JAMA AUGUST 10, 2021

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

Fernando G. Zampieri, Flávia R. Machado, et al. (The BaSICS Investigators and the BRICNet)

Bottom Line

In this large, double-blind, factorial randomized clinical trial, the use of a balanced crystalloid solution (Plasma-Lyte 148) compared to 0.9% saline did not significantly reduce 90-day mortality in critically ill adults requiring fluid resuscitation.

Key Findings

1. The primary outcome of 90-day all-cause mortality occurred in 26.4% of patients in the balanced solution group and 27.2% in the saline group (adjusted hazard ratio, 0.97; 95% CI, 0.90 to 1.05; P = 0.47).

2. No significant differences were observed in key secondary renal outcomes, including the incidence of stage 2 or 3 acute kidney injury (27.0% balanced vs 27.2% saline) or the requirement for renal replacement therapy (1.0% balanced vs 1.1% saline).

3. Prespecified subgroup analyses did not reveal a clear mortality benefit for balanced solutions across major patient categories, including those with sepsis or elective surgical admissions.

4. Post-hoc analyses have generated hypotheses regarding potential benefits in specific subpopulations, though the overall trial failed to demonstrate a clinical advantage.

Study Design

Design

RCT

Double-Blind

Sample

10,520

Patients

Duration

90 days

Median

Setting

Multicenter, Brazil

Population Critically ill adults admitted to the ICU with at least one risk factor for acute kidney injury who required fluid expansion and were expected to remain in the ICU for more than 24 hours.

Intervention Plasma-Lyte 148 (balanced solution) for all fluid resuscitation and maintenance.

Comparator 0.9% saline solution for all fluid resuscitation and maintenance.

Outcome 90-day all-cause mortality

Study Limitations

• Nearly 70% of patients received non-study intravenous fluid boluses prior to randomization, which may have diluted the treatment effect (contamination).

• The use of open-label fluids for maintenance or medication dilution, while allowed, introduces potential for confounding.

• Approximately 48% of the study population comprised elective surgical admissions, a lower-risk group that may have obscured potential benefits in more severe phenotypes.

• The trial was conducted in a single country, which may limit the generalizability of findings to health systems with different fluid resuscitation practices.

Clinical Significance

The results of the BaSICS trial, alongside other large-scale contemporary trials like the PLUS trial, suggest that for a general ICU population, the choice between balanced crystalloids and 0.9% saline may not significantly impact hard clinical outcomes like mortality or kidney failure, challenging the previously established narrative of saline-induced harm.

Historical Context

For decades, the safety of 0.9% saline—the most common resuscitation fluid—was debated due to its association with hyperchloremic metabolic acidosis and potential renal injury. Prior to BaSICS, observational studies and smaller trials (such as SMART and SALT-ED) suggested balanced solutions might improve outcomes, leading to a shift in clinical practice toward balanced crystalloids in many centers. BaSICS remains one of the largest and most robustly designed trials to test this clinical question.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Explain the physiological rationale behind why 0.9% saline is considered 'non-physiological' compared to balanced solutions like Plasma-Lyte 148, and identify the specific metabolic disturbance it is known to cause.

Key Response

0.9% saline contains 154 mmol/L of sodium and 154 mmol/L of chloride, which is significantly higher than human plasma chloride (approx. 100 mmol/L). This excess chloride can lead to hyperchloremic metabolic acidosis. The physiological mechanism involves the Strong Ion Difference (SID); increasing chloride narrows the SID, forcing a rise in hydrogen ion concentration to maintain electroneutrality.

Resident

In light of the BaSICS trial findings, how should a clinician approach fluid selection for a patient with a traumatic brain injury (TBI) compared to a patient with septic shock?

Key Response

BaSICS found no mortality benefit for balanced solutions in the general ICU population, but a subgroup analysis suggested potential harm (increased mortality) with balanced solutions in TBI patients. This is likely because many balanced solutions are slightly hypotonic compared to saline, potentially increasing intracranial pressure. For septic shock, the choice remains more flexible, but saline is often avoided in favor of balanced fluids only if severe hyperchloremic acidosis is a concern.

Fellow

The BaSICS trial used a 2x2 factorial design to study both fluid type and infusion rate. Discuss the potential for 'contamination' from pre-randomization fluid administration and how it might have influenced the study's ability to detect a difference between 0.9% saline and Plasma-Lyte 148.

Key Response

Critically ill patients often receive significant volumes of fluid (usually 0.9% saline) in the Emergency Department or during initial resuscitation before ICU enrollment. In BaSICS, patients received a median of 1.5L of fluid prior to randomization. This 'contamination' reduces the cumulative difference in chloride exposure between the two groups, potentially diluting the treatment effect and pushing the results toward the null.

Attending

Given that BaSICS, PLUS, and SMART trials collectively show no clear mortality benefit for balanced crystalloids, what specific clinical or institutional factors (besides mortality) should now guide the selection of primary resuscitation fluids in a high-volume ICU?

Key Response

Since mortality is unaffected, decision-making should shift to 'secondary' outcomes and logistics: cost (saline is significantly cheaper), drug compatibility (many antibiotics/vasopressors are incompatible with the calcium or acetate in balanced fluids), and specific electrolyte states (avoiding saline in hyperchloremic acidosis vs. avoiding balanced fluids in TBI or certain hyperkalemic states).

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the statistical power and effect size assumptions in the BaSICS trial: was the study's primary endpoint (90-day mortality) the most sensitive measure for the biological mechanism of chloride-induced renal injury, or should a composite renal endpoint have been prioritized?

Key Response

BaSICS was powered to detect a 3.5% absolute risk reduction in mortality. This is a very large effect size for a single intervention (fluid type). While mortality is the gold standard, renal-specific outcomes (like Major Adverse Kidney Events - MAKE) are more directly linked to the pathophysiology of chloride. The lack of a mortality benefit may reflect a type II error regarding organ-specific protection that does not translate into a survival advantage.

Journal Editor

As a peer reviewer, how would you evaluate the 'separation' achieved between the treatment arms in BaSICS, and does the relatively modest volume of study fluid administered (median 2.9L over 3 days) limit the trial's generalizability to the most volume-depleted or 'fluid-responsive' patient cohorts?

Key Response

A critical threat to validity in fluid trials is 'low dose' of the intervention. If the difference in chloride exposure is small because the total volume of fluid given is low, the study cannot definitively rule out harm from high-volume saline. Editors would flag that BaSICS reflects 'standard' ICU fluid maintenance rather than 'aggressive' initial resuscitation, where chloride-driven differences might be more pronounced.

Guideline Committee

How do the results of the BaSICS trial compare to the 2021 Surviving Sepsis Campaign (SSC) recommendations, and should the 'weak recommendation, low quality of evidence' for balanced crystalloids be downgraded to 'neutral'?

Key Response

The 2021 SSC guidelines suggested using balanced crystalloids over 0.9% saline for sepsis. However, BaSICS (and the subsequent PLUS trial) showed no benefit. While the recommendation may remain 'weak' due to the potential for AKI prevention seen in the SMART trial, the guideline committee must now acknowledge that for the primary outcome of mortality, 0.9% saline is a safe and evidence-based alternative in general ICU populations.

Clinical Landscape

Noteworthy Related Trials

2015

SPLIT Trial

n = 2,278 · JAMA

Tested

Balanced crystalloids (Plasma-Lyte 148)

Population

ICU patients requiring fluid resuscitation

Comparator

0.9% saline

Endpoint

Acute kidney injury (RIFLE criteria)

Key result: There was no difference in the proportion of patients with acute kidney injury between the balanced crystalloid and saline groups.

2018

SMART Trial

n = 15,802 · NEJM

Tested

Balanced crystalloids (lactated Ringer's or Plasma-Lyte A)

Population

Critically ill adults in the ICU

Comparator

0.9% saline

Endpoint

Major adverse kidney events within 30 days (MAKE30)

Key result: Balanced crystalloids resulted in a lower rate of major adverse kidney events than saline among critically ill adults.

2018

SALT-ED Trial

n = 13,347 · NEJM

Tested

Balanced crystalloids (lactated Ringer's or Plasma-Lyte A)

Population

Non-critically ill adults in the emergency department

Comparator

0.9% saline

Endpoint

Hospital-free days at 28 days

Key result: Balanced crystalloids were associated with a lower risk of major adverse kidney events than saline in non-critically ill patients.

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