original articleT h e n e w e ngl a

original article
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
124 n engl j med 367;2 nejm.org july 12, 2012
Hydroxyethyl Starch 130/0.42 versus
Ringer’s Acetate in Severe Sepsis
Anders Perner, M.D., Ph.D., Nicolai Haase, M.D.,
Anne B. Guttormsen, M.D., Ph.D., Jyrki Tenhunen, M.D., Ph.D.,
Gudmundur Klemenzson, M.D., Anders Åneman, M.D., Ph.D.,
Kristian R. Madsen, M.D., Morten H. Møller, M.D., Ph.D., Jeanie M. Elkjær, M.D.,
Lone M. Poulsen, M.D., Asger Bendtsen, M.D., M.P.H., Robert Winding, M.D.,
Morten Steensen, M.D., Pawel Berezowicz, M.D., Ph.D., Peter Søe-Jensen, M.D.,
Morten Bestle, M.D., Ph.D., Kristian Strand, M.D., Ph.D., Jørgen Wiis, M.D.,
Jonathan O. White, M.D., Klaus J. Thornberg, M.D., Lars Quist, M.D.,
Jonas Nielsen, M.D., Ph.D., Lasse H. Andersen, M.D., Lars B. Holst, M.D.,
Katrin Thormar, M.D., Anne-Lene Kjældgaard, M.D., Maria L. Fabritius, M.D.,
Frederik Mondrup, M.D., Frank C. Pott, M.D., D.M.Sci., Thea P. Møller, M.D.,
Per Winkel, M.D., D.M.Sci., and Jørn Wetterslev, M.D., Ph.D.,
for the 6S Trial Group and the Scandinavian Critical Care Trials Group*
The authors’ affiliations are listed in the
Appendix. Address reprint requests to
Dr. Perner at the Department of Intensive
Care 4131, Rigshospitalet, Blegdamsvej 9,
DK-2100 Copenhagen, Denmark, or at
[e-mail].
*Members of the Scandinavian Starch
for Severe Sepsis/Septic Shock (6S) trial
group are listed in the Supplementary
Appendix, available at NEJM.org.
This article was published on June 27, 2012,
and updated on July 12, 2012, at NEJM.org.
N Engl J Med 2012;367:124-34.
DOI: 10.1056/NEJMoa1204242
Copyright © 2012 Massachusetts Medical Society.
A BS TR AC T
Background
Hydroxyethyl starch (HES) is widely used for fluid resuscitation in intensive care
units (ICUs), but its safety and efficacy have not been established in patients with
severe sepsis.
Methods
In this multicenter, parallel-group, blinded trial, we randomly assigned patients
with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42
(Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal body
weight per day. The primary outcome measure was either death or end-stage kidney
failure (dependence on dialysis) at 90 days after randomization.
RESULTS
Of the 804 patients who underwent randomization, 798 were included in the modi-
fied intention-to-treat population. The two intervention groups had similar baseline
characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned
to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to
Ringer’s acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36;
P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period,
87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement
therapy versus 65 patients (16%) assigned to Ringer’s acetate (relative risk, 1.35; 95%
CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively,
had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results
were supported by multivariate analyses, with adjustment for known risk factors for
death or acute kidney injury at baseline.
CONCLUSIONS
Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an
increased risk of death at day 90 and were more likely to require renal-replacement
therapy, as compared with those receiving Ringer’s acetate. (Funded by the Danish
Research Council and others; 6S ClinicalTrials.gov number, NCT00962156.)
The New England Journal of Medicine
Downloaded from nejm.org on August 18, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
Starch or Ringer’s Acetate in Severe Sepsis
n engl j med 367;2 nejm.org july 12, 2012 125
Intravenous fluids are the mainstayof treatment for patients with hypovolemiadue to severe sepsis. Colloid solutions are used
to obtain rapid and lasting circulatory stabiliza-
tion, but there are limited data to support this
practice.1 The Surviving Sepsis Campaign guide-
lines recommend the use of either colloids or
crystalloids,2 but high-molecular-weight hydroxy-
ethyl starch (HES) may cause acute kidney failure
in patients with severe sepsis, as observed in two
randomized trials.3,4 Those trials had substantial
limitations, and participants received HES solu-
tions with a molecular weight of 200 kD and a
substitution ratio (the number of hydroxyethyl
groups per glucose molecule) of more than 0.4.3,4
These solutions have largely been replaced by
HES solutions with a lower molecular weight and
a lower substitution ratio, HES 130/0.4.5,6 There
are limited data about the effects of HES 130/0.4
in patients with severe sepsis,7 and its routine use
has recently been discouraged.8
Given the lack of efficacy data and concerns
about safety, we conducted the Scandinavian Starch
for Severe Sepsis/Septic Shock (6S) trial to evaluate
the effects of HES 130/0.4 as compared with
Ringer’s acetate on the composite outcome of
death or end-stage kidney failure in patients with
severe sepsis.
ME THODS
Trial Design and Oversight
Patients were screened and underwent random-
ization between December 23, 2009, and Novem-
ber 15, 2011, in Denmark, Norway, Finland, and
Iceland after the appropriate approvals. Patients
were screened at 26 general intensive care units
(ICUs) in 13 university and 13 nonuniversity hos-
pitals. Written informed consent was obtained
from patients or their legal surrogates before en-
rollment. In all cases, consent was obtained from
the patient when possible. If consent was with-
drawn or not granted, we asked the patient or sur-
rogate for permission to continue registration of
trial data and to use these data in the analyses. The
protocol, including details on trial conduct and
procedures and the statistical analysis plan, has
been published previously9 and is available with
the full text of this article at NEJM.org. B. Braun
Medical provided trial fluids to all trial sites free
of charge. Neither the funders nor B. Braun Med-
ical had influence on the protocol, trial conduct,
or data analyses or reporting. The steering com-
mittee vouches for the accuracy and completeness
of the data and the analysis and the fidelity of the
study to the protocol, and it made the decision to
submit the manuscript for publication. The writ-
ing committee had full access to all data and wrote
the manuscript with input from all authors. The
trial was endorsed by the European Clinical Re-
search Infrastructures Network.
This trial was an investigator-initiated, multi-
center, blinded, stratified, parallel-group clinical
trial with a computer-generated allocation se-
quence and centralized, blinded randomization.
We randomly assigned patients with severe sep-
sis in a 1:1 ratio to fluid resuscitation with either
HES 130/0.42 or Ringer’s acetate. Treatment as-
signments were concealed from patients, clini-
cians, research staff, the data monitoring and
safety committee, the statistician, and the writing
committee when it wrote the first draft for the
abstract (for details, see the Supplementary Ap-
pendix, available at NEJM.org). Randomization
was stratified according to the presence or ab-
sence of shock, the presence or absence of active
hematologic cancer, and admission to a univer-
sity or nonuniversity hospital, because these char-
acteristics might have influenced the outcome.10,11
The conduct of the trial and the safety of the
participants were overseen by the data monitor-
ing and safety committee, which performed an
interim analysis after 400 patients had under-
gone randomization.
Patients
We screened patients 18 years of age or older who
needed fluid resuscitation in the ICU, as judged by
the ICU clinicians, and who fulfilled the criteria
for severe sepsis within the previous 24 hours12
(for details, see the Supplementary Appendix).
Patients were excluded for the reasons shown in
Figure 1.
Interventions
Trial fluid (6% HES 130/0.42 in Ringer’s acetate
[Tetraspan 6%, B. Braun] or Ringer’s acetate
[Sterofundin ISO, B. Braun]; see the Supplemen-
tary Appendix for electrolyte content) was used
when ICU clinicians judged that volume expansion
was needed in the ICU for a maximum of 90 days.
Trial fluid was delivered in identical bags (Ecobag,
B. Braun), which were fully covered in custom-
made black, opaque plastic bags and sealed by
staff members who were not involved in data reg-
istration or patient care. The maximum daily dose
The New England Journal of Medicine
Downloaded from nejm.org on August 18, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
126 n engl j med 367;2 nejm.org july 12, 2012
was 33 ml per kilogram of ideal body weight (for
details, see the Supplementary Appendix). If doses
higher than the maximum daily dose were re-
quired, unmasked Ringer’s acetate was used, re-
gardless of the treatment assignment. In the event
of severe bleeding, a severe allergic reaction, or
the commencement of renal-replacement therapy
for acute kidney injury, trial fluid was permanent-
ly stopped and 0.9% saline or Ringer’s lactate
was given for volume expansion in the ICU until
804 Underwent randomization
1211 Patients were assessed for eligibility
407 Were excluded
6 Were 10% of body surface
9 Had intracranial bleeding
21 Had serum potassium >6 mmol per liter
within 6 hr before screening
25 Were included in another ICU trial
15 Withdrew from active therapy
152 Received >1000 ml of synthetic colloid
51 Were excluded because consent could
not be obtained
4 Were excluded after randomization
2 Underwent randomization without consent
2 Were excluded during the

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original articleT h e n e w e ngl a nd j o u r na l o f m e dic i n e124 n engl j med 367;2 nejm.org july 12, 2012Hydroxyethyl Starch 130/0.42 versusRinger’s Acetate in Severe SepsisAnders Perner, M.D., Ph.D., Nicolai Haase, M.D.,Anne B. Guttormsen, M.D., Ph.D., Jyrki Tenhunen, M.D., Ph.D.,Gudmundur Klemenzson, M.D., Anders Åneman, M.D., Ph.D.,Kristian R. Madsen, M.D., Morten H. Møller, M.D., Ph.D., Jeanie M. Elkjær, M.D.,Lone M. Poulsen, M.D., Asger Bendtsen, M.D., M.P.H., Robert Winding, M.D.,Morten Steensen, M.D., Pawel Berezowicz, M.D., Ph.D., Peter Søe-Jensen, M.D.,Morten Bestle, M.D., Ph.D., Kristian Strand, M.D., Ph.D., Jørgen Wiis, M.D.,Jonathan O. White, M.D., Klaus J. Thornberg, M.D., Lars Quist, M.D.,Jonas Nielsen, M.D., Ph.D., Lasse H. Andersen, M.D., Lars B. Holst, M.D.,Katrin Thormar, M.D., Anne-Lene Kjældgaard, M.D., Maria L. Fabritius, M.D.,Frederik Mondrup, M.D., Frank C. Pott, M.D., D.M.Sci., Thea P. Møller, M.D.,Per Winkel, M.D., D.M.Sci., and Jørn Wetterslev, M.D., Ph.D.,for the 6S Trial Group and the Scandinavian Critical Care Trials Group*The authors’ affiliations are listed in theAppendix. Address reprint requests toDr. Perner at the Department of IntensiveCare 4131, Rigshospitalet, Blegdamsvej 9,DK-2100 Copenhagen, Denmark, or [e-mail].*Members of the Scandinavian Starchfor Severe Sepsis/Septic Shock (6S) trialgroup are listed in the SupplementaryAppendix, available at NEJM.org.This article was published on June 27, 2012,and updated on July 12, 2012, at NEJM.org.N Engl J Med 2012;367:124-34.DOI: 10.1056/NEJMoa1204242Copyright © 2012 Massachusetts Medical Society.A BS TR AC TBackgroundHydroxyethyl starch (HES) is widely used for fluid resuscitation in intensive careunits (ICUs), but its safety and efficacy have not been established in patients withsevere sepsis.MethodsIn this multicenter, parallel-group, blinded trial, we randomly assigned patientswith severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42(Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal bodyweight per day. The primary outcome measure was either death or end-stage kidneyfailure (dependence on dialysis) at 90 days after randomization.RESULTSOf the 804 patients who underwent randomization, 798 were included in the modi-fied intention-to-treat population. The two intervention groups had similar baselinecharacteristics. At 90 days after randomization, 201 of 398 patients (51%) assignedto HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned toRinger’s acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36;P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period,87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacementtherapy versus 65 patients (16%) assigned to Ringer’s acetate (relative risk, 1.35; 95%CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively,had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The resultswere supported by multivariate analyses, with adjustment for known risk factors fordeath or acute kidney injury at baseline.CONCLUSIONSPatients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had anincreased risk of death at day 90 and were more likely to require renal-replacementtherapy, as compared with those receiving Ringer’s acetate. (Funded by the DanishResearch Council and others; 6S ClinicalTrials.gov number, NCT00962156.)The New England Journal of MedicineDownloaded from nejm.org on August 18, 2013. For personal use only. No other uses without permission. Copyright © 2012 Massachusetts Medical Society. All rights reserved.Starch or Ringer’s Acetate in Severe Sepsisn engl j med 367;2 nejm.org july 12, 2012 125Intravenous fluids are the mainstayof treatment for patients with hypovolemiadue to severe sepsis. Colloid solutions are usedto obtain rapid and lasting circulatory stabiliza-tion, but there are limited data to support thispractice.1 The Surviving Sepsis Campaign guide-lines recommend the use of either colloids orcrystalloids,2 but high-molecular-weight hydroxy-ethyl starch (HES) may cause acute kidney failurein patients with severe sepsis, as observed in tworandomized trials.3,4 Those trials had substantiallimitations, and participants received HES solu-tions with a molecular weight of 200 kD and asubstitution ratio (the number of hydroxyethylgroups per glucose molecule) of more than 0.4.3,4These solutions have largely been replaced byHES solutions with a lower molecular weight anda lower substitution ratio, HES 130/0.4.5,6 Thereare limited data about the effects of HES 130/0.4in patients with severe sepsis,7 and its routine usehas recently been discouraged.8Given the lack of efficacy data and concernsabout safety, we conducted the Scandinavian Starchfor Severe Sepsis/Septic Shock (6S) trial to evaluatethe effects of HES 130/0.4 as compared withRinger’s acetate on the composite outcome ofdeath or end-stage kidney failure in patients withsevere sepsis.ME THODSTrial Design and OversightPatients were screened and underwent random-ization between December 23, 2009, and Novem-ber 15, 2011, in Denmark, Norway, Finland, andIceland after the appropriate approvals. Patientswere screened at 26 general intensive care units(ICUs) in 13 university and 13 nonuniversity hos-pitals. Written informed consent was obtainedfrom patients or their legal surrogates before en-rollment. In all cases, consent was obtained fromthe patient when possible. If consent was with-drawn or not granted, we asked the patient or sur-rogate for permission to continue registration oftrial data and to use these data in the analyses. Theprotocol, including details on trial conduct andprocedures and the statistical analysis plan, hasbeen published previously9 and is available withthe full text of this article at NEJM.org. B. BraunMedical provided trial fluids to all trial sites freeof charge. Neither the funders nor B. Braun Med-ical had influence on the protocol, trial conduct,or data analyses or reporting. The steering com-mittee vouches for the accuracy and completenessof the data and the analysis and the fidelity of thestudy to the protocol, and it made the decision tosubmit the manuscript for publication. The writ-ing committee had full access to all data and wrotethe manuscript with input from all authors. Thetrial was endorsed by the European Clinical Re-search Infrastructures Network.This trial was an investigator-initiated, multi-center, blinded, stratified, parallel-group clinicaltrial with a computer-generated allocation se-quence and centralized, blinded randomization.We randomly assigned patients with severe sep-sis in a 1:1 ratio to fluid resuscitation with eitherHES 130/0.42 or Ringer’s acetate. Treatment as-signments were concealed from patients, clini-cians, research staff, the data monitoring andsafety committee, the statistician, and the writingcommittee when it wrote the first draft for theabstract (for details, see the Supplementary Ap-pendix, available at NEJM.org). Randomizationwas stratified according to the presence or ab-sence of shock, the presence or absence of active
hematologic cancer, and admission to a univer-
sity or nonuniversity hospital, because these char-
acteristics might have influenced the outcome.10,11
The conduct of the trial and the safety of the
participants were overseen by the data monitor-
ing and safety committee, which performed an
interim analysis after 400 patients had under-
gone randomization.
Patients
We screened patients 18 years of age or older who
needed fluid resuscitation in the ICU, as judged by
the ICU clinicians, and who fulfilled the criteria
for severe sepsis within the previous 24 hours12
(for details, see the Supplementary Appendix).
Patients were excluded for the reasons shown in
Figure 1.
Interventions
Trial fluid (6% HES 130/0.42 in Ringer’s acetate
[Tetraspan 6%, B. Braun] or Ringer’s acetate
[Sterofundin ISO, B. Braun]; see the Supplemen-
tary Appendix for electrolyte content) was used
when ICU clinicians judged that volume expansion
was needed in the ICU for a maximum of 90 days.
Trial fluid was delivered in identical bags (Ecobag,
B. Braun), which were fully covered in custom-
made black, opaque plastic bags and sealed by
staff members who were not involved in data reg-
istration or patient care. The maximum daily dose
The New England Journal of Medicine
Downloaded from nejm.org on August 18, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
T h e n e w e ngl a nd j o u r na l o f m e dic i n e
126 n engl j med 367;2 nejm.org july 12, 2012
was 33 ml per kilogram of ideal body weight (for
details, see the Supplementary Appendix). If doses
higher than the maximum daily dose were re-
quired, unmasked Ringer’s acetate was used, re-
gardless of the treatment assignment. In the event
of severe bleeding, a severe allergic reaction, or
the commencement of renal-replacement therapy
for acute kidney injury, trial fluid was permanent-
ly stopped and 0.9% saline or Ringer’s lactate
was given for volume expansion in the ICU until
804 Underwent randomization
1211 Patients were assessed for eligibility
407 Were excluded
6 Were <18 yr of age
138 Underwent renal-replacement therapy
1 Underwent kidney or liver transplantation
5 Had burn injury >10% of body surface
9 Had intracranial bleeding
21 Had serum potassium >6 mmol per liter
within 6 hr before screening
25 Were included in another ICU trial
15 Withdrew from active therapy
152 Received >1000 ml of synthetic colloid
51 Were excluded because consent could
not be obtained
4 Were excluded after randomization
2 Underwent randomization without consent
2 Were excluded during the