1. Publication
- Title: Inhaled Sedation in Acute Respiratory Distress Syndrome: The SESAR Randomized Clinical Trial
- Acronym: SESAR
- Year & Journal: JAMA, published May 13, 2025 (2025;333(18):1608-1617)
- Citation: Jabaudon M, Quenot JP, Badie J, et al; for the SESAR investigators. Inhaled Sedation in Acute Respiratory Distress Syndrome: The SESAR Randomized Clinical Trial. JAMA. 2025;333(18):1608-1617. doi:10.1001/jama.2025.3169
2. Context & Rationale
Background: ARDS carries high mortality (35-46%) and frequently requires deep sedation (often with neuromuscular blockade and prone positioning) for lung-protective ventilation. Volatile anesthetics (sevoflurane/isoflurane), delivered via anesthetic-conserving devices, offer proposed advantages (rapid titratability, bronchodilation, anti-inflammatory effects), and a pilot trial suggested improved oxygenation/biomarkers with sevoflurane — but was not powered for patient-centered outcomes, leaving a genuine evidence gap for ARDS-specific use.
Research Question/Hypothesis: In adults with moderate-to-severe ARDS, does inhaled sedation with sevoflurane improve ventilator-free days at day 28 compared with intravenous sedation with propofol?
Why This Matters: Sedative choice is a potentially important co-intervention affecting ventilation, hemodynamics, and downstream organ injury in ARDS; this was designed as a definitive patient-centered-outcome test following promising but underpowered pilot data.
3. Design & Methods
- Study Type: Phase 3, randomized, open-label, assessor-blinded clinical trial
- Setting & Centers: 37 ICUs, France; enrolled May 2020 – October 2023, 90-day follow-up
- Population:
- Inclusion: Adults with early moderate-to-severe ARDS (PaO2:FiO2 <150 mmHg with PEEP ≥8 cmH2O)
- Exclusions: Not detailed in available trial text
- Intervention: Inhaled sedation with sevoflurane, up to 7 days
- Comparator: Intravenous sedation with propofol, up to 7 days
- Randomization: 687 patients
- Blinding: Open-label treatment delivery, assessor-blinded outcome evaluation
- Statistical Power & Follow-Up: Primary outcome: ventilator-free days at day 28. Secondary: 90-day survival, ICU length of stay, AKI incidence. Tidal volumes and PEEP were protocol-compliant and similar in both arms during the 7-day intervention.
4. Key Results
687 patients randomized.
Outcome | Sevoflurane (Inhaled) | Propofol (IV) | Notes |
Ventilator-free days at day 28 (primary) | Median 0.0 (IQR 0.0–11.9) | Median 0.0 (IQR 0.0–18.7) | Sevoflurane arm had significantly fewer ventilator-free days |
90-day survival | Lower | Higher | ~9 percentage-point absolute increase in mortality with sevoflurane; NNH ≈11 |
Total duration of sedation | 7 days (median, both arms) | 7 days (median, both arms) | No difference |
ICU length of stay | Longer | Shorter | More days in ICU with sevoflurane |
Acute kidney injury | Higher rate | Lower rate | Greater AKI incidence with sevoflurane |
Baseline comparability: ARDS severity and vasopressor needs were similar between groups; control-group (propofol) mortality aligned with prior ROSE trial benchmarks, arguing against an unusually low control-arm mortality explaining the result.
5. Internal Validity Assessment
- Randomization & Allocation: Randomized across 37 French ICUs; specific concealment mechanics not detailed in available trial text.
- Protocol Adherence & Separation: Tidal volumes and PEEP levels during the 7-day intervention were protocol-compliant and similar in both arms, ruling out ventilation-strategy differences as a confounder for the mortality difference.
- Blinding & Detection Bias: Open-label treatment delivery (inherent to comparing an inhaled vs IV agent) but assessor-blinded outcome evaluation reduces detection bias for ventilator-free-day ascertainment.
- Missing Data & Sensitivity Analyses: Baseline ARDS severity and vasopressor needs were comparable between arms, and control-group mortality aligned with the established ROSE trial benchmark — both support that the observed harm signal reflects a true treatment effect rather than baseline imbalance.
- Overall Internal Validity Conclusion: Strong — well-conducted, adequately powered (687-patient) trial with assessor-blinded outcomes, protocol-compliant co-interventions, and a consistent, coherent pattern of harm across the primary outcome, mortality, ICU stay, and AKI — a genuinely concerning, internally consistent signal rather than an isolated finding.
6. External Validity Assessment
- Population Representativeness: French, moderate-to-severe ARDS population (Berlin criteria) — directly representative of the population for whom deep sedation and volatile-anesthetic use is being considered.
- Practice Context: Requires anesthetic-conserving device infrastructure for inhaled sedation delivery — a specific equipment requirement not universal across all ICUs.
- Overall External Validity Conclusion: Good for ARDS populations in ICUs with anesthetic-conserving device capability; findings should be considered directly applicable given the trial's rigor and consistency.
7. Strengths & Limitations
Strengths:
- Large (687-patient), well-powered, definitive patient-centered-outcome trial following an underpowered pilot signal
- Assessor-blinded outcome evaluation
- Protocol-compliant, comparable co-interventions (tidal volume, PEEP) between arms
- Internally consistent harm signal across multiple outcome domains (ventilator-free days, mortality, ICU stay, AKI)
Limitations:
- Open-label treatment delivery (unavoidable for comparing inhaled vs IV agents)
- Single-country (France) trial
- Contradicts some prior smaller-trial and systematic-review signals suggesting inhaled sedation might reduce time to awakening/extubation — an important tension requiring careful interpretation of context (ARDS-specific, prolonged, deep sedation vs shorter general ICU sedation)
8. Interpretation & Practice Impact
- Clinical Implications: Does not support using inhaled sevoflurane sedation in moderate-to-severe ARDS — the trial found a clear, statistically significant harm signal (fewer ventilator-free days, higher mortality, more AKI) compared with propofol.
- Mechanistic Coherence: The internally consistent pattern of harm (worse ventilator-free days, mortality, AKI, and ICU stay all moving in the same direction) strengthens confidence that this reflects a genuine adverse effect of prolonged sevoflurane sedation in this specific severely ill ARDS population, rather than a chance finding.
- Systems-Level Takeaway: ICUs using or considering volatile anesthetic sedation for ARDS should be aware this trial found harm, not benefit — a genuinely practice-relevant caution given ongoing interest in inhaled sedation modalities.
9. Controversies & Subsequent Evidence
- Editorial Commentary: An accompanying JAMA editorial (Venkatesh, "Sevoflurane sedation in acute respiratory distress syndrome") and a subsequent JAMA letter to the editor ("Acute Respiratory Distress Syndrome and Inhaled Sedation") engaged directly with the unexpected harm signal, given prior literature (a systematic review of 9 RCTs, 2012-2022) suggesting volatile sedation reduced time to awakening/extubation and ICU length of stay in broader ICU populations.
- Guideline Integration: A subsequent Bayesian network meta-analysis noted SESAR (687 patients) carried substantial weight (~78.2%) in pooled estimates suggesting volatile sedation may be associated with increased mortality — SESAR's large size and rigor mean it substantially shapes the current evidence synthesis on this question. The device manufacturer (Sedana Medical) issued a public comment on the publication, given commercial interest in this therapy area.
10. Summary & Executive Takeaway
Summary: SESAR randomized 687 French ICU patients with moderate-to-severe ARDS to inhaled sevoflurane or intravenous propofol sedation for up to 7 days. Sevoflurane resulted in fewer ventilator-free days at day 28 and lower 90-day survival (approximately 9 percentage-point absolute mortality increase, NNH~11), along with more ICU days and higher AKI incidence.
Overall Takeaway: Contrary to prior smaller-trial signals suggesting benefit from inhaled sedation, this large, rigorous trial found inhaled sevoflurane sedation causes harm in moderate-to-severe ARDS — worse ventilator-free days, higher mortality, and more AKI compared with propofol — a genuinely important cautionary finding for a modality with growing commercial and clinical interest.
11. Bibliography
- Jabaudon M, Boucher P, Imhoff E, et al. Sevoflurane for Sedation in Acute Respiratory Distress Syndrome (pilot). Am J Respir Crit Care Med. 2017.
- Venkatesh B. Sevoflurane sedation in acute respiratory distress syndrome [editorial]. JAMA. 2025;333(18):1586-1588.
- National Heart, Lung, and Blood Institute PETAL Network. Early Neuromuscular Blockade in ARDS (ROSE). N Engl J Med. 2019;380:1997-2008.