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The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock

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Abstract

Rationale

Use of etomidate in the critically ill is controversial due to its links with an inadequate response to corticotropin and potential for excess mortality. In a septic shock population, we tested the hypotheses that etomidate administration induces more non-responders to corticotropin and increases mortality and that hydrocortisone treatment decreases mortality in patients receiving etomidate.

Methods

An a-priori sub-study of the CORTICUS multi-centre, randomised, double-blind, placebo-controlled trial of hydrocortisone in septic shock. Use and timing of etomidate administration were collected. Endpoints were corticotropin response and all-cause 28-day mortality in patients receiving etomidate.

Measurements and main results

Five hundred patients were recruited, of whom 499 were analysable; 96 (19.2%) were administered etomidate within the 72 h prior to inclusion. The proportion of non-responders to corticotropin was significantly higher in patients who were given etomidate in the 72 h before trial inclusion than in other patients (61.0 vs. 44.6%, P = 0.004). Etomidate therapy was associated with a higher 28-day mortality in univariate analysis (P = 0.02) and after correction for severity of illness (42.7 vs. 30.5%; P = 0.06 and P = 0.03) in our two multi-variant models. Hydrocortisone administration did not change the mortality of patients receiving etomidate (45 vs. 40%).

Conclusions

The use of bolus dose etomidate in the 72 h before study inclusion is associated with an increased incidence of inadequate response to corticotropin, but is also likely to be associated with an increase in mortality. We recommend clinicians demonstrate extreme caution in the use of etomidate in critically ill patients with septic shock.

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Acknowledgments

This study was supported by the European Commission contract QLK2-CT-2000-00589, the European Society of Intensive Care Medicine, the International Sepsis Forum, the Gorham Foundation and Roche Diagnostics GmbH, Mannheim/Penzberg, Germany, who provided Elecsys® Cortisol immunoassay. The EU Commission and other sponsors had no role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data or in the preparation, review or approval of the manuscript. This research study is endorsed and supported by the ECCRN of the ESICM. The activities of the CORTICUS research group endorsed by the ECCRN of the ESICM do not represent official statements and positions of the ESICM.

Conflicts of interest statement

B.H.C. has received a consulting fee, grant support and lecture fees from Eli Lilly. C.S. reports having served as a member of a data-monitoring and safety committee for Artisan Pharma, Inc., Chiron/Novartis Corporation and Hutchinson Technology incorporated. C.S. reports having served as a consultant for AstraZeneka, Eisai Corporation, Eli Lilly and GlaxoSmithKline. C.S. reports having received grant support from the European Commission, Takeda and Eisai Corporation. C.S. reports having been paid lecture fees by Eli Lilly. D.A. has no conflicts of interest. S.C. has no conflicts of interest. M.G. has no conflicts of interest. S.G. has no conflicts of interest. P.-F.L. has received consulting fees from Eli Lilly. J.L.V. has no conflicts of interest. K.F. has no conflicts of interest. M.S. has received consulting fees from Eli Lilly and Ferring. D.P. has received consulting fees from Edwards Life Sciences, Eli Lilly and Hutchinson Technology and grant support from Eli Lilly and Hutchinson Technology. Y.G.W. has no conflicts of interest. There are no other potential conflicts of interest relevant for this article.

Author information

Authors and Affiliations

  1. Health Services Research Unit, University of Aberdeen, 3rd Floor, Health Sciences Building, Foresterhill, Aberdeen, AB25 2ZD, UK

    Brian H. Cuthbertson

  2. Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel

    Charles L. Sprung, Serge Goodman & Yoram G. Weiss

  3. General Intensive Care Unit, Raymond Poincaré Hospital (AP-HP), University of Versailles, SQY, Garches, France

    Djillali Annane

  4. Biostatistics Department, St Louis Hospital, Paris, France

    Sylvie Chevret

  5. Intensive Care Unit, Ipswich Hospital NHS Trust, Ipswich, UK

    Mark Garfield

  6. Department of Critical Care Medicine, St Luc University Hospital, UCL, Brussels, Belgium

    Pierre-Francois Laterre

  7. Intensive Care Unit, Erasme University Hospital, Brussels, Belgium

    Jean Louis Vincent

  8. Analytica International GmbH, Untere Herrenstr, Lörrach, Germany

    Klaus Freivogel

  9. Department of Anaesthesiology and Intensive Care Medicine, Friedrich-Schiller Universitat, Jena, Germany

    Konrad Reinhart

  10. Department of Medicine, Wolfson Institute of Biomedical Research, University College London, London, UK

    Mervyn Singer

  11. Reanimation, Hopital Lariboisiere, Paris, France

    Didier Payen

Authors
  1. Brian H. Cuthbertson
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  2. Charles L. Sprung
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  3. Djillali Annane
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  4. Sylvie Chevret
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  5. Mark Garfield
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  6. Serge Goodman
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  7. Pierre-Francois Laterre
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  8. Jean Louis Vincent
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  9. Klaus Freivogel
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  10. Konrad Reinhart
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  11. Mervyn Singer
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  12. Didier Payen
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  13. Yoram G. Weiss
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Corresponding author

Correspondence to Brian H. Cuthbertson.

Additional information

On behalf of the Corticus Study Group.

Appendix

Appendix

Steering Committee: C. Sprung (Chairman); D. Annane; J. Briegel; D. Keh; R. Moreno; D. Pittet; M. Singer; Y. Weiss.

Safety and Efficacy Monitoring Committee: J. Cohen (Chairman); C. Dore; T. Evans; N. Soni, F. Sorenson (Imor/Analytica).

Study Coordinating Center: C. Sprung (Physician Coordinator); J. Benbenishty (Nurse Coordinator); A. Avidan, E. Ludmir; J. Kabiri; K. Furmanov; B. Hain; O. Kalugin; I. Zack.

Clinical Evaluation Committee: Y. Weiss (Chairman); D. Annane; J. Briegel; S. Goodman; D. Keh; R. Moreno; M. Singer; C. Sprung.

Berlin Coordinating Center: D. Keh (Chairman); A. Gossinger.

French Coordinating Center: D. Annane (Chairman); N. Zinsou, D. Friedman.

Corticus Investigators: Austria: LKH Feldkirch, Feldkirch (P. Fae); Krankenhaus Barmherzige Schwestern, Linz (J. Reisinger); Universitaetsklinik fuer Innere Medizin II, Wien (G. Heinz); Belgium: Hopital St. Joseph, Arlon (M. Simon); Department of Critical Care Medicine, St Luc University Hospital, UCL, Brussels (P.-F. Laterre, X. Wittebole, MN France); University Hospital Erasme, Brussels (J.L. Vincent, D. DeBacker); CHU Charleroi, Charleroi (P. Biston). France: Hopital de Caen, Caen (C. Daubin); Hopital Raymond Poincare, Garches (D. Annane, D. Lipiner, V. Maxime); Hopital Huriez, Lille (B. Vallet); Hopital Caremeau, Nimes (J.Y. Lefrant); Hopital Saint-Antoine, Paris (G. Offenstadt); Hopital Lariboisiere, Paris (D. Payen, A.C. Lukaszewicz). Germany: Zentralklinikum Augsburg, Augsburg (H. Forst, G. Neeser, Y. Barth); Charite Universitaetsmedizin Berlin, Campus Virchow-Klinikum (D. Keh, J.Langrehr, M.Oppert, C.Spies), Campus Mitte (C. Spies, S.Rosseau), Campus Benjamin Franklin (J. Weimann); Evangelisches Waldkrankenhaus Spandau, Berlin (M. Reyle Hahn); St. Joseph—Krankenhaus, Berlin (M. Schmutzler); Vivantes Klinikum Spandau, Berlin (K.J. Slama), Vivantes Klinikum Neukoelln, Berlin (H.Gerlach), Vivantes Klinikum im Friedrichshain,Berlin (S. Veit); Klinikum Ernst von Bergmann, Potsdam (D. Pappert); Inst. For Anaesthesia and Operative Intensive Care Medicine, Darmstadt (M. Welte, L. Von Beck); University Hospital Carl Gustav Carus, Dresden (C. Marx); Krankenhaus Hennigsdorf, Hennigsdorf (A. Lange); Friedrich-Schiller Universitaet, Jena (K. Reinhart, F. Bloos, F. Brunkhorst); Klinikum Kempten-Oberallgaeu, Kempten (M. Haller); Klinikum of Landshut, Landshut (U. Helms,); Klinikum Mannheim, Mannheim (A. Kalenka, F. Fiedler); Klinik fuer Anaesthesiologie, Klinikum der Universitaet, Ludwig-Maximilians-Universitaet, Munich (J. Briegel); Department of Surgery, Klinikum der Universitaet—Grosshadern, Munich (W. Hartl); Staedtisches Krankenhaus Muenchen—Harlaching, Munich (M. Klimmer, T. Helmer); Universitaet Erlangen-Namberg, Nuernberg (M. Baumgaertel); Klinikum Ernst von Bergman, Potsdam (D. Pappert). Israel: Haemek Hospital, Afula (A. Lev); Hadassah Medical Organization, Jerusalem (Y. Weiss, C. Sprung, J. Benbenishty, O. Shatz); Belinson Medical Centre, Petach Tikva (P. Singer); Ichilov Hospital, Tel Aviv (A. Nimrod). Italy: Policlinico di Tor Vergata, Rome (S. Natoli); Centro di Rianimazione, Ospedale S. Eugenio, Rome (F. Turani). The Netherlands: Erasmus University Medical Center, Rotterdam (B. Van der Hoven). Portugal: Hospital de St. Antonio do Capuchos, Lisbon (R. Moreno, R. Matos). UK: Aberdeen Royal Infirmary, Aberdeen (B.H. Cuthbertson, S. Roughton); The Ipswich Hospital NHS, Ipswich (M. Garfield); The General Infirmary at Leeds, Leeds (A. Mallick); University College London Hospitals NHS Foundation Trust, London (M. Singer, M McKendry); Southampton General Hospital, Southampton (T. Woodcock).

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Cuthbertson, B.H., Sprung, C.L., Annane, D. et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med 35, 1868–1876 (2009). https://doi.org/10.1007/s00134-009-1603-4

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