Massive Pulmonary Edema and Death After Prostacyclin Infusion in a Patient With Pulmonary Veno-occlusive Disease

doi:10.1378/chest.113.1.237

Chest

Volume 113, Issue 1, January 1998, Pages 237-240

https://doi.org/10.1378/chest.113.1.237 Get rights and content

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension associated with fibrotic occlusion of the smaller pulmonary veins. Although vasodilator therapy is effective in many patients with primary pulmonary hypertension, the role of vasodilators in PVOD is unclear because of concerns about precipitating pulmonary edema. Recently, however, there have been reports of successful therapy with oral vasodilators or intravenous administration of prostacyclin in patients with PVOD. In contrast, a patient with PVOD is described who developed acute pulmonary edema and respiratory failure during low-dose prostacyclin infusion, leading to death. This report suggests that vasodilators, especially prostacyclin, must be used with extreme caution in patients with known PVOD.

Section snippets

Clinical Data

A 42-year-old African-American woman underwent evaluation of progressive dyspnea on exertion, which began in February 1995. She had no prior medical problems and no relevant family history or occupational exposures. She smoked one pack of cigarettes per day for 20 years. By September of 1996, she developed significant oxygen desaturation detected by pulse oximetry with minimal activity. Pulmonary function tests revealed an FEV₁ value of 1.35 L (50% predicted), an FVC value of 1.64 L (50%

Discussion

PVOD is a rare form of pulmonary hypertension characterized by fibrotic occlusion of the smaller pulmonary veins. In most cases, the cause is unknown, although various associations have been described, especially with certain chemotherapeutic agents.² The true incidence of PVOD is not known, but it is estimated that 6% of patients clinically believed to have PPH will have evidence of PVOD at the time of autopsy.³ Differentiation between PPH and PVOD is difficult on clinical grounds alone.

Conclusion

This case has several important implications for the management of patients with pulmonary hypertension. Although previous reports suggested prostacyclin may be safe in patients with PVOD, the experience reported here suggests that even in very low doses prostacyclin can produce acute decompensation in patients with PVOD. Thus, consideration must be given to the diagnosis of PVOD in all patients with suspected PPH. The diagnosis of PVOD should be suspected when patients with pulmonary

References (10)

LJ Rubin
ACCP consensus statement: primary pulmonary hypertension
Chest
(1993)
GA Salzman et al.
Prolonged survival in pulmonary veno-occlusive disease treated with nifedipine
Chest
(1989)
LL Davis et al.
Effect of prostacyclin on microvascular pressures in a patient with pulmonary veno-occlusive disease
Chest
(1995)
RB Barst et al.
A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension
N Engl J Med
(1996)
DA Ellis et al.
Pulmonary veno-occlusive disease after chemotherapy
Thorax
(1986)

There are more references available in the full text version of this article.

Cited by (198)

Patient-specific and gene-corrected induced pluripotent stem cell-derived endothelial cells elucidate single-cell phenotype of pulmonary veno-occlusive disease
2022, Stem Cell Reports
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension characterized by the preferential remodeling of the pulmonary venules. Hereditary PVOD is caused by biallelic variants of the EIF2AK4 gene. Three PVOD patients who carried the compound heterozygous variants of EIF2AK4 and two healthy controls were recruited and induced pluripotent stem cells (iPSCs) were generated from human peripheral blood mononuclear cells (PBMCs). The EIF2AK4 c.2965C>T variant (PVOD#1), c.3460A>T variant (PVOD#2), and c.4832_4833insAAAG variant (PVOD#3) were corrected by CRISPR-Cas9 in PVOD-iPSCs to generate isogenic controls and gene-corrected-iPSCs (GC-iPSCs). PVOD-iPSC-endothelial cells (ECs) exhibited a decrease in GCN2 protein and mRNA expression when compared with control and GC-ECs. PVOD-ECs exhibited an abnormal EC phenotype featured by excessive proliferation and angiogenesis. The abnormal phenotype of PVOD-ECs was normalized by protein kinase B inhibitors AZD5363 and MK2206. These findings help elucidate the underlying molecular mechanism of PVOD in humans and to identify promising therapeutic drugs for treating the disease.
Inhaled Selective Pulmonary Vasodilator Use After Cardiac Surgery: Broader Insights From a Study Describing Significant Changes in Drug Utilization and Savings After Implementation of a Guideline Favoring Inhaled Epoprostenol
2022, Journal of Cardiothoracic and Vascular Anesthesia
Pulmonary capillary hemangiomatosis-predominant vasculopathy in a patient with rheumatoid arthritis-associated interstitial lung disease: An autopsy report
2020, Respiratory Medicine Case Reports
Pulmonary capillary hemangiomatosis (PCH) is a rare cause of pulmonary hypertension (PH) associated with poor prognosis. Clinically, it is characterized by severe hypoxemia, centrilobular ground-glass opacities on computed tomography, and pulmonary congestion triggered by pulmonary vasodilating therapy. In some cases, PCH has been reported to develop with other disorders including connective tissue disease; however, to date, no reports have described PCH in a patient with rheumatoid arthritis. We report a case of a 59-year-old male PCH patient with rheumatoid arthritis and associated pulmonary fibrosis. He was initially diagnosed with severe group 3 PH and received sildenafil, which generated a favorable hemodynamic response. However, 5 years later, his pulmonary hemodynamics deteriorated, and he died at the age of 67. An autopsy was performed, and thickening of alveolar septa and capillary proliferation, pathological features of PCH, were extensively observed in both lungs. We discuss when PCH developed, how sildenafil improved his hemodynamics, and how PCH could be clinically detected by noninvasive evaluations.
Unique wreath-like smooth muscle proliferation of the pulmonary vasculature in pulmonary veno-occlusive disease versus pulmonary arterial hypertension
2020, Journal of the Formosan Medical Association
Pulmonary veno-occlusive disease (PVOD) is a rare but fatal cause of pulmonary hypertension reported to be linked to mutations of eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4), also known as general control nonderepressible 2 kinase (GCN2). PVOD is difficult to diagnose and often initially misdiagnosed as other types of idiopathic pulmonary arterial hypertension (IPAH). To rapidly and correctly identify PVOD patients and explore the possible pathogenesis, we thoroughly investigated histopathological features and GCN2 protein levels in non-PAH, PVOD and PAH patients.
Lung specimens were examined for histopathological changes, including those of pulmonary arteries and veins, by Masson's trichrome, modified Verhoeff's and α-SMA staining in the PVOD, IPAH, and non-PAH groups. GCN2 and α-SMA expression in lung tissue was examined by immunohistochemistry and western blotting.
PVOD and IPAH patients showed significant intimal and medial thickening of muscular pulmonary arteries compared with non-PAH patients. PVOD patients had more prominent intimal and medial thickening of muscular pulmonary veins than the other two groups. Interestingly, specialized muscle bundles surrounding the tunica adventitia of the pulmonary artery and vein were observed in PVOD patients. A significant decrease in GCN2 expression in the PVOD group was confirmed by immunohistochemistry and western blotting.
Our study is the first to show remarkable histological structures, including the wreath-like arrangement of a hyperplastic muscle bundle in the adventitia of pulmonary arteries, in PVOD patients as a diagnostic clue and to disclose the biological difference between PAH and PVOD in a Taiwanese population.
Pulmonary Edema Following Initiation of Parenteral Prostacyclin Therapy for Pulmonary Arterial Hypertension: A Retrospective Study
2019, Chest
Citation Excerpt :
In severe cases, a “deconditioned” LV may not be able to accommodate increased pulmonary blood flow after initiation of prostacyclin therapy. PAH-targeted therapies are known to cause pulmonary edema in PVOD and PCH,4,5 albeit in the absence of incidence data.3,4,31 PVOD and PCH are rare forms of pulmonary hypertension, representing 0.4% of cases in a large pulmonary hypertension registry.6
Pulmonary edema may complicate the use of pulmonary arterial hypertension (PAH)-targeted therapies. We aimed to determine the proportion of patients who develop pulmonary edema after initiation of parenteral prostacyclin therapy, to identify its risk factors, and to assess its implications for hospital length of stay and mortality.
A retrospective cohort study of patients with PAH at the initiation of parenteral prostacyclin between 1997 and 2015 enrolled in the Cleveland Clinic PAH registry. Pulmonary edema was defined as at least one symptom or clinical sign and radiographic evidence of pulmonary edema. We determined patient characteristics predictive of pulmonary edema as well as the association between pulmonary edema and hospital length of stay (LOS) and 6-month mortality.
One hundred and fifty-five patients were included (median age, 51 years; female, 72%; white, 85%; idiopathic, 64%; and connective tissue disease [CTD], 23%). Pulmonary edema developed in 33 of 155 patients (21%). Independent predictors of pulmonary edema were high right atrial pressure (RAP), CTD etiology, and the presence of three or more risk factors for left heart disease (LHD). Pulmonary edema was associated with a 4.5-day increase in hospital LOS (95% CI, 1.4-7.5 days; P < .001) and a 4-fold increase in 6-month mortality (OR, 4.3; 95% CI, 1.28-14.36; P = .031).
Pulmonary edema occurred in 21% of patients with PAH initiated on parenteral prostacyclin. Three or more risk factors for LHD, CTD-PAH, and a high baseline RAP were independent predictors of pulmonary edema. Pulmonary edema was associated with a prolonged hospital LOS and increased 6-month mortality.
Use of vasodilators for the treatment of pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: A systematic review
2019, Respiratory Investigation
There are several medications available to treat pulmonary arterial hypertension (PAH): PAH-targeted drugs. However, in patients with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH), rare diseases that cause pulmonary hypertension, the effectiveness and safety of vasodilators, including PAH-targeted drugs, are unclear.
We searched English-language publications listed in three electronic databases (PubMed, Cochrane Library, and the Japan Medical Abstracts Society). Reports with efficacy outcomes (survival, improvement in 6-minute walk distance, and pulmonary vascular resistance) and data on development of pulmonary edema after administration of vasodilators to patients with PVOD/PCH were selected (1966 to August 2015).
We identified 20 reports that met our criteria. No randomized controlled or prospective controlled studies were reported. The survival time ranged from 71 minutes to 4 years or more after initiation of vasodilators. Most of the reported cases showed an improvement in the 6-minute walk distance and pulmonary vascular resistance. Pulmonary edema was reported in 15 articles, some cases of which were lethal.
The present study demonstrates the potential efficacy and difficulties in the use of vasodilators in patients with PVOD/PCH; however, drawing a firm conclusion was difficult because of the lack of randomized controlled trials. Further research is needed to ascertain if vasodilator use is beneficial and safe in patients with PVOD/PCH.

View all citing articles on Scopus

View full text

Chest

Selected ReportsMassive Pulmonary Edema and Death After Prostacyclin Infusion in a Patient With Pulmonary Veno-occlusive Disease

Section snippets

Clinical Data

Discussion

Conclusion

Chest

Chest

Chest

A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Pulmonary veno-occlusive disease after chemotherapy

Thorax

Selected Reports
Massive Pulmonary Edema and Death After Prostacyclin Infusion in a Patient With Pulmonary Veno-occlusive Disease