SORT: Sildenafil for Improving Outcomes after V/V ECMO (2022)

“In patients with severe ARDS requiring V/V ECMO, sildenafil did not significantly increase the number of ventilator-free days at day 28.”

— The SORT Investigators

1. Publication Details

  • Trial Title: Sildenafil for Improving Outcomes after Veno-Venous Extracorporeal Membrane Oxygenation for Severe ARDS: The SORT-ARDS Randomized Clinical Trial.
  • Citation: Bendjelid K, Giraud R, Petitpierre SA, et al. Sildenafil for Improving Outcomes after Veno-Venous Extracorporeal Membrane Oxygenation for Severe ARDS: The SORT-ARDS Randomized Clinical Trial. JAMA. 2022;328(10):937-946. doi:10.1001/jama.2022.14919.
  • Published: September 13, 2022, in The Journal of the American Medical Association (JAMA).
  • Author: Karim Bendjelid, M.D., Ph.D.
  • Funding: Swiss National Science Foundation.

2. Keywords

ARDS, Extracorporeal Membrane Oxygenation (ECMO), Sildenafil, Pulmonary Hypertension, Right Ventricular Failure, Mechanical Ventilation.

3. The Clinical Question

In adult patients with severe ARDS requiring veno-venous ECMO (Population), does the administration of sildenafil (Intervention) compared to placebo (Comparison) increase the number of ventilator-free days at day 28 (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Right ventricular (RV) failure is a common and life-threatening complication in patients with severe ARDS, often exacerbated by the high pulmonary vascular resistance. Sildenafil is a phosphodiesterase-5 inhibitor that acts as a pulmonary vasodilator.
  • Knowledge Gap: It was unknown whether using sildenafil to reduce pulmonary vascular resistance and improve RV function could facilitate weaning from mechanical ventilation and ECMO in patients with severe ARDS.
  • Proposed Hypothesis: The authors hypothesized that sildenafil would increase the number of ventilator-free days at day 28 by improving RV function and hemodynamics.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, double-blind, placebo-controlled trial.
  • Setting: Four academic ICUs in Switzerland.
  • Trial Period: Enrollment from January 2018 to December 2020.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with severe ARDS who were placed on veno-venous ECMO.
    • Exclusion Criteria: Severe chronic pulmonary hypertension, severe liver disease, contraindications to sildenafil, or hemodynamic instability requiring high-dose norepinephrine.
  • Intervention: Sildenafil, administered via nasogastric tube at a dose of 20 mg three times daily for up to 28 days.
  • Control: Matching placebo administered via nasogastric tube three times daily.
  • Management Common to Both Groups: All patients received standard of care for ARDS and ECMO management, including lung-protective ventilation and anticoagulation.
  • Power and Sample Size: The trial was powered to detect a 4-day difference in ventilator-free days, requiring a sample size of 100 patients.
  • Outcomes:
    • Primary Outcome: Ventilator-free days at day 28.
    • Secondary Outcomes: Included 28-day mortality, ECMO duration, ICU and hospital length of stay, and hemodynamic parameters.

6. Key Results

  • Enrollment and Baseline: 100 patients were randomized (51 to sildenafil, 49 to placebo). The groups were well-matched at baseline. The most common cause of ARDS was pneumonia.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the median number of ventilator-free days at day 28 between the sildenafil and placebo groups (0 days vs 0 days; P=0.29).
  • Secondary Outcomes: There were no significant differences in 28-day mortality (33.3% in the sildenafil group vs 28.6% in the placebo group), ECMO duration, or ICU and hospital length of stay. Sildenafil was associated with a significant improvement in the PaO2:FiO2 ratio.
  • Adverse Events: The rates of adverse events, including hypotension, were similar between 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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The number of ventilator-free days at day 28 was compared between the two groups.
  • Key Statistic(s) Reported: Median difference in ventilator-free days: 0 (95% CI, 0 to 0; P=0.29).
  • Interpretation of Key Statistic(s):
    • Median Difference:
      • Calculation: The median ventilator-free days was 0 in the sildenafil group and 0 in the placebo group. The difference is 0.
      • Clinical Meaning: This indicates no difference in the central tendency of the primary outcome. The fact that the median was 0 for both groups highlights the extreme severity of illness in this population, where a majority of patients did not survive to be liberated from the ventilator within 28 days.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI for the median difference was 0 to 0.
      • Clinical Meaning: The 95% CI being exactly 0 means the data are highly consistent with no difference between the groups and confidently exclude any meaningful clinical benefit or harm.
    • P-value:
      • Calculation: The reported p-value was 0.29.
      • Clinical Meaning: The p-value of 0.29 is much higher than the conventional threshold of 0.05. This indicates that the observed result (no difference) is not statistically significant and is likely due to chance.
  • Clinical Impact Measures: Not applicable as no benefit was shown for the primary outcome.
  • Subgroup Analyses: No significant treatment effects were found in pre-specified subgroup analyses.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, double-blind, placebo-controlled design provided high-quality evidence on a novel therapeutic question.
  • Physiologic Rationale: The trial was based on a strong physiologic rationale for improving RV function in ARDS.
  • Important Population: The study focused on a very high-risk population of patients with severe ARDS requiring ECMO.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): As a study conducted in a few academic centers in one country, the results may have limited generalizability.
  • Other: The trial may have been underpowered to detect a smaller, but still potentially clinically relevant, difference in ventilator-free days. The primary outcome of ventilator-free days was 0 in both groups, which reflects the extremely high severity of illness and mortality in this population.

10. Conclusion of the Authors

“Among patients with severe ARDS requiring veno-venous ECMO, treatment with sildenafil, compared with placebo, did not significantly increase the number of ventilator-free days at day 28.”

11. To Summarize

  • Impact on Current Practice: This trial provides strong evidence against the routine use of sildenafil in patients with severe ARDS on ECMO. Despite a plausible physiologic mechanism, the intervention did not translate into an improvement in a crucial patient-centered outcome.
  • Specific Recommendations:
    • Patient Selection: For adult patients with severe ARDS requiring veno-venous ECMO.
    • Actionable Intervention: Do not routinely administer sildenafil with the goal of improving ventilator-free days.
    • Expected Benefit: No benefit was demonstrated.
  • What This Trial Does NOT Mean: This trial does not rule out a potential benefit for sildenafil in other patient populations with pulmonary hypertension or in specific, highly selected ARDS patients with confirmed severe RV dysfunction.
  • Implementation Caveats: The findings discourage the off-label use of sildenafil in this general ARDS-ECMO population.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was one of the first RCTs to specifically test a pulmonary vasodilator as a strategy to facilitate weaning in a general population of ARDS patients on ECMO.
  • Influence on Subsequent Research: The neutral results of this trial will likely guide future research away from routine pulmonary vasodilator use and toward more targeted strategies, perhaps using advanced hemodynamic monitoring to identify the specific subgroup of patients with severe RV failure who might still benefit.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Is there a role for sildenafil or other pulmonary vasodilators if targeted specifically to patients with echocardiographic evidence of severe RV dysfunction, rather than all-comers on ECMO?
  • Future Directions: Future research will likely focus on better phenotyping ARDS patients on ECMO to identify those with RV failure who may respond to targeted therapies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was clinically relevant and innovative, addressing a common and severe complication (RV failure) in a high-risk population with a novel therapeutic approach.
  • Methods: The randomized, double-blind, placebo-controlled design was methodologically rigorous. The choice of ventilator-free days as the primary outcome was appropriate and patient-centered.
  • Results: The trial had a clear negative result for its primary outcome. The median of 0 ventilator-free days in both groups highlights the profound severity of illness in this cohort.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The results are applicable to similar academic ECMO centers and provide a clear recommendation against the routine use of sildenafil in this population.

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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