Abstract
Continuous intravenous epoprostenol (prostacyclin) produces hemodynamic and symptomatic responses and improves survival in patients with severe primary pulmonary hypertension refractory to conventional medical therapy. However, it has been recently shown that short-term infusion of epoprostenol can produce pulmonary edema in pulmonary veno-occlusive disease, presumably because of increased pulmonary perfusion in the presence of downstream vascular obstruction. We describe two additional cases of pulmonary edema complicating continuous intravenous epoprostenol in patients displaying severe pulmonary hypertension and pulmonary capillary hemangiomatosis, a rare condition characterized by the proliferation of thin-walled microvessels in the alveolar walls. This report indicates that epoprostenol therapy should not be used in patients with severe pulmonary hypertension secondary to pulmonary capillary hemangiomatosis.
Epoprostenol (prostaglandin I2, prostacyclin), a potent vasodilator and inhibitor of platelet aggregation produced by vascular endothelium, reduces pulmonary vascular resistance and increases cardiac output and oxygen delivery when administered acutely to patients with primary pulmonary hypertension (PPH) (1). Continuous intravenous epoprostenol produces substantial and sustained hemodynamic and symptomatic responses as well as improves survival in severe PPH refractory to conventional medical therapy (2-5).
The pathologic changes of PPH may be limited to the pulmonary arterial circulation (hypertensive pulmonary arteriopathy), or it may involve veins, capillaries, and arteries (pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis) (6). Rubin and colleagues (2, 5) have recently indicated that short-term infusion of epoprostenol can produce pulmonary edema in pulmonary veno-occlusive disease, presumably because of increased pulmonary perfusion in the presence of downstream vascular obstruction (2, 5). In the present report, we describe two additional cases of pulmonary edema complicating continuous intravenous epoprostenol in patients displaying severe pulmonary hypertension and pulmonary capillary hemangiomatosis, a rare condition characterized by the proliferation of thin-walled microvessels in the alveolar walls (6-12).
A 34-yr-old white woman was admitted to our hospital because of dyspnea, functional Class III of the NYHA. Her personal history was unremarkable except for oral contraceptive use and two pregnancies. Physical examination showed a loud pulmonic component of the second heart sound. An electrocardiogram showed a pattern of right ventricular hypertrophy. Right ventricular hypertrophy and dilatation were seen by echocardiography. Pulmonary embolism was excluded with a negative perfusion scan. Right-heart catheterization revealed a right atrial pressure of 16 mm Hg, a mean pulmonary arterial pressure of 60 mm Hg, a cardiac index of 1.61 L/min/m2, a pulmonary vascular resistance of 37.5 U/m2, and a mixed venous oxygen saturation of 39%. Multiple pulmonary capillary wedge pressure measurements did not show elevated values. No significant vasodilation was found with inhaled nitric oxide. A chest radiograph showed discrete alterations, including a convex main pulmonary artery, ill-defined basal interstitial infiltrates, and minimal right pleural effusion. High resolution computed tomodensitometry of the chest demonstrated patchy reticulonodular interstitial opacities, minimal right pleural effusion, and thickened interlobular and intralobular septae (Figure 1). Bronchoalveolar lavage examination did not find elevated numbers of iron-laden macrophages. Surgical lung biopsy could not be performed because of severely impaired clinical status and hemodynamics. The patient's name was put on the list for lung transplantation, and continuous epoprostenol infusion was started up to 12 ng/kg/min. The patient's clinical status rapidly worsened with dyspnea functional Class IV and syncopes. Chest radiography and high resolution computed tomodensitometry deteriorated with marked pulmonary edema and pleural effusion (Figure 1). Epoprostenol therapy was progressively reduced and subsequently stopped. However, in the absence of efficient therapeutic alternatives, the patient died a few days later from refractory right heart failure. Postmortem examination of the lungs established the diagnosis of pulmonary capillary hemangiomatosis, showing patterns of congestion and proliferating capillaries lining both sides of alveolar walls. Pulmonary veins from this patient showed muscularization, intimal fibrosis, and reduced lumen (Figure 2).
Fig. 1. (A) High-resolution computed tomography of the chest prior to long-term epoprostenol therapy, showing scattered nodular interstitial opacities, thickened interlobular and intralobular septae, and minimal right pleural effusion. (B) High resolution computed tomography of the chest 8 wk after initiation of long-term epoprostenol therapy, showing marked nodular interstitial opacities, thickened interlobular and intralobular septae, and right pleural effusion.
[More] [Minimize]
Fig. 2. (A) Low-power view of pulmonary capillary hemangiomatosis showing patterns of congestion and proliferating capillaries (hematoxylin-eosin stain, object lens 10, Patient 1). (B) Higher-power view of pulmonary capillary hemangiomatosis showing proliferating capillaries lining both sides of alveolar walls (hematoxylin-eosin stain, object lens 40, Patient 1). (C ) Medium-sized pulmonary vein from a patient displaying pulmonary capillary hemangiomatosis showing muscularization, intimal fibrosis, and reduced lumen (hematoxylin-eosin stain, object lens 25, Patient 1).
A 25-yr-old white woman was referred to our center because of dyspnea graded functional Class III according to New York Heart Association (NYHA) criteria. Fatal PPH had developed in an elder sister in 1978. Her personal history was unremarkable except for oral contraceptive use. Physical examination revealed a left parasternal heave and a loud pulmonic component of the second heart sound. Chest radiography and computed tomodensitometry showed a convex main pulmonary artery, a normal vascular pattern, and no pulmonary congestion. An electrocardiogram showed right ventricular hypertrophy. Right ventricular hypertrophy and dilatation were seen by echocardiography. Pulmonary embolism was excluded with a negative perfusion scan. Right-heart catheterization revealed a right atrial pressure of 15 mm Hg, mean pulmonary arterial pressure of 69 mm Hg, a cardiac index of 2.37 L/min/m2, a pulmonary vascular resistance of 29.1 U/m2, and a mixed venous oxygen saturation of 52%. Multiple pulmonary capillary wedge pressure measurements did not demonstrate elevated values. No significant vasodilation was found with inhaled nitric oxide or orally administered calcium channel blockers. The patient's name was put on the list for lung transplantation, and continuous epoprostenol infusion was started up to 8 ng/kg/min. The patient's condition rapidly deteriorated with dyspnea at rest and syncopes, and chest radiography and high resolution computed tomodensitometry demonstrated marked pulmonary edema and pleural effusion. Despite the progressive weaning of epoprostenol therapy, the patient died from refractory right heart failure. Postmortem examination of the lungs revealed pulmonary capillary hemangiomatosis with patterns of pulmonary vein muscularization, congestion, and proliferating capillaries lining both sides of alveolar walls.
Continuous infusion of epoprostenol improves hemodynamic characteristics, exercise tolerance, quality of life, and survival in patients with PPH in NYHA functional Classes III and IV (2-4). Drug-induced side effects are usually minor, including jaw pain, cutaneous erythema, diarrhea, and arthralgia (2-5). However, infusion of epoprostenol can produce pulmonary edema in pulmonary veno-occlusive disease, a condition characterized by hypertensive lesions involving primarily the pulmonary veins (i.e., postcapillary) (6), presumably by increasing pulmonary capillary hydrostatic pressure (2, 5). In the present report, we describe two patients with pulmonary capillary hemangiomatosis who displayed severe pulmonary edema with continuous intravenous epoprostenol, suggesting that severe side effects of epoprostenol infusion can be observed in both pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. This finding confirms and extends previous observations highlighting the similarities between these two conditions (6, 13, 14): on the one hand, occlusion of pulmonary veins by fibrous tissue containing small vascular channels has been described in pulmonary capillary hemangiomatosis, therefore resulting in a “secondary” pulmonary veno-occlusive disease (6-13); on the other hand, it has been recently established that human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease (14). These close pathologic features and the occurrence of pulmonary edema with continuous epoprostenol in both conditions suggest that these disorders may overlap (6, 13, 14). In our patients, evidence of proliferating capillaries lining both sides of alveolar walls was associated with mild to moderate pulmonary vein involvement (muscularization and intimal fibrosis).
The present report indicates that epoprostenol therapy should not be used in patients with severe pulmonary hypertension secondary to pulmonary capillary hemangiomatosis. However, the diagnosis of pulmonary capillary hemangiomatosis in the living patient is difficult and in most patients illness is not recognized until signs of marked pulmonary hypertension have developed (13). Combined evidence of pulmonary hypertension, hemoptysis, elevated numbers of iron-laden bronchoalveolar macrophages, interstitial lung infiltrates, and pleural effusion pleads in favor of the disease (13). Patients with pulmonary capillary hemangiomatosis may not initially present with a high index of suspicion. Retrospective analysis of our patients with pulmonary capillary hemangiomatosis indicates that clinical presentation can be indistinguishable from that of classic hypertensive pulmonary arteriopathy.
Initial chest radiograph was subnormal in Patient 2 and showed mild interstitial reticulondular infiltrates and right pleural effusion in Patient 1. In this latter case, high resolution computed tomography of the chest, showing patchy reticulonodular interstitial infiltrates and thickened intralobular and interlobular septae, was unusual for PPH. The cornerstone of the diagnosis of pulmonary capillary hemangiomatosis is pathology. However, transbronchial biopsy is contraindicated and open-lung biopsy is hazardous, especially in patients with severe disease (13, 15), emphasizing the need for new diagnostic tools in this patient population. In the light of the present report, early recognition of pulmonary capillary hemangiomatosis appears to be of clinical importance because of severe clinical deterioration occurring during otherwise efficient pulmonary vasodilator therapy. This emphasizes the need for new noninvasive strategies in the diagnosis of this disease. In our institution we now recommend systematically performing high resolution computed tomographic scan of the chest before initiating vasodilator therapy in patients with primary pulmonary hypertension and to repeat this procedure in case of subsequent clinical deterioration with vasodilators. The evidence of diffuse bilateral reticulonodular thickening of interlobular septae, intralobular nodular opacities, multifocal regions of lobular and centrilobular ground glass opacification, hilar adenomegaly, and pleural effusion is unusual in patients displaying isolated pulmonary hypertensive arteriopathy and should therefore lead to additional investigations and, if necessary, open-lung biopsy (16 and unpublished data of Dufour and colleagues).
Alternatives to epoprostenol therapy have to be discussed in patients displaying severe pulmonary hypertension and pulmonary capillary hemangiomatosis. Oral vasodilators such as calcium channel blockers are not indicated in the absence of a marked fall in pulmonary vascular resistance during acute challenge test with inhaled nitric oxide (5). Moreover long-term treatment with calcium channel blockers may promote pulmonary edema in pulmonary hypertension complicating pulmonary capillary hemangiomatosis (10). Lung and heart-lung transplantation are appropriate treatments in those severe conditions (5, 11, 17). However, the current shortage of organ donors emphasizes the need for effective bridge therapies while the patients are waiting for a lung transplantation list. Successful strategies, including long-term treatment with continuous inhaled nitric oxide, have been recently reported in severe PPH (18). Interestingly, both patients described in our report did not clinically deteriorate with acute inhalation of nitric oxide, whereas severe clinical impairment developed with continuous intravenous epoprostenol. The reason for this discrepancy is still unclear, but it may be related to the fact that nitric oxide selectively vasodilates pulmonary arteries without increasing cardiac output (19), unlike intravenously administered epoprostenol, which vasodilates both the pulmonary and the systemic arteries, and increases cardiac output (1, 5).
Angiogenesis inhibitors such as interferon should be evaluated in these patients. Interferon therapy has produced interesting results in Kaposi's sarcoma (20) and in a single case report of pulmonary capillary hemangiomatosis (13). Further advances in the understanding of angiogenesis may lead to new therapeutic strategies in this patient population (21).
Supported in part by a grant form Université Paris-Sud.
| 1. | Rubin L. J., Groves B. M., Reeves J. T., Frosolono M., Handel F., Cato A. E.Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation661982334338 |
| 2. | Rubin L. J., Mendoza J., Hood M., McGoon M., Barst R., Williams W., Diehl J. H., Crow J., Long W.Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol): results of a randomized trial. Ann. Intern. Med.1121990485491 |
| 3. | Barst R. J., Rubin L. J., McGoon M. D., Caldwell E. G., Long W. A., Levy P. S.Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann. Intern. Med.1211994409415 |
| 4. | Barst R. J., Rubin L. J., Long W. A., McGoon M., Rich S., Badesch D., Groves B. M., Tapson V. F., Bourge R. C., Brundage B. H., Koerner S. K., Langelben D., Keller C. A., Murani S., Uretsky B. F., Clayton L. M., Jöbsis M. M., Blackburn S. D., Shortino D., Crow J. W.A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N. Engl. J. Med.3341996296301 |
| 5. | Rubin L. J.Primary pulmonary hypertension. N. Engl. J. Med.3361997111117 |
| 6. | Pietra, G. G. 1997. The pathology of primary pulmonary hypertension. In L. Rubin and S. Rich, editors. Primary pulmonary hypertension. Marcel Dekker, New York. 19–61. |
| 7. | Wagenvoort C. A., Beestri A., Spijker J.Capillary haemangiomatosis of the lung. Histopathology21978401406 |
| 8. | Magee F., Wright J. L., Kay M. J., Deretz D., Donevan R., Churg A.Pulmonary capillary hemangiomatosis. Am. Rev. Respir. Dis.1321985922925 |
| 9. | Tron V., Magee F., Wright L., Colby T., Churg A.Pulmonary capillary hemangiomatosis. Hum. Pathol.17198611441150 |
| 10. | Langleben D., Heneghan J. M., Batten A. P., Wang N.-S., Fitch N., Schlesinger R. D., Guerraty A., Rouleau J. L.Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann. Intern. Med.1091988106109 |
| 11. | Faber C. N., Yousem S. A., Dauber J. H., Griffith B. P., Hardesty R. L., Paradis I. L.Pulmonary capillary hemangiomatosis: a report of three cases and a review of the literature. Am. Rev. Respir. Dis.1401989808813 |
| 12. | Eltorky M. A., Headley A. S., Winer-Muram H., Garrett H. E., Griffin J. P.Pulmonary capillary hemangiomatosis: a clinicopathologic review. Ann. Thorac. Surg.571994772776 |
| 13. | White C. W., Sondheimer H. M., Crouch E. C., Wilson H., Fan L. L.Treatment of pulmonary hemangiomatosis with recombinant interferon alpha-2a. N. Engl. J. Med.320198911971200 |
| 14. | Schraufnagel D. E., Sekosan M., McGee T., Thakkar M. B.Human alveolar capillaries undergo angiogenesis in pulmonary veno-occlusive disease. Eur. Respir. J.91996346350 |
| 15. | Nicot P., Moser K. M.Primary pulmonary hypertension: the risk and benefit of lung biopsy. Circulation80198914861488 |
| 16. | Swenson S. J., Tashjian J. H., Myers J. L., Engeler C. E., Patz E. F., Edwards W. D., Douglas W. W., Pulmonaryveno-occlusive disease: CT findings in eight patientsAJR Am. J. Roentgenol.1671996937940 |
| 17. | Reitz B. A., Wallwork J. L., Hunt S. A., Penncock J. L., Billingham M. E., Oyer P. E., Stinson E. B., Shumway N. E.Heart-lung transplantation: successful therapy for patients with pulmonary vascular disease. N. Engl. J. Med.3061982557564 |
| 18. | Snell G. I., Salamonsen R. F., Bergin P., Esmore D. S., Khan S., Williams T. J.Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am. J. Respir. Crit. Care Med.151199512631266 |
| 19. | Sitbon O., Brenot F., Denjean A., Bergeron A., Parent F., Azarian R., Hervé P., Raffestin B., Simonneau G.Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose-response study and comparison with prostacyclin. Am. J. Respir. Crit. Care Med.1511995384389 |
| 20. | Groopman J. E., Gottlieb M. S., Goodman J., Mitsuyasu R. T., Conant M. A., Prince H., Fahey J. L., Derezin M., Weinstein W. M., Casavante C., Rothman J., Rudnik S. A., Volberding P. A.Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann. Intern. Med.1001984671676 |
| 21. | Folkman J.Successful treatment of an angiogenic disease. N. Engl. J. Med.320198912111212 |
