Balanced Crystalloids versus Normal Saline in Sepsis: A Critical Appraisal for the Modern Intensivist

Dr Neeraj Manikath , claude.ai

Abstract

Background: The choice between balanced crystalloids and normal saline for fluid resuscitation in sepsis remains one of the most debated topics in critical care medicine. Recent landmark trials have provided conflicting evidence regarding mortality outcomes and renal safety.

Objective: To critically evaluate the current evidence comparing balanced crystalloids and normal saline in septic patients, with emphasis on mortality, renal outcomes, and practical considerations for clinical practice.

Methods: Comprehensive review of randomized controlled trials, meta-analyses, and observational studies published between 2012-2024, focusing on sepsis-specific outcomes.

Results: The SMART trial demonstrated a 1.1% absolute mortality reduction with balanced crystalloids, while the PLUS trial found no mortality difference in ICU patients. Balanced solutions consistently show reduced incidence of major adverse kidney events (MAKE) but at increased cost.

Conclusions: Current evidence suggests modest benefits of balanced crystalloids over normal saline in sepsis, particularly for renal outcomes. The choice should be individualized based on patient factors, resource availability, and institutional protocols.

Keywords: sepsis, crystalloids, normal saline, balanced solutions, fluid resuscitation, critical care

Introduction

Sepsis affects over 48 million people globally each year, with fluid resuscitation remaining a cornerstone of early management according to the Surviving Sepsis Campaign guidelines. The fundamental question of which crystalloid solution to use has evolved from academic curiosity to clinical imperative, particularly following recent high-quality randomized controlled trials that have challenged traditional practices.

The physiological rationale for balanced crystalloids centers on their closer approximation to human plasma composition, theoretically avoiding the hyperchloremic metabolic acidosis associated with large-volume normal saline administration. However, the translation of physiological plausibility to clinical outcomes has proven more complex than initially anticipated.

Physiological Foundations

Normal Saline: The Historical Standard

Normal saline (0.9% sodium chloride) contains 154 mEq/L each of sodium and chloride, significantly exceeding physiological plasma concentrations (sodium ~140 mEq/L, chloride ~100 mEq/L). This supraphysiological chloride content has several consequences:

Hyperchloremic metabolic acidosis through the Stewart approach to acid-base balance
Renal vasoconstriction mediated by tubuloglomerular feedback mechanisms
Increased risk of acute kidney injury through multiple pathways including reduced renal blood flow

Balanced Crystalloids: Physiological Rationale

Balanced solutions (Plasma-Lyte A, Lactated Ringer's, Hartmann's solution) contain:

Lower chloride concentrations (98-109 mEq/L)
Physiological pH (7.0-7.4)
Buffer systems (lactate, acetate, or gluconate)
Additional electrolytes (potassium, calcium, magnesium)

Clinical Pearl: The term "balanced" refers to electrolyte composition, not osmolality. All commonly used crystalloids are isotonic.

Landmark Clinical Trials

The SMART Trial (2018): A Paradigm Shift

The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) randomized 15,802 critically ill adults to balanced crystalloids versus saline. Key findings included:

Primary Outcomes:

MAKE-30 (death, new RRT, or persistent renal dysfunction): 14.3% vs 15.4% (OR 0.91, 95% CI 0.82-1.01, p=0.06)
30-day in-hospital mortality: 10.3% vs 11.1% (absolute reduction 0.8%, OR 0.91, 95% CI 0.78-1.06)

Sepsis Subgroup Analysis (n=1,641):

Significant mortality reduction: 25.2% vs 29.4% (absolute reduction 4.2%, OR 0.80, 95% CI 0.67-0.97)
MAKE-30 reduction: 32.7% vs 36.3% (OR 0.85, 95% CI 0.72-1.01)

Clinical Hack: The sepsis subgroup showed the most pronounced benefit, suggesting that sicker patients derive greater advantage from balanced solutions.

The PLUS Trial (2022): Challenging the Narrative

The Plasma-Lyte 148 versus Saline (PLUS) trial randomized 5,037 ICU patients across Australia and New Zealand:

Primary Outcomes:

90-day mortality: 21.8% vs 22.0% (absolute difference -0.2%, 95% CI -3.3 to 2.9%, p=0.90)
MAKE-30: 22.7% vs 24.5% (absolute difference -1.8%, 95% CI -4.7 to 1.1%)

Key Differences from SMART:

Higher baseline mortality (22% vs 11%)
Different balanced solution (Plasma-Lyte 148 vs multiple solutions)
Shorter enrollment period with higher acuity patients

Oyster Alert: The PLUS trial's null result may reflect the diminishing returns of interventions in higher-acuity populations or differences in baseline care standards.

Meta-Analyses and Systematic Reviews

Zampieri et al. (2021) - Comprehensive Meta-Analysis

Analysis of 21 RCTs (n=20,213 patients) demonstrated:

Mortality reduction: RR 0.91 (95% CI 0.84-0.99, p=0.02)
AKI reduction: RR 0.91 (95% CI 0.85-0.98, p=0.009)
RRT requirement: RR 0.87 (95% CI 0.78-0.97, p=0.01)

Hammond et al. (2022) - Sepsis-Specific Analysis

Focused analysis of septic patients (n=3,710) revealed:

Mortality: RR 0.84 (95% CI 0.73-0.97, p=0.02)
AKI: RR 0.80 (95% CI 0.68-0.95, p=0.009)

Teaching Point: Meta-analyses consistently favor balanced crystalloids, but individual trial heterogeneity remains significant.

Special Populations and Clinical Contexts

Traumatic Brain Injury: A Notable Exception

The BEST-TRIP trial demonstrated increased mortality with balanced crystalloids in severe TBI patients, attributed to:

Hypotonic effects causing cerebral edema
Calcium interference with coagulation
Potassium-induced cardiac effects in the setting of catecholamine excess

Clinical Pearl: Normal saline remains preferred for TBI resuscitation despite general trends favoring balanced solutions.

Pediatric Considerations

Limited pediatric data suggests similar trends to adults, but with important caveats:

Lower baseline chloride tolerance
Higher risk of hyperchloremic acidosis
Different volume distribution kinetics

Economic Considerations

Direct Costs

United States pricing (approximate):

Normal saline: $1-3 per liter
Lactated Ringer's: $2-4 per liter
Plasma-Lyte A: $4-8 per liter

Cost-Effectiveness Analysis

Semler et al. (2020) economic evaluation of SMART trial data:

Incremental cost per QALY: $18,916 (highly cost-effective)
Break-even analysis: Cost difference <$8.90 per liter remains cost-effective

Resource-Limited Settings: The cost differential becomes significant in low-resource environments where:

Normal saline may cost $0.50-1.00 per liter
Balanced solutions may cost $3-5 per liter
Daily fluid requirements can exceed 3-4 liters per patient

Practical Hack: In resource-limited settings, consider hybrid approaches using balanced solutions for initial resuscitation followed by normal saline for maintenance.

Clinical Pearls and Practical Considerations

Decision-Making Framework

Choose Balanced Crystalloids When:

Sepsis or septic shock
Large volume resuscitation anticipated (>2L)
Pre-existing renal dysfunction
Metabolic acidosis present
Cost considerations manageable

Consider Normal Saline When:

Traumatic brain injury
Significant hyperkalemia
Resource constraints
Concurrent need for medication compatibility

Monitoring Parameters

Essential Monitoring:

Serial lactate levels
Chloride and anion gap
Urine output and creatinine
Base deficit/bicarbonate

Advanced Monitoring:

Strong ion difference (SID)
Apparent strong ion difference (SIDa)
Unmeasured anions

Implementation Strategies

Institutional Approaches:

Default Policy: Balanced crystalloids as standard with specific indications for saline
Selective Strategy: Choice based on diagnosis and clinical factors
Hybrid Approach: Balanced for resuscitation, saline for maintenance

Oyster: Institutional standardization may be more important than the specific choice, as it reduces variability and cognitive load.

Future Directions and Research Gaps

Ongoing Trials

BEST-FLUIDS: Large pragmatic trial in sepsis
BaSICS: Brazilian sepsis trial with mortality primary endpoint
CRISTAL-ED: Emergency department initiation strategies

Research Priorities

Optimal timing of fluid type selection
Volume thresholds for differential benefit
Biomarker-guided fluid selection
Pediatric and obstetric populations
Resource-stratified implementation strategies

Controversial Areas and Expert Opinions

The Chloride Debate

Liberalists argue:

Hyperchloremia is well-tolerated in healthy individuals
Cost considerations outweigh modest clinical benefits
Historical use demonstrates acceptable safety profile

Restrictionists contend:

Even modest mortality benefits justify routine use
Renal protection has long-term implications
Physiological rationale strongly favors balanced solutions

Statistical Significance vs. Clinical Significance

The debate centers on whether statistically significant but numerically small differences (0.8-1.1% mortality reduction) justify:

Increased costs
Supply chain complexity
Training requirements

Teaching Moment: This exemplifies the challenge of implementing evidence-based medicine when effect sizes are modest but potentially clinically meaningful at population levels.

Practice Recommendations

Surviving Sepsis Campaign 2021 Update

Current guidelines suggest:

Weak recommendation for balanced crystalloids over normal saline
Based on low certainty evidence
Acknowledges resource and availability considerations

Professional Society Positions

American College of Critical Care Medicine:

Endorses balanced crystalloids when available and cost-effective
Recognizes normal saline as acceptable alternative

European Society of Intensive Care Medicine:

Similar position with emphasis on individualized decision-making

Key Take-Home Messages

For the Practicing Intensivist

Balanced crystalloids likely offer modest benefits over normal saline in sepsis, particularly for renal outcomes
The absolute benefit is small but potentially meaningful at population level
Cost-effectiveness is favorable in high-resource settings but questionable in resource-limited environments
Patient-specific factors should guide individual decisions
Institutional standardization may be more important than specific fluid choice

Clinical Pearls Summary

"The sepsis benefit": Sickest patients show greatest differential benefit
"The volume threshold": Benefits become apparent with >1-2L administration
"The TBI exception": Normal saline remains preferred for severe head injury
"The cost crossover": Break-even point is approximately $9 per liter price difference

Oysters (Common Misconceptions)

"Balanced always means better": Not true in TBI or severe hyperkalemia
"Normal saline is dangerous": Overstated; it remains safe for most applications
"The mortality benefit is large": Modest absolute benefit (~1%) in most populations
"Cost doesn't matter": Significant issue in resource-limited settings

Conclusions

The crystalloid debate represents modern evidence-based medicine at its most nuanced. While balanced crystalloids appear to offer modest advantages over normal saline in sepsis, the clinical significance of these benefits must be weighed against practical considerations including cost, availability, and patient-specific factors.

The practicing intensivist should approach this decision with equipoise, recognizing that both solutions are acceptable choices with different risk-benefit profiles. The emphasis should be on early, adequate resuscitation rather than prolonged deliberation over fluid type.

As the field awaits results from ongoing large-scale trials, a pragmatic approach favoring balanced crystalloids when readily available and cost-effective, while maintaining normal saline as an acceptable alternative, appears most reasonable.

The ultimate goal remains optimal patient outcomes through evidence-informed, resource-conscious, and individualized care.

References

Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med. 2018;378(9):829-839.
Finfer S, Micallef S, Hammond N, et al. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med. 2022;386(9):815-826.
Zampieri FG, Machado FR, Biondi RS, et al. Effect of intravenous fluid treatment with a balanced solution vs 0.9% saline solution on mortality in critically ill patients: the BaSICS randomized clinical trial. JAMA. 2021;326(9):1-12.
Hammond NE, Zampieri FG, Di Tanna GL, et al. Balanced crystalloids versus saline in critically ill adults - a systematic review with meta-analysis. Crit Care Med. 2022;50(1):23-32.
Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819-828.
Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA. 2015;314(16):1701-1710.
Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA. 2012;308(15):1566-1572.
Semler MW, Kellum JA. Balanced crystalloid solutions. Am J Respir Crit Care Med. 2019;199(8):952-960.
Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.
Hammond NE, Taylor C, Saxena M, et al. Resuscitation fluid choices to preserve the endothelial glycocalyx. Crit Care. 2020;24(1):482.

Conflicts of Interest: None declared

Funding: No external funding received

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Sunday, July 27, 2025