Impact of Balanced Crystalloids vs Saline by Resuscitation Strategy in Sepsis

The optimal crystalloid for sepsis resuscitation and whether choice should differ under restrictive vs liberal strategy remains uncertain. Do outcomes differ by fluid type within liberal vs restrictive resuscitation strategies? We performed a secondary analysis of the Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis study. Patients were categorized by the predominant crystalloid in the first 24 hours (> 80%; balanced crystalloids [BCs], normal saline [NS], or mixed) and were stratified by randomized resuscitation strategy (liberal vs restrictive). The primary outcome was death before discharge by day 90. Secondary outcomes included new renal replacement therapy (RRT), organ support-free days, and adverse events. Analysis used inverse probability weighting with covariate balancing and tested a fluid-type by strategy interaction. Among 1,563 patients, 423 patients (27%) received BCs, 226 patients (15%) received NS, and 914 patients (58%) receiving mixed fluids. The association of fluid type with mortality varied by strategy (χ 2 = 118.5 with 9 degrees of freedom; P < .001). For new RRT, the strategy by fluid interaction was significant ( F 4,1,518 = 2.5; P = .041); for RRT-free days, it was not ( F 4,1,437 = 0.369; P = .831). In the liberal arm, adjusted mortality was lower with BCs than NS or mixed fluids (BCs, 12.6% [95% CI, 10.4-15.1]; NS, 16.8% [95% CI, 14.3-19.7]; mixed fluids, 16.1% [95% CI, 13.6-18.9]). In the restrictive arm, adjusted mortality was higher with BCs than NS (BCs, 16.3% [95% CI, 13.9-19.1]; NS, 13.2% [95% CI, 10.9-15.9]; mixed fluids, 14.1% [95% CI, 11.8-16.8]). For new RRT, NS vs BCs was lower in the liberal arm (1.6% vs 2.9%; adjusted OR, 0.43; 95% CI, 0.20-0.90; P = .02) with no difference in the restrictive arm (5.1% vs 3.7%; OR, 1.42; 95% CI, 0.85-2.37; P = .18). RRT-free days were similar across arms. Outcomes differed by fluid type and resuscitation strategy. In the liberal arm, BCs were associated with lower mortality than NS or mixed fluids; this was not seen with a restrictive strategy. Early sepsis resuscitation should consider both fluid composition and strategy.