Why physiology will continue to guide the choice between balanced crystalloids and normal saline: a systematic review and meta-analysis

Background: Crystalloids are the most frequently prescribed drugs in intensive care medicine and emergency medicine. Thus, even small differences in outcome may have major implications, and therefore, the choice between balanced crystalloids versus normal saline continues to be debated. We examined to what extent the currently accrued information size from completed and ongoing trials on the subject allow intensivists and emergency physicians to choose the right fluid for their patients. Methods: Systematic review and meta-analysis with random effects inverse variance model. Published randomized controlled trials enrolling adult patients to compare balanced crystalloids versus normal saline in the setting of intensive care medicine or emergency medicine were included. The main outcome was mortality at the longest follow-up, and secondary outcomes were moderate to severe acute kidney injury (AKI) and initiation of renal replacement therapy (RRT). Trial sequential analyses (TSA) were performed, and risk of bias and overall quality of evidence were assessed. Additionally, previously published meta-analyses, trial sequential analyses and ongoing large trials were analysed for included studies, required information size calculations and the assumptions underlying those calculations. Results: Nine studies (n = 32,777) were included. Of those, eight had data available on mortality, seven on AKI and six on RRT. Meta-analysis showed no significant differences between balanced crystalloids versus normal saline for mortality (P = 0.33), the incidence of moderate to severe AKI (P = 0.37) or initiation of RRT (P = 0.29). Quality of evidence was low to very low. Analysis of previous meta-analyses and ongoing trials showed large differences in calculated required versus accrued information sizes and assumptions underlying those. TSA revealed the need for extremely large trials based on our realistic and clinically relevant assumptions on relative risk reduction and baseline mortality. Conclusions: Our meta-analysis could not find significant differences between balanced crystalloids and normal saline on mortality at the longest follow-up, moderate to severe AKI or new RRT. Currently accrued information size is smaller, and the required information size is larger than previously anticipated. Therefore, completed and ongoing trials on the topic may fail to provide adequate guidance for choosing the right crystalloid. Thus, physiology will continue to play an important role for individualizing this choice.