The Discovery of Inhaled Prostanoids for Pulmonary Hypertension

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). In contrast, intravenous PGI2 increased shunt flow concomitant with its lung vasodilatory effect (Figure 1b). Beyond these initial measurements, the prostacyclin inhalation was continued over several days in these ARDS patients, adapted to the individual course of the disease. Since then, although never critically evaluated in large-scale randomized clinical trials, inhalation of aerosolized PGI2 has been used in adult and subsequently also in neonatal intensive care medicine, with numerous PubMed-listed publications addressing its efficacy. One of the patients described in this first observation, a 22-year-old man with ARDS due to Candida albicans septicemia, had pre-existing pulmonary hypertension (PH; PVR ~ 770 dyn*sec-1*cm-5), but nevertheless responded with marked PVR reduction to the prostacyclin aerosolization (Figure 1a). This observation prompted the next step in developing prostanoid inhalation for PH. In the same year, 1993, Marliese K., a 56-year-old woman with severe CREST syndrome-associated PH, was referred from Saarland to Berlin for evaluation for heart–lung transplantation, which ultimately was not carried out. However, the colleagues in Berlin told her about our experience with the one ARDS/PH patient, and she took her own initiative to be transported in a bedridden state to our center, immediately confronting us with her wish “to try whatever we can, as she is close to dying.” Indeed, she was obviously in a low cardiac output state due to a failing right heart, with prominent jugular veins and severe peripheral edema. Though not approved and based only on very limited experimental experience, our group, then also including Horst Olschewski from the PH team and Thomas Schmehl and Tobias Gessler as aerosol experts, decided to construct a jet nebulizer-based device (Figure 2b) and employ iloprost, which was marketed in Germany as Ilomedin® for intravenous infusion in Winiwarter-Buerger disease (Thromboangiitis obliterans), for aerosolization, due to its substantially longer half-life compared to PGI2. We chose a nebulized dose of 17 μg iloprost (assumed inhaled dose of 3–5 μg) as a “best guess,” and the hemodynamic response to this first iloprost inhalation ever is given in Figure 2a/left, taken from the original publication [2]: the mean pulmonary artery pressure dropped from 75 mmHg to a minimum of 50 mmHg, the cardiac output increased from 2.7 L/min to a maximum of 4.5 L/min, and venous congestion and thoracic oppression of the patient immediately improved. As all effects leveled off within 90 min, we decided to start immediately a regimen with 6 inhalations distributed over the day, with the subsequent 1-year period under this regimen shown in Figure 2a/right. This observation encouraged our aerosol group in Giessen to get engaged in the construction of advanced nebulizer devices over the subsequent years. Naturally, this knowledge spread rapidly among PH patients in Germany, where outpatient continuous PGI2 infusion was not available at that time, with further patients starting this regimen, including Bruno Kopp, who was diagnosed with familial pulmonary arterial hypertension and based on his personal experience founded ph e.V., the German PH patient organization. The presentation of these findings, along with some persuasion, encouraged Schering AG, the company marketing Ilomedin, to start a standard drug approval process, including inhalation toxicology studies, with Sylvia Nikkho playing a crucial role in these efforts. A positive phase III trial, published in the NEJM 2002 [3], finally paved the way for worldwide approval of inhaled iloprost for group 1 PH. Further studies extended this approach to show additive efficacy when combining inhaled iloprost with phosphodiesterase inhibitors [4, 5] and to demonstrate pulmonary vasodilatory potency also in ILD-associated PH with largely maintained gas exchange [6]. Moreover, when first employing inhaled treprostinil for aerosolization in PH, we noticed comparable efficacy but pharmacokinetic and dose-response differences [7], with the optimized regimen then entered into an international randomized controlled phase III trial [8] as basis of the FDA approval of inhaled treprostinil for PH. Marliese K, the first patient ever to inhale iloprost, recovered impressively, returning to a normal daily routine, and lived for another 10 years under this regimen, later complemented by sildenafil and bosentan when these agents became available. Her bravery in fighting the disease inspired us to dare new ways, opened novel treatment options for a multitude of PH patients, and gave birth to the Giessen PH center. The author has nothing to report. The author received no specific funding for this work. The author has nothing to report. The author declares no conflicts of interest.