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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

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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

Trial registration

www.clinicaltrials.gov (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)

Résumé

Objectif

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.

Méthode

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.

Résultats

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.

Conclusion

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

Enregistrement de l’étude

www.clinicaltrials.gov (NCT00927654); enregistrée le 25 juin 2009.

Notes

Acknowledgements

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)

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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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