New England Journal of Medicine MARCH 01, 2018

Balanced Crystalloids versus Saline in Noncritically Ill Adults

Wesley H. Self, Matthew W. Semler, Jonathan P. Wanderer, et al.

Bottom Line

In this large, pragmatic, single-center trial of noncritically ill adults, the use of balanced crystalloids compared with normal saline for intravenous fluid resuscitation in the emergency department did not increase hospital-free days but was associated with a lower incidence of major adverse kidney events within 30 days (MAKE30).

Key Findings

1. There was no significant difference in the primary outcome of hospital-free days between the balanced crystalloid and saline groups (median, 25 days in both groups; adjusted odds ratio with balanced crystalloids, 0.98; 95% CI, 0.92 to 1.04; P=0.41).

2. Balanced crystalloids resulted in a statistically significantly lower incidence of major adverse kidney events within 30 days (MAKE30) compared with saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

3. The MAKE30 composite endpoint included death from any cause, new renal-replacement therapy, or persistent renal dysfunction, demonstrating a clinical benefit regarding renal safety with balanced crystalloids in the noncritically ill population.

Study Design

Design

RCT

Open-Label

Sample

13,347

Patients

Duration

30 days

Median

Setting

Single center, US

Population Adult patients treated in the emergency department who received at least 500 mL of intravenous isotonic crystalloid and were subsequently admitted to a non-ICU hospital setting.

Intervention Balanced crystalloids (primarily lactated Ringer's solution or Plasma-Lyte A) administered for intravenous resuscitation in the emergency department.

Comparator 0.9% saline (normal saline) administered for intravenous resuscitation in the emergency department.

Outcome Hospital-free days (days alive after discharge before day 28).

Study Limitations

• The study was conducted at a single academic medical center, which may limit the generalizability of the findings to other clinical settings.

• The trial utilized an open-label, unblinded design, which could introduce bias in fluid administration or clinical decision-making, although the pragmatic, crossover structure was intended to mitigate such effects.

• The study was restricted to fluid administration occurring in the emergency department, with limited data on subsequent fluid therapy or clinical management after hospital admission.

• The difference in the secondary endpoint of MAKE30 was largely driven by surrogate laboratory markers of kidney function, rather than more severe outcomes like mortality, which did not differ between the groups.

Clinical Significance

The SALT-ED trial, alongside the related SMART trial, challenged the long-standing clinical practice of using 0.9% normal saline as the default resuscitation fluid. By demonstrating that balanced crystalloids (such as lactated Ringer's or Plasma-Lyte) are associated with improved renal outcomes compared to saline in both noncritically and critically ill populations, the findings provide strong support for the preferential use of balanced crystalloids for intravenous fluid resuscitation in the emergency department.

Historical Context

For decades, 0.9% normal saline was widely considered the 'standard' crystalloid for intravenous fluid therapy. However, its high chloride concentration (154 mEq/L) relative to plasma can cause hyperchloremic metabolic acidosis and has been linked in observational studies to renal vasoconstriction and acute kidney injury. The SALT-ED trial emerged as a landmark pragmatic, cluster-crossover study designed to rigorously test this hypothesis in a real-world emergency department setting, moving beyond earlier, smaller, or retrospective evidence.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological mechanism by which high-chloride intravenous fluids, such as 0.9% normal saline, can theoretically impair renal function compared to balanced crystalloids?

Key Response

Infusion of 0.9% saline (154 mEq/L of chloride) leads to hyperchloremia, which causes renal afferent arteriolar vasoconstriction and decreased glomerular filtration rate (GFR). This occurs via the tubuloglomerular feedback mechanism where increased chloride delivery to the macula densa triggers local signaling to constrict the inflow vessel. Balanced crystalloids (like Lactated Ringer's or Plasma-Lyte) have chloride concentrations closer to physiological levels (98-103 mEq/L), mitigating this risk.

Resident

In a noncritically ill patient presenting to the emergency department, the SALT-ED trial showed no difference in hospital-free days but a reduction in MAKE30. How should this composite endpoint influence your choice of fluid for initial resuscitation?

Key Response

MAKE30 is a composite of death, new renal-replacement therapy, or persistent renal dysfunction (doubling of creatinine). In SALT-ED, the absolute risk reduction was small (4.7% vs 5.6%), but given that balanced crystalloids and saline are similar in cost and availability, the lower incidence of adverse renal events suggests balanced crystalloids should be the default choice for most patients requiring significant volume resuscitation to prevent iatrogenic kidney injury.

Fellow

The SALT-ED trial was conducted concurrently with the SMART trial (in critically ill patients). How do the results of SALT-ED specifically inform the management of patients with baseline renal insufficiency or those presenting with hyperchloremia?

Key Response

Subgroup analyses in the SALT-ED and SMART trials suggested that the benefit of balanced crystalloids was most pronounced in patients with higher baseline creatinine or those receiving larger volumes of fluid. For a fellow, this implies that while balanced crystalloids are generally preferred, they are specifically indicated in 'high-risk' renal patients where even minor changes in chloride load could tip the balance toward persistent renal dysfunction or the need for renal replacement therapy.

Attending

Considering SALT-ED was a single-center, pragmatic trial, what are the primary challenges in translating these findings to a universal institutional protocol for all non-ICU admissions?

Key Response

The pragmatic, cluster-randomized crossover design at Vanderbilt allowed for massive enrollment but limits generalizability due to the 'single-center' effect (local practice patterns). Attendings must weigh the 1% absolute risk reduction in MAKE30 against institutional logistics, such as the compatibility of Lactated Ringer's with certain medications (e.g., ceftriaxone or blood products) and the historical dominance of saline in nursing and pharmacy workflows.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of 'Hospital-Free Days' as a primary endpoint in SALT-ED versus the secondary composite endpoint of MAKE30 in terms of statistical power and clinical relevance.

Key Response

Hospital-free days is a 'global' outcome measure that captures both mortality and length of stay, but it is often insensitive to specific physiological insults like acute kidney injury (AKI). MAKE30 is a more specific 'patient-centered' renal outcome. The trial may have been underpowered to see a difference in hospital-free days because noncritically ill patients have a high baseline 'ceiling' for recovery, whereas the MAKE30 components are more directly influenced by the biochemical differences between the fluids.

Journal Editor

What are the potential threats to internal validity posed by the unblinded, pragmatic design of the SALT-ED trial, specifically regarding the ascertainment of the MAKE30 endpoint?

Key Response

Because the trial was unblinded, clinicians knew which fluid the patient was receiving. This could lead to 'ascertainment bias'—for instance, a clinician might be more likely to re-order a creatinine test or delay discharge if they knew a patient received a fluid they perceive as 'riskier' (saline), or conversely, they might more aggressively monitor patients on balanced fluids. However, the use of objective laboratory data for the MAKE30 composite partially mitigates this concern.

Guideline Committee

Based on the SALT-ED and SMART trials, should clinical guidelines for the management of non-hemorrhagic shock be updated to make a 'Strong Recommendation' for balanced crystalloids over saline?

Key Response

Currently, many guidelines (like the Surviving Sepsis Campaign) provide a 'weak' recommendation for balanced crystalloids due to low-to-moderate quality evidence. SALT-ED provides high-quality evidence in the non-ICU population. The committee must decide if a 1% ARR in a composite endpoint (MAKE30) warrants a 'Strong' recommendation. While saline is not 'contraindicated,' the cumulative evidence from these trials suggests that current guidelines should likely be updated to favor balanced crystalloids as the preferred initial resuscitation fluid in most adult populations.

Clinical Landscape

Noteworthy Related Trials

2015

SPLIT Trial

n = 2,278 · JAMA

Tested

Plasma-Lyte 148

Population

ICU patients

Comparator

0.9% Saline

Endpoint

Acute kidney injury (RIFLE criteria)

Key result: No significant difference in the incidence of acute kidney injury or other clinical outcomes was observed between fluid groups. The results were neutral, contrasting with later larger trials.

2018

SMART Trial

n = 15,802 · NEJM

Tested

Balanced crystalloids

Population

Critically ill adults in the ICU

Comparator

Saline

Endpoint

Major Adverse Kidney Events within 30 days (MAKE30)

Key result: The use of balanced crystalloids resulted in a lower rate of MAKE30 compared to saline among critically ill adults. This trial demonstrated that fluid choice significantly impacts renal outcomes in the intensive care setting.

2022

PLUS Trial

n = 5,037 · NEJM

Tested

Plasma-Lyte 148

Population

Critically ill adults

Comparator

0.9% Saline

Endpoint

90-day all-cause mortality

Key result: Balanced crystalloid solution did not result in a lower risk of death at 90 days compared with saline. The study challenged the superiority of balanced solutions regarding mortality in broad ICU populations.

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