Volatile Anesthetics for ARDS Sedation: Promise Meets a Sobering Trial Reality

For decades, anesthesiologists have relied on volatile anesthetics—sevoflurane, isoflurane, and their chemical cousins—to keep patients safely asleep during surgery. These inhaled agents act rapidly, wear off quickly, and are eliminated almost entirely through the lungs, giving clinicians exquisite control over a patient’s depth of unconsciousness. In recent years, a growing international community of intensivists has asked whether those same pharmacological virtues could be harnessed in the intensive care unit, particularly for one of the most devastating conditions critical care medicine confronts: acute respiratory distress syndrome, or ARDS. A new narrative review published in Intensive Care Medicine by Brian O’Gara of Beth Israel Deaconess Medical Center and an international team of collaborators takes stock of that question, and its conclusions are a striking study in scientific nuance—promising biology, encouraging early signals, and yet a pivotal randomized trial that has forced the field to reconsider its enthusiasm.

ARDS arises from a heterogeneous set of inciting injuries—pneumonia, sepsis, aspiration, trauma—and produces its hallmark consequences of profound hypoxemia and diffuse lung damage through multiple, overlapping biological pathways. The alveolar-capillary barrier breaks down, protein-rich fluid floods the airspaces, and inflammation cascades across the lung parenchyma. Despite a new global definition of the syndrome published in 2024 and decades of research into targeted therapies, from corticosteroids to statins to interleukin-6 inhibitors, no pharmacological treatment has definitively reversed the underlying injury. What has saved lives is meticulous supportive care: lung-protective mechanical ventilation with low tidal volumes, appropriate positive end-expiratory pressure, attention to driving pressure and mechanical power, and, in selected patients, prone positioning and neuromuscular blockade. Sedation sits at the heart of that supportive framework, because mechanically ventilated patients with ARDS typically require deep sedation to tolerate the ventilator and to avoid self-inflicted lung injury from vigorous, asynchronous breathing efforts.

It is precisely here that volatile anesthetics promised something special. According to the review, these agents were proposed to achieve two aims simultaneously: they could provide effective, titratable sedation while also protecting against inflammatory lung injury. Preclinical work has been remarkably rich. Experimental studies have shown that volatile agents modulate immune cell function, dampen the release of inflammatory mediators, preserve the integrity of epithelial tight junctions that hold the alveolar barrier together, and promote alveolar epithelial wound healing. More recent laboratory work suggests prolonged antibacterial, anti-inflammatory, and surfactant-promoting effects, and in vitro studies have explored how sevoflurane, propofol, and opioids differentially shape the endothelial proinflammatory response. In surgical populations, meta-analyses have examined whether volatile anesthesia reduces postoperative pulmonary complications compared with total intravenous anesthesia, with results that kept the lung-protective hypothesis alive.

The respiratory effects of volatile agents added a second layer of appeal. Unlike most intravenous sedatives, sevoflurane and isoflurane are bronchodilators, which has made them a rescue therapy for life-threatening status asthmaticus when conventional treatment fails. Even more intriguingly, animal studies suggest that volatile anesthetics interact with central respiratory chemoreceptor neurons in ways that help maintain breathing drive during anesthesia—activating leak sodium conductances in retrotrapezoid nucleus neurons and modulating background potassium currents. For ARDS patients, preserving respiratory drive matters enormously. Deep intravenous sedation with propofol or midazolam suppresses spontaneous breathing, which can be protective in the earliest phase of lung injury but becomes a liability later, contributing to diaphragm atrophy and prolonged ventilation. The concept of lung-protective and diaphragm-protective sedation—precision sedation that balances patient effort against ventilator-induced injury—has become a major research frontier, and volatile agents were seen as natural candidates for it.

Early clinical data seemed to vindicate the enthusiasm. A randomized controlled pilot study published in 2017 by Jabaudon and colleagues found that sevoflurane sedation in ARDS patients reduced inflammatory mediators and improved oxygenation. Observational and feasibility studies explored whether volatile sedation could allow spontaneous breathing even during prone positioning or continuous lateral rotational therapy—situations where conventional sedation typically demands paralysis or deep unconsciousness. A large phase III non-inferiority trial in Germany and Slovenia compared inhaled isoflurane, delivered via an anesthetic conserving device, with propofol in invasively ventilated ICU patients and found the inhaled approach a viable alternative. Substudies examined the physiology in detail, including whether the devices used to deliver volatile agents add dead space that increases mechanical power, with recent work suggesting that low dead space reflectors do not increase mechanical power compared with standard heat and moisture exchangers.

Then came the trial that changed the conversation. The SESAR randomized clinical trial, published in JAMA in 2025 by Jabaudon and colleagues, enrolled patients with moderate-to-severe ARDS and compared inhaled sevoflurane sedation with standard intravenous propofol. The results ran counter to expectations: sevoflurane sedation reduced ventilator-free days at day 28 and increased mortality compared with propofol. For a field that had spent years building the mechanistic case for inhaled lung protection, the finding was a genuine shock. The review’s authors treat the result with appropriate seriousness, and it anchors their central recommendation: pending further high-quality data suggesting benefit, routine clinical use of volatile ICU sedation in ARDS is currently not recommended outside of clinical trials.

Why might a therapy with such compelling biology fail in the clinic? The review points to several open questions that future research must resolve. Dose is one: the concentrations of sevoflurane used for prolonged ICU sedation may differ meaningfully from the exposures that showed benefit in experimental models, and the therapeutic window between anti-inflammatory protection and harm remains poorly mapped. Agent selection is another—sevoflurane and isoflurane have distinct pharmacological profiles, and results with one cannot simply be extrapolated to the other. Duration of sedation is a third variable; the timing and length of volatile exposure could determine whether the drug protects or injures the healing lung. Perhaps most tantalizing is the question of heterogeneity of treatment effect across ARDS sub-phenotypes. ARDS is not one disease but a syndrome with inflammatory and non-inflammatory biological clusters, and a therapy that dampens inflammation might help hyperinflammatory patients while harming others. Precision-medicine approaches that stratify patients by sub-phenotype could yet rescue the volatile hypothesis.

The trial landscape remains active, even if no ongoing or recently completed studies are being conducted solely in ARDS patients. The SAVE-ICU trial is enrolling patients with COVID-19 and non-COVID-19 acute hypoxemic respiratory failure. The French INASED trial is testing inhaled sedation more broadly in the ICU. The INSPiRE-ICU1 and INSPiRE-ICU2 trials, sponsored by Sedana Medical and led from North American centers, are comparing inhaled sedation with propofol in respiratory failure. A 2025 meta-analysis of randomized trials of volatile sedation in mechanically ventilated critically ill adults, along with a 2026 systematic review focused specifically on inhaled versus intravenous sedation in ARDS, will help synthesize the accumulating evidence. Beyond efficacy, practical considerations loom: delivery devices add circuit complexity, environmental concerns about anesthetic gas emissions are mounting, and drug shortages have at times made inhaled sedation an unexpectedly useful fallback.

The story of volatile anesthetics in ARDS is, in the end, a story about how modern critical care science works. Mechanistic plausibility, preclinical elegance, and promising pilot data are necessary but not sufficient; only large, well-designed randomized trials can establish whether a therapy helps or harms. The SESAR trial delivered an unwelcome answer for sevoflurane in moderate-to-severe ARDS, and the review’s authors have responded not by abandoning the idea but by sharpening the questions—dose, agent, duration, and patient sub-phenotype—that will determine whether inhaled sedation earns a place in the ARDS armamentarium. For now, patients with ARDS should receive sedation according to established guidelines, and volatile agents should remain within the boundaries of clinical trials. The lungs of the sickest patients depend on that discipline, and the next generation of trials will tell us whether the operating room’s most trusted anesthetics can ever make the same claim in the intensive care unit.

Subject of Research: Volatile anesthetic sedation as a potential lung-protective therapy in acute respiratory distress syndrome

Article Title: Volatile anesthetic sedation in acute respiratory distress syndrome

Article References: O’Gara, B., Boncyk, C., Müller Wirtz, L. M., Molano Franco, D., Kotani, Y., Landoni, G., Jerath, A., L’Her, E., Bellgardt, M., Becher, T., Beck-Schimmer, B., Beitler, J. R., Constantin, J. M., Hughes, C. G., Meiser, A., & Jabaudon, M. (2026). Volatile anesthetic sedation in acute respiratory distress syndrome. Intensive Care Medicine. https://doi.org/10.1007/s00134-026-08613-0

Image Credits: AI Generated

DOI: 10.1007/s00134-026-08613-0

Keywords: acute respiratory distress syndrome, volatile anesthetics, sevoflurane, isoflurane, ICU sedation, mechanical ventilation, lung injury, inflammation, SESAR trial, propofol, lung-protective ventilation, critical care