Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients (REFACED Sepsis)-protocol for a multicenter, randomized, clinical, proof-of-concept trial

Marie Kristine Jessen, Lars Wiuff Andersen, Marie-Louise Holm Thomsen, Peter Kristensen, Wazhma Hayeri, Ranva Espegård Hassel, Anders Perner, Jens Aage Kølsen Petersen, Hans Kirkegaard, Marie Kristine Jessen, Lars Wiuff Andersen, Marie-Louise Holm Thomsen, Peter Kristensen, Wazhma Hayeri, Ranva Espegård Hassel, Anders Perner, Jens Aage Kølsen Petersen, Hans Kirkegaard

Abstract

Background: Intravenous fluids are often used in the treatment of sepsis. The better strategy regarding fluid volume is debated, but preliminary data in patients with septic shock or sepsis-related hypotension favor restrictive fluid administration. We describe the protocol and statistical analysis plan for the Restrictive Fluid Administration vs. Standard of Care in Emergency Department Sepsis Patients (REFACED Sepsis)-a multicenter, randomized clinical proof-of-concept trial. The aim of the REFACED Sepsis trial is to test if a restrictive intravenous fluid protocol in emergency department patients with sepsis without shock is feasible and decreases the intravenous fluid volume administered in comparison to standard care.

Methods: This is an investigator-initiated, multicenter, randomized, parallel-group, open-labeled, feasibility trial investigating volumes of crystalloid fluid within 24 h in 124 patients with sepsis without shock enrolled at three emergency departments in the Central Denmark Region. Patients are allocated to two different intravenous fluid regimens: a restrictive approach using four trigger criteria for fluid administration vs. standard care. The primary, feasibility outcome is total intravenous, crystalloid fluid volume within 24 h, and key secondary outcomes include protocol violations, total fluids (intravenous and oral) within 24 h, and serious adverse reactions and suspected unexpected serious adverse reactions. Status: The trial started in November 2021, and the last patient is anticipated to be included in January 2022.

Discussion: Sepsis is very common in emergency department patients and fluid administration is very frequently administered in these patients. However, the evidence to guide fluid administration is very sparse. This feasibility trial will be the foundation for a potential future large-scale trial investigating restrictive vs. standard fluid administration in patients with sepsis.

Trial registration: EudraCT number: 2021-000224-35 (date: 2021 May 03), ClinicalTrials.gov number: NCT05076435 (date: 2021 October 13), Committee on Health Research Ethics - Central Denmark Region: 1-10-72-163-21 (date: 2021 June 28).

Keywords: Emergency department; Fluid therapy; Infection; Sepsis.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Inclusion criteria, exclusion criteria and treatment algorithms

References

    1. Henriksen DP, Laursen CB, Jensen TG, et al. Incidence rate of community-acquired sepsis among hospitalized acute medical patients-a population-based survey. Crit Care Med. 2015;43:13–21.
    1. Wang HE, Shapiro NI, Angus DC, et al. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35:1928–1936.
    1. Capp R, Horton CL, Takhar SS, et al. Predictors of patients who present to the emergency department with sepsis and progress to septic shock between 4 and 48 hours of emergency department arrival. Crit Care Med. 2015;43:983–988.
    1. Glickman SW, Cairns CB, Otero RM, et al. Disease progression in hemodynamically stable patients presenting to the emergency department with sepsis. Acad Emerg Med. 2010;17:383–390.
    1. Arnold RC, Sherwin R, Shapiro NI, et al. Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department. Acad Emerg Med. 2013;20:433–440.
    1. Jessen MK, Mackenhauer J, Hvass AM, et al. Predictors of intensive care unit transfer or death in emergency department patients with suspected infection. Eur J Emerg Med. 2015;22:176–180.
    1. Paoli CJ, Reynolds MA, Sinha M, Gitlin M, Crouser E. Epidemiology and costs of Sepsis in the United States-An analysis based on timing of Diagnosis and Severity Level. Crit Care Med. 2018;46(12):1889–1897. doi: 10.1097/CCM.0000000000003342.
    1. Whiles BB, Deis AS, Simpson SQ. Increased time to initial antimicrobial administration is associated with progression to septic shock in severe sepsis patients. Crit Care Med. 2017;45:623–629.
    1. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med. 2017;43:625–632.
    1. Hammond NE, Finfer SR, Li Q, et al. Health-related quality of life in survivors of septic shock: 6-month follow-up from the ADRENAL trial. Intensive Care Med. 2020;46:1696–1706.
    1. Winters BD, Eberlein M, Leung J, et al. Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med. 2010;38:1276–1283.
    1. Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med. 2014;190:62–69.
    1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45:486–552.
    1. Ueyama H, Kiyonaka S. Predicting the need for fluid therapy-does fluid responsiveness work? J Intensive Care. 2017;5:34.
    1. Malbrain ML, Marik PE, Witters I, et al. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intens Ther. 2014;46:361–380.
    1. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376:2235–2244.
    1. Boyd JH, Forbes J, Nakada TA, et al. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39:259–265.
    1. Kelm DJ, Perrin JT, Cartin-Ceba R, et al. 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. 2015;43:68–73.
    1. Wu X, Hu Z, Yuan H, et al. Fluid resuscitation and markers of glycocalyx degradation in severe sepsis. Open Med (Wars). 2017;12:409–416.
    1. Malbrain MLNG, Van Regenmortel N, Saugel B, De Tavernier B, Van Gaal PJ, Joannes-Boyau O, Teboul JL, Rice TW, Mythen M, Monnet X. Principles of fluid management and stewardship in septic shock: it is time to consider the four D's and the four phases of fluid therapy. Ann Intensive Care. 2018;8(1):66. doi: 10.1186/s13613-018-0402-x.
    1. Sethi M, Owyang CG, Meyers C, et al. Choice of resuscitative fluids and mortality in emergency department patients with sepsis. Am J Emerg Med. 2018;36:625–629.
    1. Shaw AD, Raghunathan K, Peyerl FW, et al. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Med. 2014;40:1897–1905.
    1. Byrne L, Obonyo NG, Diab SD, et al. Unintended consequences: fluid resuscitation worsens shock in an ovine model of endotoxemia. Am J Respir Crit Care Med. 2018;198:1043–1054.
    1. Messmer AS, Zingg C, Müller M, Gerber JL, Schefold JC, Pfortmueller CA. Fluid overload and mortality in adult critical care patients-A systematic review and meta-analysis of observational studies. Crit Care Med. 2020;48(12):1862–1870. doi: 10.1097/CCM.0000000000004617.
    1. Hjortrup PB, Haase N, Wetterslev J, et al. Associations of hospital and patient characteristics with fluid resuscitation volumes in patients with severe sepsis: post hoc analyses of data from a multicentre randomised clinical trial. PLoS One. 2016;11:e0155767.
    1. Angus DC, Barnato AE, Bell D, et al. A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators. Intensive Care Med. 2015;41:1549–1560.
    1. Keijzers G, Macdonald SP, Udy AA, et al. The Australasian Resuscitation In Sepsis Evaluation: Fluids or vasopressors in emergency department sepsis (ARISE FLUIDS), a multi-centre observational study describing current practice in Australia and New Zealand. Emerg Med Australas. 2020;32:586–598.
    1. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, Oczkowski S, Levy MM, Derde L, Dzierba A, Du B, Aboodi M, Wunsch H, Cecconi M, Koh Y, Chertow DS, Maitland K, Alshamsi F, Belley-Cote E, Greco M, Laundy M, Morgan JS, Kesecioglu J, McGeer A, Mermel L, Mammen MJ, Alexander PE, Arrington A, Centofanti JE, Citerio G, Baw B, Memish ZA, Hammond N, Hayden FG, Evans L, Rhodes A. Surviving Sepsis campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) Crit Care Med. 2020;48(6):e440–69. doi: 10.1097/CCM.0000000000004363.
    1. Jessen MK, Andersen LW, Thomsen MH, et al. Twenty-four-hour fluid administration in emergency department patients with suspected infection: a multicenter, prospective, observational study. Acta Anaesthesiol Scand. 2021;65:1122–1142.
    1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49:e1063–e1143.
    1. Harris T, Coats TJ, Elwan MH. Fluid therapy in the emergency department: an expert practice review. Emerg Med J. 2018;35:511–515.
    1. Perner A, Gordon AC, Angus DC, et al. The intensive care medicine research agenda on septic shock. Intensive Care Med. 2017;43:1294–1305.
    1. Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42:1695–1705.
    1. Macdonald SPJ, Keijzers G, Taylor DM, et al. Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): a pilot randomised controlled trial. Intensive Care Med. 2018;44:2070–2078.
    1. Meyhoff TS, Møller MH, Hjortrup PB, et al. Lower vs higher fluid volumes during initial management of sepsis: a systematic review with meta-analysis and trial sequential analysis. Chest. 2020;157:1478–1496.
    1. Website for the REFACED Sepsis trial. 2021.
    1. ICH Harmonised Tripartite Guideline. Integrated Addendum To ICH E6(R1): Guideline For Good Clinical Practice E6(R2). Vol 20172016. .
    1. ICH Harmonised Tripartite Guideline. General Considerations for Clinical Trials E8. Vol 20171997. .
    1. ICH Harnomised Tripartite Guidelines. Statistical Principles for Clinical Trials. Vol 20171998. .
    1. Chan AW, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158:200–207.
    1. Chan AW, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. Bmj. 2013;346:e7586.
    1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Jama. 2016;315:801–810.
    1. Ait-Oufella H, Lemoinne S, Boelle PY, et al. Mottling score predicts survival in septic shock. Intensive Care Med. 2011;37:801–807.
    1. Kellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1) Crit Care. 2013;17:204.
    1. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332.
    1. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869.
    1. International conference on harmonisation; guidance on statistical principles for clinical trials; availability--FDA. Notice. Fed Regist. 1998;63(179):49583–98.
    1. Taichman DB, Sahni P, Pinborg A, et al. Data sharing statements for clinical trials - a requirement of the international committee of medical journal editors. N Engl J Med. 2017;376:2277–2279.
    1. Meyhoff TS, Hjortrup PB, Møller MH, et al. Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-protocol and statistical analysis plan. Acta Anaesthesiol Scand. 2019;63:1262–1271.
    1. 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. Liberal versus restrictive intravenous fluid therapy for early septic shock: rationale for a randomized trial. Ann Emerg Med. 2018;72(4):457–66. 10.1016/j.annemergmed.2018.03.039. Epub 2018 May 10.
    1. Savović J, Jones HE, Altman DG, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med. 2012;157:429–438.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner