How It Really Happened-the Development of Inhaled Iloprost for Pulmonary Arterial Hypertension

Horst Olschewski

https://doi.org/10.1002/pul2.70191 

In 1988, I had spent over 2 years at the Physiological Institute, working on the competition between skin- and muscle blood flow for cardiac output in man during exercise, when I started my residency in Internal Medicine. There I met Werner Seeger, who was a consultant and was directing the Intensive Care Unit at that time. He enrolled me in his research group, which focused on acute respiratory stress syndrome (ARDS), a condition characterised by a ventilation-perfusion mismatch that results in competition for blood flow between well- and poorly ventilated lung areas, a topic I had previously explored in my scientific work. Werner's group had established the Multiple Inert Gas Elimination Technique (MIGET) and used it in a rabbit ARDS model regularly [1]. They had also published a clinical ARDS study, comparing the effects of prostacyclin, either applied as an infusion or as inhalation, showing that the inhaled drug was both pulmonary and intrapulmonary selective, which was beneficial for maintaining systemic arterial blood pressure and systemic oxygenation [2].

We hypothesized that pulmonary selectivity would be of utmost importance in severe pulmonary hypertension and published a perspective on this in a German journal. As a response, a PH patient came to us who had already visited many hospitals all over Germany, where she was offered different treatments, reaching from intravenous prostacyclin to heart-lung transplantation—but she had refused all of these options. She was a charming woman in her early 50-ies, running a successful business in the south of Germany, and suffered from the CREST syndrome with very severe Raynaud syndrome and PH with right heart failure, but no lung fibrosis in the high-resolution CT. She was eager to undergo right heart catheterization and try inhaled NO, inhaled prostacyclin, and intravenous prostacyclin to see her individual responses.

After we had received approval from the ethics commission and her written informed consent, I did the right heart catheter in our ICU. Her pulmonary pressure was the highest I had ever seen, cardiac output was poor and during the investigation she had a severe Raynaud attack, up to her elbows. Inhaled NO had impressive pulmonary vasodilative effects and inhaled prostacyclin was even stronger and immediately stopped her Raynaud attack. The duration of the pulmonary hemodynamic effects was only 15 min, but she said this was a great experience. We had to find a pharmacological solution to avoid very frequent inhalations and the risk of a rebound pulmonary hypertensive crisis. Werner figured out that in Germany, a stable prostacyclin analog was available for infusion in Burger's syndrome, a very rare disease of the systemic arteries. The drug came in small ampoules and was manufactured and delivered by Schering, Berlin. We did another right heart catheterization in our patient and noticed hemodynamic effects comparable to inhaled prostacyclin, however, the effect duration was much longer. Our patient said she had not been so well on a single day in the last years and insisted on getting this drug on a regular basis. We provided her with an inhaler and with drug which she diligently used on our ward. We watched her very carefully for any adverse effects, however, she reported only beneficial effects. After an inhalation, the relief of dyspnea and the improvement of skin blood flow had a duration of 3–4 h. Therefore, we advised her to repeat the inhalations every 3 h, resulting in 6 inhalations per day. This regimen caused an impressive clinical recovery with no adverse effects [3]. She also tolerated the night pause very well.

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