Editorial <\/p>\n\n\n\n
Critically ill patients receiving invasive mechanical ventilation for acute hypoxemic respiratory failure or acute respiratory distress syndrome often require continuous sedation to ensure comfort, facilitate lung-protective ventilation, and prevent self-inflicted lung injury.1<\/a><\/sup>\u00a0However, conventional intravenous sedatives carry a high burden of adverse events: benzodiazepines are linked to delirium and coma,2<\/a><\/sup>\u00a0propofol can cause hemodynamic instability or infusion syndrome,2<\/a><\/sup>\u00a0and \u03b1-2 agonists like dexmedetomidine may precipitate bradycardia or prove insufficient for deep sedation.3<\/a>,4<\/a><\/sup>\u00a0Consequently, finding a sedative strategy that achieves optimal patient comfort without accumulating toxicity remains a major clinical challenge.<\/p>\n\n\n\n Inhaled volatile anesthetics, primarily isoflurane and sevoflurane, have emerged as appealing alternatives for sedation in the intensive care unit (ICU). Indeed, isoflurane is approved in several European countries following a regulatory-oriented trial by Meiser and colleagues in adults (demonstrating noninferiority to propofol for maintaining a Richmond Agitation-Sedation Scale [RASS] score of \u22121 to \u22124),5<\/a><\/sup> and the phase 3 IsoCOMFORT trial in children (demonstrating noninferiority to midazolam for maintaining a COMFORT-B score of 11 to 22).6<\/a><\/sup> Both of these registration trials evaluated a short exposure to isoflurane (up to 48 hours), while clinical effectiveness trials have evaluated patient-centered outcomes over longer administration periods. Preclinical and early clinical data suggest that volatile anesthetics possess beneficial anti-inflammatory, bronchodilatory, and lung-protective properties.7<\/a><\/sup> These findings led to the hypothesis that inhaled sedation could mitigate ventilator-induced lung injury and improve outcomes in acute respiratory distress syndrome.8<\/a><\/sup> However, this clinical optimism was challenged by the sevoflurane-based SESAR trial, which reported fewer ventilator-free days, a higher incidence of acute kidney injury, and numerically higher 90-day mortality in patients randomized to sevoflurane compared with propofol.9<\/a><\/sup><\/a><\/p>\n\n\n\n In this issue of JAMA<\/em>, Jerath and colleagues10<\/a><\/sup> report the results of the SAVE-ICU trial, the largest multicenter, pragmatic, randomized clinical trial of inhaled sedation to date. The investigators should be commended for successfully conducting and completing this landmark trial under the challenging operational constraints of the COVID-19 pandemic. Nearly 800 mechanically ventilated adults with acute hypoxemic respiratory failure were randomized to an isoflurane-based inhaled sedation strategy or usual care intravenous sedation, with primary mortality analysis conducted in 769 patients due to 11 postrandomization consent withdrawals. The primary outcome of all-cause hospital mortality did not differ significantly between the groups (42.5% in the isoflurane group vs 43.8% in the usual care group; risk ratio, 0.98 [95% CI, 0.84 to 1.14]). Similarly, there were no differences in ICU-free or ventilator-free days at day 30. While these findings demonstrate that routine isoflurane sedation does not improve survival compared with usual care, the absence of a harm signal (particularly regarding mortality and kidney safety) contrasts sharply with the results of the SESAR trial.<\/a><\/p>\n\n\n\n This divergence in safety profiles has often been discussed in the context of differences in hepatic metabolism, with sevoflurane undergoing approximately 2% biotransformation compared with only 0.2% for isoflurane. However, the exact mechanisms of volatile-associated kidney injury, including nephrogenic diabetes insipidus, remain largely unknown and subject to debate. Although inorganic fluoride accumulation has historically been postulated as a primary driver of tubular toxicity, the overall metabolism of sevoflurane is minor.<\/a><\/p>\n\n\n\n Clinical kidney impairment is likely multifactorial, representing a \u201csecond hit\u201d in which the volatile agent acts in synergy with hemodynamic instability, concomitant nephrotoxic agents, or the specific endothelial and tubular injury associated with severe SARS-CoV-2 infection, which affected 55% of patients in SESAR but only 26% in SAVE-ICU. Furthermore, SAVE-ICU does not warrant a definitive conclusion of absolute organ safety for isoflurane. Because of its pragmatic design, the trial did not record prospective daily laboratory values, such as serum creatinine or liver enzyme levels, relying instead on investigator-reported adverse events. Notably, abnormal liver function occurred in 1.3% of the isoflurane group vs 0% of the usual care group (P<\/em>\u2009=\u2009.02). Crucially, these episodes were not transient, subclinical laboratory fluctuations, but serious adverse events that mandated immediate and permanent treatment discontinuation. Without granular daily monitoring, subclinical kidney or hepatic toxicity cannot be fully ruled out, reflecting an inherent limitation in the trial\u2019s ability to exclude organ injury.<\/a><\/p>\n\n\n\n A second critical finding in SAVE-ICU concerns the depth of sedation. The trial was designed to reflect contemporary guidelines prioritizing light sedation. However, the isoflurane group experienced fewer delirium- and coma-free days, driven by a longer duration of coma. Daily assessments reveal that approximately 80% of patients in the isoflurane group were in deep sedation (RASS score \u22124 to \u22125) on days 1 and 2, a rate that declined slowly and was consistently higher than in the intravenous usual care group. This sedation depth profile exposes a key titration challenge. The SAVE-ICU protocol used the RASS to guide titration, yet this scale is unmeasurable during neuromuscular blockade, a cointervention received by more than 55% of patients in both groups. To prevent awareness and oversedation under neuromuscular blockade, objective monitoring of expired anesthetic concentrations is essential. Although the trial protocol outlines continuous bedside gas monitoring targeting a minimum of 0.6 minimum alveolar concentration during paralysis, these parameters were not reported in the article or its supplement. Without these patient-level data, it is impossible to determine whether the prolonged coma observed under isoflurane reflects an intrinsic pharmacodynamic effect of the drug or systematic overdosage due to the absence of reported, concentration-guided titration.<\/a><\/p>\n\n\n\n This challenge is further compounded by a high rate of concomitant intravenous sedation in the isoflurane group. Daily cosedation fluctuated between 49.9% and 55.4% and exhibited extreme site-to-site variability, ranging from 5.2% to 100%. This high degree of heterogeneity in cosedation significantly confounds any evaluation of both treatment efficacy and tolerance, including the observed differences in coma duration. Ultimately, this highlights the clinical difficulty of conflating sedation-depth effects with agent-specific properties, because prolonged deep sedation is independently associated with adverse outcomes. The lack of detailed reporting on intermediate RASS categories during weaning further limits the ability to evaluate whether isoflurane could have achieved lighter sedation targets in a more standardized clinical protocol.<\/a><\/p>\n\n\n\n The pragmatic omission of granular clinical data in SAVE-ICU also conceals potential respiratory hazards. The anesthetic-conserving device used in the trial adds approximately 50 mL of instrumental dead space to the ventilator circuit. To maintain normocapnia, clinicians must increase minute ventilation by raising respiratory rates, tidal volumes, or driving pressures. When respiratory compliance is already severely compromised, as in moderate to severe acute respiratory distress syndrome, even minor increases in instrumental dead space can significantly elevate the mechanical power delivered to the lungs, potentially magnifying the risk of ventilator-induced lung injury.11<\/a><\/sup> Because SAVE-ICU did not collect daily ventilator parameters, the physiological impact of the device\u2019s dead space remains unmeasured. The 1.0% incidence of severe hypercapnia and respiratory acidosis in the isoflurane group highlights these real clinical consequences, underscoring the need for careful monitoring of ventilation-device interactions in patients with low respiratory compliance. Future protocols should consider alternative device configurations, such as placing the conserving device on the inspiratory limb of the circuit, which eliminates instrumental dead space at the cost of higher agent consumption.<\/a><\/p>\n\n\n\n Last, SAVE-ICU\u2019s broad eligibility (COVID-19 or ratio of partial pressure of arterial oxygen [Pao2<\/sub>] to fraction of inspired oxygen [Fio2<\/sub>] up to 300 mm Hg) and inclusion of heterogeneous extrapulmonary conditions (nearly 50% cardiac arrest or trauma) contrast with SESAR\u2019s severe, homogeneous cohort of pulmonary acute respiratory distress syndrome (Pao2<\/sub>:Fio2<\/sub> ratio <150 mm Hg with a positive end-expiratory pressure \u22658 cm H2<\/sub>O). This clinical diversity, combined with the lack of granular ventilatory and hemodynamic data reported in SAVE-ICU, limits the ability to extrapolate these neutral findings to the most severely ill patients with acute respiratory distress syndrome. Future trials could leverage predictive enrichment strategies targeting specific subphenotypes of patients most likely to benefit from volatile anesthetics.<\/a><\/p>\n\n\n\n Where does this leave clinicians? To date, no large-scale randomized trial, including the registration trials in adults and children, SESAR, and now SAVE-ICU, has demonstrated that inhaled sedation improves survival or shortens mechanical ventilation compared with standard intravenous sedation. This lack of benefit is highlighted by a recent meta-analysis of randomized trials reporting a potential signal of excess mortality with inhaled sedation (although that finding was heavily driven by the weight of the SESAR trial).12<\/a><\/sup> While SAVE-ICU reported no overall differences in quality of life at 3 months, its domain-specific disability scores revealed worse recovery in self-care and domestic activities in the isoflurane group. This signal of persistent functional impairment may align with the trial\u2019s longer ICU coma duration, highlighting the critical need for longer-term cognitive and functional data. In this regard, the US-based INSPIRE-ICU 1 and 2 trials\u2014which similarly evaluate a short-term (48-hour) noninferiority protocol\u2014will provide key 6-month cognitive and functional data,13<\/a><\/sup> while the French INASED trial will evaluate delirium outcomes.14<\/a><\/sup> Until these data are available, inhaled sedation cannot yet be considered a first-line replacement for standard intravenous regimens, although it may represent a valuable option for difficult sedation, status asthmaticus, or severe bronchospasm.15<\/a><\/sup> For routine use, its potential clinical benefits must be carefully balanced against its unmeasured physiological costs, as well as the substantial environmental footprint of volatile anesthetics as potent greenhouse gases and the financial barriers associated with specialized delivery devices and staff training.15<\/a><\/sup><\/p>\n","protected":false},"excerpt":{"rendered":" Editorial Inhaled Sedation in Acute Respiratory F […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31951"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=31951"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31951\/revisions"}],"predecessor-version":[{"id":31952,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31951\/revisions\/31952"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=31951"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=31951"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=31951"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}