Protocolized Care for Early Septic Shock (ProCESS)

The ProCESS study is large, 5-year, multicenter study of alternative resuscitation strategies for septic shock. The study hypothesizes that there are "golden hours" in the initial management of septic shock where prompt, rigorous, standardized care can improve clinical outcomes.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock; Severe Sepsis
• Intervention / Treatment: Procedure: Early Goal Directed Therapy (EGDT); Procedure: Protocolized Standard Care (PSC); Procedure: Usual Care (UC)

Detailed Description

Septic shock is a condition of acute organ dysfunction due to severe infection, with a mortality of up to 50%. Current efforts to improve care are limited by little practical evidence regarding the interventions in and timing of sepsis therapies. ProCESS is a prospective, randomized, three-arm parallel-group trial of alternative resuscitation strategies for early septic shock. The study objective is to improve the management of septic shock by exploring the clinical, biological, and economic aspects of alternative resuscitation strategies. This will be done by comparing two alternative resuscitation strategies to usual care in subjects with septic shock.

Comparisons:

1. Early Goal Directed Therapy (EGDT) - The subjects' blood pressure and blood oxygen levels will be monitored via the insertion of a central venous catheter (CVC). The study team will use this information to give fluid, blood and heart medications in a structured fashion. The central venous catheter to be used in this plan is FDA approved and routinely used in hospitals.
2. Protocolized Standard Care (PSC) - The subjects' blood pressure and blood oxygen levels will be monitored with standard equipment (without the CVC). The study team will use this information to prescribe fluid and heart medications in a structured fashion. CVCs will only be used when standard IVs cannot give the proper amount of fluids and medicines. Blood transfusions will be given according to currently recommended guidelines.
3. Usual Care (UC) - Subjects will be treated according to their attending physician's standard treatment plan and without any influence from the study team.

The primary hypotheses to be tested sequentially are that: protocolized resuscitation (EGDT and PSC) results in lower hospital mortality than usual care and Early Goal Directed Therapy results in lower hospital mortality than Protocolized Standard Care. These hypotheses will be tested on all enrolled subjects.

The study is powered to find an absolute mortality reduction (ARR) of ~6-7%. Based on the control arm mortality rate, we originally estimated a sample size of 1950. During the trial, the ProCESS Coordinating Center monitored the overall mortality rate, and appreciated that it was markedly lower than originally projected. Therefore, following a series of new calculations, in February 2013, the trial was re-sized to 1350 patients (450 patients per arm). The new size preserves the same power to find the same ARR. The resizing was fully blinded and approved by the NIH.

• Study Type: Interventional
• Enrollment (Actual): 1351
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90033
      • LA County & USC Medical Center
    • Palo Alto, California, United States, 94025
      • Stanford University School of Medicine
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
  • Connecticut
    • Norwalk, Connecticut, United States, 06856
      • Norwalk Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
    • Washington, District of Columbia, United States, 20037
      • George Washington University Medical Center
  • Florida
    • Tampa, Florida, United States, 33601
      • Tampa General Hospital
  • Illinois
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Research Institute
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • Louisiana State University Health Sciences Center/Shreveport
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Baltimore
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • New York
    • Brooklyn, New York, United States, 11203
      • State University of New York - Downstate Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Ohio
    • Akron, Ohio, United States, 44304-1619
      • Summa Health System
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey College of Medicine; Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Medical Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Shadyside Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37403
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78752
      • University Medical Center Brackenridge
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Health Sciences Center
    • Salt Lake City, Utah, United States, 84157
      • Intermountain Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• At least 18 years of age
• Suspected infection

• Two or more systemic inflammatory response syndrome (SIRS) criteria

  • Temperature </= 36˚ C or >/= 38˚C
  • Heart rate >/= 90 beats per minute
  • Mechanical ventilation for acute respiratory process or respiratory rate >/= 20 breaths per minute or PaC02 < 32 mmHg
  • WBC >/= 12,000/mm³ OR </= 4,000/mm³ OR > 10% bands
• Refractory hypotension (a systolic blood pressure < 90 mm Hg despite an IV fluid challenge of at least 1,000 mLs over a 30 minute period) or evidence of hypoperfusion (a blood lactate concentration >/= 4 mmol/L)

Exclusion criteria:

• Known pregnancy
• Primary diagnosis of acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, status asthmaticus, major cardiac arrhythmia, active gastrointestinal hemorrhage, seizure, drug overdose, burn or trauma
• Requirement for immediate surgery
• ANC < 500/mm³
• CD4 < 50/mm³
• Do-not-resuscitate status
• Advanced directives restricting implementation of the protocol
• Contraindication to central venous catheterization
• Contradiction to blood transfusion (e.g., Jehovah's Witness)
• Treating physician deems aggressive care unsuitable
• Participation in another interventional study
• Transferred from another in-hospital setting

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Early Goal Directed Therapy (EGDT) - The study team will insert a central venous catheter (CVC) for continuous monitoring of the subjects' central venous pressure (CVP) and central venous oxygen saturation (Scv02). The study team will use this information to give fluid, blood, and heart medications in a structured fashion. The CVC is FDA approved and routinely used in hospitals.	Procedure: Early Goal Directed Therapy (EGDT); Subjects will have a CVC inserted for continuous monitoring of their CVP and Scv02. Early structured treatment will be provided based on subjects' CVP, mean arterial pressure (MAP) and Scv02 measurements.
Experimental: 2; Protocolized Standard Care (PSC)- The study team will monitor the subjects' blood pressure and blood oxygen level with routine equipment. The study team will use this information to give fluid and heart medications in a structured fashion. CVCs will only be used when standard IVs are unable to give the proper amount of fluids and medicines. Blood transfusions will be given according to currently recommended guidelines.	Procedure: Protocolized Standard Care (PSC); Routine equipment will be used to monitor subjects' blood pressure and oxygen levels. Early structured treatment is based on the subjects' systolic blood pressure and the study doctors' judgment of fluid status and perfusion status.
Active Comparator: 3; Usual Care - The attending physicians will treat the subjects according to their standard treatment plan and without any influence from the study team. A member of the study team will simply observe and record what happens.	Procedure: Usual Care (UC); Attending physicians will provide routine care to subjects. Study measurements and treatments will be based on the physicians'/sites' standard practices.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital Mortality	The primary study outcome is hospital mortality (defined as the number of deaths prior to discharge or 60 days, whichever comes first). The secondary outcomes are duration of survival (90 day and 1 year) and clinical evidence of organ dysfunction.	prior to discharge or 60 days, whichever comes first

Secondary Outcome Measures

Outcome Measure	Time Frame
Changes in Markers of Inflammation, Oxidative Stress, Cellular Hypoxia and Coagulation/Thrombosis.	study hour 0, 6, 24 & 72
Resource Use and Costs of Alternative Resuscitation Strategies	at discharge or 60 days, whichever comes first

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Institute of General Medical Sciences (NIGMS)
• Investigators: Principal Investigator: Derek C. Angus, MD, MPH, University of Pittsburgh; Principal Investigator: John A. Kellum, MD, University of Pittsburgh; Principal Investigator: Donald M. Yealy, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307.
• Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.
• Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts--blood transfusion. N Engl J Med. 1999 Feb 11;340(6):438-47. doi: 10.1056/NEJM199902113400606. No abstract available.
• Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006 Dec 28;355(26):2725-32. doi: 10.1056/NEJMoa061115. Erratum In: N Engl J Med. 2007 Jun 21;356(25):2660.
• O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979 Sep;35(3):549-56.
• Maki DG, Stolz SM, Wheeler S, Mermel LA. Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter. A randomized, controlled trial. Ann Intern Med. 1997 Aug 15;127(4):257-66. doi: 10.7326/0003-4819-127-4-199708150-00001.
• Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001 Jul;29(7):1303-10. doi: 10.1097/00003246-200107000-00002.
• Dellinger RP. Cardiovascular management of septic shock. Crit Care Med. 2003 Mar;31(3):946-55. doi: 10.1097/01.CCM.0000057403.73299.A6. No abstract available.
• Kochanek KD, Smith BL. Deaths: preliminary data for 2002. Natl Vital Stat Rep. 2004 Feb 11;52(13):1-47.
• Rivers EP, Ander DS, Powell D. Central venous oxygen saturation monitoring in the critically ill patient. Curr Opin Crit Care. 2001 Jun;7(3):204-11. doi: 10.1097/00075198-200106000-00011.
• Feezor RJ, Baker HV, Mindrinos M, Hayden D, Tannahill CL, Brownstein BH, Fay A, MacMillan S, Laramie J, Xiao W, Moldawer LL, Cobb JP, Laudanski K, Miller-Graziano CL, Maier RV, Schoenfeld D, Davis RW, Tompkins RG; Inflammation and Host Response to Injury, Large-Scale Collaborative Research Program. Whole blood and leukocyte RNA isolation for gene expression analyses. Physiol Genomics. 2004 Nov 17;19(3):247-54. doi: 10.1152/physiolgenomics.00020.2004.
• McGee WT, Ackerman BL, Rouben LR, Prasad VM, Bandi V, Mallory DL. Accurate placement of central venous catheters: a prospective, randomized, multicenter trial. Crit Care Med. 1993 Aug;21(8):1118-23. doi: 10.1097/00003246-199308000-00008.
• Dodd RY, Notari EP 4th, Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor population. Transfusion. 2002 Aug;42(8):975-9. doi: 10.1046/j.1537-2995.2002.00174.x.
• Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004 Sep;32(9):1928-48. doi: 10.1097/01.ccm.0000139761.05492.d6.
• Rady MY, Smithline HA, Blake H, Nowak R, Rivers E. A comparison of the shock index and conventional vital signs to identify acute, critical illness in the emergency department. Ann Emerg Med. 1994 Oct;24(4):685-90. doi: 10.1016/s0196-0644(94)70279-9. Erratum In: Ann Emerg Med 1994 Dec;24(6):1208.
• Yealy DM, Delbridge TR. The shock index: all that glitters.. Ann Emerg Med. 1994 Oct;24(4):714-5. No abstract available.
• Rady MY, Rivers EP, Nowak RM. Resuscitation of the critically ill in the ED: responses of blood pressure, heart rate, shock index, central venous oxygen saturation, and lactate. Am J Emerg Med. 1996 Mar;14(2):218-25. doi: 10.1016/s0735-6757(96)90136-9.
• Fiorentino M, Xu Z, Smith A, Singbartl K, Palevsky PM, Chawla LS, Huang DT, Yealy DM, Angus DC, Kellum JA; ProCESS and ProGReSS-AKI Investigators. Serial Measurement of Cell-Cycle Arrest Biomarkers [TIMP-2] . [IGFBP7] and Risk for Progression to Death, Dialysis, or Severe Acute Kidney Injury in Patients with Septic Shock. Am J Respir Crit Care Med. 2020 Nov 1;202(9):1262-1270. doi: 10.1164/rccm.201906-1197OC.
• Massey MJ, Hou PC, Filbin M, Wang H, Ngo L, Huang DT, Aird WC, Novack V, Trzeciak S, Yealy DM, Kellum JA, Angus DC, Shapiro NI; ProCESS investigators. Microcirculatory perfusion disturbances in septic shock: results from the ProCESS trial. Crit Care. 2018 Nov 20;22(1):308. doi: 10.1186/s13054-018-2240-5.
• Hou PC, Filbin MR, Wang H, Ngo L, Huang DT, Aird WC, Yealy DM, Angus DC, Kellum JA, Shapiro NI; ProCESS Investigators( *). Endothelial Permeability and Hemostasis in Septic Shock: Results From the ProCESS Trial. Chest. 2017 Jul;152(1):22-31. doi: 10.1016/j.chest.2017.01.010. Epub 2017 Jan 19.
• ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

Helpful Links

• ProCESS Study Web Site

Study record dates

Study Major Dates

• Study Start: March 1, 2008
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: July 18, 2007
• First Submitted That Met QC Criteria: August 1, 2007
• First Posted (Estimate): August 2, 2007

Study Record Updates

• Last Update Posted (Estimate): January 26, 2017
• Last Update Submitted That Met QC Criteria: December 1, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: septic shock; sepsis; cost-effectiveness; emergency medicine; resuscitation; critical care medicine; sepsis-induced organ dysfunction; early goal directed therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock
• Other Study ID Numbers: P50GM076659 (U.S. NIH Grant/Contract)