.709 0.88
Art = arterial; ArtP = arterial pressure; av02 diff = arteriovenous oxygen difference; CO = cardiac output; HR = heart rate; O2 = oxygen; PA = pulmonary artery; PAP = pulmonary artery pressure; PA WP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; Rp/Rs = pulmonary to systemic vascular resistance ratio; SVR = systemic vascular resistance; TPR = total pulmonary resistance.
and cardiac output had returned toward normal, Additional trials with vasodilators were not attempted, and the patient was discharged without medication.
Discussion Prolonged pUlmonary arteriolar vasoconstriction of unknown origin is thought to be an element in the pathogenesis of idiopathic pUlmonary hypertension (14), suggesting that vasodilator therapy should be beneficial in this disorder. Success with several agents supports this reasoning (1-7), but optimism has been tempered by limited clinical efficacy, adverse hemodynamic consequences and death (8-12). Although an increase in pulmonary artery pressure has been noted after the use of hydralazine, it has been associated with a reduction of pUlmonary vascular resistance and increased pulmonary blood flow (9). Our observations are heretofore undescribed and are not readily explicable, Laboratory error could not be reasonably incriminated because changes in arteriovenous oxygen difference confirmed the direction of the changes in cardiac output. Pulmonary artery wedge pressure could only be obtained at baseline for technical reasons, However, changes in total pulmonary resistance were similar to those of pulmonary vascular resistance. Therefore, the potential error introduced by assuming a constant pulmonary artery wedge pressure does not account for our observations, Possible mechanisms. The mechanisms responsible for these changes are not clear, The vasodilating effects of
nitroglycerin cause a decrease in systemic vascular resistance and right atrial pressure. However, we observed an increase in systemic vascular resistance and no change in right atrial pressure, A decrease in inotropic state might explain several of our findings; however, nitroglycerin has Figure 1. Electrocardiogram and aortic (Ao) and pulmonary artery (PA) pressures at baseline and 1 minute after nitroglycerin (POST NTG) administration recorded on the same gain (each horizontal line equals 10 mm Hg) and at the same paper speed (25 mm/s).
492
HOlT ET AL. PULMONARY HYPERTENSION
never been demonstrated to have myocardial depressant properties. Pulmonary artery pressure may be increased by reflex sympathetic vasoconstriction. The increase in heart rate we observed after nitroglycerin administration is consistent with enhanced sympathetic tone. However, although sympathetic nerve stimulation can increase pulmonary vascular resistance (15), there is evidence that a vasodilating response due to betaz-receptor stimulation may predominate when pulmonary vascular tone is increased (16). Nitroglycerin may increase venous admixture and the pulmonary dead space to tidal volume ratio (17), thereby lowering arterial partial pressure of oxygen (Po 2 ); but pulmonary vasoconstriction in response to hypoxia induced by this mechanism is unlikely in view of the minimal changes that occurred in arterial Po 2 • A primary increase in pulmonary vascular resistance leading to an increase in pulmonary artery pressure, a decrease in cardiac output and a secondary increase in systemic vascular resistance may explain our patient's unusual response to nitroglycerin. Implications. Although the mechanisms of the paradoxical increase in pulmonary vascular resistance in response to nitroglycerin remain speculative, it is important to draw attention to this potentially lethal complication, and to reemphasize the need for careful hemodynamic monitoring when administering potent vasodilator drugs to patients with idiopathic pulmonary hypertension.
References l. Shettigar UR, Hultgren HN, Specter M, Martin R, Davies DH. Primary pulmonary hypertension: favorable effect of isoproterenol. N Engl J Med 1976;295:1414-5. 2. Ruskin IN, Hutter AM Jr. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979;90:772-4.
JACC Vol. 6, No.2 August 1985:490-2
3. Rubin U, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 1980;302:69-73. 4. Klinke WP, Gilbert JAL. Diazoxide in primary pulmonary hypertension. N Engl J Med 1980;302:91-2. 5. Landmark K, Refsum AM, Simonsen S, Storstein O. Verapamil and pulmonary hypertension. Acta Med Scand 1978;204:299-302. 6. Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart J 1980;44:352-6. 7. Szczeklik J, Duriel JS, Mysik M, Pyzik Z, Krol R, Horzela T. Effects of prostaglandin El on pulmonary circulation in patients with pulmonary hypertension. Br Heart J 1978;40: 1397-40 l. 8. Hermiller JB, Bambach D, Thompson MJ, et al. Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 1982;97:480-9. 9. Packer M, Greenberg B, Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Engl J Med 1982;306: 1326-3l. 10. Cohen ML, Kronzon I. Adverse hemodynamic effects of phentolamine in primary pulmonary hypertension. Ann Intern Med 1981;95:591-3. II. Rubino JM, Schroeder JS. Diazoxide in treatment of primary pulmonary hypertension (letter). Br Heart J 1979;42:362-3. 12. Elkayarn U, Frishman WH, Yoran C, Strom J, Sonnenblick EH, Cohen MN. Unfavorable hemodynamic and clinical effects of isoproterenol in primary pulmonary hypertension. Cardiovasc Med 1978;3: 1177-80. 13. Pearl RG, Rosenthal MH, Schroeder JS, Ashton CPT. Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann Intern Med 1983;99:9-13. 14. Edwards WD, Edwards JE. Clinical primary pulmonary hypertension, three pathological types. Circulation 1977;56:884-8. 15. Kadowitz PJ, Hyman AL. Effect of sympathetic nerve stimulation on pulmonary vascular resistance in the dog. Circ Res 1973;32:221-7. 16. Hyman AL, Nandiwada P, Knight DS, Kadowitz PS. Pulmonary vasodilator responses to catecholamines and sympathetic nerve stimulation in the cat. Circ Res 1981;48:407-15. 17. Mookherjee S, Fuleihan D, Warner RA, Varda S, Obeid AL. Effects of sublingual nitroglycerin on resting pulmonary gas exchange and hemodynamics in man. Circulation 1978;57: 106-10.
JACC Vol. 6, No.2 August 1985:490-2
Paradoxical Pulmonary Vasoconstriction Induced by Nitroglycerin in Idiopathic Pulmonary Hypertension BRIAN HOlT, MD, GABRIEL GREGORATOS, MD, FACC, RALPH SHABETAI, MD, FACC San Diego, California
Administration of intravenous nitroglycerin in a patient with idiopathic pulmonary hypertension resulted in an increase in pulmonary artery pressure associated with a decrease in blood How that is best explained by an
increase in pulmonary vascular resistance. This observation highlights the need for hemodynamic monitoring when potent vasodilators are used in this disorder. (J Am Coil CardioI1985;6:490-2)
Interest in the use of systemic vasodilators in pulmonary hypertension has been spurred by a number of reports demonstrating significant beneficial hemodynamic effects (1-7). Although these agents have been effective in some patients, success has been limited, and reports of adverse effects including death have appeared (8-12). A major limiting factor has been the reduction of systemic vascular resistance and the resultant systemic arterial hypotension. In addition, a decrease in pulmonary vascular resistance may be accompanied by an increase in pulmonary blood flow that prevents a decrease in pulmonary artery pressure. Nitroglycerin, a preferential venodilator, has recently been shown to be highly effective in patients with pulmonary hypertension (13). We describe here a previously unreported adverse hemodynamic effect of intravenous nitroglycerin in a patient with idiopathic pulmonary hypertension.
fusion reduced both pulmonary and systemic vascular resistances, but pulmonary artery pressure did not decrease. Treatment with hydralazine, 50 mg every 6 hours, resulted in no significant change in symptoms over a 1 year period of follow-up. In 1982, a second cardiac catheterization (Table 1) revealed worsening of pUlmonary hypertension. Infusions of phentolamine and verapamil did not decrease pulmonary vascular resistance. Accordingly, hydralazine was discontinued and the patient was discharged without drug treatment. Further deterioration prompted a third catheterization. The blood pressure was 110no mm Hg, the pulse 74 beats/min and the venous pressure 8 cm H20. A left parasternal impulse was noted. The second heart sound was split narrowly with an increased pulmonary component. A grade 2/6 systolic ejection munnur that did not change with respiration was heard at the left sternal border. Cardiac catheterization and effect of nitroglycerin. The current cardiac catheterization study revealed that the patient's pulmonary hypertension had not increased since 1982 (Table 1). The cardiac output measured by thennodilution was consistent with the measured arteriovenous oxygen difference. As expected, the pulmonary vascular resistance was greatly elevated. The systemic vascular resistance was slightly elevated, and the ratio between the two resistances was 0.82. One minute after administration of 200 f,Lg of nitroglycerin by Swan-Ganz catheter, pulmonary artery pressure increased and aortic pressure decreased (Fig. 1). The cardiac output measured by thennodilution decreased 23% from 4.2 to 3.2 liters/min and the arteriovenous oxygen difference widened from 5.0 to 5.4 vol %, a 7% reduction of cardiac output assuming a constant oxygen consumption. These changes were accompanied by an increase in pulmonary vascular, total pulmonary and systemic vascular resistances calculated from standard fonnulas. Ten minutes after nitroglycerin infusion, intravascular pressures
Case Report Clinical features. A 15 year old Hispanic girl with idiopathic pulmonary hypertension was admitted to University of California-San Diego Medical Center in February 1984 for cardiac catheterization. She was well until 1980 when she developed hoarseness, exertional fatigue and dyspnea. Technetium lung scan showed no evidence of emboli and disclosed the characteristic fint> mottled appearance of pulmonary hypertension. In 1OSl, cardiac catheterization (Table 1) revealed moderate pulmonary hypertension, no shunts and nonnal cardiac output. Phentolamine and tolazoline in-
From the University of California Medical Center, San Diego, California. Manuscript received November 20, 1984; revised manuscript received February 20, 1985, accepted March 14, 1985. Address for requests: Brian Hoit, MD, University of California Medical Center, 225 Dickinson Street, H8IlA, Sail Diego, California 92103. © 1985 by the American College of Cardiology
0735-1097/85/$3.30
HOlT ET AL. PULMONARY HYPERTENSION
lACC Vol. 6, No.2 August 1985:490-2
491
Table 1. Results of Sequential Cardiac Catheterization Studies 2/8/S4
1J4/S2 6/26/S1
(no medication) PAP (mm Hg) PAP mean (mm Hg) PAWP mean (mm Hg) RAP mean (mm Hg) ArtP (mm Hg) ArtP mean (mm Hg) CO (liters/min) HR (beats/min) Art O2 saturation (%) PA O2 saturation (%) av02 diff (vol %) PVR (dynes's'cm ') TPR (dynes·s'cm ') SVR (dynes's'cm ') Rp/Rs
70/35 50
5
(hydralazine. 50 mg every 6 hours) 103/49 69 6
100/62 78 4.54
120/65 S5 4.36
4.R 793 SRI 1.339 0.59
4.7 1,156 1.266 1,486 0.78
I Minute
Control 100/50 70 9 4 100165
7R 4.22 75 96.7 66.5 5.0 1.156 1.327 1.402 0.82
After NTG
10 Minutes After NTG
115/65 80
110/55 75
4 S5/60 74 3.26 93 '!6 64.6 5.4 1.742 1,963 1.717 1.01
5 110/68 80 3.51 76
1,504 1,709 1.709 0.88
Art = arterial; ArtP = arterial pressure; av02 diff = arteriovenous oxygen difference; CO = cardiac output; HR = heart rate; O2 = oxygen; PA = pulmonary artery; PAP = pulmonary artery pressure; PA WP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; Rp/Rs = pulmonary to systemic vascular resistance ratio; SVR = systemic vascular resistance; TPR = total pulmonary resistance.
and cardiac output had returned toward normal, Additional trials with vasodilators were not attempted, and the patient was discharged without medication.
Discussion Prolonged pUlmonary arteriolar vasoconstriction of unknown origin is thought to be an element in the pathogenesis of idiopathic pUlmonary hypertension (14), suggesting that vasodilator therapy should be beneficial in this disorder. Success with several agents supports this reasoning (1-7), but optimism has been tempered by limited clinical efficacy, adverse hemodynamic consequences and death (8-12). Although an increase in pulmonary artery pressure has been noted after the use of hydralazine, it has been associated with a reduction of pUlmonary vascular resistance and increased pulmonary blood flow (9). Our observations are heretofore undescribed and are not readily explicable, Laboratory error could not be reasonably incriminated because changes in arteriovenous oxygen difference confirmed the direction of the changes in cardiac output. Pulmonary artery wedge pressure could only be obtained at baseline for technical reasons, However, changes in total pulmonary resistance were similar to those of pulmonary vascular resistance. Therefore, the potential error introduced by assuming a constant pulmonary artery wedge pressure does not account for our observations, Possible mechanisms. The mechanisms responsible for these changes are not clear, The vasodilating effects of
nitroglycerin cause a decrease in systemic vascular resistance and right atrial pressure. However, we observed an increase in systemic vascular resistance and no change in right atrial pressure, A decrease in inotropic state might explain several of our findings; however, nitroglycerin has Figure 1. Electrocardiogram and aortic (Ao) and pulmonary artery (PA) pressures at baseline and 1 minute after nitroglycerin (POST NTG) administration recorded on the same gain (each horizontal line equals 10 mm Hg) and at the same paper speed (25 mm/s).
492
HOlT ET AL. PULMONARY HYPERTENSION
never been demonstrated to have myocardial depressant properties. Pulmonary artery pressure may be increased by reflex sympathetic vasoconstriction. The increase in heart rate we observed after nitroglycerin administration is consistent with enhanced sympathetic tone. However, although sympathetic nerve stimulation can increase pulmonary vascular resistance (15), there is evidence that a vasodilating response due to betaz-receptor stimulation may predominate when pulmonary vascular tone is increased (16). Nitroglycerin may increase venous admixture and the pulmonary dead space to tidal volume ratio (17), thereby lowering arterial partial pressure of oxygen (Po 2 ); but pulmonary vasoconstriction in response to hypoxia induced by this mechanism is unlikely in view of the minimal changes that occurred in arterial Po 2 • A primary increase in pulmonary vascular resistance leading to an increase in pulmonary artery pressure, a decrease in cardiac output and a secondary increase in systemic vascular resistance may explain our patient's unusual response to nitroglycerin. Implications. Although the mechanisms of the paradoxical increase in pulmonary vascular resistance in response to nitroglycerin remain speculative, it is important to draw attention to this potentially lethal complication, and to reemphasize the need for careful hemodynamic monitoring when administering potent vasodilator drugs to patients with idiopathic pulmonary hypertension.
References l. Shettigar UR, Hultgren HN, Specter M, Martin R, Davies DH. Primary pulmonary hypertension: favorable effect of isoproterenol. N Engl J Med 1976;295:1414-5. 2. Ruskin IN, Hutter AM Jr. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979;90:772-4.
JACC Vol. 6, No.2 August 1985:490-2
3. Rubin U, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 1980;302:69-73. 4. Klinke WP, Gilbert JAL. Diazoxide in primary pulmonary hypertension. N Engl J Med 1980;302:91-2. 5. Landmark K, Refsum AM, Simonsen S, Storstein O. Verapamil and pulmonary hypertension. Acta Med Scand 1978;204:299-302. 6. Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart J 1980;44:352-6. 7. Szczeklik J, Duriel JS, Mysik M, Pyzik Z, Krol R, Horzela T. Effects of prostaglandin El on pulmonary circulation in patients with pulmonary hypertension. Br Heart J 1978;40: 1397-40 l. 8. Hermiller JB, Bambach D, Thompson MJ, et al. Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 1982;97:480-9. 9. Packer M, Greenberg B, Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Engl J Med 1982;306: 1326-3l. 10. Cohen ML, Kronzon I. Adverse hemodynamic effects of phentolamine in primary pulmonary hypertension. Ann Intern Med 1981;95:591-3. II. Rubino JM, Schroeder JS. Diazoxide in treatment of primary pulmonary hypertension (letter). Br Heart J 1979;42:362-3. 12. Elkayarn U, Frishman WH, Yoran C, Strom J, Sonnenblick EH, Cohen MN. Unfavorable hemodynamic and clinical effects of isoproterenol in primary pulmonary hypertension. Cardiovasc Med 1978;3: 1177-80. 13. Pearl RG, Rosenthal MH, Schroeder JS, Ashton CPT. Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann Intern Med 1983;99:9-13. 14. Edwards WD, Edwards JE. Clinical primary pulmonary hypertension, three pathological types. Circulation 1977;56:884-8. 15. Kadowitz PJ, Hyman AL. Effect of sympathetic nerve stimulation on pulmonary vascular resistance in the dog. Circ Res 1973;32:221-7. 16. Hyman AL, Nandiwada P, Knight DS, Kadowitz PS. Pulmonary vasodilator responses to catecholamines and sympathetic nerve stimulation in the cat. Circ Res 1981;48:407-15. 17. Mookherjee S, Fuleihan D, Warner RA, Varda S, Obeid AL. Effects of sublingual nitroglycerin on resting pulmonary gas exchange and hemodynamics in man. Circulation 1978;57: 106-10.