To describe and compare the design of three independent but collaborating multicenter trials of early goal-directed resuscitation for severe sepsis and septic shock.
We reviewed the three current trials, one each in the USA (ProCESS: protocolized care for early septic shock), Australasia (ARISE: Australasian resuscitation in sepsis evaluation), and the UK (ProMISe: protocolised management in sepsis). We used the 2010 CONSORT (consolidated standards of reporting trials) statement and the 2008 CONSORT extension for trials assessing non-pharmacologic treatments to describe and compare the underlying rationale, commonalities, and differences.
All three trials conform to CONSORT guidelines, address the same fundamental questions, and share key design elements. Each trial is a patient-level, equal-randomized, parallel-group superiority trial that seeks to enroll emergency department patients with inclusion criteria that are consistent with the original early goal-directed therapy (EGDT) trial (suspected or confirmed infection, two or more systemic inflammatory response syndrome criteria, and refractory hypotension or elevated lactate), is powered to detect a 6–8 % absolute mortality reduction (hospital or 90-day), and uses trained teams to deliver EGDT. Design differences appear to primarily be driven by between-country variation in health care context. The main difference between the trials is the inclusion of a third, alternative resuscitation strategy arm in ProCESS.
Harmonization of study design and methods between severe sepsis trials is feasible and may facilitate pooling of data on completion of the trials.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310
Levy MM, Fink M, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256
Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, For the Early Goal-Directed Therapy Collaborative Group (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377
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 (2008) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36:296–327
Micek ST, Roubinian N, Heuring T, Bode M, Williams J, Harrison C, Murphy T, Prentice D, Ruoff BE, Kollef MH (2006) Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med 34(11):2707–2713
Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA (2007) Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med 35:1105–1112
McIntyre LA, Hebert PC, Fergusson D, Cook DJ, Aziz A (2007) A survey of Canadian intensivists’ resuscitation practices in early septic shock. Crit Care 11:R74
Jones AE, Kline JA (2005) Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med 33:1888–1889
Sivayoham N (2007) Management of severe sepsis and septic shock in the emergency department: a survey of current practice in emergency departments in England. Emerg Med J 24:422
Ho BC, Bellomo R, McGain F, Jones D, Naka T, Wan L, Braitberg G (2006) The incidence and outcome of septic shock patients in the absence of early-goal directed therapy. Crit Care 10:R80
Peake S, Webb S, Delaney A (2007) Early goal-directed therapy of septic shock: we honestly remain skeptical. Crit Care Med 35:994–995
Chapman M, Gattas D, Suntharalingam G (2005) Why is early goal-directed therapy successful—is it the technology? Crit Care 9:307–308
Huang DT, Clermont G, Dremsizov TT, Angus DC (2007) Implementation of early goal-directed therapy for severe sepsis and septic shock: a decision analysis. Crit Care Med 35:2090–2100
Moher D, Schulz KF, Altman D (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 285:1987–1991
Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 7:e1000251
Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P (2008) Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med 148:295–309
Marik PE, Lipman J (2007) The definition of septic shock: implications for treatment. Crit Care Res 9:101–103
Peake SL, Bailey M, Bellomo R, Cameron PA, Cross A, Delaney A, Finfer S, Higgins A, Jones DA, Myburgh JA, Syres GA, Webb SA, Williams P (2009) Australasian resuscitation of sepsis evaluation (ARISE): a multi-centre, prospective, inception cohort study. Resuscitation 80:811–818
Maskin LP, Attie S, Setten M, Rodriguez PO, Bonelli I, Stryjewski ME, Valentini R (2010) Accuracy of weight and height estimation in an intensive care unit. Anaesth Intensive Care 38:930–934
Soliman HM, Vincent JL (2010) Prognostic value of admission serum lactate concentrations in intensive care unit patients. Acta Clin Belg 65:176–181
Kruse O, Grunnet N, Barfod C (2011) Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med 19:74
Shapiro NI, Howell MD, Talmor D, Nathanson LA, Lisbon A, Wolfe RE, Weiss JW (2005) Serum lactate as a predictor of mortality in emergency department patients with infection. Ann Emerg Med 45:524–528
Gallagher EJ, Rodriguez K, Touger M (1997) Agreement between peripheral venous and arterial lactate levels. Ann Emerg Med 29:479–483
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, For the PROWESS Study Group (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709
Halperin H, Paradis N, Mosesso V Jr, Nichol G, Sayre M, Ornato JP, Gerardi M, Nadkarni VM, Berg R, Becker L, Siegler M, Collins M, Cairns CB, Biros MH, Vanden Hoek T, Peberdy MA (2007) Recommendations for implementation of community consultation and public disclosure under the food and drug administration’s “Exception from informed consent requirements for emergency research”: a special report from the American Heart Association Emergency Cardiovascular Care Committee and Council on Cardiopulmonary, Perioperative and Critical Care: endorsed by the American College of Emergency Physicians and the Society for Academic Emergency Medicine. Circulation 116:1855–1863
Reade MC, Huang DT, Bell D, Coats TJ, Cross AM, Moran JL, Peake SL, Singer M, Yealy DM, Angus DC (2010) Variability in management of early severe sepsis. Emerg Med J 27:110–115
Minneci PC, Eichacker PQ, Danner RL, Banks SM, Natanson C, Deans KJ (2008) The importance of usual care control groups for safety monitoring and validity during critical care research. Intensive Care Med 34:942–947
Carlbom DJ, Rubenfeld GD (2007) Barriers to implementing protocol-based sepsis resuscitation in the emergency department–results of a national survey. Crit Care Med 35:2525–2532
Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E (1999) A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340:409–417
Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, Tomlanovich MC (2004) Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 32:1637–1642
Hollenberg SM, Ahrens TS, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Susla GM, Vincent JL (1999) Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 27:639–660
The ARDS Network authors for the ARDS Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308
Cohen J, Guyatt G, Bernard GR, Calandra T, Cook D, Elbourne D, Marshall J, Nunn A, Opal S, On behalf of a UK Medical Research Council International Working Party (2001) New strategies for clinical trials in patients with sepsis and septic shock. Crit Care Med 29:880–886
Taori G, Ho KM, George C, Bellomo R, Webb SA, Hart GK, Bailey MJ (2009) Landmark survival as an end-point for trials in critically ill patients–comparison of alternative durations of follow-up: an exploratory analysis. Crit Care 13:R128
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA (2010) Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 303:739–746
University of Pittsburgh (2013) Protocolized care for early septic shock (ProCESS). http://www.clinicaltrials.gov/ct2/show/NCT00510835?term=process+sepsis&rank=1. Accessed 13 June 2013
ARISE, ANZICS APD Management Committee (2007) The outcome of patients with sepsis and septic shock presenting to emergency departments in Australia and New Zealand. Crit Care Resusc 9:8–18
Angus DC, Laterre PF, Helterbrand J, Ely EW, Ball DE, Garg R, Weissfeld LA, Bernard GR (2004) The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med 32:2199–2206
Weycker D, Akhras KS, Edelsberg J, Angus DC, Oster G (2003) Long-term mortality and medical-care charges in patients with severe sepsis. Crit Care Med 31:2316–2323
Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M, Lacchetti C, Leung TW, Darling E, Bryant DM, Bucher HC, Schunemann HJ, Meade MO, Cook DJ, Erwin PJ, Sood A, Sood R, Lo B, Thompson CA, Zhou Q, Mills E, Guyatt GH (2005) Randomized trials stopped early for benefit: a systematic review. JAMA 294:2203–2209
Hillman K, Chen J, Cretikos M, Bellomo R, Brown D, Doig G, Finfer S, Flabouris A (2005) Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet 365:2091–2097
Tu JV, Willison D, Silver F, Fang JM, Richards J, Kapral MK (2004) The impracticability of obtaining informed consent in the Registry of the Canadian Stroke Network. Stroke 35:325
Dawson L, Zarin DA, Emanuel EJ, Friedman LM, Chaudhari B, Goodman SN (2009) Considering usual medical care in clinical trial design. PLoS Med 6:e1000111
Reade MC, Delaney A, Bailey MJ, Harrison DA, Yealy DM, Jones PG, Rowan KM, Bellomo R, Angus DC (2010) Prospective meta-analysis using individual patient data in intensive care medicine. Intensive Care Med 36:11–21
Reade MC, Delaney A, Bailey MJ, Angus DC (2008) Bench-to-bedside review: avoiding pitfalls in critical care meta-analysis–funnel plots, risk estimates, types of heterogeneity, baseline risk and the ecologic fallacy. Crit Care 12:220
Aberegg SK, Richards DR, O’Brien JM (2010) Delta inflation: a bias in the design of randomized controlled trials in critical care medicine. Crit Care 14:R77
Chalmers I, Altman DG, McHaffie H, Owens N, Cooke RW (2013) Data sharing among data monitoring committees and responsibilities to patients and science. Trials 14:102
O’Brien PC, Fleming TR (1979) A multiple testing procedure for clinical trials. Biometrics 35:549–556
Harvey SE, Elbourne D, Ashcroft J, Jones CM, Rowan K (2006) Informed consent in clinical trials in critical care: experience from the PAC-Man Study. Intensive Care Med 32:2020–2025
Coordinator center staff for each trial (in alphabetical order): ProCESS: T. Eaton, E. Gimbel, K. Wofford. ARISE: A. Jovanovska, G. Syres, D. Rajbhandari. ProMISe: R. Jahan, H. Muskett, S. Power, J. Tan. This study was supported by (ProCESS) National Institute of Health P50GM076659 and GM076659-S1, (ARISE) National Health and Medical Research Council Project Grant 491075, (ProMISe) National Institute for Health Research Health Technology Assessment programme HTA 07/37/47.
This article was written by the ProCESS/ARISE/ProMISe Methodology Writing Committee, on behalf of the ProCESS investigators, the ARISE investigators for the ANZICS Clinical Trials Group, and the ProMISe investigators. The members of the Committee are listed in the Appendix. The work was conducted by the University of Pittsburgh, the Australian and New Zealand Intensive Care Research Centre, Monash University, and the Intensive Care National Audit and Research Centre.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Appendix: members of ProCESS/ARISE/ProMISe methodology writing committee
Appendix: members of ProCESS/ARISE/ProMISe methodology writing committee
ProCESS (after Chair, authors are listed alphabetically): David T. Huang, MD, MPH (Chair)1,2,3, Derek C. Angus, MD, MPH1,2, Amber Barnato, MD1,4, MPH, Scott R. Gunn, MD2,3, John A. Kellum, MD1,2, Diana K. Stapleton, RN, BS1,2, Lisa A. Weissfeld, PhD1,5, MS, Donald M. Yealy, MD3.
ARISE (after first two, authors are listed alphabetically): Sandra L. Peake, BM BS, BSc (Hons) PhD, FCICM11,17,18, Anthony Delaney MBBS MSc FCICM, FACEM12,13, Rinaldo Bellomo MBBS, MD, FRACP, FJFICM6,7,8,9, Peter Cameron MBBS, MD, FACEM10,11, Alisa Higgins MPH, BPhysio (Hons)14, Anna Holdgate, MBBS (Hons), MMed, FACEM15,16, Belinda Howe RN, CCCert, BAppSc (Nursing)14, Steven A. Webb MBBS, PhD, FRACP, FCICM, MPH14,19,20, Patricia Williams RGN, BN Int. Care17,18.
ProMISe: Tiffany M. Osborn, MD, MPH21, Paul R. Mouncey MSc21, David A. Harrison PhD21, Sheila E. Harvey PhD21, Kathryn M. Rowan, PhD21.
1. The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Center.
2. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
3. Department of Emergency Medicine, University of Pittsburgh, Pittsburgh, PA.
4. Department of Internal Medicine, Division of General Internal Medicine, Center for Research on Health Care.
5. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
6. School of Medicine, University of Melbourne, Melbourne, VIC, Australia.
7. School of Medicine, Monash University, Melbourne, VIC, Australia.
8. Howard Florey Institute, Melbourne University, Melbourne, VIC, Australia.
9. Department of Intensive Care Medicine, Austin Hospital, Heidelberg, VIC, Australia.
10. Department of Emergency Medicine, Alfred Hospital, Melbourne, VIC, Australia.
11. Department of Epidemiology and Preventive Medicine, School of Public Health and Preventative Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
12. Intensive Care Unit, Royal North Shore Hospital, Sydney, NSW, Australia.
13. Northern Clinical School, Sydney Medical School, University of Sydney, NSW, Australia.
14. Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
15. South West Clinical School, University of New South Wales, Sydney, NSW, Australia.
16. Department of Emergency Medicine, Liverpool Hospital, Sydney, NSW, Australia.
17. Department of Intensive Care Medicine, The Queen Elizabeth Hospital, School of Medicine, Adelaide, SA, Australia.
18. Discipline of Acute Care Medicine, Faculty of Health Science, University of Adelaide, SA, Australia.
19. Intensive Care Unit, Royal Perth Hospital, Perth, WA, Australia.
20. School of Medicine, Pharmacology and Public Health, University of Western Australia, Perth, WA, Australia.
21. Intensive Care National Audit and Research Centre (ICNARC), Napier House, 24 High Holborn, London, UK.
Rights and permissions
About this article
Cite this article
The ProCESS/ARISE/ProMISe Methodology Writing Committee. Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: methodology of ProCESS, ARISE, and ProMISe. Intensive Care Med 39, 1760–1775 (2013). https://doi.org/10.1007/s00134-013-3024-7
- Septic shock
- Clinical trial
- Severe sepsis
- Early goal-directed therapy
- Study design