Hydrocortisone for Prevention of Septic Shock (HYPRESS)

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

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.

Study Overview

• Status: Completed
• Conditions: Severe Sepsis
• Intervention / Treatment: Drug: Hydrocortisone; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 380
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Universitaetsklinikum Aachen, Operative Intensivmedizin Erwachsene
  • Bad Berka, Germany, 99437
    • Zentralklinik Bad Berka GmbH, Zentrum für Anaesthesie, Intensivtherapie und Notfallmedizin
  • Bad Saarow, Germany, 15526
    • HELIOS Klinikum Bad Saarow; Zentrum für Anaesthesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie
  • Berlin, Germany, 12101
    • St. Joseph Krankenhaus, Institut fue Anaesthesie, Schwerpunkt operative Intensivmedizin und SchmerztherapieAnaesthesie, operative Intensiv- und Notfallmedizin
  • Berlin, Germany, 12157
    • Vivantes Auguste-Viktoria-Klinikum, Klinik fuer Anaesthesiologie, Intensivmedizin und Schmerztherapie
  • Berlin, Germany, 12351
    • Vivantes Klinikum Neukoelln,Klinik fuer Innere Medizin, Kardiologie und konservative Intensivmedizin
  • Berlin, Germany, 12351
    • Vivantes Klinikum-Neukoelln, Klinik fuer Anaesthesie, operative Intensivmedizin und Schmerztherapie
  • Berlin, Germany, 12621
    • Vivantes Klinikum Hellersdorf, Klinik fuer Anaesthesie, operative Intensivmedizin und Schmerztherapie
  • Berlin, Germany, 13125
    • Helios Klinikum Berlin Buch, Klinik für Intensivmedizin
  • Berlin, Germany, 13353
    • Charité Universitaetsmedizin Berlin, Campus Virchow-Klinikum und Campus Mitte, Med. Klinik mit Schwerpunkt Infektiologie und Pneumologie
  • Berlin, Germany, 13353
    • Charité Universitaetsmedizin Berlin, Campus Virchow-Klinikum und Mitte Klinik für Anaesthesiologie und operative Intensivmedizin
  • Berlin, Germany, 13353
    • Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Med. Klinik mit Schwerpunkt Nephrologie und internistische Intensivmedizin
  • Berlin, Germany, 13509
    • Vivantes Humboldt-Klinikum, Klinik für Innere Medizin - Kardiologie und konservative Intensivmedizin
  • Bonn, Germany, 53105
    • Rheinische Friedrich-Wilhelms-Universitaet, Klinik für Anaesthesiologie und Operative Intensivmedizin
  • Dresden, Germany, 01067
    • Krankenhaus Dresden-Friedrichstadt, Klinik für Anaesthesiologie und Intensivmedizin
  • Dresden, Germany, 01307
    • Universitaetsklinik Carl Gustav Carus Dresden
  • Erfurt, Germany, 99089
    • Helios Klinikum Erfurt, Klinik fuer Anaesthesie, Intensivmedizin und Schmerztherapie
  • Freiburg, Germany, 79106
    • Universitaetsklinikum Freiburg, Anaesthesiologische Universitaetsklinik - Abteilung Anaesthesiologie und Intensivtherapie
  • Greifswald, Germany, 17475
    • Ernst Moritz Arndt Universitaet Greifswald, Klinik und Poliklinik für Anaesthesiologie und Intensivmedizin
  • Halle (Saale), Germany, 06097
    • Medizinische Fakultaet der Martin-Luther-Universitaet Halle-Wittenberg - Universitaetsklinikum Halle (Saale)
  • Halle (Saale), Germany, 06120
    • Krankenhaus Martha-Maria Halle-Doelau GmbH
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf, Klinik für Intensivmedizin
  • Heidenheim, Germany, 89522
    • Klinikum Heidenheim, Klinik für Anaesthesiologie und operative Intensivmedizin
  • Henningsdorf, Germany, 16716
    • Klinik Henningsdorf der Oberhavel-Kliniken GmbH, Abteilung für Anaesthesie und Intensivmedizin
  • Jena, Germany, 07747
    • Friedrich Schiller Universität, Klinik für Anaesthesiologie und Intensivmedizin
  • Kiel, Germany, 24105
    • Universitaetsklinikum Schleswig Holstein Campus Kiel, Klinik für Anaesthesiologie und Operative Intensivmedizin
  • Koeln, Germany, 50935
    • St. Elisabeth-Krankenhaus Köln-Hohenlind, Klinik für Anaesthesiologie und operative Intensivmedizin
  • Koeln, Germany, 51058
    • Kliniken der Stadt Koeln - Krankenhaus Merheim, Klinik für Anaesthesiologie und operative Intensivmedizin
  • Leipzig, Germany, 04103
    • Universitaetsklinikum Leipzig AöR, Klinik und Poliklinik für Anaesthesiologie und Intensivtherapie
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg GmbH, Klinik fuer Anaesthesiologie, Intensivmedizin, Notfallmedizin und Schmerztherapie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Application is identical to experimental arm
Experimental: Hydrocortisone	Drug: Hydrocortisone; 50 mg loading dose, continuous infusion of 200 mg/d for 5 d, 100 mg/d for 2d, 50 mg/d for 2 d, and 25 mg/d for 2 d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Septic shock	14 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality	28, 90, and 180 days; ICU and hospital
Length of stay	ICU and hospital (3-6 months)
Time to death	28, 90, and 180 days
Time to septic shock	14 days
Mechanical ventilation	until ICU discharge
Renal replacement therapy	until ICU discharge
Organ dysfunction (SOFA score)	until ICU discharge but day 14 at maximum
Frequency of weaning failure	until ICU discharge
Frequency and severity of muscle weakness	until ICU discharge
Frequency of gastrointestinal bleeding	28 days
Frequency of secondary infections	28 days
Delir	ICU discharge
Hypernatremia	14 days
Hyperglycemia	14 days
Other adverse events	28 days
Posttraumatic stress disorder / health-related quality of life	Hosptal discharge and 180 days after hospital discharge
Immune response to hydrocortisone	6 days
Adrenal function	baseline

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: German Federal Ministry of Education and Research; SepNet - Critical Care Trials Group; Coordination Centre for Clinical Trials Leipzig
• Investigators: Principal Investigator: Konrad Reinhart, MD, University Hospital Jena; Dept. of Anesthesiology an Intensive Care Medicine; Study Chair: Didier Keh, MD, Charité Universitaetsmedizin Berlin, Dept. of Anesthsiology and Intensive Care Medicine; Study Director: Frank M Brunkhorst, MD, University Hospital Jena, Dept. of Anesthesiology and Intensive Care Medicine; Study Director: Markus Loeffler, MD, University Leipzig, Coordination Center of Clinical Studies (KKSL)

Publications and helpful links

General Publications

• 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.
• 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.
• 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. Erratum In: Crit Care Med. 2008 Apr;36(4):1394-6.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Competence Network Sepsis (SepNet)

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: April 29, 2008
• First Submitted That Met QC Criteria: April 29, 2008
• First Posted (Estimate): May 1, 2008

Study Record Updates

• Last Update Posted (Estimate): September 27, 2013
• Last Update Submitted That Met QC Criteria: September 26, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: Shock; Sepsis; Glucocorticoids; Hydrocortisone; Septic
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Anti-Inflammatory Agents; Hydrocortisone
• Other Study ID Numbers: HYPRESS; 01KG0701 (Other Identifier: BMBF); 2007-004401-10 (EudraCT Number)