Scandinavian Starch for Severe Sepsis/Septic Shock Trial (6S)

Effects of Hydroxyethyl Starch 130/0.4 Compared With Balanced Crystalloid Solution on Mortality and Kidney Failure in Patients With Severe Sepsis

• By tradition hydroxyethyl starch (HES) is used to obtain fast circulatory stabilisation in critically ill.
• High molecular weight HES may, however, cause acute kidney failure in patients with severe sepsis.
• Now the low molecular weight HES 130/0.4 is the preferred colloid in Scandinavian intensive care units (ICU) and 1st choice fluid for patients with severe sepsis.
• HES 130/0.4 is largely unstudied in ICU patients.
• This investigator-initiated Scandinavian multicentre trial will be conducted to assess the effects of HES 130/0.4 on mortality and endstage kidney failure in patients with severe sepsis.
• The trial will provide important data to all clinicians who resuscitate septic patients.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: Drug: 6% Hydroxyethyl starch 130/0.4; Drug: Ringers acetate

Detailed Description

Fluid is the mainstay treatment in sepsis resuscitation, but the effects of different crystalloid and colloid solutions on outcome remain unknown.

Previously, a high molecular weight hydroxyethyl starch, HES 200, was used, but this was found to cause acute kidney failure in patients with severe sepsis. As kidney failure is an independent risk factor for death in these patients, HES 200 is not used anymore. In stead a lower molecular weight starch, HES 130, has been developed. Presently, this is the preferred colloid in Scandinavian intensive care units (ICU), but the effects of HES 130 in ICU patients are currently unknown. The proposed Scandinavian multicentre study will be conducted to assess if HES 130 contributes to acute kidney failure in patients with severe sepsis. As HES 130 is widely used, the trial will provide important safety data to clinicians who resuscitate septic patients.

• Study Type: Interventional
• Enrollment (Actual): 804
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
  • Copenhagen, Denmark
    • Bispebjerg Hospital
  • Copenhagen, Denmark
    • Herlev Hospital
  • Copenhagen, Denmark
    • Hvidovre Hospital
  • Copenhagen, Denmark
    • Glostrup Hospital
  • Copenhagen, Denmark
    • Gentofte Hosptial
  • Esbjerg, Denmark
    • Esbjerg Hospital
  • Herning, Denmark
    • Herning Hospital
  • Hillerød, Denmark
    • Hillerød Hospital
  • Hjørring, Denmark
    • Hjørring Hospital
  • Holbæk, Denmark
    • Holbæk Hospital
  • Holstebro, Denmark
    • Holstebro Hospital
  • Køge, Denmark
    • Køge Hospital
  • Næstved, Denmark
    • Næstved Hospital
  • Odense, Denmark
    • Odense University Hospital
  • Slagelse, Denmark
    • Slagelse Hospital
  • Sønderborg, Denmark
    • Sønderborg Hospital
  • Vejle, Denmark
    • Vejle Hospital
• Finland
  • Helsinki, Finland
    • Dept of Intensive Care, Helsinki University Hospital
  • Kuopio, Finland
    • Dept. of Intensive Care, Kuopio University Hospital
  • Tampere, Finland
    • Dept of Intensive Care, Tampere University Hospital
• Iceland
  • Reykjavik, Iceland
    • Dept. of Intensive Care, Landspitali
• Norway
  • Bergen, Norway
    • Haukeland University Hospital
  • Stavanger, Norway
    • Stavanger University Hospital
  • Tromsø, Norway
    • Intensive Care Unit, University Hospital of North Norway
  • Trondheim, Norway
    • St Olavs Hospital, Trondheim University Hospital

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:

All adult patients who

• Undergo resuscitation in the ICU
• AND fulfillment within the previous 24 hours of the criteria for severe sepsis (SCCM/ACCP)
• AND consent is obtainable either from the patient or by proxy (physician and/or next of kin)

Exclusion Criteria:

The following patients will not be evaluated for inclusion:

• Age < 18 years old
• Previously randomised in the 6S trial
• Allergy towards hydroxyethyl starch or malic acid
• Treatment with > 1000 ml's of any synthetic colloid within the last 24 hours prior to randomisation
• Any form of renal replacement therapy
• Acute burn injury > 10% body surface area
• Severe hyperkalaemia, p-K > 6 mM
• Liver or kidney transplantation during current hospital admission
• Intracranial bleeding within current hospitalisation
• Enrollment into another ICU trial of drugs with potential action on circulation, renal function or coagulation
• Withdrawal of active therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: HES 130/0.4; Volume expansion	Drug: 6% Hydroxyethyl starch 130/0.4; Infusion for volume expansion in the ICU; Other Names: 6% Tetraspan
ACTIVE_COMPARATOR: Ringer acetate; Volume expansion	Drug: Ringers acetate; Infusion for volume expansion in the ICU; Other Names: Ringerfundin / Sterofundin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mortality or dialysis-dependency	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		1 year
Hospital length of stay		90 days
Mortality		28 days
Mortality		6 months
Severity organ failure assessment score	Excluding Glascow coma score	Day 5
Days free of ventilation	Among survivors	90 days
Days free of dialysis	Among survivors	90 days
Serious adverse reactions	Severe bleeding or severe allergic reactions	Followed up until ICU discharge; consequently the time frame will vary among patients
Need of dialysis/haemofiltration		Within 90 days
Need of ventilation		Within 90 days
Kidney failure	Severity organ failure assessment score > 2 in the renal component	Followed up until ICU discharge; consequently the time frame will vary among patients
Coagulation analyses	At selected hospitals whole-blood and biochemical coagulation analyses constitute additional secondary endpoints	5 days
NGAL	At selected trial sites will plasma and urinary NGAL be analysed at randomisation to assess the predictive value for dialyse and kidney failure	5 days

Collaborators and Investigators

• Sponsor: Anders Perner
• Collaborators: Rigshospitalet, Denmark; University of Copenhagen; B. Braun Melsungen AG; Copenhagen Trial Unit, Center for Clinical Intervention Research
• Investigators: Principal Investigator: Anders Perner, MD, PhD, ICU, Rigshospitalet, University of Copenhagen; Study Director: Nicolai Haase, MD, Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Perner A, Haase N, Wetterslev J, Aneman A, Tenhunen J, Guttormsen AB, Klemenzson G, Pott F, Bodker KD, Badstolokken PM, Bendtsen A, Soe-Jensen P, Tousi H, Bestle M, Pawlowicz M, Winding R, Bulow HH, Kancir C, Steensen M, Nielsen J, Fogh B, Madsen KR, Larsen NH, Carlsson M, Wiis J, Petersen JA, Iversen S, Schoidt O, Leivdal S, Berezowicz P, Pettila V, Ruokonen E, Klepstad P, Karlsson S, Kaukonen M, Rutanen J, Karason S, Kjaeldgaard AL, Holst LB, Wernerman J; Scandinavian Critical Care Trials Group. Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial. Trials. 2011 Jan 27;12:24. doi: 10.1186/1745-6215-12-24.
• Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH, Elkjaer JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Soe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjaeldgaard AL, Fabritius ML, Mondrup F, Pott FC, Moller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124-34. doi: 10.1056/NEJMoa1204242. Epub 2012 Jun 27. Erratum In: N Engl J Med. 2012 Aug 2;367(5):481.
• Ostrowski SR, Haase N, Muller RB, Moller MH, Pott FC, Perner A, Johansson PI. Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study. Crit Care. 2015 Apr 24;19(1):191. doi: 10.1186/s13054-015-0918-5.
• Perner A, Haase N, Winkel P, Guttormsen AB, Tenhunen J, Klemenzson G, Muller RG, Aneman A, Wetterslev J. Long-term outcomes in patients with severe sepsis randomised to resuscitation with hydroxyethyl starch 130/0.42 or Ringer's acetate. Intensive Care Med. 2014 Jul;40(7):927-34. doi: 10.1007/s00134-014-3311-y. Epub 2014 May 8.
• Muller RG, Haase N, Wetterslev J, Perner A. Effects of hydroxyethyl starch in subgroups of patients with severe sepsis: exploratory post-hoc analyses of a randomised trial. Intensive Care Med. 2013 Nov;39(11):1963-71. doi: 10.1007/s00134-013-3090-x. Epub 2013 Sep 14.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): March 1, 2012
• Study Completion (ACTUAL): March 1, 2012

Study Registration Dates

• First Submitted: August 18, 2009
• First Submitted That Met QC Criteria: August 18, 2009
• First Posted (ESTIMATE): August 19, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): July 10, 2012
• Last Update Submitted That Met QC Criteria: July 9, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Shock; Sepsis; Fluid therapy; Plasma expanders
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Plasma Substitutes; Blood Substitutes; Hydroxyethyl Starch Derivatives
• Other Study ID Numbers: 2008-262; EudraCT no. 2009-010104-28