Balanced Crystalloids versus Saline in Noncritically Ill Adults
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In noncritically ill adults presenting to the emergency department, resuscitation with balanced crystalloids compared to normal saline did not increase hospital-free days but was associated with a modest decrease in major adverse kidney events.
Key Findings
Study Design
Study Limitations
Clinical Significance
While balanced crystalloids did not change overall length of stay or short-term mortality (hospital-free days) in noncritically ill patients, the reduction in major adverse kidney events with balanced solutions highlights their potential safety advantage. Given that balanced crystalloids (like Lactated Ringer's) and normal saline have comparable costs and availability, these findings support utilizing balanced crystalloids as the default initial resuscitation fluid for patients in the emergency department, particularly for those with pre-existing renal dysfunction.
Historical Context
For decades, 0.9% normal saline was the undisputed default intravenous fluid worldwide despite its supraphysiologic chloride concentration (154 mEq/L), which observational data linked to hyperchloremic metabolic acidosis, renal vasoconstriction, and acute kidney injury. The SALT-ED trial was published simultaneously in 2018 with its sister trial, SMART (which evaluated critically ill ICU patients). Together, these landmark cluster-crossover trials represented a major paradigm shift in the 'Fluid Wars,' providing high-quality pragmatic evidence that challenged the routine use of normal saline in favor of balanced solutions. Subsequent large global trials (such as BaSICS and PLUS) have since added nuance, suggesting that any benefit of balanced fluids might be modest and highly context-dependent.
Guided Discussion
High-yield insights from every perspective
What is the pathophysiological mechanism by which large volumes of 0.9 percent sodium chloride (normal saline) can lead to a decreased glomerular filtration rate compared to balanced crystalloids?
Key Response
Normal saline has a high chloride concentration (154 mEq/L) compared to plasma. Excess chloride delivery to the macula densa triggers tubuloglomerular feedback, causing afferent arteriolar vasoconstriction. This decreases the glomerular filtration rate (GFR) and can contribute to acute kidney injury, while also causing a non-anion gap hyperchloremic metabolic acidosis.
Given the findings of the SALT-ED trial favoring balanced crystalloids, in which specific clinical scenarios in the emergency department would 0.9 percent normal saline still be the preferred initial resuscitation fluid?
Key Response
Normal saline remains the fluid of choice for patients with traumatic brain injury to avoid worsening cerebral edema (since Lactated Ringers is slightly hypotonic) and for patients with severe volume depletion accompanied by hypochloremic metabolic alkalosis (such as from severe vomiting) where aggressive chloride repletion is therapeutically necessary.
The SALT-ED trial demonstrated a modest reduction in Major Adverse Kidney Events at 30 days (MAKE30). When dissecting this composite outcome, which specific components drove the statistical difference, and how does this impact your interpretation of the treatment effect?
Key Response
MAKE30 is a composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (final creatinine at least 200 percent of baseline). The difference was primarily driven by the persistent renal dysfunction component, not mortality or new dialysis. While persistent creatinine elevation is a valid marker of kidney injury, it is arguably less patient-centered than death or dialysis, adding important nuance to the clinical significance of the effect.
The absolute risk reduction for MAKE30 in the balanced crystalloid group was less than 1 percent. How do you justify a departmental or system-wide change in fluid selection protocols based on such a marginal absolute difference?
Key Response
Although the absolute risk reduction is small (approximately 0.9 percent), intravenous fluids are among the most universally prescribed therapies in acute care. Applying this small ARR to millions of emergency department patients translates to tens of thousands of prevented AKI events globally at the population level. Since balanced crystalloids cost the same as normal saline and have similar safety profiles, this represents a massive public health impact for a zero-cost intervention.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The SALT-ED trial utilized a pragmatic, multiple-crossover cluster-randomized design where fluid type was assigned by calendar month. What are the methodological and statistical trade-offs of this design, particularly regarding the intra-cluster correlation coefficient?
Key Response
The cluster-crossover design allows for seamless integration into clinical workflow, maximizing enrollment and generalizability while virtually eliminating selection bias. However, patients within the same cluster (e.g., the same ED in a specific month) may be correlated. If the statistical analysis fails to properly account for the intra-cluster correlation coefficient using mixed-effects models or generalized estimating equations, the standard errors will be artificially small, increasing the risk of a Type I error.
The SALT-ED trial was unblinded, meaning treating clinicians were aware of the assigned fluid for the month. As a peer reviewer, how might this lack of blinding introduce ascertainment bias, specifically concerning the secondary composite outcome of MAKE30?
Key Response
Without blinding, clinicians with preconceived biases about saline-induced nephrotoxicity might alter their practice, such as preferentially checking follow-up serum creatinine levels in the saline group or adjusting total fluid volumes. Because the MAKE30 outcome is heavily driven by the persistent renal dysfunction component, disparate rates of creatinine testing between the groups could artificially inflate the diagnosis of renal dysfunction in the saline arm, threatening the internal validity of the secondary outcome.
How should the results of the SALT-ED trial, synthesized with its sister trial SMART, influence the strength of recommendation and level of evidence in the Surviving Sepsis Campaign guidelines regarding initial fluid resuscitation?
Key Response
Historically, Surviving Sepsis Campaign guidelines recommended crystalloids broadly, with saline acting as the default in practice. The combined evidence from SALT-ED (noncritically ill) and SMART (critically ill) provides moderate to high-quality evidence that balanced crystalloids reduce the incidence of acute kidney injury. This justifies updating the guidelines to issue a conditional or strong recommendation explicitly favoring balanced crystalloids over normal saline for the initial resuscitation of sepsis, moving away from viewing all crystalloids as equivalent.
Clinical Landscape
Noteworthy Related Trials
SPLIT Trial
Tested
Buffered crystalloid (Plasma-Lyte 148)
Population
Patients receiving crystalloid fluid therapy in the ICU
Comparator
0.9% Sodium Chloride (Saline)
Endpoint
Proportion of patients with acute kidney injury (AKI)
SMART Trial
Tested
Balanced crystalloids (Lactated Ringer's or Plasma-Lyte A)
Population
Critically ill adults in the ICU
Comparator
0.9% Normal Saline
Endpoint
Major Adverse Kidney Events within 30 days (MAKE30)
BaSICS Trial
Tested
Balanced crystalloid solution (Plasma-Lyte 148)
Population
Critically ill patients in the ICU
Comparator
0.9% Saline
Endpoint
90-day mortality
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