REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial

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Macdonald, Stephen PJ
Taylor, David M
Keijzers, Gerben
Arendts, Glenn
Fatovich, Daniel M
Kinnear, Frances B
Brown, Simon GA
Bellomo, Rinaldo
Burrows, Sally
Fraser, John F
Litton, Edward
Ascencio-Lane, Juan Carlos
Anstey, Matthew
Winearls, James
et al.
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2017
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Abstract

Background Guidelines recommend an initial intravenous (IV) fluid bolus of 30 ml/kg isotonic crystalloid for patients with sepsis and hypotension. However, there is a lack of evidence from clinical trials to support this. Accumulating observational data suggest harm associated with the injudicious use of fluids in sepsis. There is currently equipoise regarding liberal or restricted fluid-volume resuscitation as first-line treatment for sepsis-related hypotension. A randomised trial comparing these two approaches is, therefore, justified. Methods/design The REstricted Fluid REsuscitation in Sepsis-associated Hypotension trial (REFRESH) is a multicentre, open-label, randomised, phase II clinical feasibility trial. 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. Discussion 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.

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Trials

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18

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1

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© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Cardiovascular medicine and haematology

Clinical sciences

Clinical sciences not elsewhere classified

Science & Technology

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Sepsis

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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; Winearls, J; et al., REstricted Fluid REsuscitation in Sepsis-associated Hypotension (REFRESH): study protocol for a pilot randomised controlled trial, Trials, 2017, 18 (1), pp. 399

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