Respiratory Distress Outcomes Better With Intravenous vs Inhaled Sedative

 

• Inhaled sevoflurane significantly reduced ventilator-free days and 90-day survival versus IV propofol in moderate to severe ARDS.
• Inhaled volatile sedatives grew in popularity for prolonged use in mechanically ventilated patients during the COVID pandemic.
• Sevoflurane was used for up to 7 days in the trial, much longer than the typically few hours of use in surgery.

For patients with moderate to severe acute respiratory distress syndrome (ARDS), prolonged sedation with the inhaled volatile agent sevoflurane resulted in worse outcomes than intravenous propofol, the randomized SESAR trial showed.

Sevoflurane reduced ventilator-free days through day 28 by a median of 2.1 compared with propofol (standardized HR 0.76, 95% CI 0.50-0.97), reported researchers led by Matthieu Jabaudon, MD, PhD, of CHU Clermont-Ferrand in France, in JAMAopens in a new tab or window.

The inhaled sedative also reduced 90-day survival by a relative 31%, with a rate of 47.1% versus 55.7% on propofol (HR 1.31, 95% CI 1.05-1.62) in the findings that were simultaneously presented at the International Symposium on Intensive Care and Emergency Medicine in Brussels.

Inhaled anesthetic use was popularized during the COVID-19 sedative shortages, and interest persisted due to an association with reduced sedative and analgesic needs, the researchers noted.

However, the trial's findings "challenge proposed oxygenation benefits in ARDS, suggested by smaller and preclinical studies" and are in line with subsequent negative clinical studies in patients with hypoxemic acute respiratory failure, Jabaudon's group said.

One potential reason for the failure was the duration of exposure in the trial compared with the typical few hours of use as a general anesthetic, noted Balasubramanian Venkatesh, MD, of the George Institute for Global Health in New South Wales, Australia, and colleagues in an opinion pieceopens in a new tab or window accompanying the paper in JAMA.

"Sevoflurane is associated with cardiovascular depressant effects, nephrotoxicity, and formation of degradation products with carbon dioxide absorbent systems," they wrote. "Whether the longer duration of exposure in the SESAR trial (7 days) accentuated these effects and was a critical factor in influencing outcomes is unknown."

While an "elegant, pragmatic trial testing a challenging, innovative intervention in the sickest patients," the group concluded, "[t]hese findings do not support the routine use of sevoflurane for sedation in critically ill patients with moderate to severe ARDS."

The SESAR trial included 687 patients at 37 French intensive care units (ICUs) who had moderate to severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure of ≥8 cm H₂O). The patients were randomized to sedation with sevoflurane or propofol for up to 7 days (median 5 and 6 days, respectively).

Sedation in both groups was titrated to a clinical sedation score, and more of the sevoflurane-treated patients received additional sedation (148 vs 64 patients). Clinicians decided on sedation choices after day 7 and on use of respiratory rescue therapies and weaning from mechanical ventilation. The clinical team wasn't blinded to intervention group, although the outcome assessors were.

All patients received low-tidal-volume ventilation with high positive end-expiratory pressure starting within 2 hours of randomization and continuing for up to 7 days.

Among the secondary outcomes, sevoflurane had higher 7-day mortality (19.4% vs 13.5%; relative risk 1.44, 95% CI 1.02-2.03) and fewer ICU-free days through day 28 (median difference -2.5, 95% CI -3.7 to -1.4) compared with propofol.

Venkatesh's group pointed out that the difference in mortality rates at day 90 between sevoflurane and propofol was most pronounced in the non-COVID-19 ARDS subgroup (51.6% vs 34.6%), albeit without a statistically significant interaction. COVID-19 pneumonia was the predominant cause of ARDS in the study population.

In terms of safety, there was more acute kidney injury and five instances of nephrogenic diabetes insipidus in the sevoflurane group. "The adverse kidney effects could be due to elevated plasma fluoride (a by-product of sevoflurane metabolism) although the fluoride concentrations were not verified," Venkatesh and colleagues noted. "There were also two instances of malignant hyperthermia, a known but normally extremely rare adverse effect of inhaled anesthetics during surgery."

Limitations of the trial included lack of double-blinding, apparent sedation interruption in only a small proportion of patients in both groups, and no data on fluid volumes administered, concomitant opioid analgesia, delirium, and other important characteristics.

"Our findings may have important clinical implications because inhaled sedation has garnered growing attention in ICU patients with ARDS or those at risk for the syndrome," Jabaudon and team concluded. "However, this trial does not inform whether outcomes would have differed with shorter durations of sevoflurane or with the use of other volatile anesthetics such as isoflurane. Such knowledge gaps may be addressed by ongoing trials of inhaled isoflurane sedation for mechanically ventilated ICU patients."

Disclosures

The trial was funded by the French Ministry of Health, the European Society of Anesthesiology and Intensive Care, and Sedana Medical.

Jabaudon reported personal fees from AbbVie and Sedana Medical outside the submitted work.

Co-authors also reported relationships with industry, including Sedana Medical.

Venkatesh reported a leadership fellowship from the National Health and Medical Research Council of Australia paid to the George Institute for Global Health. A co-author disclosed similar funding.

Primary Source

JAMA

Source Reference: opens in a new tab or windowJabaudon M, et al "Inhaled sedation in acute respiratory distress syndrome: The SESAR randomized clinical trial" JAMA 2025; DOI: 10.1001/jama.2025.3169.

Secondary Source

JAMA

Source Reference: opens in a new tab or windowVenkatesh B, et al "Sevoflurane sedation in acute respiratory distress syndrome: Time to put it to sleep" JAMA 2025; DOI: 10.1001/jama.2025.3023.

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