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Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial

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Abstract

Purpose

We assessed the effects of a protocol restricting resuscitation fluid vs. a standard care protocol after initial resuscitation in intensive care unit (ICU) patients with septic shock.

Methods

We randomised 151 adult patients with septic shock who had received initial fluid resuscitation in nine Scandinavian ICUs. In the fluid restriction group fluid boluses were permitted only if signs of severe hypoperfusion occurred, while in the standard care group fluid boluses were permitted as long as circulation continued to improve.

Results

The co-primary outcome measures, resuscitation fluid volumes at day 5 and during ICU stay, were lower in the fluid restriction group than in the standard care group [mean differences −1.2 L (95 % confidence interval −2.0 to −0.4); p < 0.001 and −1.4 L (−2.4 to −0.4) respectively; p < 0.001]. Neither total fluid inputs and balances nor serious adverse reactions differed statistically significantly between the groups. Major protocol violations occurred in 27/75 patients in the fluid restriction group. Ischaemic events occurred in 3/75 in the fluid restriction group vs. 9/76 in the standard care group (odds ratio 0.32; 0.08–1.27; p = 0.11), worsening of acute kidney injury in 27/73 vs. 39/72 (0.46; 0.23–0.92; p = 0.03), and death by 90 days in 25/75 vs. 31/76 (0.71; 0.36–1.40; p = 0.32).

Conclusions

A protocol restricting resuscitation fluid successfully reduced volumes of resuscitation fluid compared with a standard care protocol in adult ICU patients with septic shock. The patient-centred outcomes all pointed towards benefit with fluid restriction, but our trial was not powered to show differences in these exploratory outcomes.

Trial registration

NCT02079402.

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Acknowledgments

The CLASSIC trial was funded by the Danish Medical Research Council (09-066938) and supported by Rigshospitalets Research Council, the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (the ACTA Foundation) and the Ehrenreich Foundation. The funders of the study had no influence on the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. We are grateful to the clinical staff of doctors and nurses at the participating ICUs for their important contribution and to patients and relatives for their consent to participate.

The CLASSIC trial investigators

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

Trial site investigators (in Denmark unless otherwise specified): Rigshospitalet: P.B. Hjortrup, A. Perner, N. Haase, K.R. Uhre, L.H. Nislev, L. Russell, C. Claudius, U.G. Pedersen, M.B. Madsen, M.H. Møller, M. Ibsen, K. Thornberg, F. Sjövall, F. Mondrup, H.C. Thorsen-Meyer, L. Quist, L. Vestergaard, C. Lund, J. Wiis, R. Hein-Rasmussen, C.P. Holler, J.O. White, S. Asghar; Randers Hospital: H. Bundgaard, D. Flye, K. Knudsen, B. Hougaard; Aalborg Hospital: B.S. Rasmussen, S.L. Thomsen, S.N. Granum; Herning Hospital: R. Winding, S. Haubjerg, L. Friholdt, N. Dey, M. Nygaard; Holbæk Hospital: H.H. Bülow, J.M. Elkjær, A. Aaen, S. Grangaard, L. Christensen, M. Hjort, S. Larsen; Helsinki University Hospital, Finland: V. Pettilä, E. Wilkman, M. Valkonen, S. Sutinen, L. Pettilä; Holstebro Hospital: D. Lodahl, R.V.M. Andersen; Nordsjællands Hospital: R.E. Berthelsen, M. Bestle, S. Lauritzen, L. Valbjørn; Herlev Hospital: H. Christensen.

Author information

Authors and Affiliations

  1. Department of Intensive Care, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Peter B. Hjortrup, Nicolai Haase, Martin B. Madsen & Anders Perner

  2. Department of Intensive Care, Randers Hospital, Randers, Denmark

    Helle Bundgaard

  3. Department of Intensive Care, Aalborg University Hospital, Aalborg, Denmark

    Simon L. Thomsen

  4. Department of Intensive Care, Herning Hospital, Herning, Denmark

    Robert Winding

  5. Department of Intensive Care, Helsinki University Hospital, Helsinki, Finland

    Ville Pettilä

  6. Department of Intensive Care, Holbæk Hospital, Holbæk, Denmark

    Anne Aaen

  7. Department of Intensive Care, Holstebro Hospital, Holstebro, Denmark

    David Lodahl

  8. Department of Intensive Care, Nordsjællands Hospital, Hillerød, Denmark

    Rasmus E. Berthelsen

  9. Department of Intensive Care, Herlev Hospital, Herlev Municipality, Denmark

    Henrik Christensen

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

    Per Winkel & Jørn Wetterslev

  11. Centre for Research in Intensive Care, Copenhagen, Denmark

    Anders Perner

Authors
  1. Peter B. Hjortrup
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  2. Nicolai Haase
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  5. Robert Winding
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  6. Ville Pettilä
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  7. Anne Aaen
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  8. David Lodahl
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  9. Rasmus E. Berthelsen
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  10. Henrik Christensen
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  11. Martin B. Madsen
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  12. Per Winkel
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  13. Jørn Wetterslev
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  14. Anders Perner
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Consortia

The CLASSIC Trial Group

The Scandinavian Critical Care Trials Group

Corresponding author

Correspondence to Anders Perner.

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Conflicts of interest

The Department of Intensive Care, Rigshospitalet receives research funds from CSL Behring, Switzerland, Fresenius Kabi, Germany, and Ferring Pharmaceuticals, Denmark.

Additional information

The members of the CLASSIC Trial Group are listed in the Acknowledgments.

Take-home message: A fluid restriction protocol in septic shock resulted in less resuscitation fluid being given to fewer patients. The patient-centred outcomes all pointed towards benefit with fluid restriction, but our trial was not powered to show differences in these exploratory outcomes.

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Hjortrup, P.B., Haase, N., Bundgaard, H. et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 42, 1695–1705 (2016). https://doi.org/10.1007/s00134-016-4500-7

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  • DOI: https://doi.org/10.1007/s00134-016-4500-7

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