FACTT: Fluid Management in Acute Lung Injury (2006)

“Neither a liberal nor a conservative fluid-management strategy had a significant effect on the primary outcome of 60-day mortality. However, the conservative strategy improved lung function and shortened the duration of mechanical ventilation and intensive care.”

  • The ARDS Clinical Trials Network

1. Publication Details

  • Trial Title: Comparison of Two Fluid-Management Strategies in Acute Lung Injury
  • Citation: The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. DOI: 10.1056/NEJMoa062200
  • Published: June 15, 2006, in The New England Journal of Medicine
  • Author: The National Heart, Lung, and Blood Institute (NHLBI) ARDS Clinical Trials Network
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Acute Lung Injury, ARDS, Fluid Management, Fluid Restriction, Pulmonary Artery Catheter, Central Venous Catheter, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute lung injury (ALI) (Population), does a conservative fluid-management strategy (Intervention) compared to a liberal fluid-management strategy (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: A positive fluid balance was known to be associated with worse outcomes in patients with ARDS. However, it was a major clinical dilemma whether this was a marker of illness severity or if a restrictive fluid strategy could actually improve outcomes. The “dry lung” hypothesis suggested that limiting fluids would reduce pulmonary edema and improve lung function.
  • Knowledge Gap: There was no high-quality evidence from a large randomized trial to determine the optimal fluid-management strategy after initial resuscitation in patients with ARDS. It was unknown if a conservative strategy would be beneficial or if it would risk worsening shock and non-pulmonary organ dysfunction.
  • Proposed Hypothesis: The authors hypothesized that a conservative fluid-management strategy would be superior to a liberal strategy in reducing 60-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, 2×2 factorial, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 20 hospitals in the ARDS Network in the United States.
  • Trial Period: Enrollment ran from June 2000 to October 2005.
  • Population:
    • Inclusion Criteria: Adult patients intubated and mechanically ventilated with acute lung injury (ALI), defined by a PaO2:FiO2 ratio of ≤300.
    • Exclusion Criteria: Included end-stage renal disease on dialysis, severe chronic liver disease, and recent cardiac surgery.
  • Intervention: Patients were randomized in a factorial design to two interventions:
  • Fluid Strategy: A conservative strategy (targeting a low central venous pressure [CVP] or pulmonary-artery occlusion pressure [PAOP]) vs. a liberal strategy (targeting a high CVP or PAOP).
  • Hemodynamic Monitoring: Use of a pulmonary-artery catheter (PAC) vs. a central venous catheter (CVC) to guide fluid and vasopressor therapy.
  • Control: The control groups were the liberal fluid strategy and the CVC strategy.
  • Management Common to Both Groups: All patients were managed with a low tidal volume ventilation strategy. The fluid strategy was followed for 7 days.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 88% power to detect an 8% absolute risk reduction in 60-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80-90% is considered standard).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 60 days.
    • Secondary Outcomes: Included ventilator-free days, ICU-free days, and organ dysfunction scores.

6. Key Results

  • Enrollment and Baseline: 1000 patients were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 60-day mortality between the fluid-strategy groups. 121 of 497 patients (24.3%) in the conservative group died, compared with 127 of 503 patients (25.3%) in the liberal group (p=0.73).
  • Secondary Outcomes: The conservative-fluid strategy resulted in a significantly higher number of ventilator-free days (mean, 14.6 vs. 11.2 days; p<0.001) and ICU-free days (mean, 13.4 vs. 11.2 days; p<0.001). Patients in the conservative group also had improved oxygenation and lung function scores. There was no significant difference in the rate of shock.
  • Adverse Events: The incidence of adverse events was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.73 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, factorial design provided high-quality evidence on two important questions simultaneously.
  • Generalizability: The pragmatic design and inclusion of 20 diverse hospitals make the findings highly generalizable to a broad population of patients with ARDS.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The study focused on mortality and other important patient-centered outcomes like ventilator-free days.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted in a specific population with ARDS, and the results may not apply to other critically ill patients (e.g., those with septic shock without ARDS).
  • Other: The fluid management protocols were complex and based on invasive hemodynamic monitoring (CVP or PAOP), which may be difficult to replicate perfectly in all settings.

10. Conclusion of the Authors

  • The authors concluded that a conservative strategy of fluid management did not improve survival but did improve lung function and shorten the duration of mechanical ventilation and ICU stay as compared with a liberal strategy.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that provided the first strong evidence to support a conservative fluid strategy in ARDS after the initial resuscitation phase. It shifted the paradigm from “keeping patients wet” to “keeping patients dry.”
  • Specific Recommendations:
    • Patient Selection: For adult patients with ARDS who are no longer in the initial phase of shock resuscitation.
    • Actionable Intervention: A conservative fluid management strategy, aimed at achieving a neutral or negative fluid balance, should be pursued.
    • Expected Benefit: This strategy can be expected to reduce the duration of mechanical ventilation and ICU stay.
  • What This Trial Does NOT Mean: This trial does NOT mean that patients should not receive adequate fluid resuscitation during the initial phase of shock. The protocol was only initiated after patients were stabilized.
  • Implementation Caveats: A conservative fluid strategy requires careful and frequent monitoring of hemodynamics and renal function to avoid causing hypoperfusion.

12. Context and Related Studies

  • Building on Previous Evidence: The FACTT trial (2006) was designed to provide a definitive answer to the “wet vs. dry” debate in ARDS, which was based on strong physiological reasoning and observational data (e.g., Bouchard et al. 2009).
  • Influence on Subsequent Research: The positive findings for the conservative strategy in this trial have been highly influential in shaping modern fluid management guidelines for ARDS. It also spurred further research into conservative fluid strategies in other critical illnesses, such as sepsis (e.g., the CLASSIC (2022) and CLOVERS (2023) trials).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal method for guiding a conservative fluid strategy (e.g., CVP, ultrasound, or other markers) remains an area of investigation.
  • Future Directions: Future research is focused on “de-resuscitation” and on identifying which specific patients benefit most from a conservative fluid strategy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a fundamental and controversial aspect of ARDS management.
  • Methods: The large, multicenter, factorial RCT design was appropriate and robust. The main methodological weakness is the open-label design. The use of a highly protocolized approach in both arms is a strength.
  • Results: The study reported a clear neutral finding for its primary outcome of mortality but a statistically significant and clinically important benefit for key secondary outcomes (ventilator-free days and ICU-free days).
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable to the management of ARDS after initial resuscitation. This is a classic example of a trial that, while “negative” for its primary outcome, was still profoundly practice-changing due to its strong positive findings on important secondary outcomes.

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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