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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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.
KeywordsCritical 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.
- 1.Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39:165–228CrossRefPubMedGoogle Scholar
- 4.Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DM (2011) Mortality after fluid bolus in African children with severe infection. N Engl J Med 364:2483–2495CrossRefPubMedGoogle Scholar
- 5.Hjortrup PB, Haase N, Wetterslev J, Perner A (2016) Associations of hospital and patient characteristics with fluid resuscitation volumes in patients with severe sepsis: post hoc analyses of data from a multicentre randomised clinical trial. PLoS One 11:e0155767CrossRefPubMedPubMedCentralGoogle Scholar
- 9.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 (2012) Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 367:124–134CrossRefPubMedGoogle Scholar
- 10.ICH Steering Committee (1998) International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH Harmonised Tripartite Guideline for Statistical Principles for Clinical Trials, 3rd edn. Brookwood Medical Publications, LondonGoogle Scholar
- 17.Angus DC, Barnato AE, Bell D, Bellomo R, Chong CR, Coats TJ, Davies A, Delaney A, Harrison DA, Holdgate A, Howe B, Huang DT, Iwashyna T, Kellum JA, Peake SL, Pike F, Reade MC, Rowan KM, Singer M, Webb SA, Weissfeld LA, Yealy DM, Young JD (2015) A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med 41:1549–1560CrossRefPubMedGoogle Scholar
- 18.Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della RG, Aldecoa C, Artigas A, Jog S, Sander M, Spies C, Lefrant JY, De BD (2015) Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med 41:1529–1537CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De Backer D, Divatia J, Du B, Evans L, Ferrer R, Girardis M, Koulenti D, Machado F, Simpson SQ, Tan CC, Wittebole X, Levy M (2015) The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med 41:1620–1628CrossRefPubMedGoogle Scholar
- 22.Vaara ST, Korhonen AM, Kaukonen KM, Nisula S, Inkinen O, Hoppu S, Laurila JJ, Mildh L, Reinikainen M, Lund V, Parviainen I, Pettila V (2012) Fluid overload is associated with an increased risk for 90-day mortality in critically ill patients with renal replacement therapy: data from the prospective FINNAKI study. Crit Care 16:R197CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, Nebrich L, Nibro HL, Rasmussen BS, Lauridsen JR, Nielsen JS, Oldner A, Pettila V, Cronhjort MB, Andersen LH, Pedersen UG, Reiter N, Wiis J, White JO, Russell L, Thornberg KJ, Hjortrup PB, Muller RG, Moller MH, Steensen M, Tjader I, Kilsand K, Odeberg-Wernerman S, Sjobo B, Bundgaard H, Thyo MA, Lodahl D, Maerkedahl R, Albeck C, Illum D, Kruse M, Winkel P, Perner A (2014) Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 371:1381–1391CrossRefPubMedGoogle Scholar
- 24.Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L (2014) Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 370:1412–1421CrossRefPubMedGoogle Scholar
- 25.Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le TY, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Herve F, du CD, Guerin C, Mercat A, Teboul JL, Radermacher P (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593CrossRefPubMedGoogle Scholar