SMART: Balanced Crystalloids vs Saline in the ICU (2018)

“Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.”

— The SMART Investigators

1. Publication Details

  • Trial Title: Balanced Crystalloids versus Saline in Critically Ill Adults.
  • Citation: Semler MW, Self WH, Wanderer JP, et al; for the SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829-839. doi:10.1056/NEJMoa1711584.
  • Published: March 1, 2018, in The New England Journal of Medicine.
  • Author: Matthew W. Semler, M.D., M.Sc.
  • Funding: Vanderbilt Institute for Clinical and Translational Research.

2. Keywords

Intravenous Fluids, Crystalloid Solutions, Balanced Crystalloids, Saline, Critical Illness, Septic Shock, Acute Kidney Injury (AKI).

3. The Clinical Question

In critically ill adults admitted to the ICU (Population), does the use of balanced crystalloids (Intervention) compared to 0.9% saline (Comparison) for intravenous fluid administration reduce the incidence of Major Adverse Kidney Events within 30 days (MAKE-30) (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Saline (0.9% sodium chloride) was the most commonly used intravenous fluid in ICUs, but its supraphysiologic chloride concentration was associated with hyperchloremic metabolic acidosis and acute kidney injury (AKI) in observational studies.
  • Knowledge Gap: Despite theoretical risks, there was no large-scale, randomized trial evidence to determine if using balanced crystalloids (which have a more physiologic electrolyte composition) instead of saline improved patient-centered outcomes in a broad population of critically ill adults.
  • Proposed Hypothesis: The authors hypothesized that the use of balanced crystalloids would result in a lower incidence of the composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.

5. Study Design and Methods

  • Design: A pragmatic, cluster-randomized, multiple-crossover trial.
  • Setting: Five intensive care units (medical, surgical, trauma, cardiothoracic, and neurologic) at a single, large academic medical center in the United States (Vanderbilt University Medical Center).
  • Trial Period: Enrollment from June 2015 to April 2017.
  • Population:
    • Inclusion Criteria: All adults (age ≥18) admitted to one of the participating ICUs.
    • Exclusion Criteria: No specific exclusion criteria were applied at the patient level, consistent with the pragmatic design.
  • Intervention: Balanced crystalloids (clinician’s choice of Lactated Ringer’s solution or Plasma-Lyte A) as the default isotonic fluid for the ICU during assigned months.
  • Control: Saline (0.9% sodium chloride) as the default isotonic fluid for the ICU during assigned months.
  • Management Common to Both Groups: The type of crystalloid available in each ICU was alternated monthly according to the cluster randomization schedule. All other aspects of patient care were at the discretion of the clinical team.
  • Power and Sample Size: The trial was powered to detect a 2.5 percentage point difference in the primary outcome, requiring approximately 14,000 patients.
  • Outcomes:
    • Primary Outcome: 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).
    • Secondary Outcomes: Included individual components of MAKE-30, 28-day ventilator-free days, 28-day vasopressor-free days, and ICU and hospital length of stay.

6. Key Results

  • Enrollment and Baseline: 15,802 patients were included in the analysis (7942 in the balanced-crystalloids group; 7860 in the saline group). Baseline characteristics were well-balanced.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The balanced-crystalloids group had a significantly lower incidence of MAKE-30 compared to the saline group (14.3% vs 15.4%; P=0.04).
  • Secondary Outcomes: There were no significant differences in the individual components of the primary outcome when analyzed separately, nor in ventilator-free days or length of stay.
  • Adverse Events: The incidence of adverse events was similar in the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a multivariable logistic regression model.
  • Primary Outcome Analysis: The proportion of patients experiencing a MAKE-30 event was compared between the two groups.
  • Key Statistic(s) Reported: Adjusted Odds Ratio (aOR) for MAKE-30: 0.90 (95% CI, 0.82 to 0.99; P=0.04).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR): The odds of experiencing a major adverse kidney event within 30 days were 10% lower for patients receiving balanced crystalloids compared to those receiving saline.
    • Confidence Interval (CI): The 95% CI ranges from an 18% reduction to a 1% reduction in odds. Because the upper bound is below 1.0, the result is statistically significant.
    • P-value: The p-value of 0.04 is below the 0.05 threshold, indicating the result is statistically significant.
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR): 1.1% (15.4% – 14.3%).
    • Number Needed to Treat (NNT): 94 (1 / 0.011). To prevent one Major Adverse Kidney Event, 94 critically ill patients would need to be treated with balanced crystalloids instead of saline.
  • Subgroup Analyses: The benefit of balanced crystalloids appeared to be greater in patients with sepsis and in those with pre-existing acute kidney injury.

8. Strengths of the Study

  • Study Design and Conduct: The pragmatic, cluster-randomized, multiple-crossover design was highly innovative, allowing for the efficient enrollment of a very large number of patients and minimizing selection bias.
  • Generalizability: The pragmatic design, enrolling all adults admitted to five different types of ICUs, increases the external validity of the findings to a broad population of critically ill patients.
  • Statistical Power: The very large sample size provided adequate power to detect a small but clinically important difference in the primary outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which could introduce performance bias, though the primary outcome was a composite of objective endpoints.
  • External Validity (Generalizability): As a single-center study, the results may not be generalizable to all hospital systems, although the diversity of ICUs mitigates this.
  • Other: The difference in the primary outcome was driven by all components of the composite, but no single component was statistically significant on its own. The volume of fluid administered was relatively small (median ~1 liter).

10. Conclusion of the Authors

“Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.”

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial. Along with its companion trial in the emergency department (SALT-ED), it provided the first large-scale, high-quality evidence that the choice of isotonic crystalloid fluid has a significant impact on patient-centered outcomes. It has led to a major shift in clinical practice worldwide, away from saline and toward balanced crystalloids as the default fluid for most critically ill patients.
  • Specific Recommendations:
    • Patient Selection: For the broad population of critically ill adults requiring intravenous isotonic fluid.
    • Actionable Intervention: Use balanced crystalloids (e.g., Lactated Ringer’s or Plasma-Lyte) as the default intravenous fluid instead of 0.9% saline.
    • Expected Benefit: A small but significant reduction in the composite outcome of death or major adverse kidney events, with an NNT of 94.
  • What This Trial Does NOT Mean: This trial does not mean that saline is “toxic” or should never be used. It may be appropriate in specific situations, such as correcting hypochloremic metabolic alkalosis or in patients with traumatic brain injury where a slightly hypertonic solution is desired.
  • Implementation Caveats: The cost difference between balanced crystalloids and saline is generally minimal, making this a highly feasible and cost-effective intervention.

12. Context and Related Studies

  • Building on Previous Evidence: The SMART trial was designed to definitively answer the question raised by years of physiologic studies and observational data that had suggested potential harm from saline.
  • Influence on Subsequent Research: This trial, along with SALT-ED (2018), has become a cornerstone of modern fluid resuscitation evidence. It has influenced numerous international guidelines. Subsequent large trials likeBaSICS (2021) and PLUS (2022), conducted in different settings and populations, did not find a significant difference in mortality, leading to ongoing debate, but SMART remains highly influential due to its pragmatic design and positive finding for the MAKE-30 endpoint.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Why did subsequent large trials (BaSICS, PLUS) not replicate the positive findings of SMART? Does the benefit of balanced crystalloids vary significantly based on the patient’s underlying diagnosis (e.g., sepsis vs. trauma) or the volume of fluid administered?
  • Future Directions: Research is ongoing to better understand which specific patient populations derive the most benefit from balanced crystalloids and to clarify the role of different fluid types in specific clinical scenarios.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was of fundamental importance to critical care, addressing one of the most common interventions provided in the ICU (IV fluid administration).
  • Methods: The pragmatic, cluster-randomized, multiple-crossover design was a methodologically innovative and powerful approach to answer this question efficiently and with high external validity.
  • Results: The trial found a statistically significant, albeit small, benefit for balanced crystalloids for the primary composite outcome. The NNT of 94 indicates a modest effect size, but one that is highly significant on a population level given the ubiquity of IV fluid use.
  • Conclusions and Applicability: The authors’ conclusion is well-supported by the data. The results are highly applicable to a broad range of critically ill patients and provide a strong rationale to favor balanced crystalloids over saline as the default fluid in the ICU.

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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