Intensive Care Medicine

, Volume 42, Issue 11, pp 1695–1705 | Cite as

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

  • Peter B. Hjortrup
  • Nicolai Haase
  • Helle Bundgaard
  • Simon L. Thomsen
  • Robert Winding
  • Ville Pettilä
  • Anne Aaen
  • David Lodahl
  • Rasmus E. Berthelsen
  • Henrik Christensen
  • Martin B. Madsen
  • Per Winkel
  • Jørn Wetterslev
  • Anders Perner
  • The CLASSIC Trial Group
  • The Scandinavian Critical Care Trials Group
Seven-Day Profile Publication



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.


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.


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).


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



Critical care Fluid therapy Intensive care Resuscitation Sepsis Septic Shock 



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.

Compliance with ethical standards

Conflicts of interest

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

Supplementary material

134_2016_4500_MOESM1_ESM.pdf (1.2 mb)
Supplementary material 1 (PDF 1188 kb)
134_2016_4500_MOESM2_ESM.pdf (630 kb)
Supplementary material 2 (PDF 629 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2016

Authors and Affiliations

  • Peter B. Hjortrup
    • 1
  • Nicolai Haase
    • 1
  • Helle Bundgaard
    • 2
  • Simon L. Thomsen
    • 3
  • Robert Winding
    • 4
  • Ville Pettilä
    • 5
  • Anne Aaen
    • 6
  • David Lodahl
    • 7
  • Rasmus E. Berthelsen
    • 8
  • Henrik Christensen
    • 9
  • Martin B. Madsen
    • 1
  • Per Winkel
    • 10
  • Jørn Wetterslev
    • 10
  • Anders Perner
    • 1
    • 11
  • The CLASSIC Trial Group
  • The Scandinavian Critical Care Trials Group
  1. 1.Department of Intensive Care, Copenhagen University HospitalRigshospitaletCopenhagenDenmark
  2. 2.Department of Intensive CareRanders HospitalRandersDenmark
  3. 3.Department of Intensive CareAalborg University HospitalAalborgDenmark
  4. 4.Department of Intensive CareHerning HospitalHerningDenmark
  5. 5.Department of Intensive CareHelsinki University HospitalHelsinkiFinland
  6. 6.Department of Intensive CareHolbæk HospitalHolbækDenmark
  7. 7.Department of Intensive CareHolstebro HospitalHolstebroDenmark
  8. 8.Department of Intensive CareNordsjællands HospitalHillerødDenmark
  9. 9.Department of Intensive CareHerlev HospitalHerlev MunicipalityDenmark
  10. 10.Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University HospitalRigshospitaletCopenhagenDenmark
  11. 11.Centre for Research in Intensive CareCopenhagenDenmark

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