Major Trials
Sepsis
Sections
Early-Goal Directed Therapy
Fluid Volume
Antimicrobial Administration
Duration of Antimicrobial
Early Vasopressor
Circulatory Support
Corticosteroids
Anticoagulants
Anti-Inflammatory Agents 1
Anti-Inflammatory Agents 2
Miscellaneous Therapies
Miscellaneous Diagnostics
Fluids
Early Goal Directed Therapy
Rivers Trial
Triumvirate
- Mouncey. Trial of Early, Goal-Directed Resuscitation for Septic Shock. (ProMISe Trial). N Engl J Med 2015;epublished March 17th
- The ARISE Investigators. Goal-Directed Resuscitation for Patients with Early Septic Shock. New Engl J Med 2014;epublished October 1st
- The ProCESS Investigators. A Randomized Trial of Protocol-Based Care for Early Septic Shock (ProCESS study). New Engl J Med 2014;epublished March 18th
Volume
Volume
- The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension (CLOVERS). N Engl J Med 2023;388:499-510
- Meyhoff. Restriction of Intravenous Fluid in ICU Patients with Septic Shock (CLASSIC). N Engl J Med 2022;386:2459-2470
- Maitland. Mortality after Fluid Bolus in African Children with Severe Infection (FEAST Trial). N Engl J Med 2011
Type
Starch
- Perner. Hydroxyethyl Starch 130/0.4 versus Ringer's Acetate in Severe Sepsis (6S). N Eng J Med 2012; 367:124-134
- Guidet. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 versus 0.9% NaCl fluid replacement in patients with severe sepsis: the CRYSTMAS study. Crit Care 2012;16:R94
- Brunkhorst. Intensive insulin therapy and pentastarch resuscitation in severe sepsis (VISEP). N Eng J Med 2008;358:125-139
Antimicrobials
Duration of Administration
Continuous vs Intermittent
- Dulhunty. Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis. The BLING III Randomized Clinical Trial. JAMA 2024;332;(8):629-637
- Monti. Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis. The MERCY Randomized Clinical Trial. JAMA 2023;epublished June 16th
Duration of Therapy
Biomarker-Guided
- Voiriot. Combined use of a multiplex PCR and serum procalcitonin to reduce antibiotic exposure in critically ill patients with community-acquired pneumonia: the MULTI-CAP randomized controlled trial. Intensive Care Med 2025;epublished July 15th
- Dark. Biomarker-Guided Antibiotic Duration for Hospitalized Patients With Suspected Sepsis. The ADAPT-Sepsis Randomized Clinical Trial. JAMA 2024;epublished December 9th
- Bouadma. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomized controlled trial. Lancet. 2010;375:463-474
Ventilator-Associated Pneumonia
- Micek. A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. Chest. 2004;125:1791-1799
- Chastre. Comparison of 8 vs. 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290:2588-2598.
Abdominal Sepsis
Circulatory Support
Early Vasopressor
Noradrenaline
- The National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med 2023;epublished January 21st
- Permpikul. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med 2019;199(9):1097-1105
Catecholamines
Adrenergic Agonism
- Ramaswamy. Double-Blind Randomized Clinical Trial Comparing Dopamine and Epinephrine in Pediatric Fluid-Refractory Hypotensive Septic Shock. Pediatr Crit Care Med 2016;epublished September 23rd
- Myburgh. A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008;34(12):2226-2234
- Annane. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: A randomised trial. Lancet 2007;370:676-684
Beta Adrenergic Antagonism
Corticosteroids
Hydrocortisone
- The REMAP-CAP Investigators. Effect of hydrocortisone on mortality in patients with severe community-acquired pneumonia. Intensive Care Med 2025;epublished April 22nd
- Venkatesh. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL). N Engl J Med 2018;2018;378:797-808
- Keh. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis. The HYPRESS Randomized Clinical Trial. JAMA 2016;epublished October 3rd
- COIITSS Study Investigators. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010 Jan 27;303(4):341-8.
- Sprung. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS). N Engl J Med 2008;358:111-124
Hydrocortisone & Fludrocortisone
- Annane. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS). N Engl J Med 2018;378:809-818
- Venkatesh. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL). N Engl J Med 2018;2018;378:797-808
- Keh. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis. The HYPRESS Randomized Clinical Trial. JAMA 2016;epublished October 3rd
- COIITSS Study Investigators. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010 Jan 27;303(4):341-8.
- Sprung. Hydrocortisone Therapy for Patients with Septic Shock (CORTICUS). N Engl J Med 2008;358:111-124
- Annane. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871
Hydrocortisone, Thiamine & Vitamin C
- Sevransky. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis. The VICTAS Randomized Clinical Trial. JAMA 2021;325(8):742-750
- Moskowitz. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock. The ACTS Randomized Clinical Trial. JAMA 2020;324(7):642-650
- Hwang. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med 2020;epublished August 11th
- Chang. Combined Treatment With Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock. A Randomized Controlled Trial. Chest 2020;158(1):174–182
- Iglesias. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis. The ORANGES Trial. Chest 2020;158(1):164–173
- Fujii. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic ShockThe VITAMINS Randomized Clinical Trial. JAMA 2020;323(5):423-431
see also Endocrine Trials
Anticoagulants
Protein C
Activated Protein C
- Ranieri. Drotrecogin Alfa (Activated) in Adults with Septic Shock ( PROWESS-SHOCK Study). N Engl J Med 2012;366:2055-206
- Dhainaut. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Medicine 2009;35(7):1187–95
- Nadel. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomized controlled trial (RESOLVE) . Lancet 2007;369:836-43
- Edward. Drotrecogin Alfa (Activated) for Adults with Severe Sepsis and a Low Risk of Death (ADDRESS). N Engl J Med 2005;353:1332-41
- Bernard. Efficacy and safety of recombinant human activated protein C for severe sepsis (PROWESS). N Engl J Med 2001;344:699-709
- Bernard. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 2001;29(11):2051–9
Zymogen Protein C
Antithrombin III
- Wiedermann. High-dose antithrombin III in the treatment of severe sepsis in patients with a high risk of death: Efficacy and safety. Crit Care Med 2006;34:285–29
- Warren. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: A randomized controlled trial. JAMA 2001;286:1869–1878
Anti-Inflammatory Therapies
Anti-IL-1
- Opal. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med 1997;25:1115–112
- Fisher. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. JAMA 1994;271:1836–184
Anti-TNF
- Abraham. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients. Crit Care Med 2001;29:503–510
- Abraham. Double-blind randomised controlled trial of monoclonal antibody to human tumor necrosis factor in treatment of septic shock. Lancet 1998;351:929–933
Interferon
Anti-PAF
- Opal. Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med 2004;32:332–341
- Dhainaut. Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: A phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 sepsis investigator group. Crit Care Med 1998;26:1963–1971
Bradykinin Inhibitors
Statins
- Truwit. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014;370:2191–2200
- Papazian. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: A randomized clinical trial. JAMA 2013;310:1692–1700
- Kruger. A Multicentre Randomised Trial of Atorvastatin Therapy in Intensive Care Patients with Severe Sepsis. Am J Respir Crit Care Med 2013;187(7):743-750
Endotoxin Inhibitors
- Livigni. Efficacy of coupled plasma filtration
adsorption (CPFA) in patients with septic shock: A multicenter randomised controlled clinical trial. BMJ Open 2014;4:e003536 - Dellinger. Effect of targeted polymyxin B hemoperfusion on 28-day mortality in patients with septic shock and elevated endotoxin level: The EUPHRATES randomized clinical trial. JAMA 2018;320:1455–1463
- Cruz. Early use of polymyxin B hemoperfusion in abdominal septic shock: The EUPHAS randomized
controlled trial. JAMA 2009;301:2445–2452 - Angus. E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: A randomized controlled trial. E5 Study Investigators. JAMA 2000;283:1723–1730
- Ziegler. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med 1991;324:429–436
Nitric Oxide Inhibition
- Vincent. Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX). Crit Care Med 2015;43:57–64
- Lopez. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock. Crit Care Med 2004;32: 21–30
Alkaline Phosphatase
- Pickkers. Effect of human recombinant alkaline phosphatase on 7-day creatinine clearance in patients with sepsis-associated acute kidney injury: A randomized clinical trial. JAMA 2018;320:1998–200
- Heemskerk. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med 2009;37:417.e1
Lactoferrin
Miscellaneous Therapies
Remote Ischaemic Conditioning
Miscellaneous Diagnostics
last updated April 23rd, 2025