Intensive Care Medicine

, Volume 44, Issue 12, pp 2070–2078 | Cite as

Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial

  • Stephen P. J. MacdonaldEmail author
  • Gerben Keijzers
  • David McD Taylor
  • Frances Kinnear
  • Glenn Arendts
  • Daniel M. Fatovich
  • Rinaldo Bellomo
  • David McCutcheon
  • John F. Fraser
  • Juan-Carlos Ascencio-Lane
  • Sally Burrows
  • Edward Litton
  • Amanda Harley
  • Matthew Anstey
  • Ashes Mukherjee
  • for the REFRESH trial investigators



To determine if a regimen of restricted fluids and early vasopressor compared to usual care is feasible for initial resuscitation of hypotension due to suspected sepsis.


A prospective, randomised, open-label, clinical trial of a restricted fluid resuscitation regimen in the first 6 h among patients in the emergency department (ED) with suspected sepsis and a systolic blood pressure under 100 mmHg, after minimum 1000 ml of IV fluid. Primary outcome was total fluid administered within 6 h post randomisation.


There were 99 participants (50 restricted volume and 49 usual care) in the intention-to-treat analysis. Median volume from presentation to 6 h in the restricted volume group was 2387 ml [first to third quartile (Q1–Q3) 1750–2750 ml]; 30 ml/kg (Q1–Q3 32–39 ml/kg) vs. 3000 ml (Q1–Q3 2250–3900 ml); 43 ml/kg (Q1–Q3 35–50 ml/kg) in the usual care group (p < 0.001). Median duration of vasopressor support was 21 h (Q1–Q3 9–42 h) vs. 33 h (Q1–Q3 15–50 h), (p = 0.13) in the restricted volume and usual care groups, respectively. At 90-days, 4 of 48 (8%) in the restricted volume group and 3 of 47 (6%) in the usual care group had died. Protocol deviations occurred in 6/50 (12%) in restricted group and 11/49 (22%) in the usual care group, and serious adverse events in four cases (8%) in each group.


A regimen of restricted fluids and early vasopressor in ED patients with suspected sepsis and hypotension appears feasible. Illness severity was moderate and mortality rates low. A future trial is necessary with recruitment of high-risk patients to determine effects on clinical outcomes in this setting.


Fluid therapy Sepsis Septic shock Emergency medicine Critical care Resuscitation 



REFRESH trial investigators and participating sites: Armadale Health Service, WA (David McCutcheon, Ashes Mukherjee, Anton Leonard, Jonathan Burcham); Austin Health, VIC (David Taylor, Rinaldo Bellomo); Fiona Stanley Hospital, WA (Glenn Arendts, Edward Litton); Gold Coast University Hospital, QLD (Gerben Keijzers, Amanda Harley, James Winearls); Royal Hobart Hospital (Juan Carlos Ascencio-Lane, Simon Brown, David Cooper); Royal Perth Hospital/Centre for Clinical Research in Emergency Medicine, WA (Stephen Macdonald [steering committee chair], Daniel Fatovich, Lisa Smart); Sir Charles Gairdner Hospital, WA (Ioana Vlad, Bradley Wibrow, Matthew Anstey); The Prince Charles Hospital, QLD (Frances Kinnear, John Fraser). Trial Management and Coordination: Ellen Macdonald, Sophie Damianopoulos. Data Safety Monitoring Committee: Anthony Brown, Robert Boots, Michael Phillips. Trial endorsed by the Australasian College for Emergency Medicine Clinical Trials Group.


The REFRESH trial was an investigator-initiated study funded in part by a grant from the Emergency Medicine Foundation, Queensland, Australia EMSS-229R24-2015, and supported by the participating institutions.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Supplementary material

134_2018_5433_MOESM1_ESM.pdf (672 kb)
Supplementary material 1 (PDF 672 kb)


  1. 1.
    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851CrossRefPubMedGoogle Scholar
  3. 3.
    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Silversides JA, Major E, Ferguson AJ, Mann EE, McAuley DF, Marshall JC, Blackwood B, Fan E (2017) Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory distress syndrome following the resuscitation phase of critical illness: a systematic review and meta-analysis. Intensive Care Med 43:155–170CrossRefPubMedGoogle Scholar
  5. 5.
    Perner A, Cecconi M, Cronhjort M, Darmon M, Jakob SM, Pettila V, van der Horst ICC (2018) Expert statement for the management of hypovolemia in sepsis. Intensive Care Med 44:791–798CrossRefPubMedGoogle Scholar
  6. 6.
    National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr., Hite RD, Harabin AL (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564–2575CrossRefGoogle Scholar
  7. 7.
    Byrne L, Obonyo NG, Diab SD, Dunster KR, Passmore MR, Boon AC, See Hoe L, Pedersen S, Hashairi Fauzi M, Pretti Pimenta L, Van Haren F, Anstey CM, Cullen L, Tung JP, Shekar K, Maitland K, Fraser JF (2018) Unintended consequences; fluid resuscitation worsens shock in an ovine model of endotoxemia. Am J Respir Crit Care Med. CrossRefPubMedGoogle Scholar
  8. 8.
    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, on behalf of the FEAST trial group (2011) Mortality after fluid olus in Africal children with severe infection. N Engl J Med 364:2483–2495CrossRefPubMedGoogle Scholar
  9. 9.
    Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR (2017) Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension. JAMA 318:1233–1240CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Waechter J, Kumar A, Lapinsky SE, Marshall J, Dodek P, Arabi Y, Parrillo JE, Dellinger RP, Garland A, Cooperative Antimicrobial Therapy of Septic Shock Database Research Group (2014) Interaction between fluids and vasoactive agents on mortality in septic shock: a multicenter, observational study. Crit Care Med 42:2158–2168CrossRefPubMedGoogle Scholar
  11. 11.
    Bai X, Yu W, Ji W, Lin Z, Tan S, Duan K, Dong Y, Xu L, Li N (2014) Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care 18:532CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rowan KM, Angus DC, Bailey M, Barnato AE, Bellomo R, Canter RR, Coats TJ, Delaney A, Gimbel E, Grieve RD, Harrison DA, Higgins AM, Howe B, Huang DT, Kellum JA, Mouncey PR, Music E, Peake SL, Pike F, Reade MC, Sadique MZ, Singer M, Yealy DM, the PRISM Investigators (2017) Early, goal-directed therapy for septic shock: a patient-level meta-analysis. N Engl J Med 376:2223–2234CrossRefPubMedGoogle Scholar
  13. 13.
    Hamzaoui O, Georger JF, Monnet X, Ksouri H, Maizel J, Richard C, Teboul JL (2010) Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit Care 14:R142CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hallengren M, Astrand P, Eksborg S, Barle H, Frostell C (2017) Septic shock and the use of norepinephrine in an intermediate care unit: mortality and adverse events. PLoS One 12:e0183073CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Byrne L, Van Haren F (2017) Fluid resuscitation in human sepsis: time to rewrite history? Ann Intensive Care 7:4CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Finfer S, Myburgh J, Bellomo R (2018) Intravenous fluid therapy in critically ill adults. Nat Rev Nephrol 14:541–557CrossRefPubMedGoogle Scholar
  17. 17.
    Macdonald SPJ, Keijzers G, Taylor DM, Kinnear FB, Arendts G, Fatovich DM, Bellomo R, McCutcheon D, Fraser JF, Burrows S, Ascencio-Lane JC, Litton E, Harley A, Anstey M, Mukherjee A (2018) Restricted fluid resuscitation in sepsis associated hypotension (REFRESH): a propsective, multicentre, clinical feasibility trial. Intensive Care Med Exp 6:21 (Abstract presented at Sepsis 2018, Bangkok Thailand, 1 October 2018) CrossRefGoogle Scholar
  18. 18.
    Self WH, Semler MW, Bellomo R, Brown SM, deBoisblanc BP, Exline MC, Ginde AA, Grissom CK, Janz DR, Jones AE, Liu KD, Macdonald SPJ, Miller CD, Park PK, Reineck LA, Rice TW, Steingrub JS, Talmor D, Yealy DM, Douglas IS, Shapiro NI, CLOVERS Protocol Committee and NHLBI Prevention and Early Treatment of Acute Lung Injury (PETAL) Network Investigators (2018) Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial. Ann Emerg Med 72:457–466CrossRefPubMedGoogle Scholar
  19. 19.
    Macdonald SPJ, Taylor DM, Keijzers G, Arendts G, Fatovich DM, Kinnear FB, Brown SGA, Bellomo R, Burrows S, Fraser JF, Litton E, Ascencio-Lane JC, Anstey M, McCutcheon D, Smart L, Vlad I, Winearls J, Wibrow B (2017) Restricted fluid resuscitation in sepsis-associated hypotension (REFRESH): study protocol for a pilot randomised controlled trial. Trials 18:399CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P, the ARISE Investigators (2014) Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496–1506CrossRefPubMedGoogle Scholar
  21. 21.
    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42:377–381CrossRefGoogle Scholar
  22. 22.
    Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC (2015) Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock 43:68–73CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Acheampong A, Vincent JL (2015) A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 19:251CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sirvent JM, Ferri C, Baro A, Murcia C, Lorencio C (2015) Fluid balance in sepsis and septic shock as a determining factor of mortality. Am J Emerg Med 33:186–189CrossRefPubMedGoogle Scholar
  25. 25.
    Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D (2017) Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med 43:625–632CrossRefPubMedGoogle Scholar
  26. 26.
    Hjortrup PB, Haase N, Bundgaard H, Thomsen SL, Winding R, Pettila V, Aaen A, Lodahl D, Berthelsen RE, Christensen H, Madsen MB, Winkel P, Wetterslev J, Perner A, CLASSIC Trial Group, Scandinavian Critical Care Trials Group (2016) Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 42:1695–1705CrossRefPubMedGoogle Scholar
  27. 27.
    Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, Christophi C, Leslie K, McGuinness S, Parke R, Serpell J, Chan MTV, Painter T, McCluskey S, Minto G, Wallace S, Australian and New Zealand College of Anaesthetists Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group (2018) Restrictive versus liberal fluid therapy for major abdominal surgery. N Engl J Med 378:2263–2274CrossRefPubMedGoogle Scholar
  28. 28.
    Perner A, Gordon AC, Angus DC, Lamontagne F, Machado F, Russell JA, Timsit JF, Marshall JC, Myburgh J, Shankar-Hari M, Singer M (2017) The intensive care medicine research agenda on septic shock. Intensive Care Med 43:1294–1305CrossRefPubMedGoogle Scholar
  29. 29.
    Inwald DP, Canter R, Woolfall K, Mouncey P, Zenasni Z, O’Hara C, Carter A, Jones N, Lyttle MD, Nadel S, Peters MJ, Harrison DA, Rowan KM, PERUKI (Paediatric Emergency Research in the UK and Ireland) and PICS SG (Paediatric Intensive Care Society Study Group) (2018) Restricted fluid bolus volume in early septic shock: results of the fluids in shock pilot trial. Arch Dis Child. (Epub ahead of print) CrossRefPubMedGoogle Scholar
  30. 30.
    Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG (2018) Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population. Intensive Care Med 44:409–417CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature and ESICM 2018

Authors and Affiliations

  • Stephen P. J. Macdonald
    • 1
    • 2
    • 3
    Email author
  • Gerben Keijzers
    • 4
    • 5
    • 6
  • David McD Taylor
    • 7
    • 8
  • Frances Kinnear
    • 9
  • Glenn Arendts
    • 1
    • 2
    • 10
  • Daniel M. Fatovich
    • 1
    • 2
    • 3
  • Rinaldo Bellomo
    • 11
  • David McCutcheon
    • 1
    • 2
    • 3
    • 12
  • John F. Fraser
    • 13
  • Juan-Carlos Ascencio-Lane
    • 14
  • Sally Burrows
    • 2
  • Edward Litton
    • 15
  • Amanda Harley
    • 4
  • Matthew Anstey
    • 16
  • Ashes Mukherjee
    • 12
  • for the REFRESH trial investigators
  1. 1.Centre for Clinical Research in Emergency MedicineHarry Perkins Institute of Medical ResearchPerthAustralia
  2. 2.Medical SchoolUniversity of Western AustraliaPerthAustralia
  3. 3.Emergency DepartmentRoyal Perth HospitalPerthAustralia
  4. 4.Emergency DepartmentGold Coast University HospitalGold CoastAustralia
  5. 5.School of MedicineBond UniversityGold CoastAustralia
  6. 6.School of Medical SciencesGriffith UniversityGold CoastAustralia
  7. 7.Emergency DepartmentAustin HospitalMelbourneAustralia
  8. 8.Department of MedicineUniversity of MelbourneMelbourneAustralia
  9. 9.Emergency DepartmentThe Prince Charles HospitalBrisbaneAustralia
  10. 10.Emergency DepartmentFiona Stanley HospitalPerthAustralia
  11. 11.Department of Intensive CareAustin HospitalMelbourneAustralia
  12. 12.Emergency DepartmentArmadale-Kelmscott Memorial HospitalPerthAustralia
  13. 13.Critical Care Research GroupThe Prince Charles HospitalBrisbaneAustralia
  14. 14.Emergency DepartmentRoyal Hobart HospitalHobartAustralia
  15. 15.Department of Intensive CareFiona Stanley HospitalPerthAustralia
  16. 16.Department of Intensive CareSir Charles Gairdner HospitalPerthAustralia

Personalised recommendations