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Long-term outcomes in patients with severe sepsis randomised to resuscitation with hydroxyethyl starch 130/0.42 or Ringer’s acetate

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Abstract

Purpose

We assessed long-term mortality and hospitalisation in patients with severe sepsis resuscitated with hydroxyethyl starch (HES) or Ringer’s acetate.

Methods

This was an investigator-initiated, parallel-grouped, blinded randomised trial using computer-generated allocation sequence and centralised allocation data that included 804 patients with severe sepsis needing fluid resuscitation in 26 general intensive care units (ICUs) in Scandinavia. Patients were allocated to fluid resuscitation using either 6 % HES 130/0.42 or Ringer’s acetate during ICU admission. We assessed mortality rates at 6 months, 1 year and at the time of longest follow-up and days alive and out of hospital at 1 year.

Results

The vital status of all patients was obtained at a median of 22 (range 13–36) months after randomisation. Mortality rates in the HES versus Ringer’s groups at 6 months were 53.3 (212/398 patients) versus 47.5 % (190/400) [relative risk 1.12; 95 % confidence interval (CI) 0.98–1.29; P = 0.10], respectively; at 1 year, 56.0 (223/398) versus 51.5 % (206/400) (1.09; 95 % CI 0.96–1.24; P = 0.20), respectively; at the time of longest follow-up, 59.8 (238/398) versus 56.3 % (225/400) (1.06; 95 % CI 0.94–1.20; P = 0.31), respectively. Percentage of days alive and out of hospital at 1 year in the HES versus Ringer’s groups was 24 (0–87 days) versus 63 % (0–90) (P = 0.07).

Conclusions

The long-term mortality rates did not differ in patients with severe sepsis assigned to HES 130/0.42 versus Ringer’s acetate, but we could not reject a 24 % relative increased or a 4 % relative decreased mortality at 1 year with HES at the 95 % confidence level.

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Conflicts of interest

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: The 6S trial was funded by the Danish Medical Research Council (271-08-0691 and 09-066938) and supported by Rigshospitalets Research Council and the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (the ACTA foundation) and endorsed by the European Clinical Research Infrastructures Network (ECRIN). B Braun AG delivered trial fluids to all trial sites free of charges. Neither the funding organisations nor B Braun had any influence on (1) the design and conduct of the study; (2) the collection, management, analysis and interpretation of the data; (3) the preparation, review or approval of the manuscript; (4) the decision to submit the manuscript for publication. AP is head of research in his ICU, which receives research funds from CSL Behring, Switzerland, Fresenius Kabi, Germany, COSMED, Italy and Bioporto Diagnostics A/S, Denmark and has received a speaker’s fee from LFP SA, France. B Braun AG has covered his travel expenses for presenting 6S-data at the German Anaesthetic Congress 2012.

Author information

Authors and Affiliations

  1. Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark

    Anders Perner, Nicolai Haase & Rasmus G. Müller

  2. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark

    Per Winkel & Jørn Wetterslev

  3. Department of Anaesthesia and Intensive Care, Haukeland University Hospital, Bergen, Norway

    Anne B. Guttormsen

  4. Department of Clinical Medicine 1, University of Bergen, Bergen, Norway

    Anne B. Guttormsen

  5. Critical Care Medicine Research Group in Department of Intensive Care Medicine, Tampere University Hospital, Tampere, Finland

    Jyrki Tenhunen

  6. Department of Surgical Sciences/Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden

    Jyrki Tenhunen

  7. Department of Anaesthesia and Intensive Care, Landspitali, Reykjavik, Iceland

    Gudmundur Klemenzson

  8. Department of Intensive Care, Liverpool Hospital, Sydney, Australia

    Anders Åneman

Authors
  1. Anders Perner
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  2. Nicolai Haase
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  3. Per Winkel
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  4. Anne B. Guttormsen
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  5. Jyrki Tenhunen
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  6. Gudmundur Klemenzson
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  7. Rasmus G. Müller
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  8. Anders Åneman
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  9. Jørn Wetterslev
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Corresponding author

Correspondence to Anders Perner.

Additional information

Take-home message:

The long-term mortality rates did not differ in patients with severe sepsis assigned to HES 130/0.42 versus Ringer’s acetate, but the trial was not powered to show this. As 90-day mortality differed, the data indicate that the harmful effects of HES occurred within the first months after randomisation.

On behalf of the 6S trial group, and the Scandinavian Critical Care Trials Group.

Members of the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial group are listed in the Appendix.

Trial registration: clinicaltrials.gov NCT00962156.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 26 kb)

Appendix

Appendix

The 6S trial investigators

Steering Committee: Anders Perner (Chair), Nicolai Haase, Anne B. Guttormsen, Jyrki Tenhunen, Gudmundur Klemenzson, Anders Åneman and Jørn Wetterslev.

Management Committee: Anders Perner (Chair), Nicolai Haase and Jørn Wetterslev.

Scientific Committee: Simon Finfer, Andre Vercueil, Lars S. Rasmussen and Frank Brunkhorst.

Data Monitoring and Safety Committee: Daniel De Backer (Chair), Peter Dalgaard and Kathy Rowan.

Writing Committee: Anders Perner (Chair), Nicolai Haase and Jørn Wetterslev.

Trial site investigators (in Denmark unless otherwise specified): Rigshospitalet: A. Perner, N. Haase, M.N. Kjær, K.R. Uhre, V. Knudsen, V. Christiansen, A. Schulze, J. Wiis, J.O. White, K. Thornberg, L.Quist, F. Sjøvall, N. Wesche, N. Reiter, I.L. Jarnvig; Næstved Hospital: K.R. Madsen, A. L. Kjældgaard, M. L. Fabritius, F. Mondrup, K.F. Sommer, L. F. Pedersen; Bispebjerg Hospital: M.H. Møller, F.C. Pott, J.A. Petersen, A. Lindhardt, K. Møller, A. Haraldson, C. Pedersen; Holbæk Hospital: H.H. Bülow, J.M. Elkjær, T. P. Møller, L.H. Andersen, L.B. Holst, J.F. Schmidt, S.T. Nielsen, F.P. Treschow, M. Overgaard, H. Ahlstrøm, S. Grangaard, J.H. Bruun, S. Larsen; Køge Hospital: L.M. Poulsen, M.V. Madsen, B. Bang; Glostrup Hospital: A. Bendtsen, Herning Hospital R. Winding, K.V. Jepsen, S. Haubjerg, N. Dey, J. Hjørringsgaard; Hvidovre Hospital: M. Steensen, J. Nielsen, C. Albek, S. Petersen, A. Christensen, A. Kristensen; Vejle Hospital: P.Berezowicz; Herlev Hospital: P. Søe-Jensen, H. Tousi; Hillerød Hospital: M. Bestle, K. Nielsen, T. Kold, K. Grundahl; Stavanger University Hospital, Norway: K. Strand, O. Larsen; Slagelse Hospital: S. Iversen, O. Schøidt; Hjørring Hospital: M. Pawlowicz, M. Kruse, H.S. Rasmussen, L.O. Nielsen; Haukeland University Hospital, Bergen, Norway: A.B. Guttormsen, B. Sjøbø; Sønderborg Hospital: S. Leivdal; Tromsø University Hospital, Norway: L.M. Ytrebø; Tampere University Hospital, Finland: J. Tenhunen, S. Karlsson, A. Kukkurainen, S. Kortelainen, M.L. Peltola, S. Varila; Gentofte Hospital: K. Thormar, P.M. Bådstøløkken; Landspitali, Reykjavik, Iceland: G. Klemenzson, S. Karason; Helsinki University Hospital, Finland: V. Pettilä, M. Kaukonen, L. Pettilä, S. Sutinen; Odense University Hospital: M. Carlson, N.H. Lassen, U.L. Larsen, K.D. Jung; Holstebro Hospital: C. Kancir; Kuopio University Hospital, Finland: J. Rutanen, E. Ruokonen, S. Rissanen, K. Kontra; Trondheim University Hospital, Norway: P. Klepstad; Esbjerg Hospital: R.E. Berthelsen, K.D. Bødker, B. Dilling.

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Perner, A., Haase, N., Winkel, P. et al. Long-term outcomes in patients with severe sepsis randomised to resuscitation with hydroxyethyl starch 130/0.42 or Ringer’s acetate. Intensive Care Med 40, 927–934 (2014). https://doi.org/10.1007/s00134-014-3311-y

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