Intravenous epoprostenol

Intravenous epoprostenol increases exercise tolerance, improves pulmonary hemodynamics, and improves survival in patients with primary pulmonary hypertension. However, there are limitations to intravenous administration, and a significant proportion of patients develop catheter-related problems, such as thrombosis, pump failure, and catheter-related sepsis. In an attempt to improve delivery, several trials of aerosolized prostacyclin have been undertaken, primarily in patients with primary pulmonary hypertension. 

Further cases of pulmonary edema have been reported during continuous intravenous epoprostenol in patients with severe pulmonary hypertension and pulmonary capillary hemangiomatosis, a rare condition characterized by proliferation of thin-walled microvessels in the alveolar walls (3). This report suggests that epoprostenol should not be used in such patients. 

Krowka, M.X, Frantz, R.P., McGoon, M.D., Severson, C., Plevak, D.X, Wiesner, R.H. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin) a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 1999 30 641-648... 

New York Heart Association (NYHA) class III or IV or six-minute walk tests less than 332 meters do poorly (6). Of note, the prognosis of patients treated in the modern era with intravenous epoprostenol is improved. Although survival data is limited, comparisons are made to outdated historical controls of the 1991 NIH study, and most randomized clinical data are limited to industry-sponsored studies of 12- to 16-week duration with extension phases. This disease has a female predominance, with a mean age of diagnosis of 36.4 years. 

Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. Ann Intern Med 2000 132(3) 425-34. 

Barst R, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (Prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996 334(5) 296-301. 

Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005 172 1586-9. 

Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension a randomized trial. Ann Intern Med 2008 149(8) 521-30. 

Epoprostenol is the natural occurring prostacyclin which is formed in vascular endothelial cells. It increases cyclic AMP in the thrombocyte and is a strong platelet aggregation inhibitor. It is used to prevent thrombotic complications during hemodialysis when heparin is contraindicated. As its duration of action is no longer than 30 minutes it has to be given as an intravenous infusion. 

Anticoagulants and continuous intravenous infusion of epoprostenol are the standard treatments for primary pulmonary hypertension. However, their combined use increases the likelihood of hemorrhagic complications, as demonstrated in a retrospective study of 31 consecutive patients with primary pulmonary hypertension (mean age, 29 years, 10 men, 21 women), nine of whom had 11 bleeding episodes nine episodes were cases of alveolar hemorrhage and two patients had severe respiratory distress (9). The mean dose of epoprostenol at the time of the first bleeding episode was 89 ng/kg/minute. More of the patients who had a bleeding episode died (67% versus 41%). 

Prostacyclin lowers peripheral, pulmonary, and coronary resistance. It has been used to treat both primary pulmonary hypertension and secondary pulmonary hypertension, which sometimes occurs after mitral valve surgery. A commercial preparation of prostacyclin (epoprostenol) is approved for treatment of primary pulmonary hypertension, in which it appears to improve symptoms and prolong survival. However, because of its extremely short plasma half-life, the drug must be administered as a continuous intravenous infusion through a central line. Several prostacyclin analogs with longer half-lives have been developed and treprostinil was recently approved for use in pulmonary hypertension (Horn, 2002). This drug is administered by continuous subcutaneous infusion. 

Side effects, such as headache and jaw pain, are observed, but the major drawbacks with epoprostenol therapy relate to its delivery. Epoprostenol has an extremely short half-life in the blood (2-3 min) and therefore must be administered by continuous intravenous infusion via a surgically implanted central vein catheter. This can lead to complications such as local infections, sepsis, or catheter-associated thrombosis. In addition, interruption of therapy due, for example, to pump failure can lead to a life-threatening rebound of symptoms. The compound itself is unstable at room temperature and must be stored in the refrigerator. Despite these severe drawbacks, i.v. epoprosenol remains a useful treatment for patients presenting with WHO class IV PAH. The problems with epoprostenol have led to the development of alternative agents. 

The cyclo-oxygenase metabolite prostacyclin is a potent, short-lived vasodilator and antithrombotic agent. Intravenous administration of the commercially available form of prostacyclin, epoprostenol, relieves the symptoms of primary pulmonary hypertension by dilating the pulmonary vasculature [99]. A stable prostacyclin analogue, iloprost, appears to be similarly effective when administered as an aerosol and obviates the logistical problems associated with maintained intravenous administration [100]. 

Answer A. During fetal development, the ductus arteriosus is kept open by prostaglandins. For temporary maintenance of patency in the infant, the PGEj analog alprostadil is used. Closure of the ductus in the infant can often be accomplished by intravenous indometha-cin, which 4 PG synthesis by inhibiting COX. Epoprostenol is a prostacyclin analog used in primary pulmonary hypertension. 

Limited evidence su ests that the combined use of intravenous high-dose epoprostenol and warfarin may increase the risk of pulmonary haemorrhage. Continuous subcutaneous treprostinil did not alter the pharmacokinetics or the INR in response to singledose warfarin, and also did not appear to increase the risk of bleeding when used with warfarin in clinical studies. Because these prostaglandins inhibit platelet a regation, some caution is appropriate on combined use with anticoagulants. 

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