REstricted Fluid REsuscitation in Sepsis-related Hypotension (REFRESH)

Comparing a ‘restricted volume’ and ‘standard volume’ approaches to fluid resuscitation in patients with sepsis

Grant ID: EMSS-229R24-2015

Project Summary

The REFRESH study is a multicentre, open-label, randomised, phase II clinical feasibility trial. This is the first randomised trial examining fluid volume for initial resuscitation in septic shock in an industrialised country. A pragmatic, open-label design will establish the feasibility of undertaking a large, international, multicentre trial with sufficient power to assess clinical outcomes. The embedded biomarker study aims to provide mechanistic plausibility for a larger trial by defining the effects of fluid volume on markers of systemic inflammation and the vascular endothelium.

Participants will be patients presenting to the emergency departments of Australian metropolitan hospitals with suspected sepsis and a systolic blood pressure of < 100 mmHg, persisting after a 1000-ml fluid bolus with isotonic crystalloid. Participants will be randomised to either a second 1000-ml fluid bolus (standard care) or maintenance rate fluid only, with the early commencement of a vasopressor infusion to maintain a mean arterial pressure of > 65 mmHg, if required (restricted fluid). All will receive further protocolised fluid boluses (500 ml or 250 ml, respectively), if required during the 6-h study period. The primary outcome measure is total volume administered in the first 6 h. Secondary outcomes include fluid volume at 24 h, organ support 'free days' to day 28, 90-day mortality, and a range of feasibility and process-of-care measures. Participants will also undergo serial measurement, over the first 24 h, of biomarkers of inflammation, endothelial cell activation and glycocalyx degradation for comparison between the groups.


There were 99 participants (50 restricted volume and 49 usual care) recruited to the studys. 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 The team concluded that 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. A large national trial is now running: ARISE Fluids. Dr Stephen Macdonald was awarded a 2018 Global Sepsis Award. An initiative of the Global Sepsis Alliance for his work on the REFRESH trial. The awards recognise and honour excellent sepsis awareness and education initiatives, as well as to recognise major achievements of governments, organisations, and individuals, consistent with the aims of the World Sepsis Declaration and the World Sepsis Day Movement.


Macdonald, S.P. and Shapiro, N.I., 2018. Liberal or restricted fluid resuscitation in critical illness: Shifting the needle back towards equipoise. Emergency Medicine Australasia: EMA, 30(4), pp.446-447.

Macdonald, S.P., Williams, J.M., Shetty, A., Bellomo, R., Finfer, S., Shapiro, N. and Keijzers, G., 2017. Sepsis in the emergency department–Part 1: Definitions and outcomes. Emergency Medicine Australasia, 29(6), pp.619-625.

Shetty, A., Macdonald, S.P., Keijzers, G., Williams, J.M., Tang, B., De Groot, B., Thompson, K., Fraser, J.F., Finfer, S., Bellomo, R. and Iredell, J., 2018. Sepsis in the emergency department–Part 2: Investigations and monitoring. Emergency Medicine Australasia, 30(1), pp.4-12.

Williams, J.M., Keijzers, G., Macdonald, S.P., Shetty, A. and Fraser, J.F., 2018. Sepsis in the emergency department–Part 3: Treatment. Emergency Medicine Australasia, 30(2), pp.144-151.

Macdonald, S.P., Keijzers, G., Taylor, D.M., Kinnear, F., Arendts, G., Fatovich, D.M., Bellomo, R., McCutcheon, D., Fraser, J.F., Ascencio-Lane, J.C. and Burrows, S., 2018. Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial. Intensive care medicine, 44(12), pp.2070-2078.

Macdonald, S.P., Taylor, D.M., Keijzers, G., Arendts, G., Fatovich, D.M., Kinnear, F.B., Brown, S.G., Bellomo, R., Burrows, S., Fraser, J.F. and Litton, E., 2017. REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial. Trials, 18(1), pp.1-15.



Amount Awarded


Grant Scheme


Principal Investigator:
Prof Gerben Keijzers

Co Investigators:
Dr Stephen Macdonald
Dr Frances Kinnear
A/Prof Glenn Arendts
Prof Simon Brown
Dr Ioana Vlad
Prof David Taylor
Dr David McCutcheon
Dr Stephen Asha
Prof Daniel Fatovich

Associate Investigators:
Dr James Winearls
Dr Manoj Saxena
Prof Rinaldo Bellemo
Dr Juan Ascencio-Lane
Dr David Cooper
Dr Bradley Wibrow
Dr Matthew Anstey
Dr Lisa Smart
Dr Edward Litton
Dr Anton Leonard


Collaborating Institutions


  • Linked EMF grant: Fluid resuscitation in emergency patients with sepsis and hypotension (FLUIDS ARISE)
  • ANZCTR Clinical trial registry page
  • 2018 Global Sepsis Award
  • Podcast with A/Prof Stephen Macdonald (11/3/18)

  • Media

  • Channel 9 News_December 2017
  • 6PR radio_July 2018
  • CONTACT US +61 7 3720 5700 Suite 1B, Terraces, 19 Lang Parade, Milton Qld 4064