Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus

OBJECTIVE: Pulmonary hypertension with pathological changes similar to those observed in primary pulmonary hypertension occurs in patients with systemic lupus erythematosus (SLE). The efficacy of chronic epoprostenol therapy in SLE has not been well described. The objective of this paper is to describe our experience with long-term epoprostenol therapy in patients with pulmonary hypertension associated with SLE. DESIGN: Case series of six patients with SLE and associated pulmonary hypertension receiving chronic treatment with epoprostenol. RESULTS: All 6 patients had severe pulmonary hypertension. Mean pulmonary artery pressure (mPAP) was 57 +/- 9 mm Hg (mean +/- SD), and pulmonary vascular resistance was 14 +/- 7 units before beginning therapy with epoprostenol. In 4 patients who underwent repeat hemodynamic evaluation (9 to 16 months after starting epoprostenol), mean pulmonary artery pressure decreased by 38 +/- 21% and pulmonary vascular resistance by 58 +/- 12%. Clinically, all patients improved from New York Heart Association class III or IV to class I or II. Doses of epoprostenol ranged from 4 to 46 ng/kg/min, and the longest duration of therapy has been 2.5 years. Side effects from epoprostenol have not differed from those seen in patients with primary pulmonary hypertension, and except for one patient, there has been no exacerbation of SLE. CONCLUSION: Epoprostenol was effective for the treatment of pulmonary hypertension in this small group of patients with SLE. Further evaluation of epoprostenol therapy for patients with SLE and other diseases associated with pulmonary hypertension is warranted.     

Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension.

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2-26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0-46%). Three patients, treated for 3-9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.     

Severe erythroderma as a complication of continuous epoprostenol therapy

Epoprostenol is a vasodilator that is produced by vascular endothelial cells and is currently the "gold standard" therapy for patients with severe primary pulmonary hypertension or pulmonary hypertension secondary to collagen vascular disease. Hypersensitivity to the drug has not been reported. We report a case of a patient with pulmonary hypertension and undifferentiated connective tissue disease who, after 2 months of treatment with epoprostenol, presented with rapidly progressive erythema, scaling, nausea and vomiting, and fever. Test results from a skin biopsy specimen were consistent with a drug reaction. The patient' condition improved after rapid tapering of her epoprostenol and administration of corticosteroids. Epoprostenol may be associated rarely with severe erythroderma.     

Successful withdrawal of long-term epoprostenol therapy for pulmonary arterial hypertension

BACKGROUND: IV epoprostenol treatment of pulmonary arterial hypertension (PAH) has been believed to require an indefinite duration of therapy OBJECTIVE: To describe the successful discontinuation of long-term epoprostenol therapy in four patients DESIGN: Case reports SETTING: Outpatient clinic, tertiary-care hospital PATIENTS: Four patients with acutely nonvasoreactive, World Health Organization (WHO) functional class IV PAH received long-term epoprostenol therapy. All patients subsequently demonstrated normalization of pulmonary arterial pressures on epoprostenol treatment. These patients were selected for epoprostenol withdrawal INTERVENTION: Down-titration and discontinuation of epoprostenol RESULTS: All four patients were safely transitioned from epoprostenol to oral therapies and have maintained WHO functional class I-II for a mean of 11 months (range, 8 to 16 months). The duration of epoprostenol therapy prior to discontinuation averaged 5.7 years (range, 2.4 to 13.5 years) CONCLUSION: Epoprostenol may sufficiently reverse the pathogenic process in select patients with PAH to allow a transition to less complex and less invasive treatment modalities.     

Acute effects of sildenafil in patients with primary pulmonary hypertension receiving epoprostenol

Epoprostenol therapy has improved survival in primary pulmonary hypertension; however, only two thirds of patients are alive 3 years after starting treatment. Combined therapy with sildenafil, a phosphodiesterase 5 inhibitor, may provide additional benefit. The authors prospectively evaluated the acute hemodynamic and biochemical effects of sildenafil and inhaled nitric oxide, alone and in combination, in 8 patients with primary pulmonary hypertension receiving chronic epoprostenol. Average duration of epoprostenol therapy was 2.9 +/- 1.6 years (mean +/- SD) and mean dose was 25.7 +/- 10.8 ng/kg/min. A single 50 mg dose of sildenafil decreased mean pulmonary arterial pressure 10% (P<.05), increased cardiac output 8%, and decreased pulmonary vascular resistance 24% (P<.005). Although nitric oxide led to a similar decrease in mean pulmonary arterial pressure of 10% (P<.05), cardiac output was unchanged, resulting in a decrease in pulmonary vascular resistance of only 13%, which was not statistically different from baseline. These results suggest that sildenafil has greater acute hemodynamic effects than nitric oxide and that it can further reduce pulmonary vascular resistance in patients already demonstrating a benefit from chronic epoprostenol.     

Primary pulmonary hypertension treated with short-term epoprostenol infusion

We describe the use of short-term epoprostenol in a 61-year-old man with primary pulmonary hypertension. The patient was on a ventilator because of respiratory distress. Continuous infusion of epoprostenol was started and it initially reduced the pulmonary artery pressure by 32%. Epoprostenol was tapered, and even after discontinuation, the pulmonary artery pressure was controlled. The ventilator was removed, and the patient remained well on home oxygen therapy 3 months after discharge.     

Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival

OBJECTIVES: We sought to determine the factors associated with long-term survival in patients with primary pulmonary hypertension (PPH) treated with continuous epoprostenol infusion. BACKGROUND: Epoprostenol improves survival in patients with PPH in New York Heart Association (NYHA) functional class III or IV. However, some patients do not benefit from epoprostenol and must be considered for lung transplantation. The best timing for listing these patients on a lung transplantation program is currently unknown. METHODS: Between December 1992 and January 2001, 178 patients with PPH in NYHA functional class III or IV were treated with epoprostenol. The 6-min walk test (WT) and right-sided heart catheterization were performed at baseline, after three months on epoprostenol and thereafter once a year. RESULTS: Overall survival rates at one, two, three, and five years were 85%, 70%, 63%, and 55%, respectively. On univariate analysis, the baseline variables associated with a poor outcome were a history of right-sided heart failure, NYHA functional class IV, 6-min WT or=12 mm Hg, and mean pulmonary artery pressure <65 mm Hg. On multivariate analysis, including both baseline variables and those measured after three months on epoprostenol, a history of right-sided heart failure, persistence of NYHA functional class III or IV at three months, and the absence of a fall in total pulmonary resistance of >30%, relative to baseline, were associated with poor survival. CONCLUSIONS: Survival of patients with PPH treated with epoprostenol depends on the severity at baseline, as well as the three-month response to therapy. These findings suggest that lung transplantation should be considered in a subset of patients who remain in NYHA functional class III or IV or in those who cannot achieve a significant hemodynamic improvement after three months of epoprostenol therapy, or both.     

Epoprostenol therapy for primary pulmonary hypertension after rejection of a single donor lung.

Before prostacyclins became available, lung or heart/lung transplantation was the only effective treatment for patients with primary pulmonary hypertension (PPH) who deteriorated under supportive medical treatment. Unfortunately, acute and chronic rejections occur in a large number of cases, limiting the average survival to 4.5 yrs. A female patient, age 35 yrs, was diagnosed with PPH and underwent single lung transplantation. Despite aggressive immunosuppressive therapy, the patient had several episodes of acute rejection. Eventually, chronic rejection with bronchiolitis obliterans developed. After 5 yrs, the donor lung was no longer functional. The patient was in New York Heart Association (NYHA) class 4, had a 6-min walking distance of 50 m and a resting arterial oxygen tension (Pa,O2) of 9.8 kPa (74 mmHg) when using 3 L x min(-1) of oxygen. Epoprostenol treatment was started and the patient showed remarkable improvement. After 17 months the patient was NYHA class 2, walked 503 m in 6 min and had a resting Pa,O2 of 10.9 kPa (82 mmHg) without supplemental oxygen. In this patient, treatment with epoprostenol was effective after rejection of a single donor lung transplanted for primary pulmonary hypertension.     

Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension

OBJECTIVES: To switch patients with severe pulmonary hypertension and previous life-threatening catheter-related complications from long-term IV epoprostenol therapy to aerosolized iloprost therapy. DESIGN: Open, uncontrolled trial. SETTING: Medical ICU of a university hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary hypertension after surgical closure of atrial septal defect (mean pulmonary artery pressure > or =50 mm Hg). All were classified as New York Heart Association class II under treatment with continuous IV epoprostenol for 4 years. INTERVENTIONS: Stepwise reduction of IV epoprostenol (1 ng/kg/min steps every 3 to 10 h) during repeated inhalations of aerosolized iloprost (150 to 300 microg/d with 6 to 18 inhalations/d). Continuous pulmonary and systemic arterial monitoring were performed. RESULTS: Aerosolized iloprost reduced pulmonary artery pressure by 49%, 49%, and 45%, respectively, and increased cardiac output by 70%, 75%, and 41% in the three patients. The effect lasted for 20 min and was similar at different doses of IV epoprostenol. Persistent treatment change to inhaled iloprost could not be achieved because all patients developed signs of right heart failure. After termination of iloprost inhalations, return to standard epoprostenol therapy led to clinical and hemodynamic restoration. CONCLUSIONS: Although aerosolized iloprost demonstrated short-term hemodynamic effects, it could not be utilized as alternative chronic vasodilator in patients with severe pulmonary hypertension.     

Pregnancy and primary pulmonary hypertension : successful outcome with epoprostenol therapy

Primary pulmonary hypertension (PPH) associated with pregnancy carries a high maternal mortality rate. Short-term epoprostenol infusion has been demonstrated to improve the hemodynamic profile in patients with PPH. We report a successful maternal-fetal outcome with epoprostenol therapy during pregnancy, cesarean section, and postpartum in a patient with PPH. Epoprostenol therapy did not produce any physical or developmental abnormalities in the fetus. A favorable maternal-fetal outcome may occur with a multidisciplinary approach.     

Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension

OBJECTIVES: To evaluate the effect of long-term oral therapy with sildenafil in patients with pulmonary arterial hypertension receiving long-term IV epoprostenol. DESIGN: Open, uncontrolled trial. SETTING: University hospital. PATIENTS: Two patients with primary pulmonary hypertension and one patient with pulmonary arterial hypertension after surgical closure of an atrial septal defect. All patients were receiving continuous epoprostenol for 1.7 to 7.1 years; two patients also received inhaled iloprost for 1.8 years and 3.8 years, respectively. INTERVENTIONS: Addition of oral sildenafil, up to 200 mg/d, divided in four to six single doses, and hemodynamic measurements and the 6-min walking distance (6MWD) before and after 5 months of treatment with sildenafil. RESULTS: One patient was treated with sildenafil, 200 mg/d; two patients received 75 mg/d due to nausea and headache. Long-term treatment with sildenafil in the three patients reduced mean pulmonary artery pressure by 14%, 41%, and 22%, respectively; in two patients, pulmonary vascular resistance was decreased by 52% and 55%. The 6MWD increased by 34%, 6%, and 29%, respectively. No significant systemic hypotension or decrease of arterial oxygen saturation was seen. CONCLUSION: Sildenafil therapy may be of benefit in patients with pulmonary arterial hypertension receiving long-term infusion of epoprostenol.     

Oral sildenafil improves primary pulmonary hypertension refractory to epoprostenol.

BACKGROUND: Epoprostenol (prostaglandin I(2)) has become recognized as a therapeutic breakthrough that can improve hemodynamics and survival in patients with primary pulmonary hypertension (PPH). However, a significant number of patients have PPH that is refractory to epoprostenol, and lung transplantation has been the only remaining treatment option. METHODS AND RESULTS: The study subjects included 20 consecutive patients with PPH (mean pulmonary arterial pressure: 65+/-15 mmHg) who had received epoprostenol for more than 12 months. The patients were divided into 2 groups; responders and non-responders. In the non-responders, New York Heart Association (NYHA) functional class did not improve and mean right atrial pressure (mRA) increased to 8 mmHg or more, and additional sildenafil, a phosphodiesterase-5 inhibitor, was started. Six patients were included in the non-responders, whose mRA was 9+/-5 mmHg before and significantly increased to 13+/-3 mmHg after epoprostenol administration (p < 0.05). One patient died and the other 5 patients received oral sildenafil. The mRA of 12+/-4 mmHg (value before sildenafil) improved to 8+/-5 mmHg after sildenafil administration. Three patients were classified in the NYHA functional class 4 and improved to class 3, and 2 patients were in class 3 and remained in the same class after the addition of sildenafil. CONCLUSIONS: In patients with severe PPH refractory to epoprostenol treatment, additional oral sildenafil can improve pulmonary hemodynamics and symptoms. The combination therapy of epoprostenol and sildenafil is a new medical treatment to attempt before progressing to lung transplantation for patients with PPH refractory to epoprostenol.     

Prostanoids for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a severe condition that markedly reduces exercise capacity and survival in the affected patient population. PAH includes primary pulmonary hypertension (PPH) and pulmonary hypertension associated with collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension and HIV infection. All these conditions share virtually identical obstructive pathologic changes of the pulmonary microcirculation and probably similar pathobiologic processes. The pathophysiology is characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and death. Prostacyclin is an endogenous substance that is produced by vascular endothelial cells and induces vasodilatation, inhibition of platelet activity, and antiproliferative effects. A dysregulation of prostacyclin metabolic pathways has been shown in patients with PAH and this represents the rationale for the exogenous therapeutic administration of this substance. The clinical use of prostacyclin in patients with PAH has been made possible by the synthesis of stable analogs that possess different pharmacokinetic properties but share similar pharmacodynamic effects. Experience in humans has been initially collected with epoprostenol, which is a synthetic salt of prostacyclin. Epoprostenol has a short half-life in the circulation and requires continuous administration by the intravenous route by means of infusion pumps and permanent tunnelized catheters. In addition, epoprostenol is unstable at room temperature, and the complex delivery system required is associated with several adverse effects and potentially serious complications. For these reasons, alternatives to intravenous epoprostenol have been sought and this has led to the development of analogs that can be administered subcutaneously (treprostinil), orally (beraprost sodium) or by inhalation (iloprost). Three unblinded clinical trials and several uncontrolled trials have shown that treatment with epoprostenol improved symptoms and exercise capacity in New York Heart Association (NYHA) class III and IV PAH patients and also survival in patients with PPH. Subcutaneous treprostinil improved symptoms, exercise, hemodynamics and clinical events in the largest clinical trial ever performed in PAH, but local infusion site reactions limited efficacy in a proportion of patients. Oral beraprost sodium improved exercise capacity only in patients with PPH and is the only prostacyclin analog that has also been tested in NYHA class II patients. Inhaled iloprost has improved symptoms, exercise capacity and clinical events in patients with PAH and inoperable chronic thromboembolic pulmonary hypertension. The favorable effects of prostanoids observed in all studies coupled with different profiles of adverse events and tolerability for each prostacyclin analog allow the unique opportunity to select the most appropriate compound for the individual patient with PAH.     

Pulmonary edema during acute infusion of epoprostenol in a patient with pulmonary hypertension and limited scleroderma.

Epoprostenol (prostacyclin) is currently approved for treatment of primary pulmonary hypertension; however, it is being evaluated in other forms of pulmonary hypertension, particularly scleroderma. Side effects associated with this medication are usually minor; serious complications are most often due to the delivery system required for continuous infusion. We describe a life threatening side effect of acute epoprostenol infusion (pulmonary edema) in a patient with pulmonary hypertension associated with limited scleroderma and discuss its management and potential etiology. This is the first case where epoprostenol has been successfully reinstituted.     

Efficacy of acute inhalation of nitric oxide in patients with primary pulmonary hypertension using chronic use of continuous epoprostenol infusion.

BACKGROUND: There have only been a few reports published on combination therapy for patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Fifteen patients with PPH (4 men and 11 women, 34.5+/-12.1 years old) had received chronic administration of epoprostenol and the additive effects of inhaled nitric oxide (NO) and the hemodynamic changes were evaluated. In addition, the difference in the effect of acute NO loading before and after the epoprostenol therapy was compared in 6 of these patients. Under chronic use of epoprostenol, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance were decreased with acute inhalation of NO. However, cardiac output, mean aortic pressure and systemic vascular resistance were unchanged. As a result, the pulmonary to systemic vascular resistance ratio was reduced. Moreover, after chronic use of epoprostenol, the change (delta) in cardiac output with NO inhalation was increased and the NO-induced decrease in pulmonary vascular resistance was augmented compared to those before the induction. CONCLUSION: Nitric oxide inhalation further improved the hemodynamics when combined with chronic use of epoprostenol in PPH patients. These results suggest the possibility that combination therapies can be used in the treatment for PPH patients.     

A case of severe pulmonary hypertension associated with COPD treated with epoprostenol

A rare case of chronic obstructive pulmonary disease (COPD) with severe pulmonary hypertension (PH) was found in a 68-year-old man. COPD was diagnosed in his 50s, from which time he received home oxygen therapy. In January 2007, he was admitted due to progression of dyspnea. On admission to our hospital, arterial blood gas analysis showed severe hypoxemia. Moreover, echocardiographic findings demonstrated severe deviation of the interventricular septum toward the left ventricle, with right ventricular dilatation. Cardiac catheterization data demonstrated pulmonary arterial hypertension with a low cardiac output. Because severe PH is uncommon in patients with COPD and there was no apparent etiology of PH other than COPD, we thought this case was predominantly a pulmonary vascular disease such as idiopathic pulmonary arterial hypertension. Though we first treated this patient with bosentan, it was not effective. Therefore, he was treated with continuous infusion of epoprostenol. Epoprostenol administration along with bosentan resulted in decrease of BNP and right ventricular function improvement. We report a case of severe PH due to severe COPD treated with continuous administration of epoprostenol.     

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.     

Pulmonary hypertension and beta-thalassemia major: report of a case, its treatment, and a review of the literature

Pulmonary hypertension is a common complication of beta-thalassemia major. We report a case of successful treatment of pulmonary hypertension in a patient with beta-thalassemia major and review the literature on pulmonary hypertension and beta-thalassemia major. A 28-year-old man with beta-thalassemia major, splenectomy, hepatitis C, and hemosiderosis who presented with increasing dyspnea on exertion was diagnosed with pulmonary hypertension. After receiving continuous epoprostenol infusion and desferoxamine, his functional capacity and hemodynamic status improved. To our knowledge, this is the first case of pulmonary hypertension associated with beta-thalassemia treated with continuous epoprostenol infusion and desferoxamine. Epoprostenol, beneficial in the treatment of other types of pulmonary hypertension, may ameliorate the morbidity and mortality of pulmonary hypertension associated with thalassemia.     

Ten years' experience in continuous intravenous epoprostenol therapy in severe pulmonary arterial hypertension

INTRODUCTION: Primary pulmonary hypertension and its associated forms is a progressive and often fatal disease, the course of which has been favourably modified by prostacyclin therapy in the last decade. OBJECTIVE: The aim of this study is to analize retrospectively the efficacy of continuous intravenous epoprostenol (synthetic prostacyclin) therapy in pulmonary arterial hypertension, and to compare it with conventional therapy (anticoagulants, digoxin and diuretics). METHODS: Between 1990-2000, 31 patients with severe precapillary pulmonary hypertension in functional class III or IV went on continuous intravenous epoprostenol therapy, administered by a portable infusion pump through a Hickman catheter. We compared their survival with a group of 16 patients treated with conventional therapy alone. RESULTS: Time of follow-up was 33.25 months in the prostacyclin group and 20 months in the conventional group. The one- three- and five- year survival rates were 86%, 50% and 38% respectively for patients treated with epoprostenol compared with 40%, 40% and 8% survival rates at idetical periods for patients treated conventionally (p = 0,02). Functional class and the mean distance walked in the 6 minutes test were improved in patients treated with prostacyclin (p < 0,01). Serious complications attributable to the delivery system included 3 deaths, mainly due to infection. CONCLUSION: Continuous intravenous epoprostenol therapy improves survival and exercise capacity in patients with severe pulmonary arterial hypertension despite potentially serious complications attributable to the delivery system.