SALT-ED: Balanced Crystalloids vs Saline in the ED (2018)

“Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline.”

— The SALT-ED Investigators

1. Publication Details

  • Trial Title: Balanced Crystalloids versus Saline in Noncritically Ill Adults.
  • Citation: 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. doi:10.1056/NEJMoa1711586.
  • Published: March 1, 2018, in The New England Journal of Medicine.
  • Author: Wesley H. Self, MD, MPH.
  • Funding: Vanderbilt Institute for Clinical and Translational Research.

2. Keywords

Intravenous Fluids, Crystalloid Solutions, Balanced Crystalloids, Saline, Emergency Department, Acute Kidney Injury.

3. The Clinical Question

In non-critically ill adults requiring intravenous crystalloid fluid in the emergency department (ED) and subsequently hospitalized (Population), does the use of balanced crystalloids (Intervention) compared to 0.9% saline (Comparison) affect the number of hospital-free days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: 0.9% sodium chloride (saline) is the most frequently administered intravenous fluid, but its high chloride content can cause hyperchloremic metabolic acidosis and acute kidney injury (AKI). Balanced crystalloids have a more physiologic electrolyte composition and are a potential alternative.
  • Knowledge Gap: Despite widespread fluid use, there was a lack of large-scale, pragmatic, randomized trial evidence comparing balanced crystalloids and saline in the general population of adults treated in the ED.
  • Proposed Hypothesis: The authors hypothesized that among adults treated with intravenous crystalloids in the ED who were subsequently hospitalized to a non-ICU setting, treatment with balanced crystalloids would result in more hospital-free days than treatment with saline.

5. Study Design and Methods

  • Design: A pragmatic, single-center, unblinded, cluster-randomized, multiple-crossover trial.
  • Setting: A single, large academic medical center in the United States (Vanderbilt University Medical Center).
  • Trial Period: Enrollment occurred between January 2016 and April 2017.
  • Population:
    • Inclusion Criteria: Adults (age ≥18) who received at least 500 mL of intravenous isotonic crystalloid in the ED and were subsequently hospitalized to a non-ICU ward.
    • Exclusion Criteria: Patients discharged home from the ED or admitted directly to an intensive care unit (ICU) were excluded (ICU patients were enrolled in the parallel SMART trial).
  • Intervention: Balanced crystalloids (clinician’s choice of Lactated Ringer’s solution or Plasma-Lyte A).
  • Control: Saline (0.9% sodium chloride).
  • Management Common to Both Groups: All other aspects of patient care were determined by the treating clinicians. Clinicians could use an off-protocol crystalloid if they believed it was specifically indicated for a patient.
  • Power and Sample Size: The trial was planned for 16 months, anticipating a sample size of approximately 15,000 patients. This size was calculated to provide over 90% power to detect a difference of 0.5 hospital-free days between groups.
  • Outcomes:
    • Primary Outcome: Hospital-free days to day 28, a composite of in-hospital death and hospital length of stay.
    • Secondary Outcomes: The key secondary outcome was Major Adverse Kidney Events within 30 days (MAKE-30), a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (final creatinine ≥200% of baseline).

6. Key Results

  • Enrollment and Baseline: 13,347 patients were included in the analysis (6,708 in the balanced-crystalloids group; 6,639 in the saline group). Baseline characteristics were well-balanced.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no difference in the primary outcome of hospital-free days. The median was 25 days in both the balanced-crystalloids group and the saline group (Adjusted Odds Ratio [aOR] with balanced crystalloids, 0.98; 95% CI, 0.92 to 1.04; P=0.41).
  • Secondary Outcomes: The balanced-crystalloids group had a significantly lower incidence of MAKE-30 compared to the saline group (4.7% vs. 5.6%; aOR, 0.82; 95% CI, 0.70 to 0.95; P=0.01).
  • Adverse Events: The study did not report specific adverse events related to fluid administration, as the outcomes of interest (like AKI) were captured in the primary and secondary endpoints.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat principle was used for the primary analysis.
  • Statistical Tests Used: The primary outcome was analyzed using a multivariable proportional odds model. The secondary outcome (MAKE-30) was analyzed using logistic regression.
  • Primary Outcome Analysis: The primary outcome was analyzed as an ordinal variable, comparing hospital-free days between groups.
  • Key Statistic(s) Reported (for MAKE-30): Adjusted Odds Ratio: 0.82; 95% CI: 0.70 to 0.95; P-value: 0.01.
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR): The odds of experiencing a major adverse kidney event within 30 days were 18% lower for patients receiving balanced crystalloids compared to those receiving saline.
    • Confidence Interval (CI): The 95% CI ranges from a 30% reduction to a 5% reduction in odds, and because it does not cross 1.0, the result is statistically significant.
    • P-value: The p-value of 0.01 indicates that the observed difference is unlikely to be due to chance alone.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR): 0.9% (5.6% – 4.7%).
    • Number Needed to Treat (NNT): 111 (1 / 0.009). To prevent one Major Adverse Kidney Event within 30 days, 111 patients would need to be treated with balanced crystalloids instead of saline.
  • Subgroup Analyses: The benefit in reducing MAKE-30 was most pronounced in patients with baseline renal dysfunction or hyperchloremia.

8. Strengths of the Study

  • Study Design and Conduct: The pragmatic, cluster-randomized, multiple-crossover design minimized selection bias and contamination while maximizing real-world applicability.
  • Generalizability: The pragmatic nature, enrolling nearly all eligible patients in a large ED, increases external validity to similar settings.
  • Statistical Power: The very large sample size provided adequate power to detect small differences in outcomes.
  • Patient-Centered Outcomes: The trial used objective, patient-centered outcomes like hospital-free days and MAKE-30.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The unblinded nature of the intervention could have introduced performance bias, although this is mitigated by the objective nature of the outcomes.
  • External Validity (Generalizability): As a single-center study, the results may not be generalizable to all ED settings.
  • Other: The volume of fluid administered in the ED was relatively small (median ~1 liter), which may have underestimated the potential effect of the fluid choice.

10. Conclusion of the Authors

“Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. Treatment with balanced crystalloids resulted in a lower rate of major adverse kidney events within 30 days.”

11. To Summarize

  • Impact on Current Practice: This trial, along with its companion SMART trial in ICU patients, provides strong evidence to support the preferential use of balanced crystalloids over saline for most adult patients in the ED to reduce the risk of subsequent kidney injury.
  • Specific Recommendations:
    • Patient Selection: Adults in the ED who require intravenous fluids for resuscitation or hydration and are expected to be admitted to the hospital.
    • Actionable Intervention: Use balanced crystalloids (e.g., Lactated Ringer’s) as the default isotonic fluid instead of 0.9% saline.
    • Expected Benefit: A small but statistically significant reduction in the composite outcome of death, new dialysis, or persistent renal dysfunction, with a number needed to treat of 111.
  • What This Trial Does NOT Mean: This trial does not mean saline should be completely abandoned. It may still be appropriate in specific clinical situations, such as for patients with traumatic brain injury or significant hypochloremia.
  • Implementation Caveats: The benefit is modest, and the primary outcome of hospital-free days was not met. The benefit was greatest in patients with pre-existing renal dysfunction.

12. Context and Related Studies

  • Building on Previous Evidence: SALT-ED was designed to address the lack of large-scale evidence for fluid choice in a non-critically ill population.
  • Influence on Subsequent Research: This trial was conducted in parallel with the SMART trial (2018), which studied a critically ill ICU population and found a similar reduction in MAKE-30 with balanced crystalloids. Together, these landmark trials have significantly shifted clinical practice toward the use of balanced fluids.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Does the specific type of balanced crystalloid (e.g., Lactated Ringer’s vs. Plasma-Lyte) matter? What is the effect of fluid choice in specific populations not well-represented, like those with traumatic brain injury?
  • Future Directions: Future research could compare different types of balanced crystalloids or focus on the effect of fluid choice in specific disease states in large, multicenter trials.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a ubiquitous clinical decision (choice of IV fluid) for which high-quality evidence was lacking.
  • Methods: The pragmatic, cluster-randomized, multiple-crossover design was a methodologically rigorous and innovative approach for comparing two standard-of-care interventions. The control group (saline) was appropriate as it represented the most common practice at the time.
  • Results: The trial did not meet its primary endpoint. However, the finding of a statistically significant reduction in the key secondary outcome of MAKE-30 is clinically important, even with a modest effect size (NNT of 111).
  • Conclusions and Applicability: The authors’ conclusion is well-supported by the data. The results, especially when viewed alongside the companion SMART trial, are highly applicable to routine clinical practice in the ED. Given the low cost and wide availability of balanced crystalloids, the finding of reduced renal harm provides a strong rationale for shifting practice away from saline as the default fluid for most patients.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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