Trial of Inhaled Alprostadil to Improve Hypoxia and Pulmonary Hypertension

Introduction:

Pulmonary hypertension, defined as mean PA (pulmonary arterial) pressure of > 25 mm Hg, is an end point of a variety of conditions. These include primary pulmonary hypertension, post-operative pulmonary hypertension and as a result of increased pulmonary vascular resistance that occurs in ARDS. This is an entity distinguished by hypoxemia, non-cardiogenic pulmonary edema and bilateral infiltrates on chest X-ray. Prostacyclin (PGE1), an arachidonic acid metabolite, or its stable analogue, iloprost, has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in reducing intra-pulmonary shunting in ARDS. While the intravenous application of iloprost can cause a decrease not only of the pulmonary but also of the systemic vascular tone, the aerosolized prostacyclin can result in a selective pulmonary vasodilatation without affecting the systemic blood pressure as demonstrated in preliminary studies/reports. Furthermore, aerosolized iloprost can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilation/perfusion ratio as it occurs in ARDS, due to the redistribution of pulmonary blood flow from non-ventilated to ventilated, aerosol accessible lung regions.

Previous case reports and non-randomized studies have indicated that inhalation of aerosolized iloprost may offer a new life saving strategy in intractable pulmonary hypertension and ARDS. Further, advantages of inhaled iloprost include the lack of adverse reactions and toxic side effects as well as convenient and more cost-effective administration. Other available therapies like nitric oxide inhalation costs more, around Rs 350/liter and a total of 34-45 liters per patient is required. It is also associated with additional side effects, such as thrombocytopenia. Due to the irreversible nature of ARDS associated with high rate of mortality also affecting resource allocation in critically ill patients, we suggest carrying out this study in our intensive care unit (ICU), where the incidence is > 10% resulting in almost 90% mortality (ICU Quality Indicators Jan-Apr 20048). Iloprost is completely metabolized and excretion of metabolites is primarily via the kidneys; the elimination half-life is 30 minutes. Inhalation therapy reduces systemic absorption and hence elimination half-life.

In a previous study, aerosolized iloprost was found effective in improving the functional class of the patient, exercise capacity and improved shunting. However, large randomized trials are needed to prove the efficacy of this cost effective therapy in patients with pulmonary hypertension and ARDS.

Objectives: