Log in | Register

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

Stephen P. J. Macdonald| 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
Original
Volume 44, Issue 12 / December , 2018

Pages 2070 - 2078

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

References

  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 315:801–810
    • View reference on publisher's website
  2. Angus DC, van der Poll T (2013) Severe sepsis and septic shock. N Engl J Med 369:840–851
    • View reference on publisher's website
  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 43:304–377
  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 43:155–170
  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 44:791–798
  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 354:2564–2575
    • View reference on publisher's website
  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. https://doi.org/10.1164/rccm.201801-0064oc
    • View reference on publisher's website
  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 364:2483–2495
    • View reference on publisher's website
  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 318:1233–1240
    • View reference on publisher's website
  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 42:2158–2168
    • View reference on publisher's website
  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 18:532
    • View reference on publisher's website
  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 376:2223–2234
    • View reference on publisher's website
  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:R142
    • View reference on publisher's website
  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:e0183073
    • View reference on publisher's website
  15. Byrne L, Van Haren F (2017) Fluid resuscitation in human sepsis: time to rewrite history? Ann Intensive Care 7:4
    • View reference on publisher's website
  16. Finfer S, Myburgh J, Bellomo R (2018) Intravenous fluid therapy in critically ill adults. Nat Rev Nephrol 14:541–557
    • View reference on publisher's website
  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)
    • View reference on publisher's website
  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 72:457–466
    • View reference on publisher's website
  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 18:399
    • View reference on publisher's website
  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 371:1496–1506
    • View reference on publisher's website
  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 42:377–381
    • View reference on publisher's website
  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 43:68–73
    • View reference on publisher's website
  23. Acheampong A, Vincent JL (2015) A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care 19:251
    • View reference on publisher's website
  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 33:186–189
    • View reference on publisher's website
  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 43:625–632
  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 42:1695–1705
  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 378:2263–2274
    • View reference on publisher's website
  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 43:1294–1305
  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. https://doi.org/10.1136/archdischild-2018-314924(Epub ahead of print)
    • View reference on publisher's website
  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 44:409–417

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement