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

Abstract

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.