Balanced crystalloids compared to normal saline for fluid therapy in critically ill adult patients: Systematic review and meta-analysis protocol

IntroductionThe choice of intravenous fluid for fluid therapy in critically ill adult patients remains a matter of debate. Currently, crystalloids are used more often than colloids, with ongoing controversy over the relative efficacy and safety of buffered salt solutions (BSS) versus normal saline (0.9% sodium chloride). In 2021 two large pragmatic trials enrolling critically ill patients will add substantial new data to address this controversy. We will conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) that will include the data from these two trials to provide clinicians with the most up to date evidence and robust evidence to guide their choice of crystalloid fluids.Methods and analysisWe will include RCTs that compare the effect of buffered salt solutions to normal saline for fluid resuscitation and/or fluid therapy in critically ill adults, on all-cause mortality and other patient centred outcomes. We will perform a search that includes the electronic databases MEDLINE and EMBASE, and clinical trial registries. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data, with discrepancies resolved by a third reviewer. We will report study characteristics and assess risk of bias using the Cochrane Risk-of-Bias tool. We will perform Hartung-Knapp-Sidik-Jonkman random-effects aggregate data meta-analysis whenever it is feasible to do so. We will evaluate overall certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.Ethics and disseminationThis systematic review and meta-analysis does not require ethical approval as it does not involve primary data collection. We will publish our results in a peer-reviewed scientific journal and present them at national and international scientific conferences.PROSPERO registration numberCRD42021243399Strengths and limitations of this review [box]This systematic review will provide up-to-date evidence to answer the focused clinical question: In adult patients who are critically ill, does administering balanced crystalloid solutions for fluid therapy reduce mortality and other patient-centered outcomes, compared with administering 0.9% sodium chloride?We will conduct a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines, searching three electronic databases, clinical trial registries and published conference abstracts, with two independent reviewers evaluating studies and extracting data.A meta-analysis will assess the primary outcome of all-cause mortality at 90 days and secondary outcomes of ventilator and vasopressor free days, renal replacement therapy use, incidence of acute kidney injury, and patient quality of life outcomes.The limitations of this review include the clinical heterogeneity of the included trials, diversity of the targeted population receiving fluid therapy, variability in the composition of balanced crystalloid solutions, and timing of initiation of study crystalloids. We will address all limitations with the Grading of Recommendations, Assessment, Development and Evaluations framework.