Effect of iloprost inhalation on postoperative outcome in high-risk cardiac surgical patients: a prospective randomized-controlled multicentre trial (ILOCARD)

  • Michael Winterhalter
  • Steffen RexEmail author
  • Christian Stoppe
  • Peter Kienbaum
  • Hans-Helge Müller
  • Ines Kaufmann
  • Hermann Kuppe
  • Aristidis Dongas
  • Bernhard Zwissler
  • ILOCARD Investigators
Reports of Original Investigations



Perioperative right ventricular (RV) failure due to pressure overload from pulmonary hypertension (PH) worsens postoperative outcomes after cardiac surgery. Inhaled iloprost is a potent pulmonary vasodilator improving RV performance, ameliorating myocardial and pulmonary ischemia-reperfusion injury and attenuating inflammation. We hypothesized that the prophylactic inhalation of iloprost would reduce postoperative ventilation times after cardiac surgery.


In this phase III, multicentre, randomized, double-blind, placebo-controlled trial, we randomly assigned 253 cardiac surgical patients at high risk of perioperative RV failure to the prophylactic inhalation of 20 µg iloprost or placebo before and during weaning from extracorporeal circulation. The primary endpoint was the duration of postoperative ventilation. Secondary endpoints included perioperative hemodynamics, intensive care unit and hospital length of stay, and 90-day mortality. Safety was assessed by the incidence of adverse events.


Iloprost had no significant effect on the median [interquartile range] duration of postoperative ventilation compared with placebo (720 [470–1170] min vs 778 [541–1219] min, respectively; median decrease, 65 min; 95% confidence interval [CI], − 77 to 210; P = 0.37). While the nebulization of iloprost decreased RV afterload and improved cardiac index, major secondary endpoints were not significantly affected. Ninety-day mortality occurred in 14% of the iloprost patients compared with 14% of the placebo patients (hazard ratio, 0.97; 95% CI, 0.50 to 1.89; P = 0.93). The incidence of adverse events was comparable in both groups.


The prophylactic inhalation of iloprost did not meaningfully improve the outcome in high-risk cardiac surgical patients.

Trial registration (NCT00927654); registered 25 June, 2009.

Effet de l’inhalation d’iloprost sur le pronostic postopératoire chez les patients chirurgicaux cardiaques à haut risque : une étude multicentrique randomisée et prospective (ILOCARD)



L’insuffisance cardiaque droite périopératoire due à une surcharge de pression provoquée par l’hypertension pulmonaire (HP) a un impact négatif sur le pronostic postopératoire après une chirurgie cardiaque. L’iloprost administré par inhalation est un vasodilatateur pulmonaire puissant qui améliore la performance du ventricule droit (VD), réduisant ainsi la lésion d’ischémie-reperfusion myocardique et pulmonaire et atténuant l’inflammation. Nous avons émis l’hypothèse qu’une inhalation prophylactique d’iloprost réduirait les temps de ventilation postopératoire après une chirurgie cardiaque.


Dans cette étude multicentrique de phase III, contrôlée par placebo, à double insu et randomisée, nous avons distribué aléatoirement 253 patients chirurgicaux courant un risque élevé d’insuffisance cardiaque droite périopératoire à une prophylaxie de 20 µg d’iloprost ou d’un placebo par inhalation avant et pendant le sevrage de la circulation extracorporelle. Le critère d’évaluation principal était la durée de ventilation postopératoire. Les critères d’évaluation secondaires étaient les données hémodynamiques périopératoires, la durée de séjour à l’unité de soins intensifs et à l’hôpital, et la mortalité à 90 jours. L’innocuité a été évaluée en fonction de l’incidence d’événements indésirables.


L’iloprost n’a pas eu d’effet significatif sur la durée médiane [écart interquartile] de ventilation postopératoire par rapport au placebo (720 [470–1170] min vs 778 [541–1219] min, respectivement; réduction médiane, 65 min; intervalle de confiance [IC] 95 %, − 77 à 210; P = 0,37). Bien que la nébulisation d’iloprost ait réduit la post-charge du VD et amélioré l’index cardiaque, cette manœuvre n’a pas eu d’impact significatif sur les critères d’évaluation secondaires majeurs. Une mortalité à 90 jours a été observée chez 14 % des patients ayant reçu de l’iloprost, comparativement à 14 % des patients ayant reçu un placebo (rapport de risque, 0,97; IC 95 %, 0,50 à 1,89; P = 0,93). L’incidence d’événements indésirables était comparable dans les deux groupes.


L’inhalation prophylactique d’iloprost n’a pas amélioré le pronostic des patients de chirurgie cardiaque à haut risque.

Enregistrement de l’étude (NCT00927654); enregistrée le 25 juin 2009.



The authors are indebted to Dr. rer. nat. Marion Seybold (Medical & Management Services, Biburger Weg 6, 82205 Gilching, Germany) for her substantial work as a clinical research associate on this study.

Conflicts of interest

Dr. Winterhalter: No conflicts of interest to declare; Dr. Rex has been consulting for Paion and Vifor and has received travel support and speaking honoraria from AirLiquide, B Braun, Bayer HealthCare, Biosyn, Edwards Lifesciences, Nordic Pharma, Orion Pharma, Schering, and Prostrakran. Dr. Rex has received a research grant from AirLiquide, Nordic Pharma, and Biosyn. Dr. Kienbaum has been consulting for Baxter and AirLiquide and received speaking honoraria from Orion Pharma. Dr. Kienbaum received a research grant from AirLiquide. Dr. Zwissler: No conflicts of interest to declare. Dr. Müller: No conflicts of interest to declare. Dr. Dongas: No conflicts of interest to declare. Dr. Kaufmann: No conflicts of interest to declare. Dr. Stoppe has received travel fees and speaking honoraria from Biosyn.

Editorial responsibility

This submission was handled by Dr. Hilary P. Grocott, Editor-in-Chief, Canadian Journal of Anesthesia.

Author contributions

Michael Winterhalter and Steffen Rex helped conceive, design and conduct the study, acquired and coordinated the data, contributed to the statistical analysis, interpreted the data, and wrote and revised the manuscript. Christian Stoppe helped conduct the study, acquired and interpreted the data, and wrote and revised the manuscript. Peter Kienbaum helped conceive, design and conduct the study, acquired the data, and wrote and revised the manuscript. Hans-Helge Müller helped conceive and design the study, contributed to the statistical analysis, coordinated and interpreted the data, and wrote and revised the manuscript. Ines Kaufmann helped conduct the study, acquired and interpreted the data, and wrote and revised the manuscript. Herrmann Kuppe and Aristidis Dongas helped conceive, design and conduct the study, acquired and interpreted the data, and wrote and revised the manuscript. Bernhard Zwissler helped conceive, design and conduct the study, acquired and coordinated the data, contributed to the statistical analysis, interpreted the data, and wrote and revised the manuscript.

Sources of Funding

This investigator-initiated trial was supported by Bayer Vital GmbH, Leverkusen, Germany (financial support and provision of the study medication; by Inspiration Medical, Bochum, Germany, and by Aerogen Ltd, Galway, Ireland (provision of nebulizers). Bayer Vital had no role in the design of the study, data collection and analysis, or the preparation of the manuscript. The company also had no responsibility for the conduct of the trial, had no access to the data, and did not control the decision to publish the results.

Supplementary material

12630_2019_1309_MOESM1_ESM.pdf (158 kb)
Supplementary material 1 (PDF 157 kb)


  1. 1.
    Winterhalter M, Rex S, Stoppe C, et al. The clinical significance of intraoperative iloprost inhalation on outcome of high risk cardiac surgical patients: a multicenter randomized-controlled trial. Circulation 2016; 134: A13135.Google Scholar
  2. 2.
    Millar JE, Fanning JP, McDonald CI, McAuley DF, Fraser JF. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Crit Care 2016; 20: 387.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Humbert M, Lau EM, Montani D, Jais X, Sitbon O, Simonneau G. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014; 130: 2189-208.CrossRefPubMedGoogle Scholar
  4. 4.
    Dorman BH, Bond BR, Clair MJ, et al. Temporal synthesis and release of endothelin within the systemic and myocardial circulation during and after cardiopulmonary bypass: relation to postoperative recovery. J Cardiothorac Vasc Anesth 2000; 14: 540-5.CrossRefPubMedGoogle Scholar
  5. 5.
    Tornberg DC, Angdin M, Settergen G, Liska J, Lundberg JO, Weitzberg E. Exhaled nitric oxide before and after cardiac surgery with cardiopulmonary bypass–response to acetylcholine and nitroglycerin. Br J Anaesth 2005; 94: 174-80.CrossRefPubMedGoogle Scholar
  6. 6.
    Denault AY, Pearl RG, Michler RE, et al. Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial. J Cardiothorac Vasc Anesth 2013; 27: 1212-7.CrossRefPubMedGoogle Scholar
  7. 7.
    Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000-patient database. J Heart Lung Transplant 2014; 33: 555-64.CrossRefPubMedGoogle Scholar
  8. 8.
    Denault AY, Bussières JS, Arellano R, et al. A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients. Can J Anesth 2016; 63: 1140-53.CrossRefPubMedGoogle Scholar
  9. 9.
    Rex S, Schaelte G, Metzelder S, et al. Inhaled iloprost to control pulmonary artery hypertension in patients undergoing mitral valve surgery: a prospective, randomized-controlled trial. Acta Anaesthesiol Scand 2007; 52: 65-72.CrossRefPubMedGoogle Scholar
  10. 10.
    Rex S, Devroe S. Anesthesia for pregnant women with pulmonary hypertension. Curr Opin Anaesthesiol 2016; 29: 273-81.CrossRefPubMedGoogle Scholar
  11. 11.
    Harjola VP, Mebazaa A, Čelutkienė J, et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18: 226-41.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Elmi-Sarabi M, Deschamps A, Delisle S, et al. Aerosolized vasodilators for the treatment of pulmonary hypertension in cardiac surgical patients: a systematic review and meta-analysis. Anesth Analg 2017; 125: 393-402.CrossRefGoogle Scholar
  13. 13.
    Rex S, Busch T, Vettelschoss M, de Rossi L, Rossaint R, Buhre W. Intraoperative management of severe pulmonary hypertension during cardiac surgery with inhaled iloprost. Anesthesiology 2003; 99: 745-7.CrossRefPubMedGoogle Scholar
  14. 14.
    Winterhalter M, Simon A, Fischer S, et al. Comparison of inhaled iloprost and nitric oxide in patients with pulmonary hypertension during weaning from cardiopulmonary bypass in cardiac surgery: a prospective randomized trial. J Cardiothorac Vasc Anesth 2008; 22: 406-13.CrossRefPubMedGoogle Scholar
  15. 15.
    Hoeper MM, Olschewski H, Ghofrani HA, et al. A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol 2000; 35: 176-82.Google Scholar
  16. 16.
    Kisch-Wedel H, Kemming G, Meisner F, et al. The prostaglandins epoprostenol and iloprost increase left ventricular contractility in vivo. Intensive Care Med 2003; 29: 1574-83.CrossRefPubMedGoogle Scholar
  17. 17.
    Rex S, Missant C, Claus P, Buhre W, Wouters PF. Effects of inhaled iloprost on right ventricular contractility, right ventriculo-vascular coupling and ventricular interdependence: a randomized placebo-controlled trial in an experimental model of acute pulmonary hypertension. Crit Care 2008; 12: R113.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rex S, Missant C, Segers P, Rossaint R, Wouters PF. Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility. Intensive Care Med 2008; 34: 179-89.CrossRefPubMedGoogle Scholar
  19. 19.
    Zardi EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sepsis: a systematic review. Prostaglandins Other Lipid Mediat 2007; 83: 1-24.CrossRefPubMedGoogle Scholar
  20. 20.
    Xiao CY, Hara A, Yuhki K, et al. Roles of prostaglandin I(2) and thromboxane A(2) in cardiac ischemia-reperfusion injury: a study using mice lacking their respective receptors. Circulation 2001; 104: 2210-5.CrossRefPubMedGoogle Scholar
  21. 21.
    Searcy RJ, Morales JR, Ferreira JA, Johnson DW. The role of inhaled prostacyclin in treating acute respiratory distress syndrome. Ther Adv Respir Dis 2015; 9: 302-12.CrossRefPubMedGoogle Scholar
  22. 22.
    Wittwer T, Franke UF, Ochs M, et al. Inhalative pre-treatment of donor lungs using the aerosolized prostacyclin analog iloprost ameliorates reperfusion injury. J Heart Lung Transplant 2005; 24: 1673-9.CrossRefPubMedGoogle Scholar
  23. 23.
    Wilkens H, Bauer M, Forestier N, et al. Influence of inhaled iloprost on transpulmonary gradient of big endothelin in patients with pulmonary hypertension. Circulation 2003; 107: 1509-13.CrossRefPubMedGoogle Scholar
  24. 24.
    Lessiani G, Vazzana N, Cuccurullo C, et al. Inflammation, oxidative stress and platelet activation in aspirin-treated critical limb ischaemia: beneficial effects of iloprost. Thromb Haemost 2011; 105: 321-8.CrossRefPubMedGoogle Scholar
  25. 25.
    Melby SJ, Moon MR, Lindman BR, Bailey MS, Hill LL, Damiano RJ Jr. Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis. J Thorac Cardiovasc Surg 2011; 141: 1424-30.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Lo C, Murphy D, Summerhayes R, et al. Right ventricular failure after implantation of continuous flow left ventricular assist device: analysis of predictors and outcomes. Clin Transplant 2015; 29: 763-70.CrossRefPubMedGoogle Scholar
  27. 27.
    Sharma V, Rao V, Manlhiot C, Boruvka A, Fremes S, Wasowicz M. A derived and validated score to predict prolonged mechanical ventilation in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 2017; 153: 108-15.CrossRefPubMedGoogle Scholar
  28. 28.
    Rady MY, Ryan T. Perioperative predictors of extubation failure and the effect on clinical outcome after cardiac surgery. Crit Care Med 1999; 27: 340-7.CrossRefPubMedGoogle Scholar
  29. 29.
    Lassnigg A, Hiesmayr MJ, Bauer P, Haisjackl M; Workgroup on Postoperative Intensive Care of the European Society of Intensive Care Medicine; European Workgroup of Cardiothoracic Intensivists. Effect of centre-, patient- and procedure-related factors on intensive care resource utilisation after cardiac surgery. Intensive Care Med 2002; 28: 1453-61.Google Scholar
  30. 30.
    Olschewski H, Simonneau G, Galiè N, et al.; Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-9.Google Scholar
  31. 31.
    Gavra P, Nguyen AQ, Beauregard N, Denault AY, Varin F. High-performance liquid chromatography assay using ultraviolet detection for urinary quantification of milrinone concentrations in cardiac surgery patients undergoing cardiopulmonary bypass. Biomed Chromatogr 2014; 28: 1084-9.CrossRefPubMedGoogle Scholar
  32. 32.
    Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension. Chest 2003; 124: 1294-304.CrossRefGoogle Scholar
  33. 33.
    Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 1994; 90: 2780-5.CrossRefPubMedGoogle Scholar
  34. 34.
    Grossman NL, Fiack CA, Weinberg JM, Rybin DV, Farber HW. Pulmonary hypertension associated with heart failure with preserved ejection fraction: acute hemodynamic effects of inhaled iloprost. Pulm Circ 2015; 5: 198-203.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lowson SM. Inhaled alternatives to nitric oxide. Crit Care Med 2005; 33: S188-95.CrossRefPubMedGoogle Scholar
  36. 36.
    Radomski MW, Palmer RM, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. Br J Pharmacol 1987; 92: 639-46.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Palatianos G, Michalis A, Alivizatos P, et al. Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin-induced thrombocytopenia-reactive antibodies or with true HIT (HIT reactive antibodies plus thrombocytopenia): an 11-year experience. Am J Hematol 2015; 90: 608-17.CrossRefPubMedGoogle Scholar
  38. 38.
    Haraldsson A, Kieler-Jensen N, Wadenvik H, Ricksten SE. Inhaled prostacyclin and platelet function after cardiac surgery and cardiopulmonary bypass. Intensive Care Med 2000; 26: 188-94.CrossRefPubMedGoogle Scholar
  39. 39.
    Haché M, Denault A, Bélisle S, et al. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc Surg 2003; 125: 642-9.CrossRefPubMedGoogle Scholar

Copyright information

© Canadian Anesthesiologists' Society 2019

Authors and Affiliations

  • Michael Winterhalter
    • 1
    • 2
  • Steffen Rex
    • 3
    • 4
    Email author
  • Christian Stoppe
    • 4
  • Peter Kienbaum
    • 2
  • Hans-Helge Müller
    • 5
    • 6
  • Ines Kaufmann
    • 7
    • 8
  • Hermann Kuppe
    • 9
  • Aristidis Dongas
    • 10
    • 11
  • Bernhard Zwissler
    • 7
  • ILOCARD Investigators
  1. 1.Klinik für Anästhesiologie und Schmerztherapie, Klinikum Bremen-Mitte gGmbHBremenGermany
  2. 2.Klinik für AnästhesiologieUniversitätsklinikum DüsseldorfDüsseldorfGermany
  3. 3.Department of Anesthesiology & Department of Cardiovascular SciencesUniversity Hospitals Leuven, KU LeuvenLeuvenBelgium
  4. 4.Klinik für AnästhesiologieUniversitätsklinikum der RWTH AachenAachenGermany
  5. 5.Klinische Forschung, IBE - Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität MünchenMunichGermany
  6. 6.Institut für Medizinische Biometrie und Epidemiologie, Philipps-Universität MarburgMarburgGermany
  7. 7.Klinik für AnästhesiologieLMU Klinikum der Universität MünchenMunichGermany
  8. 8.Klinik für Anästhesiologie, Operative Intensivmedizin und Schmerztherapie, Städtisches Klinikum MünchenMunichGermany
  9. 9.Institut für Anästhesiologie, Deutsches Herzzentrum BerlinBerlinGermany
  10. 10.Institut für Anästhesiologie, Herz- und Diabeteszentrum NRW, Ruhr-Universität BochumBad OeynhausenGermany
  11. 11.Klinik für Anästhesiologie und operative Intensivmedizin, Franziskus Hospital BielefeldBielefeldGermany

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