Volatile sedation in critically ills adults undergoing mechanical ventilation: not all inhaled sedatives are equivalent!

We read with interest the meta-analysis by Yamamoto et al. [1] about volatile sedation within the ICU. While the results of the analysis appear clear, there are some major comments about the studies that were analysed that put its interpretation to question.

The overall outcome of the analysis is heavily impacted by one single study, the SESAR trial [2], which weighted 78.2% in the meta-analysis. The SESAR study used sevoflurane for prolonged time in the most severe ARDS patients with the aim of demonstrating better respiratory outcomes, following a promising preliminary study by the same group that showed benefits in terms of PaO₂/FIO₂ in ARDS patients [3]. While the negative outcome in SESAR is undeniable, sedation management during the trial deviated significantly from the original protocol and from what current guidelines recommend. Hence, drawing conclusions about a therapy based on an analysis that is largely built on this one study of a very specific population, seems unsound.

Importantly, sevoflurane and isoflurane are not the same. These drugs differ in their metabolic pathways and safety profiles, and the differences have been recognized as clinically important in the last few years [4]. For this reason, pooling studies of isoflurane and sevoflurane with regard to outcomes is not appropriate and resembles comparing oranges and apples, both producing juice but very different in flavour. In recent years, the link between exposure to sevoflurane for 48 h or longer with the occurrence of nephrogenic diabetes insipidus, polyuria and hypernatremia has been clearly shown [5]. In contrast, isoflurane is not associated with renal dysfunction. Isoflurane is the only drug that has undergone regulatory scrutiny with regard to safety and is approved for long-term sedation in ICU patients. In the most important RCT of isoflurane use within the ICU (weight 8.1% within the meta-analysis), no difference in terms of mortality was observed between the isoflurane and propofol groups [6]. Isoflurane’s safety is supported by the RCTs carried out in critical care as well as peer-reviewed real-world evidence, not included in the meta-analysis [7,8,9]. These studies indicate lower mortality and other beneficial 30-day outcomes. While not RCTs, these cohort studies of isoflurane are well-performed, peer-reviewed sources of clinically meaningful information and could thus have been considered within a systematic review to better inform readers about the currently available evidence.

In a recent study from our team [10], better outcomes with isoflurane compared to IV sedation were found in cardiac arrest patients. In this propensity score-matched analysis including 87 patients receiving IV sedatives paired with 87 patients receiving isoflurane, isoflurane sedation was associated with a lower incidence of delirium (16.1% vs. 32.2%, p = 0.03), a shorter duration of mechanical ventilation (78 h vs. 167 h, p = 0.01) and a reduced ICU length of stay (7.9 vs. 8.5 days, p = 0.01). There was no difference in ICU- or 28-days mortality between the two groups (65.5% vs. 65.5%, p = 1; 64.4% vs. 66%, p = 0.88, respectively). Opioid consumption was significantly lower with isoflurane (956 vs. 1433 mg, p < 0.001). There was also a lower use of renal replacement therapy in the isoflurane group, as compared to the IV group (13.7% vs. 37.9%, p = 0.03).

Two recently completed RCTs in the US provide reassuring results on isoflurane sedation. The INSPiRE-ICU 1 and 2 studies, aiming to evaluate the efficacy and safety of isoflurane sedation, demonstrated the non-inferiority of isoflurane vs. propofol for ICU sedation and found that 30-day mortality was 5% lower in the isoflurane group (unpublished data available on clinicaltrials.gov; NCT05312385, NCT05327296).

The rationale for using isoflurane as a sedative is to modify neurological outcome (shorter time to awakening and cognitive recovery, while reducing adverse events related to sedation). ICU physicians have progressively modified their sedation regimen, often changing molecules within the same pharmacological family (ex. flunitrazepam to midazolam, propofol and dexmetomidine; morphine to fentanyl, sufentanil or remifentanil), incrementally improving outcomes and reducing iatrogenic harm. For general anaesthesia, older volatile anesthetics such as metoxyflurane and enflurane are no longer used due to data on more favourable safety profiles of drugs such as isoflurane. The same may be true for sevoflurane vs. isoflurane for ICU sedation. It is time to distinguish between these two distinctly different drugs within the family of volatile anaesthetics. A multicentric RCT using isoflurane for up to 14 days is ongoing, aiming to assess the impact of volatile sedation using isoflurane on delirium incidence in ICU patients [11]. We hope that this study will add more data of value to better understand the safety and efficacy of prolonged isoflurane sedation within the ICU.

No datasets were generated or analysed during the current study.

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Authors and Affiliations

1. Medical Intensive Care Unit, Bvd Tanguy- Prigent, CHRU de la Cavale Blanche, Brest Cedex, 29609, France

   Erwan L’Her, Christelle Teiten & Pierre Bailly

2. LATIM INSERM UMR 1101, Université de Bretagne Occidentale, 22 rue Camille Desmoulins, Brest, 29200, France

   Erwan L’Her

3. Réanimation Médicale, CHRU de la Cavale Blanche, Bvd Tanguy-Prigent, Brest Cedex, 29609, France

   Erwan L’Her

Authors

1. Erwan L’HerView author publications

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2. Christelle TeitenView author publications

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ELH wrote the manuscript; CT and PB read and approved the manuscript.

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Correspondence to Erwan L’Her.

Competing interests

Pr Erwan L’HER (ELH) is consultant for Sedana Medical and has received grants for an ongoing study about the use of isoflurane within the ICU; he is also consultant for GE Healthcare, co-founder and share-holder of Oxynov Inc. Canada and Ivanae Médical, France outside the current topicDr Christelle Teiten (CT) has no competing interestDr Pierre Bailly (PB) is the main investigator of the Inased study, promoted by CHRU de Brest and granted by Sedana; he has no other competing interest.

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L’Her, E., Teiten, C. & Bailly, P. Volatile sedation in critically ills adults undergoing mechanical ventilation: not all inhaled sedatives are equivalent!. Crit Care 29, 356 (2025). https://doi.org/10.1186/s13054-025-05603-4

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• Received: 14 July 2025

• Accepted: 05 August 2025

• Published: 14 August 2025

• DOI: https://doi.org/10.1186/s13054-025-05603-4

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