Fluid Resuscitation in Sepsis and Septic Shock; What to Give and How Much to Give: A Systematic Review of Randomized Controlled Trials

Introduction. The optimal composition and volume of intravenous fluids for sepsis resuscitation remain uncertain. We conducted a systematic review focused on two core questions: what fluid to administer and how much to give in adult sepsis and septic shock. Methods. We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials published from January 2020 to September 2025. Eligible trials enrolled adults with sepsis or septic shock and compared either fluid composition (e.g., balanced crystalloids, saline, albumin, plasma) or resuscitation volume/strategy (restrictive versus liberal or protocolized versus usual care). Two reviewers screened and extracted data; risk of bias was assessed using RoB 2. Owing to clinical heterogeneity and overlapping parent datasets, findings were synthesized qualitatively. Results. We identified contemporary multicenter RCTs and prespecified or post hoc analyses spanning ED and ICU settings. Balanced crystalloids consistently reduced hyperchloremic acidosis and showed context-dependent signals for improved short-term outcomes versus saline; absolute mortality effects were modest. Albumin and plasma-based strategies produced transient physiologic gains without durable outcome benefits. Large trials comparing volume strategies (CLASSIC, CLOVERS) showed no overall mortality difference despite approximately two liters less fluid and earlier vasopressors in restrictive arms. Subgroup data suggested advantage for restrictive, vasopressor-prioritized care in advanced chronic kidney disease, while mechanistic sub-studies demonstrated no adverse effects on cardiac strain or endothelial glycocalyx. Feasibility trials targeting non-resuscitation fluids reduced administered volumes without safety concerns. Conclusions. Current randomized evidence supports balanced crystalloids as default resuscitation fluids and indicates that clinically guided restrictive strategies are generally as safe as liberal ones, with potential benefit in fluid-intolerant phenotypes. Effectiveness depends less on a fixed fluid or volume and more on timing, patient context, and physiologic tolerance, reinforcing the paradigm of precision fluid therapy.