Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial

Matthieu Legrand^{1

2}, Edouard Jullien³, Antoine Kimmoun^{2

4}, Guillaume Geri⁵, Hafid Ait-Oufella⁶, Stanislas Abrard⁷, Samuel Gaugain⁸, Fanny Bounes⁹, Philippe Guerci^{2

10

11}, Julien Pottecher¹², Matthieu Jamme¹³, Yves Poncelin de Raucourt¹⁴, Damien Barraud¹⁵, Jean-Michel Constantin¹⁶, William Juguet¹⁷, Sigismond Lasocki¹⁸, Romain Sonneville^{19

20}, Juliette Audibert²¹, Gaëtan Plantefève²², Olivier Ellrodt²³, Anne-Laure Fedou²⁴, Marc Leone²⁵, Laurent Lefebvre²⁶, Adrien Auvet²⁷, David Chen¹, Eric Vicaut^{2

28}, François Dépret^{2

29}; I-MICRO Trial Investigators

Collaborators, Affiliations

Collaborators

I-MICRO Trial Investigators:
Alexandre Fratani, Maïté Chaussard, Quentin Ressaire, Emmanuel Dudoignon, Maxime Coutrot, Benjamin Deniau, Louis Boutin, Alexandru Cupaciu, Lucie Guillemet, Alexandre Pharaboz, Badr Louadah, Fariza Abeud, Marie-Céline Fournier, Tomas Urbina, Bruno Levy, Matthieu Mattei, Pierre Perez, Thomas Klein, Carine Thivilier, Matthieu Koszutski, Charlotte Arbelot, Benjamin Huot, Magalie Collet, Benjamin Soyer, Romain Barthelemy, Benjamin Chousterman, Manuel Kindermans, Nathan Julian, Stéphane Hecketsweiler, Julien Pottecher, Paul Henri Wicky, Lucie Le Fevre, Jean-François Timsit, Lila Bouadma, Etienne De Montmollin, Thomas Rimmele, Antoine Vieillard-Barron, Matthieu Petit, Romain Jouffroy, Mona Assefi, Alexy Tran-Dinh, Vincent Labbe, Olivier Pajot, Damien Contou, Amélie Chenal, Thomas Daix, Arnaud Desachy, Bruno Evrard, Bruno Francois, Marine Goudelin, Guillaume Gilbert, Olivier Platecker, Florence Sanchez, Amandine Sanson, Julien Vaidie, Philippe Vignon, Rostane Gaci, Stéphane Gaudry, Merhan Monchi, Nicholas Sedillot, Abdelkader Ouchenir, Emmanuel Novy, Mathieu Esposito, Maeva Campfort, Soizic Gergau, Matthieu Legrand, François Dépret, Eric Vicaut, Elodie Lemadre, Daniel De Backer, Bruno Levy, Marc Leone, Jacques Duranteau, Hafid Ait Oufella, Atul Pathak, Etienne Gayat, Olivier Sitbon

Affiliations

¹ Division of Critical Care Medicine, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California.
² French Clinical Research Infrastructure Network Initiative-Cardio Renal Clinical Trialists Network, Nancy, France.
³ Intensive Care Unit, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Versailles Saint-Quentin-en-Yvelines University, Paris, France.
⁴ Intensive Care Unit Brabois, Institut National de la Santé et de la Recherche Médicale U1116, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Lorraine University, Nancy University Hospital, Nancy, France.
⁵ Intensive Care Unit, Private Hospital Ambroise Paré Hartmann, Neuilly-sur-Seine, France.
⁶ Intensive Care Unit, Saint-Antoine University Hospital, and.
⁷ Department of Anesthesiology and Critical Care Medicine, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.
⁸ Department of Anesthesia and Critical Care, Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Paris, France.
⁹ Intensive Care Unit, Rangueil University Hospital, Toulouse, France.
¹⁰ Department of Anesthesiology and Critical Care Medicine, University Hospital of Nancy, Hôpitaux de Brabois, Vandœuvre-lès-Nancy, France.
¹¹ Institut National de la Santé et de la Recherche Médicale U1116, Acute and Chronic Circulatory Failure Unit, University of Lorraine, Nancy, France.
¹² Anesthesiology, Critical Care and Perioperative Medicine, Strasbourg University Hospital, Strasbourg, France.
¹³ Intensive Care Unit, Ouest Parisien Private Hospital, Ramsay Générale de Santé, Trappes, France.
¹⁴ Intensive Care Unit, Bourg-en-Bresse Hospital, Bourg-en-Bresse, France.
¹⁵ Intensive Care Unit, Mercy Hospital, Metz-Thionville Hospital, Metz, France.
¹⁶ Department of Anesthesia and Critical Care, La Pitié-Salpétrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
¹⁷ Intensive Care Unit, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny University, Paris, France.
¹⁸ Department of Anesthesia and Critical Care, Angers University Hospital, Angers, France.
¹⁹ Paris Cité University, Institut National de laSante et de la Recherche Medicale U1137, Paris, France.
²⁰ Intensive Care Medicine, Assistance Publique -Hôpitaux de Paris, Nord, Bichat - Claude Bernard Hospital, Paris, France.
²¹ Intensive Care Unit, Chartres Hospital, Chartres, France.
²² Intensive Care Unit, Argenteuil Hospital, Argenteuil, France.
²³ Intensive Care Unit, Melun Hospital, Melun, France.
²⁴ Intensive Care Unit, Dupuytren University Hospital, Limoges, France.
²⁵ Department of Anesthesia and Critical Care, Hospital Nord, Marseille, France.
²⁶ Intensive Care Unit, Centre Hospitalier Intercommunal Aix-Pertuis, Aix-en-Provence, France.
²⁷ Intensive Care Unit, Dax Hospital, Dax, France.
²⁸ Clinical Research Unit, Assistance Publique-Hôpitaux de Paris, Fernand-Widal Hospital, Paris, France; and.
²⁹ Anesthesiology, Critical Care and Burn Unit, Institut National de la Santé et de la Recherche Médicale U942, Assistance Publique-Hôpitaux de Paris, Paris University, Saint-Louis University Hospital, Paris, France.

PMID: 40387381
PMCID: PMC12264687 (available on 2026-07-01)
DOI: 10.1164/rccm.202410-1924OC

Clinical Trial

Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial

Matthieu Legrand et al. Am J Respir Crit Care Med. 2025 Jul.

. 2025 Jul;211(7):1211-1219.

doi: 10.1164/rccm.202410-1924OC.

Authors

Collaborators

I-MICRO Trial Investigators:
Alexandre Fratani, Maïté Chaussard, Quentin Ressaire, Emmanuel Dudoignon, Maxime Coutrot, Benjamin Deniau, Louis Boutin, Alexandru Cupaciu, Lucie Guillemet, Alexandre Pharaboz, Badr Louadah, Fariza Abeud, Marie-Céline Fournier, Tomas Urbina, Bruno Levy, Matthieu Mattei, Pierre Perez, Thomas Klein, Carine Thivilier, Matthieu Koszutski, Charlotte Arbelot, Benjamin Huot, Magalie Collet, Benjamin Soyer, Romain Barthelemy, Benjamin Chousterman, Manuel Kindermans, Nathan Julian, Stéphane Hecketsweiler, Julien Pottecher, Paul Henri Wicky, Lucie Le Fevre, Jean-François Timsit, Lila Bouadma, Etienne De Montmollin, Thomas Rimmele, Antoine Vieillard-Barron, Matthieu Petit, Romain Jouffroy, Mona Assefi, Alexy Tran-Dinh, Vincent Labbe, Olivier Pajot, Damien Contou, Amélie Chenal, Thomas Daix, Arnaud Desachy, Bruno Evrard, Bruno Francois, Marine Goudelin, Guillaume Gilbert, Olivier Platecker, Florence Sanchez, Amandine Sanson, Julien Vaidie, Philippe Vignon, Rostane Gaci, Stéphane Gaudry, Merhan Monchi, Nicholas Sedillot, Abdelkader Ouchenir, Emmanuel Novy, Mathieu Esposito, Maeva Campfort, Soizic Gergau, Matthieu Legrand, François Dépret, Eric Vicaut, Elodie Lemadre, Daniel De Backer, Bruno Levy, Marc Leone, Jacques Duranteau, Hafid Ait Oufella, Atul Pathak, Etienne Gayat, Olivier Sitbon

Affiliations

¹ Division of Critical Care Medicine, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California.
² French Clinical Research Infrastructure Network Initiative-Cardio Renal Clinical Trialists Network, Nancy, France.
³ Intensive Care Unit, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Versailles Saint-Quentin-en-Yvelines University, Paris, France.
⁴ Intensive Care Unit Brabois, Institut National de la Santé et de la Recherche Médicale U1116, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Lorraine University, Nancy University Hospital, Nancy, France.
⁵ Intensive Care Unit, Private Hospital Ambroise Paré Hartmann, Neuilly-sur-Seine, France.
⁶ Intensive Care Unit, Saint-Antoine University Hospital, and.
⁷ Department of Anesthesiology and Critical Care Medicine, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France.
⁸ Department of Anesthesia and Critical Care, Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Paris, France.
⁹ Intensive Care Unit, Rangueil University Hospital, Toulouse, France.
¹⁰ Department of Anesthesiology and Critical Care Medicine, University Hospital of Nancy, Hôpitaux de Brabois, Vandœuvre-lès-Nancy, France.
¹¹ Institut National de la Santé et de la Recherche Médicale U1116, Acute and Chronic Circulatory Failure Unit, University of Lorraine, Nancy, France.
¹² Anesthesiology, Critical Care and Perioperative Medicine, Strasbourg University Hospital, Strasbourg, France.
¹³ Intensive Care Unit, Ouest Parisien Private Hospital, Ramsay Générale de Santé, Trappes, France.
¹⁴ Intensive Care Unit, Bourg-en-Bresse Hospital, Bourg-en-Bresse, France.
¹⁵ Intensive Care Unit, Mercy Hospital, Metz-Thionville Hospital, Metz, France.
¹⁶ Department of Anesthesia and Critical Care, La Pitié-Salpétrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris, France.
¹⁷ Intensive Care Unit, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, Bobigny University, Paris, France.
¹⁸ Department of Anesthesia and Critical Care, Angers University Hospital, Angers, France.
¹⁹ Paris Cité University, Institut National de laSante et de la Recherche Medicale U1137, Paris, France.
²⁰ Intensive Care Medicine, Assistance Publique -Hôpitaux de Paris, Nord, Bichat - Claude Bernard Hospital, Paris, France.
²¹ Intensive Care Unit, Chartres Hospital, Chartres, France.
²² Intensive Care Unit, Argenteuil Hospital, Argenteuil, France.
²³ Intensive Care Unit, Melun Hospital, Melun, France.
²⁴ Intensive Care Unit, Dupuytren University Hospital, Limoges, France.
²⁵ Department of Anesthesia and Critical Care, Hospital Nord, Marseille, France.
²⁶ Intensive Care Unit, Centre Hospitalier Intercommunal Aix-Pertuis, Aix-en-Provence, France.
²⁷ Intensive Care Unit, Dax Hospital, Dax, France.
²⁸ Clinical Research Unit, Assistance Publique-Hôpitaux de Paris, Fernand-Widal Hospital, Paris, France; and.
²⁹ Anesthesiology, Critical Care and Burn Unit, Institut National de la Santé et de la Recherche Médicale U942, Assistance Publique-Hôpitaux de Paris, Paris University, Saint-Louis University Hospital, Paris, France.

PMID: 40387381
PMCID: PMC12264687 (available on 2026-07-01)
DOI: 10.1164/rccm.202410-1924OC

Abstract

Rationale: Preclinical and preliminary clinical data suggest that iloprost may improve tissue perfusion in septic shock. However, its effect on organ failure remains unclear. Objectives: To investigate whether iloprost provides organ protection in septic shock with hypoperfusion. Methods: In this multicenter, double-blind, randomized controlled trial, adults with septic shock and persistent hypoperfusion (i.e., increased capillary refill time and/or skin mottling) were randomized to receive a 48-hour intravenous infusion of iloprost or placebo. The primary outcome was the change in the Sequential Organ Failure Assessment (SOFA) score from randomization to Day 7. Secondary outcomes included mortality at Day 28, organ support-free days by Day 28, and mean daily SOFA score. Measurements and Main Results: A total of 240 patients were randomized, and 236 were included in the analysis. Median (IQR) changes in SOFA score were -4 (-7 to 7) in the iloprost group and -5 (-8 to 5) in the placebo group (median difference, 1; 95% CI, 0-3; P = 0.12). At 28 days, 48 patients (42%) had died in the iloprost group and 47 (39%) had died in the placebo group (relative risk, 1.08; 95% CI, 0.80-1.5). The median average SOFA score was 11.2 (7.4-15.9) in the iloprost group, compared with 10.5 (6.8-16.5) in the placebo group (median difference, 0.25; 95% CI, -1.1 to 1.8). Median (95% confidence interval) between-group differences in 28-day ventilation-, vasopressor-, and renal replacement therapy-free survival days were 0 (0-0), 0 (-1 to 1), and 0 (0-0), respectively. Severe adverse events occurred in 15% of patients in the iloprost group and 7% of patients in the placebo group (P = 0.06). Conclusions: Among patients with septic shock and persistent hypoperfusion, iloprost did not reduce the severity of organ failure. Clinical trial registered with www.clinicaltrials.gov (NCT03788837) and EudraCT (2018-001709-10).

Keywords: microcirculation; organ failure; prostacyclin; sepsis.

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Comment in

Prostacyclin for Patients with Septic Shock: Promise, Progress, and Perspective.
Perner A, Stensballe J. Perner A, et al. Am J Respir Crit Care Med. 2025 Jul;211(7):1116-1117. doi: 10.1164/rccm.202504-0957ED. Am J Respir Crit Care Med. 2025. PMID: 40439511 Free PMC article. No abstract available.

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Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial

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Iloprost for the Treatment of Severe Septic Shock with Persistent Hypoperfusion: A Double-Blind, Randomized Controlled Trial

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