CONFERENCE REPORTS AND EXPERT PANEL
会议报告和专家小组

(c) 2023 The Author(s) (c) 2023 作者(s)

21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.
21 个问题并提出 21 条建议，涉及以下领域：（1）定义；（2）表型；（3）高流量鼻导管氧气（HFNO）和呼吸支持策略；（4）非侵入性通气（NIV）；（5）潮气量设置；（6）呼气末正压（PEEP）和招募手法（RM）；（7）俯卧位；（8）神经肌肉阻滞；（9）体外生命支持（ECLS）。此外，临床实践指南还包括专家意见，并确定未来研究的领域。
Keywords: Acute hypoxemic respiratory failure, Acute respiratory distress syndrome, Mechanical ventilation, Extracorporeal membrane oxygenation, Prone position, Non-invasive ventilation, Prognosis, Practice guidelines
关键词：急性缺氧性呼吸衰竭，急性呼吸窘迫综合征，机械通气，体外膜氧合，俯卧位，非侵入性通气，预后，实践指南

Acute respiratory distress syndrome (ARDS) is the term applied to a spectrum of conditions with different etiologies which share common clinical-pathological characteristics including: (1) increased permeability of the alveolo-capillary membrane, resulting in inflammatory edema; (2) increased non-aerated lung tissue resulting in higher lung elastance (lower compliance); and (3) increased venous admixture and dead space, which result in hypoxemia and hypercapnia [1]. Over the last 55 years, ARDS definitions have focused primarily on the syndrome's radiological appearance and on the severity of the oxygenation defect (e.g., ratio), which reflect both the original description of the syndrome [2] and its conceptual understanding [1]. The current definition, the definition of Berlin [3], implies that at time of diagnosis the patient receives at least of positive end-expiratory pressure (PEEP). Formally, patients not receiving positive pressure can thus not be considered as suffering from ARDS. Nevertheless, a lot of patients with AHRF, especially when due to bacterial or viral pneumonia or in case of septic shock, have the same disease and are thus also considered in this guideline.
急性呼吸窘迫综合症（ARDS）是一个涵盖不同病因的病症的术语，这些病症具有共同的临床病理特征，包括：（1）肺泡-毛细血管膜的通透性增加，导致炎性水肿；（2）非通气肺组织增加，导致肺弹性增加（顺应性降低）；以及（3）静脉混合和死腔增加，导致低氧血症和高碳酸血症[1]。在过去的 55 年中，ARDS 的定义主要集中在综合症的放射学表现和氧合缺陷的严重程度（例如， 比率），这反映了综合症的最初描述[2]及其概念理解[1]。当前的定义，即柏林定义[3]，意味着在诊断时患者至少接受 的正呼气末压（PEEP）。因此，未接受正压通气的患者不能被视为患有 ARDS。 然而，许多急性呼吸衰竭患者，特别是由于细菌或病毒性肺炎或脓毒性休克引起的患者，患有相同的疾病，因此也被纳入本指南。
ARDS accounts for of admissions to intensive care unit (ICU) and of ventilated patients, with mortality up to in the severe category [4]. The recognition that patients with ARDS are susceptible to additional lung injury induced by mechanical ventilation (ventilatorinduced lung injury, VILI) [5] has led to lung-protective strategies designed to reduce total stress (transpulmonary pressure) and strain (the ratio between tidal volume and functional residual capacity) on the aerated lung tissue [6]. These strategies include lower tidal volume and plateau pressure to protect the 'baby lung' [7]; the use of PEEP and lung recruitment maneuvers (RM) to reduce the amount of non-aerated lung; and ventilation in prone position to increase lung homogeneity, improve ventilation/perfusion ratio and lung/chest wall shape matching, reduce stress and strain, and decrease the risk of VILI [8]. Ventilation in the prone position improves outcomes in patients with moderate-to-severe ARDS .
ARDS 占重症监护病房（ICU）入院人数的 ，占通气患者的 ，重症患者的死亡率高达 [4]。认识到 ARDS 患者易受到机械通气引起的额外肺损伤（通气引起的肺损伤，VILI）[5]，促使制定了旨在减少气体交换肺组织的总压力（肺内压）和应变（潮气量与功能残气量之比）的肺保护策略[6]。这些策略包括使用较低的潮气量和平台压力以保护“婴儿肺”[7]；使用 PEEP 和肺复张手法（RM）以减少非通气肺的数量；以及采用俯卧位通气以增加肺的均匀性，改善通气/灌注比和肺/胸壁形状匹配，减少应力和应变，并降低 VILI 的风险[8]。俯卧位通气改善中重度 ARDS 患者的预后 。
Concomitantly, clinicians and investigators alike have sought to avoid invasive ventilation altogether for patients with early acute hypoxemic respiratory failure (AHRF) using non-invasive respiratory support modalities (e.g., non-invasive ventilation, high-flow nasal oxygen). These therapies seek to improve oxygenation and unload respiratory muscles, thereby reducing inspiratory effort and the risk of patient-self-inflicted lung injury (P-SILI) [11], and allow time for the underlying disease to be treated without the need for sedation and tracheal intubation. For patients with more severe disease, VILI [5] can be theoretically reduced with extracorporeal support techniques which allow partial or total oxygenation and/or carbon dioxide removal and a significant reduction in ventilator mechanical power [12].
与此同时，临床医生和研究人员都试图为早期急性低氧性呼吸衰竭（AHRF）患者完全避免侵入性通气，采用非侵入性呼吸支持方式（例如，非侵入性通气、高流量鼻氧）。这些疗法旨在改善氧合，减轻呼吸肌肉负担，从而降低吸气努力和患者自我造成肺损伤（P-SILI）的风险[11]，并为基础疾病的治疗争取时间，而无需镇静和气管插管。对于病情更严重的患者，理论上可以通过体外支持技术减少通气相关肺损伤（VILI）[5]，这些技术允许部分或完全的氧合和/或二氧化碳去除，并显著降低通气机的机械功率[12]。
The aim of these guidelines is to review and summarize the literature published since the last clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM) [13] across different aspects of ARDS and AHRF, including ARDS due to coronavirus disease 2019 (COVID-19) in ICU. The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies (except for neuromuscular blockers, which are adjuncts to mechanical ventilation). The document combines a methodologically rigorous evaluation of clinical studies with expert opinion on the respiratory management of patients. This work did not include a cost-effectiveness analysis.
这些指南的目的是回顾和总结自欧洲重症监护医学会（ESICM）上一次临床实践指南（CPG）发布以来的文献，涵盖急性呼吸窘迫综合症（ARDS）和急性呼吸衰竭（AHRF）的不同方面，包括因 2019 冠状病毒病（COVID-19）导致的 ICU 中的 ARDS。本指南的范围仅限于成人患者和非药物呼吸支持策略（神经肌肉阻滞剂除外，后者是机械通气的辅助措施）。该文件结合了对临床研究的严格方法论评估和专家对患者呼吸管理的意见。此项工作未包括成本效益分析。

These guidelines were formulated by an international panel of experts on behalf of the ESICM and address three broad topics within ARDS: (1) definition; (2) phenotyping, and (3) respiratory support strategies. The ESICM Executive Committee selected these three topic areas and nominated three chairpersons (CC, LC, GG) and one methodologist (DP), who arranged the guidelines into nine domains of investigations: (1) definition; (2) phenotyping; (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) PEEP and lung RM; (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). Each domain was assigned to a group of experts within the panel, and each domain was
这些指南是由国际专家小组代表 ESICM 制定的，涉及 ARDS 的三个广泛主题：（1）定义；（2）表型；（3）呼吸支持策略。ESICM 执行委员会选择了这三个主题领域，并提名了三位主席（CC、LC、GG）和一位方法学家（DP），他们将指南安排为九个研究领域：（1）定义；（2）表型；（3）高流量鼻导管氧疗（HFNO）；（4）非侵入性通气（NIV）；（5）潮气量设置；（6）PEEP 和肺复张；（7）俯卧位；（8）神经肌肉阻滞；（9）体外生命支持（ECLS）。每个领域都分配给小组内的一组专家。
coordinated by a 'domain chair'. Panelists were invited to join one or more working groups based on their scientific expertise, geographical representation, and expressed interest. Two additional methodologists and eight patient representatives completed the guideline panel.
由“领域主席”协调。根据科学专长、地理代表性和表达的兴趣，邀请小组成员加入一个或多个工作组。两名额外的方法学家和八名患者代表组成了指南小组。

Members of each domain formulated questions according to the Patients or Population- Intervention-Comparison-Outcome (PICO) format. Each PICO question was discussed and agreed with the guideline chairs, methodologists, and the wider panel. For each PICO, a dedicated systematic literature search was performed using the PubMed search engine. For the Definition Domain 1 a systematic review of the literature was not performed and only a discussion was performed by the members on ARDS definition. Phenotypes Domain 2 conducted a systematic review of the literature, summarizing evidence without, however, performing any grading of the evidence. Most studies in this field focused on prognosis in different sub-phenotypes. Few others, investigating the effectiveness of intervention in sub-phenotypes, were meant to generate hypotheses to be verified in future trials more than providing evidence in support of treatments. For both Domains 1 and 2 we preferred a narrative approach over systematic Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessments.
各领域的成员根据患者或人群-干预-比较-结果（PICO）格式制定问题。每个 PICO 问题与指南主席、方法学家和更广泛的专家小组进行了讨论和达成一致。针对每个 PICO，使用 PubMed 搜索引擎进行了专门的系统文献检索。对于定义领域 1，没有进行系统文献综述，仅由成员对 ARDS 定义进行了讨论。表型领域 2 进行了系统文献综述，总结了证据，但没有对证据进行任何分级。该领域的大多数研究集中在不同亚表型的预后上。少数研究调查了亚表型干预的有效性，旨在生成假设以便在未来的试验中验证，而不是提供支持治疗的证据。对于领域 1 和领域 2，我们更倾向于叙述性方法，而不是系统的推荐、评估、开发和评估（GRADE）评估。
Following the literature search, pairs of reviewers from each domain reviewed the titles independently and selected the final list of full-text studies to be included in meta-analysis. The methodologists performed data extraction, synthesis, and risk of bias assessment for individual studies. Details of the meta-analysis procedures are provided in the Supplementary Methods.
在文献检索后，各领域的评审小组独立审查标题，并选择最终的全文研究列表以纳入荟萃分析。方法学家对各个研究进行了数据提取、综合和偏倚风险评估。荟萃分析程序的详细信息见补充方法。

After reviewing the results of the literature search and meta-analyses, members of each domain formulated statements (recommendations) related to each PICO/ narrative question. Recommendations were based on the integration of three main criteria: (1) certainty of evidence (as provided by the methodological assessment); (2) GRADE methodology [8], and (3) expert opinion. Proposed recommendations along with corresponding summaries of evidence were presented and discussed in four online panel-wide meetings which included patient representatives. These meetings were recorded for members who were unable to attend and for accurate reporting of the panel discussion. Following each panel-wide meeting, recommendations were revised based on the feedback received. The finalized recommendations were then sent to each panel member for anonymous online voting. Strong recommendations were phrased as "recommendations," and weak recommendations were phrased as "suggestions." Approval of a recommendation required at least of the panel to be in agreement. Recommendations with less than agreement were reformulated and re-voted until approval was achieved for all. A detailed description of the methodology is reported in the Supplementary Materials.
在审查文献检索和荟萃分析的结果后，各领域的成员制定了与每个 PICO/叙述问题相关的声明（建议）。建议基于三个主要标准的整合：（1）证据的确定性（由方法学评估提供）；（2）GRADE 方法论[8]；以及（3）专家意见。提出的建议及其相应的证据摘要在四次包括患者代表的在线全体会议中进行了展示和讨论。这些会议被录音，以便无法参加的成员和准确报告小组讨论。每次全体会议后，建议根据收到的反馈进行了修订。最终的建议随后被发送给每位小组成员进行匿名在线投票。强烈建议被表述为“建议”，而弱建议则被表述为“建议”。批准一项建议需要至少 的成员同意。对于同意少于 的建议，进行了重新表述和重新投票，直到所有建议获得 的批准。 方法论的详细描述在补充材料中报告。

ARDS was first described in 1967 by Ashbaugh and colleagues in 12 patients with new onset hypoxemia refractory to supplemental oxygen, bilateral infiltrates on chest radiograph, and reduced respiratory system compliance. Inflammation, edema, and hyaline membranes were uniformly present in lungs of non-survivors [2]. Subsequently, diagnosis of ARDS evolved from informal pattern recognition to formalized clinical definitions. The Lung Injury Score, proposed in 1988 [14] was supplanted in 1994 by the American-European Consensus Conference (AECC) definition [15], and further updated by an ESICM-sponsored process leading to the 2012 'Berlin Definition' [1, 3]. As part of these 2023 ESICM ARDS Treatment Guidelines, experts from the Definition Domain were charged with highlighting issues that should be addressed in subsequent revisions, based on knowledge accrued in the last decade which may be relevant to the current ARDS definition.
ARDS 于 1967 年由 Ashbaugh 及其同事首次描述，涉及 12 名新发低氧血症且对补充氧气无反应的患者，胸部 X 光显示双侧浸润，呼吸系统顺应性降低。非幸存者的肺部普遍存在炎症、水肿和透明膜[2]。随后，ARDS 的诊断从非正式的模式识别演变为正式的临床定义。1988 年提出的肺损伤评分在 1994 年被美欧共识会议（AECC）定义所取代[15]，并通过 ESICM 赞助的过程进一步更新，形成 2012 年的“柏林定义”[1, 3]。作为 2023 年 ESICM ARDS 治疗指南的一部分，定义领域的专家被指派强调在后续修订中应解决的问题，基于过去十年积累的知识，这些知识可能与当前的 ARDS 定义相关。
The expert panel discussed expanding the reach of the definition of ARDS and the pros and cons of this expansion. This topic is also important for the application of a definition in resource-poor settings [16]. As an example, the use of HFNO has increased in the past decade, particularly during the COVID-19 pandemic. Proponents suggest that the ARDS definition should be modified to allow patients on HFNO to be eligible for the oxygenation criterion even though they are not being ventilated with PEEP (as required by the Berlin definition). This approach has face validity in many patients with severe hypoxemia, who are treated with high flows and high on HFNO [17]. Some proponents go further to argue that the requirement for PEEP should be removed regardless of oxygen delivery device used, to allow ARDS to be diagnosed in locations without consistent access to HFNO or ventilation. Opponents argue that this approach may dilute severity of illness among patients labeled as ARDS, as it would also capture patients with a better prognosis [18] or affect comparisons among groups. Similarly, the past decade has also seen increased use of the ratio rather than the ratio as a measure of the degree of hypoxemia [19, 20]. Proponents argue that the S/F
专家小组讨论了扩展 ARDS 定义的范围及其利弊。这个话题在资源匮乏的环境中应用定义时也很重要[16]。例如，过去十年中，HFNO 的使用增加，特别是在 COVID-19 大流行期间。支持者建议修改 ARDS 定义，以允许使用 HFNO 的患者符合氧合标准，即使他们没有使用 PEEP 通气 （如柏林定义所要求的）。这种方法在许多重度低氧血症患者中具有表面有效性，他们在 HFNO 上接受高流量和高 的治疗[17]。一些支持者进一步主张，无论使用何种氧气输送设备，都应取消 PEEP 的要求，以便在没有稳定 HFNO 或通气的地方诊断 ARDS。反对者认为，这种方法可能会稀释被标记为 ARDS 患者的病情严重性，因为它也会包括预后较好的患者[18]，或者影响不同组之间的比较。 同样，过去十年中， 比率的使用也增加，而不是 比率，作为低氧血症程度的衡量标准[19, 20]。支持者认为 S/F
ratio is less invasive and more readily available, noting its use in current randomized controlled trials (RCTs) [21]. The counterargument, however, is that there are inaccuracies in measurements, particularly among patients with darker skin and those in shock and/or with poor distal perfusion. In addition, many patients are treated to keep their in excess of , resulting in an uninformative S/F ratio [22]. Finally, the inclusion of the chest radiograph criterion remains a question given its moderate-to-poor reliability [23,24] and limited availability in some settings. A recent RCT failed to demonstrate any improvement in chest X-ray interpretation after a standardized ARDS radiograph training exercise [25]. Other approaches to radiography in ARDS that have been debated over the past decade include eliminating the radiographic criterion altogether; allowing unilateral opacities to meet ARDS criteria, as pediatric critical care has done [26]; requiring computed tomography (CT) scanning to meet the full definition (more accurate but less available even in tertiary centers); and allowing lung ultrasound (more available but operating characteristics less well known and requires training in image acquisition) to meet the definition criteria.
比率的侵入性较低且更易获得，注意到其在当前随机对照试验（RCTs）中的使用。然而，反对意见是， 测量存在不准确性，特别是在皮肤较暗的患者以及处于休克和/或远端灌注不良的患者中。此外，许多患者的治疗目标是保持其 超过 ，导致 S/F 比率缺乏信息性。最后，胸部 X 光片标准的纳入仍然存在疑问，因为其可靠性中等偏低，并且在某些环境中可用性有限。最近的一项 RCT 未能证明经过标准化 ARDS X 光片培训后胸部 X 光解读的任何改善。 在过去十年中，关于急性呼吸窘迫综合症（ARDS）放射学的其他方法包括完全消除放射学标准；允许单侧不透明影像符合 ARDS 标准，正如儿科重症护理所做的那样[26]；要求进行计算机断层扫描（CT）以满足完整定义（更准确但在三级医院中可用性较低）；以及允许肺部超声（更易获得，但操作特性不太明确且需要图像获取的培训）来满足定义标准。
The panel also discussed the minimum timeframe for which patients must continue to meet criteria for ARDS. Experts agree that ARDS is not a transient phenomenon, but instead is a syndrome that takes days or weeks to resolve. The prevalence of rapidly improving ARDS ( or extubated within the first 24 h after diagnosis) in six ARDS Network trials was and increased over time [27]. If the subjects in a trial have a very low risk of the condition that the intervention is hypothesized to prevent (e.g., VILI), the trial will not verify the value of the intervention. These data prompt the question of how long diagnostic criteria must be present before patients can be diagnosed with ARDS. Experts agreed that some minimum period of stabilization and stability prior to diagnosing ARDS is likely appropriate; however, the length of this period remains uncertain. A long stabilization period would increase specificity but prevent early therapeutic interventions. Since oxygenation can be affected by clinical interventions and ventilator settings, experts have considered whether oxygenation failure in ARDS should be judged using standardized ventilator settings, which could identify higher risk patients but may add further feasibility challenges to trial enrollment and may not confer additional clinical advantages.
小组还讨论了患者必须继续满足急性呼吸窘迫综合症（ARDS）标准的最短时间框架。专家们一致认为，ARDS 不是一种短暂现象，而是一种需要数天或数周才能解决的综合症。在六项 ARDS 网络试验中，快速改善的 ARDS（ 或在诊断后 24 小时内拔管）发生率为 ，并随着时间的推移而增加[27]。如果试验中的受试者面临的条件（例如，通气相关肺损伤（VILI））的风险非常低，则该试验将无法验证干预的价值。这些数据引发了一个问题，即在患者被诊断为 ARDS 之前，诊断标准必须存在多长时间。专家们一致认为，在诊断 ARDS 之前，某个最小的稳定和稳定期可能是合适的；然而，这一时期的长度仍然不确定。较长的稳定期将增加特异性，但会阻碍早期治疗干预。 由于氧合可能受到临床干预和呼吸机设置的影响，专家们考虑在急性呼吸窘迫综合症（ARDS）中是否应使用标准化的呼吸机设置来判断氧合失败，这可能识别出高风险患者，但可能会给试验入组带来更多可行性挑战 ，并且可能不会带来额外的临床优势。
The expert panel noted the disconnect between the conceptual model of ARDS-a specific type of inflammation and host response to injury [3]-and the lack of measures of inflammation in ARDS definitions. This disconnect is due to insufficient data on operating characteristics or poor feasibility of direct measures of pulmonary inflammation or immune response [1]. While some successes have been documented with the application of sub-phenotypes of ARDS (see Domain 2), much work remains to be done to harmonize a clinically feasible definition with the conceptual pathophysiological model of ARDS. At the same time the panel discussed whether predictive validity for mortality is the best measure of an ARDS definition. Diagnostic accuracy in ARDS is challenging without a universal reference standard. Future work in refining the ARDS definition should carefully consider other facets of validity as well as reliability [30]. At the same time, we need new prospective observational studies to better categorize patients with acute non-cardiogenic hypoxemic respiratory failure, including ARDS, across a broad range of characteristics, including imaging and biomarkers, with the goal of developing more personalized treatments. Until such information becomes available, clinicians may at times wish to use the broader umbrella syndrome of acute hypoxemic respiratory failure when deciding to implement certain therapeutic strategies, particularly those that are not directed against specific ARDS mechanisms.
专家小组注意到 ARDS 的概念模型——一种特定类型的炎症和对损伤的宿主反应[3]——与 ARDS 定义中缺乏炎症测量之间的脱节。这种脱节是由于对肺炎症或免疫反应的直接测量的操作特性数据不足或可行性差[1]。虽然在应用 ARDS 的亚表型方面已经记录了一些成功（见领域 2），但仍需大量工作来协调临床可行的定义与 ARDS 的概念病理生理模型。同时，小组讨论了死亡率的预测效度是否是 ARDS 定义的最佳衡量标准。在没有通用参考标准的情况下，ARDS 的诊断准确性具有挑战性。未来在完善 ARDS 定义的工作中，应仔细考虑其他有效性和可靠性方面的因素[30]。 与此同时，我们需要新的前瞻性观察研究，以更好地对急性非心源性低氧性呼吸衰竭患者（包括 ARDS）进行分类，涵盖广泛的特征，包括影像学和生物标志物，目标是开发更个性化的治疗方案。在这些信息可用之前，临床医生在决定实施某些治疗策略时，可能会希望使用急性低氧性呼吸衰竭这一更广泛的综合征，特别是那些不针对特定 ARDS 机制的策略。

This group was charged with identifying key issues relating to phenotyping in ARDS, assessing the current literature to address these questions, and identifying the knowledge gaps to be addressed in future research.
该小组负责识别与 ARDS 表型相关的关键问题，评估当前文献以解决这些问题，并确定未来研究中需要填补的知识空白。
A systematic search was conducted to identify studies satisfying the following criteria: (1) identify a sub-phenotype as per our working definition (see below and as described in the supplement); (2) focus on phenotyping in patients with ARDS; (3) human data; (4) include patients with ARDS; (5) include sub-phenotypes showing heterogeneity of treatment effect or sub-phenotypes showing differences in patient outcome. Twenty-five papers were included in the final analysis [31-55].
进行了系统搜索，以识别满足以下标准的研究：（1）根据我们的工作定义识别亚表型（见下文及补充材料中描述）；（2）关注 ARDS 患者的表型鉴定；（3）人类数据；（4）包括 名 ARDS 患者；（5）包括显示治疗效果异质性的亚表型或显示患者结果差异的亚表型。最终分析中纳入了 25 篇论文[31-55]。

Based on the currently available literature and consensus within the working group, the following definitions were established:
根据目前可用的文献和工作组内的共识，建立了以下定义：
a. A phenotype is a clinically observable set of traits resulting from an interaction of genotype and environmental exposures (i.e., ARDS is a phenotype).
表型是由基因型和环境暴露相互作用所产生的一组临床可观察特征（即，ARDS 是一种表型）。
b. A subgroup is a subset of patients within a phenotype, which may be defined using any cut-off in a variable. This cut-off can be arbitrary, and frequently patients fall just on either side of it, resulting in patients switching subgroups (e.g., severity classification of ARDS).
b. 亚组是表型内患者的一个子集，可以使用变量中的任何临界值来定义。这个临界值可以是任意的，患者常常恰好位于其两侧，导致患者在亚组之间切换（例如， ARDS 的严重程度分类）。
c. A sub-phenotype is a distinct subgroup (of ARDS patients) that can be reliably discriminated from other subgroups based on a set or pattern of observable or measurable properties. Discrimination is typically based on a data-driven assessment of a multidimensional description of traits. Subphenotypes should also be reproducible in different populations.
c. 亚表型是一个独特的亚组（ARDS 患者），可以根据一组或一系列可观察或可测量的特征可靠地区分于其他亚组。区分通常基于对特征的多维描述的基于数据的评估。亚表型在不同人群中也应该是可重复的。
d. An endotype is a sub-phenotype with distinct functional or pathobiological mechanism, which preferably responds differently to a targeted therapy.
d. 内表型是具有不同功能或病理生物机制的亚表型，通常对靶向治疗的反应不同。

Accurate classification of the sub-phenotype is critical as exemplified by the results of LIVE trial [38]. The trial randomized patients to either standard lung-protective ventilation or a personalized treatment strategy based on radiological sub-phenotype (focal or diffuse pathology on chest radiograph). Overall, there was no benefit to a personalized treatment strategy; however, misclassification of sub-phenotype resulting in misaligned treatment strategies was common, and the results were "positive" when misclassified patients were excluded. Subphenotype classification in prospective studies likely requires: (1) on-site, real-time testing and rapid results, and (2) operator independence.
准确分类亚表型至关重要，正如 LIVE 试验的结果所示[38]。该试验将患者随机分配到标准肺保护通气或基于影像学亚表型（胸部 X 光片上的局灶性或弥漫性病变）的个性化治疗策略。总体而言，个性化治疗策略没有带来好处；然而，亚表型的错误分类导致治疗策略不匹配的情况很常见，当排除错误分类的患者时，结果是“积极的”。前瞻性研究中的亚表型分类可能需要：（1）现场实时测试和快速结果，以及（2）操作员独立性。

Question 2.3: What is the evidence for heterogeneity of treatment effect (predictive enrichment) between sub-phenotypes?
问题 2.3：不同亚表型之间治疗效果的异质性（预测性富集）的证据是什么？

Does sub-phenotyping alter patient response to an anti-inflammatory intervention in ARDS?
亚表型是否会改变 ARDS 患者对抗炎干预的反应？
In a secondary analysis of the HARP-2 trial [35], patients with the hyper-inflammatory sub-phenotype seemed to benefit from simvastatin, although the interaction term for heterogeneity of treatment effect was not statistically significant. In a secondary analysis of the SAILS trial [36], no heterogeneity of treatment effect was identified for the hypo-inflammatory and hyper-inflammatory subphenotypes and treatment with rosuvastatin. In a clustering reanalysis of the SAILS trial, 4 sub-phenotypes were described in which one group defined by high platelets and low creatinine seemed to benefit from rosuvastatin; however, these sub-phenotypes have not been reproduced in other populations [43].
在 HARP-2 试验的二次分析中[35]，具有超炎症亚表型的患者似乎从辛伐他汀中受益，尽管治疗效果异质性的交互项在统计上并不显著。在 SAILS 试验的二次分析中[36]，未发现低炎症和超炎症亚表型与罗苏伐他汀治疗之间的治疗效果异质性。在 SAILS 试验的聚类重新分析中，描述了 4 个亚表型，其中一组 以高血小板和低肌酐为特征，似乎从罗苏伐他汀中受益；然而，这些亚表型在其他人群中尚未得到重复验证[43]。

A secondary analysis of the ALVEOLI trial [31] identified heterogeneity of treatment effect between the hypoinflammatory and hyper-inflammatory sub-phenotypes and PEEP strategy adopted (higher vs lower table). A secondary analysis of the observational LUNGSAFE study [54] identified a similar pattern, in that patients with the hyper-inflammatory sub-phenotype seemed to benefit from higher PEEP, in contrast to the hypo-inflammatory sub-phenotype. In the LIVE trial described above, a personalized PEEP and prone positioning strategy based on diffuse vs focal radiographic sub-phenotype achieved a reduction in 90-day mortality, when only considering per-protocol treated patients [38]. However, this signal was diluted in the intention to treat analysis due to misclassifications of lung morphology.
对 ALVEOLI 试验的二次分析[31]发现，低炎症和高炎症亚表型之间的治疗效果存在异质性，以及采用的 PEEP 策略（高 PEEP 与低 PEEP 表）。对观察性 LUNGSAFE 研究[54]的二次分析发现了类似的模式，即高炎症亚表型的患者似乎从更高的 PEEP 中受益，而低炎症亚表型则相反。在上述 LIVE 试验中，基于弥漫性与局灶性放射学亚表型的个性化 PEEP 和俯卧位策略在仅考虑按方案治疗的患者时实现了 90 天死亡率的降低[38]。然而，由于肺形态的误分类，这一信号在意向治疗分析中被稀释。

A secondary analysis of FACTT [33] identified heterogeneity of treatment effect in that patients with the hyperinflammatory sub-phenotype seemed to benefit from a liberal fluid strategy, in contrast to the hypo-inflammatory sub-phenotype.
对 FACTT [33] 的二次分析发现治疗效果存在异质性，表现为具有超炎症亚表型的患者似乎从宽松的液体策略中受益，而低炎症亚表型的患者则相反。

Short term (up to day 90) mortality was found to be different between sub-phenotypes that are based on the following characteristics (see Supplemental Table):
短期（最多 90 天）死亡率在基于以下特征的亚表型之间存在差异（见补充表）

Several research questions remain to be addressed in future studies, particularly regarding: (1) the stability of sub-phenotypes over time, from pre-ARDS through to recovery; (2) whether sub-phenotypes are reproducible across diverse populations; (3) the accuracy and repeatability of a rapid sub-phenotype classification; (4) the pathophysiological pathways that drive the development of sub-phenotypes; (5) the quantification of the attributable mortality of each sub-phenotype; and (6) whether
未来的研究中仍需解决几个研究问题，特别是关于：（1）亚表型在时间上的稳定性，从急性呼吸窘迫综合症前期到恢复；（2）亚表型在不同人群中是否可重复；（3）快速亚表型分类的准确性和重复性；（4）驱动亚表型发展的病理生理通路；（5）每个亚表型的归因死亡率的量化；以及（6）是否
precision treatment strategy based on sub-phenotypes can improve outcomes after ICU discharge.
基于亚表型的精准治疗策略可以改善重症监护病房出院后的结果。

The effectiveness of COT (i.e., low-flow) delivered via face mask or nasal cannula is limited by low-flow rates (i.e., less than ) and lack of humidification of inspired oxygen, which can lead to patient intolerance. HFNO is well tolerated and can deliver heated, humidified oxygen at flow rates up to [57]. At higher flow rates, HFNO can deliver more consistent than COT, decrease anatomical dead space, and provide PEEP up to , depending on flow rate and breathing pattern [58]. After the publication of the FLORALI trial in 2015 [59], the use of HFNO in acute hypoxemic respiratory failure increased considerably, which was further augmented during the COVID-19 pandemic.
COT（即低流量）通过面罩或鼻导管输送的有效性受到低流量（即小于 ）和缺乏吸入氧气的湿化的限制，这可能导致患者不耐受。HFNO 耐受性良好，可以以高达 的流量输送加热、湿化的氧气[57]。在更高的流量下，HFNO 可以提供比 COT 更一致的 ，减少解剖死腔，并提供高达 的 PEEP，这取决于流量和呼吸模式[58]。自 2015 年 FLORALI 试验发布以来[59]，HFNO 在急性低氧性呼吸衰竭中的使用显著增加，在 COVID-19 大流行期间进一步增加。

We evaluated the use of HFNO for patients with AHRF rather than ARDS, given that many patients would not meet the requirement for PEEP of or more using the current Berlin definition. However, most of the patients who progress from HFNO to mechanical ventilation do end up meeting criteria for ARDS. During the COVID-19 pandemic, 93% of patients treated with HFNO who progressed to intubation met criteria for ARDS under the Berlin definition [18]. Given the increasing use of HFNO especially with the COVID-19 pandemic, there is increasing belief that ARDS definition should include those patients with acute hypoxemic respiratory failure on HFNO (see above Domain 1). As such, these PICOs and their recommendation should be applicable to ARDS being managed with HFNO. We excluded trials that included patients with acute cardiogenic pulmonary edema, exacerbation of COPD, acute hypercapnic respiratory failure, or use of HFNO post-extubation. We identified seven RCTs that formed the basis of our recommendations [59-65]. The study by Bouadma and collaborators [65], however, was included only in a sensitivity analysis because of its design and uncertainties in the interpretation of its findings (see Supplementary Materials).
我们评估了 HFNO 在 AHRF 患者中的使用，而不是在 ARDS 患者中，因为许多患者在当前柏林定义下不符合 PEEP 或更高的要求。然而，大多数从 HFNO 转为机械通气的患者最终确实符合 ARDS 的标准。在 COVID-19 大流行期间，93%接受 HFNO 治疗并进展到插管的患者在柏林定义下符合 ARDS 标准[18]。鉴于 HFNO 的使用越来越普遍，尤其是在 COVID-19 大流行期间，人们越来越相信 ARDS 的定义应包括那些在 HFNO 下出现急性低氧性呼吸衰竭的患者（见上文领域 1）。因此，这些 PICO 及其建议应适用于使用 HFNO 管理的 ARDS。我们排除了包括急性心源性肺水肿、COPD 加重、急性高碳酸血症呼吸衰竭或拔管后使用 HFNO 的患者的试验。我们确定了七项 RCT，这些 RCT 构成了我们建议的基础[59-65]。 Bouadma 及其合作者的研究[65]仅在敏感性分析中被纳入，因为其设计和对结果解释的不确定性（见补充材料）。
Among 2769 patients included in six trials with a combined 28 - or 30 -days mortality of , there was no statistically significant difference in mortality between HFNO compared to COT (relative risk (RR) 0.95, 95% confidence interval ( CI) 0.82-1.09). Further, there was no evidence for differences in treatment effect in the subgroups based on immunocompromised or COVID-19 status.
在六项试验中纳入的 2769 名患者中，28 天或 30 天的死亡率为 ，HFNO 与 COT 之间的死亡率没有统计学显著差异（相对风险（RR）0.95，95%置信区间（ CI）0.82-1.09）。此外，基于免疫功能低下或 COVID-19 状态的亚组中，治疗效果没有证据表明存在差异。
The pooled rate of intubation at 28-30 days among the six analyzed trials was . Meta-analysis identified a significant beneficial effect of HFNO compared to COT in preventing intubation (RR 0.89, 95% CI 0.81-0.97). Individual study estimates of treatment effect for risk of intubation were consistent across most included trials, except for one trial that contributed only of weight to the pooled estimate [64]. We did not identify significant differences in intubation rate between HFNO and COT in subgroups of patients based upon immunocompromised state or COVID-19 infection.
在六项分析试验中，28-30 天的插管汇总率为 。荟萃分析发现，与常规氧疗（COT）相比，高流量鼻氧（HFNO）在预防插管方面具有显著的益处（相对风险 RR 0.89，95%置信区间 0.81-0.97）。大多数纳入试验的插管风险治疗效果的个别研究估计是一致的，只有一项试验对汇总估计的权重贡献仅为 [64]。我们没有在免疫功能受损状态或 COVID-19 感染的患者亚组中发现 HFNO 和 COT 之间插管率的显著差异。

We recommend that non-mechanically ventilated patients
我们建议非机械通气的患者
with AHRF not due to cardiogenic pulmonary edema or acute exacerbation of COPD receive HFNO as compared to conventional oxygen therapy to reduce the risk of intubation
与因心源性肺水肿或 COPD 急性加重而未接受 AHRF 的患者相比，接受 HFNO 治疗的患者在降低插管风险方面优于常规氧疗
Strong recommendation; moderate level of evidence in favor
强烈推荐；中等证据支持
We are unable to make a recommendation for or against the use of HFNO over conventional oxygen therapy to reduce mortality No recommendation; high level of evidence of no effect
我们无法对使用高流量鼻氧（HFNO）相对于传统氧疗法以降低死亡率提出推荐。没有推荐；有高水平证据表明没有效果
This recommendation applies also to AHRF from COVID-19 Strong recommendation; low level of evidence in favor for intubation and no recommendation; moderate level of evidence of no effect for mortality, for indirectness.
该建议同样适用于 COVID-19 的 AHRF。强烈推荐；对插管的证据水平较低；对死亡率没有影响的证据水平中等，因间接性。

HFNO was found to be superior to COT in reducing the risk of intubation but not in reducing mortality among patients with AHFR [59-65]. Mechanical ventilation is resource-intensive and is associated with higher need for sedation and immobility, which have been associated with higher rates of complications such as delirium, nosocomial infection, mortality, worse long-term morbidity, including physical and cognitive complications. In addition, input from the patient representatives indicated that most patients would value avoiding intubation if possible. Thus, there may be benefits from preventing intubation, even in the absence of a significant improvement in mortality. HFNO is generally well tolerated by patients and is associated with similar or lower incidence of adverse event rates compared to COT. Therefore, we advocate the use of HFNO compared to COT for patients with AHRF regardless of immunocompromised or COVID-19 status.
HFNO 被发现比 COT 在降低插管风险方面更具优势，但在降低 AHFR 患者的死亡率方面并无显著差异[59-65]。机械通气资源消耗大，并且需要更高的镇静和不动性，这与更高的并发症发生率相关，如谵妄、院内感染、死亡率、以及更差的长期发病率，包括身体和认知并发症。此外，患者代表的反馈表明，大多数患者会重视尽可能避免插管。因此，即使在没有显著改善死亡率的情况下，预防插管也可能带来好处。HFNO 通常被患者良好耐受，其不良事件发生率与 COT 相比相似或更低。因此，我们倡导在免疫受损或 COVID-19 状态下，针对 AHRF 患者使用 HFNO 而非 COT。

Long-term functional outcome data are missing from randomized controlled trials investigating the use of HFNO in acute respiratory failure. As such, it is unknown whether prevention of intubation can decrease symptoms and long-term functional impairment reported by AHRF survivors. Additionally, it is not clear how long a trial of HFNO should last or whether indices such as respiratory rate - oxygenation (ROX) index or other measures should be utilized to indicate failure of HFNO and need for intubation [66]. Indeed, in some of the trials, patients who failed HFNC had a higher mortality than patients treated with conventional oxygen [59, 67]. It is not clear whether this was due to some delay in intubation or only reflected more severe disease. A future large trial comparing HFNO to COT powered for mortality may be difficult to conduct and interpret due to cross-overs, given the increased adoption of HFNO use after the COVID19 pandemic. Future clinical trials should examine how HFNO can best be delivered to maximize benefit would guide clinicians on how to use and discontinue HFNO in AHRF. In addition, long-term outcomes (e.g. cognitive, functional, and quality of life) need to be incorporated to determine the long-term impact of HFNO.
缺乏关于急性呼吸衰竭中高流量鼻氧（HFNO）使用的随机对照试验的长期功能结果数据。因此，目前尚不清楚预防插管是否能减少急性呼吸衰竭幸存者报告的症状和长期功能障碍。此外，尚不清楚 HFNO 的试验应持续多长时间，或是否应使用呼吸频率-氧合（ROX）指数或其他指标来指示 HFNO 的失败和插管的必要性[66]。实际上，在一些试验中，HFNC 失败的患者死亡率高于接受常规氧气治疗的患者[59, 67]。尚不清楚这是否由于插管延迟，还是仅反映了更严重的疾病。由于 COVID-19 大流行后 HFNO 使用的增加，未来比较 HFNO 与常规氧气治疗（COT）的大型试验在死亡率方面可能难以进行和解释。未来的临床试验应研究如何最佳地提供 HFNO，以最大化其益处，并指导临床医生如何在急性呼吸衰竭中使用和停止 HFNO。此外，长期结果（例如。 需要纳入认知、功能和生活质量等因素，以确定高流量鼻氧疗法的长期影响。

Question 3.2: In non-mechanically ventilated patients with AHRF not due to cardiogenic pulmonary edema or acute exacerbation of COPD, does HFNO compared to non-invasive ventilation reduce mortality or intubation?
问题 3.2：在非机械通气的急性高呼吸频率肺功能不全患者中，如果不是由于心源性肺水肿或慢性阻塞性肺病急性加重，使用高流量鼻氧（HFNO）与非侵入性通气相比，是否能降低死亡率或插管率？

Non-invasive ventilation improves outcomes and has been recommended for patients with acute hypercapnic respiratory failure from acute exacerbations of COPD or patients with cardiogenic pulmonary edema [68]. In most prior guidelines, no specific recommendation has been made for the use of NIV for patients with AHRF from other etiologies due to insufficient evidence. Additionally, concerns have been raised about tolerance of NIV, ability to clear secretions, worsening lung injury from large tidal volumes on inspiratory pressure support (especially given the high inspiratory demand seen in AHRF), and possible harm resulting from delaying intubation.
非侵入性通气改善了治疗效果，并已被推荐用于因慢性阻塞性肺病急性加重或心源性肺水肿导致的急性高碳酸血症呼吸衰竭患者[68]。在大多数先前的指南中，由于证据不足，未对其他病因引起的急性呼吸衰竭患者使用非侵入性通气提出具体建议。此外，人们对非侵入性通气的耐受性、清除分泌物的能力、在吸气压力支持下大潮气量可能加重肺损伤（尤其考虑到急性呼吸衰竭中观察到的高吸气需求）以及可能因延迟插管而造成的伤害表示担忧。
Early in the COVID-19 pandemic, NIV was frequently used (up to of ICU patients in Wuhan) [69]. Initial clinical practice guidelines from the National Institute of Health and Surviving Sepsis Campaign provided a weak recommendation in favor of HFNO compared to NIV for the treatment of COVID-19 pneumonia, and for use of NIV if HFNO was not available or had failed [70, 71]. This recommendation was based upon data extrapolated from non-COVID-19 related AHRF, and studies in patients with Middle East Respiratory Syndrome (MERS) that showed a high rate of intolerance and failure of NIV, with high mortality among those who failed NIV [59, 72]. In addition, concerns existed regarding the potential for increased aerosol transmission of the virus with NIV .
在 COVID-19 大流行初期，NIV 的使用频率很高（在武汉的重症监护病房中高达 的患者）[69]。国家卫生研究院和生存脓毒症运动的初步临床实践指南对 HFNO 相较于 NIV 治疗 COVID-19 肺炎提供了弱推荐，并建议在 HFNO 不可用或失败时使用 NIV [70, 71]。这一推荐基于从非 COVID-19 相关的急性呼吸衰竭（AHRF）中推断的数据，以及在中东呼吸综合症（MERS）患者中的研究，这些研究显示 NIV 的耐受性差和失败率高，且 NIV 失败者的死亡率高 [59, 72]。此外，关于 NIV 可能导致病毒气溶胶传播增加的担忧也存在