The Discovery of Inhaled Prostanoids for Pulmonary Hypertension

Werner Seeger
https://doi.org/10.1002/pul2.70192 

The establishment of the pulmonary hypertension center in Giessen, initiated in the late 1980s and further developed over the following decades by the founding team of Friedrich Grimminger, Ardeschir Ghofrani, Ralph Schermuly, and myself, has its roots in research projects on acute lung injury, ARDS. Employing the multiple gas elimination technique (MIGET), we observed severe ventilation/perfusion (V/Q) mismatch with high shunt in the ARDS lungs, accompanied by elevated pulmonary artery pressure levels. Applying systemic (intravenous) vasodilators to lower lung (micro)vascular perfusion pressures and right ventricular afterload and counteract overwhelming lung edema formation disadvantageously worsened V/Q mismatch and increased shunt flow in these severely injured lungs, most likely by interfering with hypoxic pulmonary vasoconstriction in the edema-filled regions. However, anatomical textbooks and experimental studies in our own labs had already taught us that the relevant precapillary lung vascular resistance segments are embedded within the terminal acinar structures of the lung, making them, in principle, accessible to vasoactive agents delivered via the airways to the alveolar space. We reasoned that such an approach might serve to achieve preferred pulmonary over systemic vasodilation, important for many intensive care conditions, and might enable what we called “intrapulmonary selectivity”: drug deposition in, and thus redistribution of blood flow to, well- or better-ventilated regions instead of shunt areas. To achieve this goal, our team, then also including Dieter Walmrath, focused on the aerosolization of prostacyclin (PGI2), an agent with already at that time well-known safety profile and short half-life, thus particularly suitable for intensive care conditions. The first three patients ever receiving aerosolized prostacyclin to impact the alveolar/vascular compartment of the lung were published in The Lancet, 1993 [1]. As evident from Figure 1a, taken from this publication, inhaled aerosolized PGI2 reduced pulmonary artery pressure in all ARDS patients while maintaining systemic arterial pressure and improving arterial oxygenation (paO2/FiO2) mostly by reducing shunt flow (MIGET measurements).

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