Clinical trial NCT00670254: Hydrocortisone for Prevention of Septic Shock
Official title: Placebo-controlled, Randomised, Double-blind Study to Investigate the Efficacy and Safety of Low Dose Hydrocortisone to Prevent the Development of Septic Shock in Patients With Severe Sepsis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Sepsis
Keywords: Sepsis
Septic
Shock
Glucocorticoids
Hydrocortisone
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
name: SepNet - Critical Care Trials Group
name: Coordination Centre for Clinical Trials Leipzig
First posted: 2008-05-01
Enrollment: 380
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Severe sepsis is a disease with a high mortality. Development of shock is a most serious complication and increases the risk of death considerably. Application of low dose hydrocortisone is currently recommended only in patients after severe septic shock has been established. Hydrocortisone therapy has a hemodynamic stabilizing effect and may reverse shock, however, the preventive application has not been investigated in a larger study. The study investigates whether low dose hydrocortisone prevents the development of shock in patients with severe sepsis. It is postulated that shock prevention may also affect morbidity and mortality.


Eligibility criteria: Inclusion Criteria:

* Severe sepsis according to ACCP/CCM criteria
* Onset of severe sepsis \< 48 hours
* Informed consent
* Effective contraception in fertile women

Exclusion Criteria:

* Septic shock
* Known hypersensitivity to hydrocortisone and additives
* Glucocorticoid history which warrants continuation of glucocorticoid administration
* Other indication for systemic glucocorticoid therapy
* DNR-order
* Moribund patient
* Pregnancy
* Breast feeding women
* Age \< 18 years
* Other interventional study
* Relationship to investigator

Primary outcomes:
measure: Septic shock
timeFrame: 14 days
Secondary outcomes:
measure: Mortality
timeFrame: 28, 90, and 180 days; ICU and hospital
measure: Length of stay
timeFrame: ICU and hospital (3-6 months)
measure: Time to death
timeFrame: 28, 90, and 180 days
measure: Time to septic shock
timeFrame: 14 days
measure: Mechanical ventilation
timeFrame: until ICU discharge
measure: Renal replacement therapy
timeFrame: until ICU discharge
measure: Organ dysfunction (SOFA score)
timeFrame: until ICU discharge but day 14 at maximum
measure: Frequency of weaning failure
timeFrame: until ICU discharge
measure: Frequency and severity of muscle weakness
timeFrame: until ICU discharge
measure: Frequency of gastrointestinal bleeding
timeFrame: 28 days
measure: Frequency of secondary infections
timeFrame: 28 days
measure: Delir
timeFrame: ICU discharge
measure: Hypernatremia
timeFrame: 14 days
measure: Hyperglycemia
timeFrame: 14 days
measure: Other adverse events
timeFrame: 28 days
measure: Posttraumatic stress disorder / health-related quality of life
timeFrame: Hosptal discharge and 180 days after hospital discharge
measure: Immune response to hydrocortisone
timeFrame: 6 days
measure: Adrenal function
timeFrame: baseline
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Universitaetsklinikum Aachen, Operative Intensivmedizin Erwachsene
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka GmbH, Zentrum für Anaesthesie, Intensivtherapie und Notfallmedizin
city: Bad Saarow
country: Germany
facility: HELIOS Klinikum Bad Saarow; Zentrum für Anaesthesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
city: Berlin
country: Germany
facility: St. Joseph Krankenhaus, Institut fue Anaesthesie, Schwerpunkt operative Intensivmedizin und SchmerztherapieAnaesthesie, operative Intensiv- und Notfallmedizin
city: Berlin
country: Germany
facility: Vivantes Auguste-Viktoria-Klinikum, Klinik fuer Anaesthesiologie, Intensivmedizin und Schmerztherapie
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukoelln,Klinik fuer Innere Medizin, Kardiologie und konservative Intensivmedizin
city: Berlin
country: Germany
facility: Vivantes Klinikum-Neukoelln, Klinik fuer Anaesthesie, operative Intensivmedizin und Schmerztherapie
city: Berlin
country: Germany
facility: Vivantes Klinikum Hellersdorf, Klinik fuer Anaesthesie, operative Intensivmedizin und Schmerztherapie
city: Berlin
country: Germany
facility: Helios Klinikum Berlin Buch, Klinik für Intensivmedizin
city: Berlin
country: Germany
facility: Charité Universitaetsmedizin Berlin, Campus Virchow-Klinikum und Campus Mitte, Med. Klinik mit Schwerpunkt Infektiologie und Pneumologie
city: Berlin
country: Germany
facility: Charité Universitaetsmedizin Berlin, Campus Virchow-Klinikum und Mitte Klinik für Anaesthesiologie und operative Intensivmedizin
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Med. Klinik mit Schwerpunkt Nephrologie und internistische Intensivmedizin
city: Berlin
country: Germany
facility: Vivantes Humboldt-Klinikum, Klinik für Innere Medizin - Kardiologie und konservative Intensivmedizin
city: Bonn
country: Germany
facility: Rheinische Friedrich-Wilhelms-Universitaet, Klinik für Anaesthesiologie und Operative Intensivmedizin
city: Dresden
country: Germany
facility: Krankenhaus Dresden-Friedrichstadt, Klinik für Anaesthesiologie und Intensivmedizin
city: Dresden
country: Germany
facility: Universitaetsklinik Carl Gustav Carus Dresden
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt, Klinik fuer Anaesthesie, Intensivmedizin und Schmerztherapie
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg, Anaesthesiologische Universitaetsklinik - Abteilung Anaesthesiologie und Intensivtherapie
city: Greifswald
country: Germany
facility: Ernst Moritz Arndt Universitaet Greifswald, Klinik und Poliklinik für Anaesthesiologie und Intensivmedizin
city: Halle (Saale)
country: Germany
facility: Medizinische Fakultaet der Martin-Luther-Universitaet Halle-Wittenberg - Universitaetsklinikum Halle (Saale)
city: Halle (Saale)
country: Germany
facility: Krankenhaus Martha-Maria Halle-Doelau GmbH
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf, Klinik für Intensivmedizin
city: Heidenheim
country: Germany
facility: Klinikum Heidenheim, Klinik für Anaesthesiologie und operative Intensivmedizin
city: Henningsdorf
country: Germany
facility: Klinik Henningsdorf der Oberhavel-Kliniken GmbH, Abteilung für Anaesthesie und Intensivmedizin
city: Jena
country: Germany
facility: Friedrich Schiller Universität, Klinik für Anaesthesiologie und Intensivmedizin
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig Holstein Campus Kiel, Klinik für Anaesthesiologie und Operative Intensivmedizin
city: Koeln
country: Germany
facility: St. Elisabeth-Krankenhaus Köln-Hohenlind, Klinik für Anaesthesiologie und operative Intensivmedizin
city: Koeln
country: Germany
facility: Kliniken der Stadt Koeln - Krankenhaus Merheim, Klinik für Anaesthesiologie und operative Intensivmedizin
city: Leipzig
country: Germany
facility: Universitaetsklinikum Leipzig AöR, Klinik und Poliklinik für Anaesthesiologie und Intensivtherapie
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg GmbH, Klinik fuer Anaesthesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
Study officials:
affiliation: University Hospital Jena; Dept. of Anesthesiology an Intensive Care Medicine
name: Konrad Reinhart, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité Universitaetsmedizin Berlin, Dept. of Anesthsiology and Intensive Care Medicine
name: Didier Keh, MD
role: STUDY_CHAIR
affiliation: University Hospital Jena, Dept. of Anesthesiology and Intensive Care Medicine
name: Frank M Brunkhorst, MD
role: STUDY_DIRECTOR
affiliation: University Leipzig, Coordination Center of Clinical Studies (KKSL)
name: Markus Loeffler, MD
role: STUDY_DIRECTOR
References:
citation: Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008 Jan;36(1):296-327. doi: 10.1097/01.CCM.0000298158.12101.41.
citation: Reinhart K, Brunkhorst F, Bone H, Gerlach H, Grundling M, Kreymann G, Kujath P, Marggraf G, Mayer K, Meier-Hellmann A, Peckelsen C, Putensen C, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Werdan K; Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin (DIVI); Deutschen Sepsis-Gesellschaft e.V. (DSG). [Diagnosis and therapy of sepsis. Guidelines of the German Sepsis Society Inc. and the German Interdisciplinary Society for Intensive and Emergency Medicine]. Internist (Berl). 2006 Apr;47(4):356, 358-60, 362-8, passim. doi: 10.1007/s00108-006-1595-x. German.
citation: Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007 Apr;33(4):606-18. doi: 10.1007/s00134-006-0517-7. Epub 2007 Feb 24.
citation: Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. doi: 10.1056/NEJMoa071366.
citation: Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Syst Rev. 2004;(1):CD002243. doi: 10.1002/14651858.CD002243.pub2.
citation: Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker S, Volk HD, Doecke WD, Falke KJ, Gerlach H. Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. Am J Respir Crit Care Med. 2003 Feb 15;167(4):512-20. doi: 10.1164/rccm.200205-446OC. Epub 2002 Nov 8.
citation: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992 Jun;20(6):864-74.
citation: Briegel J, Mohnle P, Keh D, Lindner JM, Vetter AC, Bogatsch H, Lange D, Frank S, Hinske LC, Annane D, Vogeser M; SepNet Critical Care Trials Group. Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study. Crit Care. 2022 Nov 7;26(1):343. doi: 10.1186/s13054-022-04224-5.
citation: Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn SO, Huter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schadler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM; SepNet-Critical Care Trials Group. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. doi: 10.1001/jama.2016.14799.