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.
Similar content being viewed by others
References
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 39:165–228
Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA (2011) Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 39:259–265
Acheampong A, Vincent JL (2015) A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 19:251
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 364:2483–2495
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:e0155767
Ait-Oufella H, Lemoinne S, Boelle PY, Galbois A, Baudel JL, Lemant J, Joffre J, Margetis D, Guidet B, Maury E, Offenstadt G (2011) Mottling score predicts survival in septic shock. Intensive Care Med 37:801–807
Wacharasint P, Nakada TA, Boyd JH, Russell JA, Walley KR (2012) Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock 38:4–10
Kellum JA, Lameire N (2013) Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 17:204
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 367:124–134
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, London
Seymour CW, Rosengart MR (2015) Septic shock: advances in diagnosis and treatment. JAMA 314:708–717
Perner A, Vieillard-Baron A, Bakker J (2015) Fluid resuscitation in ICU patients: quo vadis? Intensive Care Med 41:1667–1669
Myburgh JA, Mythen MG (2013) Resuscitation fluids. N Engl J Med 369:1243–1251
Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014) A randomized trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693
Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506
Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM (2015) Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 372:1301–1311
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 41:1549–1560
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 41:1529–1537
Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, Osborn T, Lemeshow S, Chiche JD, Artigas A, Dellinger RP (2014) Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Intensive Care Med 40:1623–1633
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 41:1620–1628
Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Jr Le Gall, Payen D (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353
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:R197
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 371:1381–1391
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 370:1412–1421
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 370:1583–1593
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
Consortia
Corresponding author
Ethics declarations
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-016-4500-7