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

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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.

          Trial registration

          Australia and New Zealand Clinical Trials Registry, ID: ACTRN12616000006448. Registered on 12 January 2016.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13063-017-2137-7) contains supplementary material, which is available to authorized users.

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          Most cited references14

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          The microcirculation is the motor of sepsis

          Can Ince (2005)
          Regional tissue distress caused by microcirculatory dysfunction and mitochondrial depression underlies the condition in sepsis and shock where, despite correction of systemic oxygen delivery variables, regional hypoxia and oxygen extraction deficit persist. We have termed this condition microcirculatory and mitochondrial distress syndrome (MMDS). Orthogonal polarization spectral imaging allowed the first clinical observation of the microcirculation in human internal organs, and has identified the pivotal role of microcirculatory abnormalities in defining the severity of sepsis, a condition not revealed by systemic hemodynamic or oxygen-derived variables. Recently, sublingual sidestream dark-field (SDF) imaging has been introduced, allowing observation of the microcirculation in even greater detail. Microcirculatory recruitment is needed to ensure adequate microcirculatory perfusion and the oxygenation of tissue cells that follows. In sepsis, where inflammation-induced autoregulatory dysfunction persists and oxygen need is not matched by supply, the microcirculation can be recruited by reducing pathological shunting, promoting microcirculatory perfusion, supporting pump function, and controlling hemorheology and coagulation. Resuscitation following MMDS must include focused recruitment of hypoxic-shunted microcirculatory units and/or resuscitation of the mitochondria. A combination of agents is required for successful rescue of the microcirculation. Single compounds such as activated protein C, which acts on multiple pathways, can be expected to be beneficial in rescuing the microcirculation in sepsis.
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            Relation between muscle Na+K+ ATPase activity and raised lactate concentrations in septic shock: a prospective study.

            Hyperlactataemia during septic shock is often viewed as evidence of tissue hypoxia. However, this blood disorder is not usually correlated with indicators of perfusion or diminished with increased oxygen delivery. Muscles can generate lactate under aerobic conditions in a process linking glycolytic ATP supply to stimulation of Na+K+ ATPase. Using in-vivo microdialysis, we tested whether inhibition of Na+K+ ATPase can reduce muscle lactate. In 14 patients with septic shock, two microdialysis probes were inserted into the quadriceps muscles and infused with lactate-free Ringer's solution in the absence or presence of 10(-7) mol/L ouabain, a specific inhibitor of Na+K+ ATPase. We measured lactate and pyruvate concentrations in both the dialysate fluid and arterial blood samples. All patients had increased blood lactate concentrations (mean 4.0 mmol/L; SD 2.1). Lactate and pyruvate concentrations were consistently higher in muscle than in arteries during the study period, with a mean positive gradient of 1.98 mmol/L (SD 0.2; p=0.001) and 230 micromol/L (30; p=0.01), respectively. Ouabain infusion stopped over production of muscle lactate and pyruvate (p=0.0001). Muscle lactate to pyruvate ratios remained unchanged during ouabain infusion with no differences between blood and muscle. Skeletal muscle could be a leading source of lactate formation as a result of exaggerated aerobic glycolysis through Na+K+ ATPase stimulation during septic shock. Lactate clearance as an end-point of resuscitation could therefore prove useful. In patients with septic shock, a high lactate concentration should be interpreted as a marker of disease, portending a bad outcome. The presence of hyperlactataemia in resuscitated septic patients should not be taken as proof of oxygen debt needing increases in systemic or regional oxygen transport to supranormal values. Lactate, instead of being regarded only as a marker of hypoxia, might be an important metabolic signal.
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              Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension

              Introduction We sought to examine the cardiac consequences of early administration of norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital. Methods We included 105 septic-shock patients who already had received volume resuscitation. All received norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by norepinephrine when the achieved MAP was ≥65 mm Hg. Results Norepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m2, stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m2, global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m2, and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with norepinephrine. Conclusions Early administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.
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                Author and article information

                Contributors
                +61 8 9224 8458 , stephen.macdonald@uwa.edu.au
                david.taylor@austin.org.au
                gerben.keijzers@health.qld.gov.au
                glenn.arendts@uwa.edu.au
                Daniel.fatovich@health.wa.gov.au
                frances.kinnear@health.qld.gov.au
                simon.brown@uwa.edu.au
                rinaldo.bellomo@austin.org.au
                sally.burrows@uwa.edu.au
                john.fraser@health.qld.gov.au
                edward.litton@health.wa.gov.au
                juan.ascencio-lane@ths.tas.gov.au
                matthew.anstey@health.wa.gov.au
                david.mccutcheon@health.wa.gov.au
                lisa.smart@research.uwa.edu.au
                ioana.vlad@health.wa.gov.au
                james.winearls@health.qld.gov.au
                Bradley.wibrow@health.wa.gov.au
                Journal
                Trials
                Trials
                Trials
                BioMed Central (London )
                1745-6215
                29 August 2017
                29 August 2017
                2017
                : 18
                : 399
                Affiliations
                [1 ]GRID grid.431595.f, Centre for Clinical Research in Emergency Medicine, , Harry Perkins Institute of Medical Research, ; Perth, WA Australia
                [2 ]ISNI 0000 0004 0453 3875, GRID grid.416195.e, Emergency Department, , Royal Perth Hospital, ; Perth, WA Australia
                [3 ]ISNI 0000 0001 0162 7225, GRID grid.414094.c, Emergency Department, , Austin Hospital, ; Melbourne, VIC Australia
                [4 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Department of Medicine, , University of Melbourne, ; Melbourne, VIC Australia
                [5 ]GRID grid.413154.6, Emergency Department, , Gold Coast University Hospital, ; Gold Coast, QLD Australia
                [6 ]ISNI 0000 0004 0405 3820, GRID grid.1033.1, School of Medicine, Bond University, ; Gold Coast, QLD Australia
                [7 ]ISNI 0000 0004 0437 5432, GRID grid.1022.1, School of Medical Sciences, Griffith University, ; Gold Coast, QLD Australia
                [8 ]ISNI 0000 0004 4680 1997, GRID grid.459958.c, Emergency Department, , Fiona Stanley Hospital, ; Perth, WA Australia
                [9 ]ISNI 0000 0004 0614 0266, GRID grid.415184.d, Emergency and Children’s Services, The Prince Charles Hospital, ; Brisbane, QLD Australia
                [10 ]ISNI 0000 0000 9575 7348, GRID grid.416131.0, Emergency Department, , Royal Hobart Hospital, ; Hobart, TAS Australia
                [11 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, Division of Emergency Medicine, Medical School, , University of Western Australia, ; Perth, WA Australia
                [12 ]ISNI 0000 0001 0162 7225, GRID grid.414094.c, Department of Intensive Care, , Austin Hospital, ; Melbourne, VIC Australia
                [13 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, School of Medicine, University of Melbourne, ; Melbourne, VIC Australia
                [14 ]ISNI 0000 0004 1936 7910, GRID grid.1012.2, School of Medicine and Pharmacology, University of Western Australia, ; Perth, WA Australia
                [15 ]ISNI 0000 0004 0614 0266, GRID grid.415184.d, Critical Care Research Group, The Prince Charles Hospital, ; Brisbane, QLD Australia
                [16 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, School of Medicine, University of Queensland, ; Brisbane, QLD Australia
                [17 ]ISNI 0000 0004 4680 1997, GRID grid.459958.c, Department of Intensive Care, , Fiona Stanley Hospital, ; Perth, WA Australia
                [18 ]ISNI 0000 0004 0437 5942, GRID grid.3521.5, Department of Intensive Care, , Sir Charles Gairdner Hospital, ; Perth, WA Australia
                [19 ]Emergency Department, Armadale Health Service, Perth, WA Australia
                [20 ]ISNI 0000 0004 0437 5942, GRID grid.3521.5, Emergency Department, , Sir Charles Gairdner Hospital, ; Perth, WA Australia
                [21 ]GRID grid.413154.6, Department of Intensive Care, , Gold Coast University Hospital, ; Gold Coast, QLD Australia
                Article
                2137
                10.1186/s13063-017-2137-7
                5576288
                28851407
                12051894-4423-4caa-9e54-60cdf1d5129e
                © The Author(s). 2017

                Open AccessThis 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.

                History
                : 31 January 2017
                : 3 August 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001078, Queensland Emergency Medicine Research Foundation;
                Award ID: EMSS-229R24-2015-KEIJZERS
                Award Recipient :
                Categories
                Study Protocol
                Custom metadata
                © The Author(s) 2017

                Medicine
                sepsis,fluid therapy,hypotension
                Medicine
                sepsis, fluid therapy, hypotension

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