What is the preferred initial fluid for resuscitation in a patient with sepsis, considering the potential for metabolic acidosis and the need to rapidly restore circulating volume?

Lactated Ringer's (LR) Should Be Used Over Normal Saline (NS) for Sepsis Resuscitation

Use lactated Ringer's or other balanced crystalloids as the preferred initial resuscitation fluid in sepsis, rather than normal saline, to reduce mortality and avoid hyperchloremic metabolic acidosis. 1, 2

Primary Recommendation

The American College of Critical Care Medicine recommends balanced crystalloids (lactated Ringer's or Plasma-Lyte) over normal saline when available for initial sepsis resuscitation (strong recommendation, moderate quality evidence). 1 This recommendation is supported by the most recent high-quality evidence from the 2025 CLOVERS trial secondary analysis, which demonstrated that lactated Ringer's reduced mortality compared to normal saline (12.2% vs 15.9%, adjusted HR 0.71,95% CI 0.51-0.99, p=0.043). 2

Volume and Timing

• Administer at least 30 mL/kg of crystalloid within the first 3 hours of sepsis recognition, regardless of which crystalloid you choose. 3, 1
• Begin resuscitation immediately—sepsis is a medical emergency and delayed resuscitation increases mortality. 3, 1

Why Lactated Ringer's Over Normal Saline

Mortality benefit: The 2025 CLOVERS analysis showed lactated Ringer's was associated with a 29% reduction in mortality hazard compared to normal saline in sepsis-induced hypotension. 2

Reduced hospital length of stay: Patients receiving lactated Ringer's had 1.6 more hospital-free days at 28 days compared to normal saline (adjusted mean difference 1.6 days, 95% CI 0.4-2.8, p=0.009). 2

Avoidance of hyperchloremic metabolic acidosis: Normal saline causes significant metabolic acidosis through increased chloride levels and decreased strong ion difference. 1, 4 A 2011 study demonstrated that 30 mL/kg of normal saline worsened metabolic acidosis (SBE dropped from -4.4 to -6.0 mEq/L, p=0.039) with increased chloride from 103 to 106 mEq/L. 4

Biochemical advantages: Normal saline causes higher serum chloride and lower serum bicarbonate levels compared to lactated Ringer's. 2

Special Populations and Comorbidities

Chronic pulmonary disease: Lactated Ringer's provides greater mortality benefit in patients with chronic pulmonary disease compared to normal saline. 5

Chronic kidney disease: The mortality benefit of lactated Ringer's is smaller and non-significant in patients with chronic kidney disease, though balanced crystalloids still reduce the risk of acute kidney injury progression. 1, 5

Moderate to severe liver disease: The benefit is smaller in these patients, and serum lactate levels rise more with lactated Ringer's (0.12 mg/dL/h higher), though this does not translate to worse outcomes. 5

Acute kidney injury: Balanced crystalloids like lactated Ringer's are safer than normal saline in patients with pre-existing AKI, as normal saline increases AKI progression risk. 1

When to Continue or Stop Fluid Administration

• Continue fluid administration as long as hemodynamic parameters improve using dynamic measures (pulse pressure variation, stroke volume variation) or static variables (blood pressure, heart rate, mental status, urine output). 3, 1
• Stop fluid administration when no improvement in tissue perfusion occurs, signs of fluid overload develop (pulmonary crackles, respiratory distress), or hemodynamic parameters stabilize. 1, 6
• In patients with respiratory compromise (e.g., large pleural effusions), administer smaller boluses of 250-500 mL and reassess after each bolus rather than giving the full 30 mL/kg rapidly. 6

Vasopressor Initiation

• If hypotension persists despite adequate fluid resuscitation, initiate norepinephrine as the first-choice vasopressor targeting MAP ≥65 mmHg. 1, 7
• Consider earlier vasopressor initiation after smaller fluid volumes in patients with respiratory compromise to avoid excessive fluid administration. 6

Critical Pitfalls to Avoid

Do not delay resuscitation: Concerns about fluid overload should not delay initial aggressive resuscitation—delayed resuscitation increases mortality. 1

Do not rely on CVP alone: Central venous pressure has poor predictive ability for fluid responsiveness; use dynamic measures when available. 1

Do not use normal saline when balanced crystalloids are available: The evidence now clearly favors balanced crystalloids for mortality reduction. 1, 2

Monitor for fluid overload: While aggressive initial resuscitation is critical, continuously reassess for signs of fluid overload and stop fluids when appropriate. 1, 6