Balanced Crystalloids versus Saline in Critically Ill Adults
NEJM, 2018 · Pragmatic unblinded cluster-randomized multiple-crossover trial (n=15,802)
Clinical question
Do balanced crystalloids reduce major adverse kidney events or mortality compared with saline in the ICU?
What the trial found
Balanced crystalloids produced a small reduction in the MAKE30 composite compared with saline. Mortality benefit was not statistically significant in the overall trial; sepsis subgroup/secondary analyses suggested lower mortality and informed later guideline preference for balanced crystalloids.
Current guideline position
Surviving Sepsis Campaign 2026 suggests balanced crystalloids over 0.9% saline for initial sepsis/septic-shock resuscitation (conditional recommendation, moderate-certainty evidence), with 0.9% saline suggested for patients with sepsis and traumatic brain injury.
Clinical interpretation
Supported preferential use of balanced crystalloids over saline in many critically ill patients; the absolute MAKE30 difference was small and the sepsis mortality finding was a prespecified subgroup result. SSC 2026 therefore suggests, rather than mandates, balanced crystalloids over saline for sepsis resuscitation (with saline favored in sepsis plus TBI).
Life-threatening organ dysfunction caused by a dysregulated host response to infection — recognized by an acute rise in SOFA score, not by infection plus fever alone.
The subset of sepsis with profound circulatory and cellular/metabolic abnormality — clinically identified by a vasopressor requirement to maintain MAP ≥ 65 mmHg plus lactate > 2 mmol/L despite adequate fluid resuscitation.
Sepsis-AKI microcirculatory decoupling, KDIGO staging, Furosemide Stress Test (FST), urine microscopy, and the AEIOU dialysis threshold framework.
Cellular dysoxia, DO2/VO2 physiology, the 4 shock phenotypes, dynamic fluid responsiveness (PLR/PPV) vs fluid tolerance (VExUS), and vasoactive pharmacology.
Stepwise 6-step interpretation algorithm, compensation formulas, albumin-corrected anion gap, delta ratio, and Stewart physicochemical (SID) principles.