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 。

We focused on patients with AHRF and excluded trials that enrolled patients with acute cardiogenic pulmonary edema, exacerbation of COPD, acute hypercapnic respiratory failure, or mechanically ventilated patients who used NIV after extubation or to facilitate extubation. We identified four RCTs that reported mortality [59, 74-76], including two RCTs that enrolled COVID-19 patients. Among other trials, we excluded a three-arm trial where the intervention in the common control arm was COT and there was no direct randomization of patients to HFNO vs NIV [60].
我们专注于急性呼吸衰竭（AHRF）患者，排除了招募急性心源性肺水肿、慢性阻塞性肺病（COPD）加重、急性高碳酸血症呼吸衰竭或在拔管后使用非侵入性通气（NIV）以促进拔管的机械通气患者的试验。我们确定了四项报告死亡率的随机对照试验（RCT）[59, 74-76]，其中包括两项招募 COVID-19 患者的 RCT。在其他试验中，我们排除了一个三臂试验，其中常规对照组的干预是持续氧疗（COT），且没有将患者直接随机分配到高流量鼻氧（HFNO）与 NIV 之间[60]。
Of the two RCTs enrolling non-COVID-19 patients, one included immunocompromised patients [76], the other non-immunocompromised patients [59]. We did not include one trial in the pooled analysis for intubation as only 7-day intubation outcome was reported [74]. Meta-analysis did not identify a significant difference comparing HFNO to NIV for either mortality (RR CI ) or intubation (RR 1.09 95% CI ).
在两项招募非 COVID-19 患者的随机对照试验中，一项包括免疫功能低下的患者[76]，另一项则包括非免疫功能低下的患者[59]。我们没有将一项试验纳入气管插管的汇总分析，因为仅报告了 7 天的气管插管结果[74]。荟萃分析未发现 HFNO 与 NIV 在死亡率（RR CI ）或气管插管（RR 1.09 95% CI ）方面存在显著差异。
Meta-analysis did not identify significant differences in mortality in HFNO vs NIV within subgroups of immunocompromised or COVID-19 patients. Regarding intubation, in the trial by Grieco et al. HFNO was associated with a significant increase in the rate of intubation at 28 days compared to NIV in patients with COVID-19 (RR 1.72 95% CI 1.06-2.79) [75]. However, the trial by Nair et al. (not included in the primary meta-analysis because it reported intubation rate only up to day 7) [74] showed a statistically significant effect in the opposite direction (a absolute risk reduction in the HFNO arm).
荟萃分析未在免疫受损或 COVID-19 患者的亚组中发现 HFNO 与 NIV 在死亡率方面的显著差异。关于插管，在 Grieco 等人的试验中，HFNO 与 COVID-19 患者在 28 天时的插管率显著增加相比 NIV（相对风险 1.72，95%置信区间 1.06-2.79）[75]。然而，Nair 等人的试验（因仅报告到第 7 天的插管率而未纳入主要荟萃分析）[74]显示出相反方向的统计学显著效应（HFNO 组的绝对风险降低为 ）。

We are unable to make a recommendation for or against the use of HFNO compared to continuous positive airway pressure (CPAP)/ NIV to reduce intubation or mortality in the treatment of unselected patients with acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema or acute exacerbation of COPD.
我们无法对 HFNO 与持续正压呼吸（CPAP）/非侵入性通气（NIV）在减少插管或死亡率方面的使用做出推荐，特别是在治疗未选择的急性低氧血症呼吸衰竭患者时，这些患者并非因心源性肺水肿或慢性阻塞性肺病急性加重而导致。
No recommendation; moderate level of evidence for mortality, low level of evidence for intubation, not in favor nor against.
没有推荐；死亡率的证据水平中等，插管的证据水平低，不支持也不反对。
We suggest that CPAP/NIV can be considered instead of HFNO for the treatment of AHRF due to COVID-19 to reduce the risk of intubation (weak recommendation, high level of evidence), but no recommendation can be made for whether CPAP/NIV can decrease mortality compared to HFNO in COVID-19. No recommendation; high level of evidence of no effect.
我们建议可以考虑使用 CPAP/NIV 替代 HFNO 治疗因 COVID-19 引起的急性呼吸衰竭，以降低插管风险（弱推荐，高水平证据），但无法对 CPAP/NIV 是否能降低 COVID-19 患者的死亡率相比 HFNO 提出推荐。没有推荐；高水平证据显示无效。

The panel suggest that clinicians managing AHRF patients with CPAP/NIV should have appropriate experience and expertise, and patients should have appropriate monitoring (e.g. clinical signs of respiratory distress, breathing pattern-tidal volume ( Vt and respiratory rate-and inspiratory effort) to avert P-SILI. Additionally, clinicians should consider how well individual patients may tolerate NIV and the risk of adverse events.
专家小组建议，管理使用 CPAP/NIV 的 AHRF 患者的临床医生应具备适当的经验和专业知识，患者应接受适当的监测（例如，呼吸窘迫的临床迹象、呼吸模式-潮气量（Vt ）和呼吸频率-以及吸气努力），以避免 P-SILI。此外，临床医生应考虑个别患者对 NIV 的耐受能力以及不良事件的风险。

There is an urgent need for RCTs that compare HFNO to NIV/CPAP for patients with AHRF using important endpoints such as mortality, intubation, and total duration of mechanical ventilation. Long-term patient follow-up and cognitive and function outcomes assessments would enable determination of whether observed differences in short-term outcomes (e.g., intubation) are associated with long-term impairment in survivors.
迫切需要进行随机对照试验（RCT），比较高流量鼻氧（HFNO）与非侵入性通气（NIV）/持续气道正压通气（CPAP）在急性呼吸衰竭（AHRF）患者中的效果，使用重要的终点指标，如死亡率、插管率和机械通气的总持续时间。对患者进行长期随访以及认知和功能结果评估将有助于确定短期结果（例如插管）中观察到的差异是否与幸存者的长期损伤相关。

Question 4.1: In non-mechanically ventilated patients with AHRF not due to cardiogenic pulmonary edema, obesity hypoventilation or acute exacerbation of COPD, does CPAP/NIV, as compared to conventional oxygen therapy reduce mortality or intubation?
问题 4.1：在非机械通气的 AHRF 患者中，如果不是由于心源性肺水肿、肥胖性通气不足或 COPD 急性加重，CPAP/NIV 与常规氧疗相比，是否能降低死亡率或插管率？

While hypoxemia and ventilatory dysfunction in patients with AHRF can be addressed with different non-invasive modalities, with differential effects on end-expiratory alveolar pressure and/or inspiratory effort [77], a concern regarding the use of CPAP/NIV is the potential delay in intubation, which might lead to worse outcomes, including increased mortality. Moreover, high transpulmonary pressures can be observed during NIV (due to either high level of support, strong inspiratory effort, or both) potentially leading to P-SILI, analogous to the ventilatorinduced lung injury described during invasive controlled ventilation [11]. The specific physiological effects need to be considered when selecting non-invasive strategies for AHRF. Of note, patients with AHRF not receiving positive pressure cannot be classified as ARDS patients using the current Berlin definition as they do not receive at least of PEEP. As previously mentioned, the ARDS definition may need include these patients who have the same disease from a pathophysiological point of view.
虽然可以通过不同的非侵入性方式解决 AHRF 患者的低氧血症和通气功能障碍，这些方式对呼气末肺泡压力和/或吸气努力有不同的影响，但使用 CPAP/NIV 的一个担忧是可能延迟插管，这可能导致更糟糕的结果，包括死亡率增加。此外，在 NIV 期间可能会观察到高的肺内压（由于支持水平高、吸气努力强或两者兼而有之），这可能导致 P-SILI，类似于在侵入性控制通气中描述的通气诱导肺损伤。选择 AHRF 的非侵入性策略时需要考虑特定的生理效应。值得注意的是，未接受正压通气的 AHRF 患者不能根据当前的柏林定义被归类为 ARDS 患者，因为他们没有接受至少 的 PEEP。如前所述，ARDS 的定义可能需要包括这些在病理生理学上具有相同疾病的患者。

We included ten randomized controlled trials which enrolled patients with non-COVID-19 and COVID-19 AHRF, immunocompetent and immunocompromised [59, 60, 78-85]. Six of these studies investigated the effect of NIV compared to COT [59, 81-85], while four compared CPAP vs. COT [60, 78-80]. One trial with CPAP performed in COVID-19 patients randomized patients either to CPAP or to HFNO vs. COT [60]. For the main analysis, we combined all ten studies, without any subgroup distinctions. We hypothesized that NIV and CPAP were similarly effective; hence, we included studies adopting either intervention for purposes of the meta-analysis. When the intervention was NIV, the type of ventilator (ICU, dedicated to NIV or home ventilator) and the type of the circuit used (single or double limb circuit) were assumed not to affect outcomes.
我们纳入了十项随机对照试验，这些试验招募了非 COVID-19 和 COVID-19 急性呼吸衰竭（AHRF）患者，包括免疫功能正常和免疫功能受损的患者[59, 60, 78-85]。其中六项研究调查了非侵入性通气（NIV）与常规氧疗（COT）的效果[59, 81-85]，而四项比较了持续气道正压通气（CPAP）与 COT[60, 78-80]。一项在 COVID-19 患者中进行的 CPAP 试验将患者随机分配到 CPAP 或高流量鼻氧（HFNO）与 COT 组[60]。在主要分析中，我们将所有十项研究合并，没有任何亚组区分。我们假设 NIV 和 CPAP 的效果相似；因此，我们纳入了采用任一干预措施的研究以进行荟萃分析。当干预为 NIV 时，假设通气机的类型（ICU、专用 NIV 或家用通气机）和使用的回路类型（单回路或双回路）不会影响结果。
We performed a primary meta-analysis focused on five RCTs with low risk of bias and individual moderate to high quality [59, 60, 78, 81, 82]. However, the risk of bias increased when the outcome was intubation, because of lack of blinding. This meta-analysis did not identify a significant effect of CPAP/NIV compared to COT on intubation (RR CI ) or hospital mortality (RR 0.89, 95% CI 0.75-1.05). A secondary analysis was performed including all studies independently from the risk of bias assessment and quality (see Supplementary Materials). This secondary analysis showed a protective effect in terms of intubation rate and mortality. However, according to our predefined statistical planned, when the results of the primary and secondary analysis were inconsistent, the primary analysis prevailed.
我们进行了一个主要的荟萃分析，重点关注五项低偏倚风险和个体中到高质量的随机对照试验（RCT）[59, 60, 78, 81, 82]。然而，当结果是插管时，由于缺乏盲法，偏倚风险增加。该荟萃分析未能发现 CPAP/NIV 与 COT 在插管（RR CI ）或医院死亡率（RR 0.89，95% CI 0.75-1.05）方面的显著效果。进行了一个次级分析，包括所有研究，而不考虑偏倚风险评估和质量（见补充材料）。该次级分析显示在插管率和死亡率方面具有保护作用。然而，根据我们预先定义的统计计划，当主要分析和次级分析的结果不一致时，以主要分析为准。
Only one study was available in COVID-19 patients [60] which reported a lower intubation rate with CPAP compared to conventional oxygen therapy but no difference in mortality.
在 COVID-19 患者中只有一项研究[60]，该研究报告显示与常规氧疗相比，使用 CPAP 的插管率较低，但死亡率没有差异。

We are unable to make a recommendation for or against the use of CPAP/NIV compared to conventional oxygen therapy for the treatment of AHRF (not related to cardiogenic pulmonary edema or acute exacerbation of COPD) to reduce mortality or to prevent intubation.
我们无法对使用 CPAP/NIV 与常规氧疗相比在治疗 AHRF（与心源性肺水肿或 COPD 急性加重无关）方面是否能够降低死亡率或防止插管做出推荐。
No recommendation; high level of evidence for mortality, moderate level of evidence for intubation.
没有推荐；死亡率的证据水平很高，插管的证据水平适中。
We suggest the use of CPAP over conventional oxygen therapy to reduce the risk of intubation in patients with acute hypoxemic respiratory failure due to COVID-19.
我们建议在因 COVID-19 引起的急性缺氧性呼吸衰竭患者中使用 CPAP，而不是传统的氧气治疗，以降低插管的风险。
Weak recommendation; low level of evidence in favor.
弱推荐；支持的证据水平低。
In this population, we are unable to make a recommendation for or against the use of CPAP over conventional oxygen therapy to reduce mortality.
在这个人群中，我们无法对使用 CPAP 与常规氧疗相比以降低死亡率提出推荐。
No recommendation; moderate level of evidence of no effect.
没有推荐；中等水平的证据表明没有效果。

Analysis of available scientific evidence does not allow conclusions regarding the use of CPAP/NIV over COT to prevent intubation or to reduce mortality in patients with non-COVID-19 AHRF. In the panel's view, it is advisable that future research should better characterize patients at inclusion to identify optimal indications for CPAP/NIV in the management of acute hypoxemic respiratory failure. Given recent physiological evidence [86], the panel suggests focusing on the potential role of high vs. low respiratory drive in determining suitability for NIV and likelihood of success.
对现有科学证据的分析无法得出关于使用 CPAP/NIV 相对于 COT 在预防插管或降低非 COVID-19 急性呼吸衰竭患者死亡率方面的结论。专家小组认为，未来的研究应更好地描述纳入患者的特征，以确定在急性低氧性呼吸衰竭管理中 CPAP/NIV 的最佳适应症。鉴于最近的生理证据[86]，专家小组建议关注高呼吸驱动与低呼吸驱动在确定 NIV 适用性和成功可能性方面的潜在作用。

Question 4.2: In patients being treated with CPAP/NIV
问题 4.2：在接受 CPAP/NIV 治疗的患者中
for AHRF, does the use of a helmet interface as compared to face mask reduce intubation or mortality?
对于 AHRF，使用头盔接口与面罩相比是否减少了插管或死亡率？

NIV in the acute care setting is usually applied via a face mask interface, which can be poorly tolerated resulting in a risk for NIV failure. Helmet is an alternative interface to deliver NIV. Several studies reported that NIV via helmet was well tolerated and reduced skin pressure injuries [87, 88]. Managing patient-ventilator synchrony can, however, be challenging during helmet NIV [89, 90], and specific expertise is needed to optimize ventilatory settings.
在急性护理环境中，非侵入性通气（NIV）通常通过面罩接口进行，这可能会导致耐受性差，从而增加 NIV 失败的风险。头盔是提供 NIV 的另一种接口。几项研究报告显示，通过头盔进行 NIV 的耐受性良好，并减少了皮肤压疮。然而，在头盔 NIV 期间，管理患者与呼吸机的同步可能具有挑战性，需要特定的专业知识来优化通气设置。

Only one small, single-center RCT was identified [91]. Eighty-three patients with hypoxemic respiratory failure requiring NIV were randomized to either face mask or helmet interface. There was a mortality reduction ( CI -41.1 to -1 ) and a reduction of intubation rate to -22.5 ) with the helmet. A second publication was a follow-up study of the same dataset, focused on functional outcomes [92]. Although the study had only moderate limitations, the panel had concerns given (a) small sample size and early termination for efficacy might cause an overestimation of the treatment effect, and (b) single-center trial might have issues related to external validity. The panel considered this study as hypothesis-generating rather than conclusive evidence of helmet superiority.
仅识别出一项小型单中心随机对照试验（RCT）[91]。83 名需要非侵入性通气（NIV）的低氧血症呼吸衰竭患者被随机分配到面罩或头盔接口组。头盔组的死亡率降低了 （ CI -41.1 至-1），插管率降低了 （ -22.5）。第二篇出版物是对同一数据集的后续研究，重点关注功能结果[92]。尽管该研究仅有中等的局限性，但专家小组对此表示担忧，因为（a）小样本量和因疗效提前终止可能导致对治疗效果的高估，以及（b）单中心试验可能存在外部效度相关的问题。专家小组认为该研究是生成假设的，而非头盔优越性的确凿证据。

We are unable to make a recommendation for or against the use of helmet interface for CPAP/NIV as compared to face mask to prevent intubation or reduce mortality in patients with acute hypoxemic respiratory failure.
我们无法对使用头盔接口与面罩相比在预防插管或减少急性缺氧性呼吸衰竭患者的死亡率方面做出推荐。
No recommendation; very low level of evidence in favor.
没有推荐；支持的证据水平非常低。

Additional studies comparing helmet and facemask interface are needed before being able to recommend one of these two interfaces compared to the other.
在能够推荐这两种接口中的一种之前，需要进行更多关于头盔和面罩接口的比较研究。

NIV can generate high transpulmonary pressure when respiratory drive and effort are high. The application of additional positive pressure assistance during inspiration could lead to higher transpulmonary pressures and total stress applied to the lung, particularly when respiratory drive is high. CPAP may thus benefit patients with acute hypoxemic respiratory failure, possibly lowering the swings in transpulmonary pressure compared to NIV.
NIV 在呼吸驱动和努力较高时可以产生高的肺脏跨压。在吸气期间施加额外的正压辅助可能会导致更高的肺脏跨压和施加在肺部的总压力，特别是在呼吸驱动较高时。因此，CPAP 可能对急性缺氧性呼吸衰竭的患者有益，可能会降低与 NIV 相比的肺脏跨压波动。

We found no randomized study that addressed this PICO question and were thus unable to make a recommendation for or against the use of NIV compared to CPAP for the treatment of ARDS.
我们没有找到任何随机研究来解决这个 PICO 问题，因此无法对使用 NIV 与 CPAP 相比治疗 ARDS 提出推荐意见。

We are unable to make a recommendation for or against the use of NIV compared to CPAP for the treatment of AHRF. No recommendation; no evidence.
我们无法对使用 NIV 与 CPAP 治疗 AHRF 进行推荐或反对。没有推荐；没有证据。

Conceptually, the use of CPAP in case of acute hypoxemic respiratory failure is of interest but there are no data available comparing this strategy with NIV.
从概念上讲，在急性缺氧性呼吸衰竭的情况下使用 CPAP 是有意义的，但没有数据可用来将这一策略与 NIV 进行比较。

Randomized studies are needed to assess whether NIV as compared to CPAP reduces the risk of intubation or decreases mortality.
需要随机研究来评估与 CPAP 相比，非侵入性通气（NIV）是否降低插管风险或减少死亡率。

Question 5.1: In adult patients ARDS and COVID-19-related ARDS, does low tidal volume ventilation alone compared with more traditional approaches to ventilation decrease mortality?
问题 5.1：在成人患者中，ARDS 和与 COVID-19 相关的 ARDS，单独使用低潮气量通气与更传统的通气方法相比，是否能降低死亡率？

In the early 1960s, researchers and clinicians showed that mechanical ventilation with small Vt caused gradual loss of lung volume with hypoxemia due to right-to-left shunting through regions with poor ventilation. Consequently, use of large tidal volumes of body
在 1960 年代初，研究人员和临床医生表明，使用小潮气量的机械通气会导致肺容量逐渐丧失，并因右向左分流通过通气不良区域而出现低氧血症。因此，使用大潮气量的 身体
weight was recommended [93]. Recognition of a number of physiological concepts changed this approach and led to the current era of lung-protective ventilation using small Vt: (i) hypercapnia and respiratory acidosis are well tolerated if the patient is well oxygenated, (ii) mechanical ventilation that allows for derecruitment and recruitment of lung units and/or over-distension of lung units associated with high transpulmonary pressures can worsen existing lung injury or may lead to de novo lung injury, and (iii) the effective pulmonary gas volume in patients with ARDS is decreased (baby lung) and thus ventilation with even 'normal Vt' can lead to over-distension and VILI. A corollary of this latter concept is that in patients with severe ARDS, regional lung over-distension can occur even if these patients are ventilated with small tidal volumes [94]. The recognition of VILI lead to the concept of "protective ventilation" as many of the pathophysiological consequences of VILI mimic those of ARDS. This development heralded current use of low Vt ventilation strategies with appropriate levels of PEEP to limit lung distention and atelectrauma.
体重被推荐[93]。对多个生理概念的认识改变了这种方法，并导致了当前使用小潮气量的肺保护通气时代：(i) 如果患者氧合良好，高碳酸血症和呼吸性酸中毒是可以耐受的；(ii) 机械通气允许肺单位的去招募和再招募，以及与高肺内压相关的肺单位过度膨胀，可能会加重现有的肺损伤或导致新的肺损伤；(iii) ARDS 患者的有效肺气体容量减少（婴儿肺），因此即使是“正常潮气量”的通气也可能导致过度膨胀和通气相关性肺损伤（VILI）。这一后者概念的一个推论是，在重度 ARDS 患者中，即使这些患者使用小潮气量通气，也可能发生区域性肺过度膨胀[94]。对 VILI 的认识导致了“保护性通气”概念的提出，因为 VILI 的许多病理生理后果与 ARDS 相似。这一发展预示着当前低潮气量通气策略的使用，结合适当水平的 PEEP，以限制肺膨胀和肺不张损伤。
Use of ventilation strategies with low Vt has been shown in animal and human studies to decrease VILI. In the clinical setting, low Vt ventilation is implemented by delivering tidal volumes in the range of predicted body weight (PBW)], without aiming for optimal gas exchange, but accepting gas exchange within safety parameters. Traditionally used approaches to invasive mechanical ventilation have not prioritized limiting VILI but have focused on normalizing arterial blood gases.
使用低潮气量的通气策略已在动物和人类研究中显示可以减少通气相关肺损伤（VILI）。在临床环境中，低潮气量通气是通过提供在预测体重（PBW）范围内的潮气量来实现的，目的是不追求最佳气体交换，而是在安全参数内接受气体交换。传统的侵入性机械通气方法并未优先考虑限制 VILI，而是专注于正常化动脉血气。

We identified seven RCTs, that met our inclusion criteria [28, 95-100], and constituted the basis of these recommendations.
我们确定了七项符合我们纳入标准的随机对照试验 [28, 95-100]，并构成了这些建议的基础。

ARDS was variably defined in the included trials. Whereas one trial included patients with a Lung Injury Score (LIS) and a risk factor for ARDS [96], another trial included patients with a LIS for , bilateral infiltrates, and at least one organ system failure [95]. Other trials included patients based on a ratio with infiltrates in at least 3 out of 4 quadrants on chest radiograph and a risk factor for ARDS [100], with bilateral infiltrates [98], on PEEP of with for 24 h that persisted for at least 24 h [28], on PEEP of with a risk factor for ARDS [97], or with bilateral infiltrates [99].
ARDS 在所包含的试验中有不同的定义。一个试验包括了肺损伤评分（LIS）为 且有 ARDS 风险因素的患者[96]，而另一个试验则包括了 LIS 为 的患者，存在 、双侧浸润以及至少一个器官系统衰竭[95]。其他试验则根据胸部 X 光片上至少有 4 个象限中 3 个象限有浸润的 比率 以及 ARDS 风险因素[100]， 有双侧浸润[98]， 在 PEEP 为 的情况下持续 24 小时且至少持续 24 小时[28]， 在 PEEP 为 的情况下有 ARDS 风险因素[97]，或 有双侧浸润[99]。
The target Vt and airway pressure limits in the intervention and control arms of the included trials were variably defined (see Table 1). Importantly, five trials were stopped early [28, 95, 96, 98, 99]. No randomized trials specifically compared these ventilator approaches in patients with COVID-19.
纳入试验的干预组和对照组中的目标潮气量和气道压力限制定义各异（见表 1）。重要的是，有五项试验提前停止[28, 95, 96, 98, 99]。没有随机试验专门比较这些通气方法在 COVID-19 患者中的效果。
We performed a primary analysis based on studies with moderate to high quality of evidence according to the GRADE method, and a secondary analysis including all the studies.
我们根据 GRADE 方法对中等到高质量证据的研究进行了初步分析，并对所有研究进行了二次分析。
The primary analysis concerning mortality included three trials and found no evidence of difference in mortality, comparing low Vt strategies to high Vt strategies (RR CI value for effect 0.768 ). The analysis of heterogeneity using the measure was inconclusive with an estimate of but substantial imprecision ( CI ranging between 0 and , Cochran's test value ).
主要关于死亡率的分析包括三项试验 ，并未发现低潮气量策略与高潮气量策略在死亡率方面存在差异的证据（相对风险 置信区间 效果值 0.768）。使用 指标的异质性分析结果不确定，估计值为 ，但存在显著的不精确性（ 置信区间在 0 和 之间，Cochran 的 检验 值 ）。
The secondary analysis was consistent with the primary analysis with RR 0.82 ( CI ) value for effect 0.069 . The analysis of heterogeneity bore inconclusive results because of its imprecision, with CI ranging between 0 and 78%, and the Cochran's test value ).
二次分析与主要分析一致，RR 0.82（ CI ） 效应值为 0.069。由于不精确，异质性分析结果不确定， CI 范围在 0%到 78%之间，Cochran 的 检验 值 ）。

Not statistically differences were found investigating ventilator-free days and barotrauma in those trials that provided this information (Supplementary Materials).
在提供此信息的试验中，调查无通气天数和气压损伤时未发现统计学差异（补充材料）。
Although the mortality summary estimate did not achieve statistical significance, in developing our
尽管死亡率摘要估计未达到统计学显著性，但在我们开发过程中

Table 1 Summary of studies comparing low vs high tidal volume ventilation
表 1 低潮气量通气与高潮气量通气比较研究的总结

Vt Tidal Volume, Paw Airway Pressure, PBW Predicted Body Weight, Adjusted Body Weight, PIP Peak airway pressure, Pplat Plateu airway pressure, Driving Pressure, Recruitment Manouver, P Prone Positioning
Vt 潮气量，Paw 气道压力，PBW 预测体重， 调整体重，PIP 峰气道压力，Pplat 平台气道压力， 驱动压力， 招募操作， P 俯卧位
recommendation statements, we considered the extremely strong physiologic rationale underpinning the use of low Vt ventilation based on animal and human studies. We downgraded the evidence for one trial that was not published in full [100]. We also downgraded the evidence for two trials that used an explicit protocol to keep PEEP in the intervention arm above the lower inflection point of the pressure-volume curve [28,96] or at in one trial [28] and permitted the use of RM [96]. Both trials were small, reported few death events, and stopped early for benefit [28, 96]. In developing this recommendation, we also considered that no new trials have published in this area since 2006, tidal volumes were variably calculated using adjusted body weight (ABW), ideal body weight (IBW) and predicted body weight (PBW), and that different gradients were achieved between study arms among the included trials. We also acknowledged that low Vt ventilation strategies may require increased sedation and/or paralysis; these effects, along with those related to permissive hypercapnia, were not explicitly evaluated.
推荐声明中，我们考虑了基于动物和人类研究的低潮气量通气使用的极强生理学依据。我们对一项未完整发表的试验的证据进行了降级[100]。我们还对两项使用明确协议将干预组的 PEEP 保持在压力-体积曲线的下拐点 以上[28,96]或在一项试验中保持在 [28]并允许使用肺复张[96]的试验的证据进行了降级。这两项试验规模较小，报告的死亡事件较少，并因获益而提前停止[28, 96]。在制定这一推荐时，我们还考虑到自 2006 年以来该领域没有新试验发表，潮气量的计算方式不一，使用了调整体重（ABW）、理想体重（IBW）和预测体重（PBW），并且在纳入的试验中，各研究组之间达成了不同的梯度。我们还承认，低潮气量通气策略可能需要增加镇静和/或麻痹；这些影响以及与允许性高碳酸血症相关的影响并未被明确评估。

In the absence of evidence directly related to use of the alternative approaches in COVID-19 patients, we downgraded the recommendation due to indirectness of evidence. However, there is no reason to expect that the underlying physiological rationale which supports the use of low tidal volumes should be different for COVID19 vs. non-COVID-19 ARDS. In developing this recommendation, we considered the balance between patients' values and preferences, desirable and undesirable effects, resource use, acceptability to involved stakeholders, feasibility, and equity.
在缺乏与 COVID-19 患者使用替代方法直接相关的证据的情况下，我们因证据的间接性而降低了推荐级别。然而，没有理由认为支持使用低潮气量的基本生理原理在 COVID-19 与非 COVID-19 急性呼吸窘迫综合症（ARDS）之间会有所不同。在制定这一推荐时，我们考虑了患者的价值观和偏好、期望和不期望的效果、资源使用、相关利益相关者的可接受性、可行性和公平性之间的平衡。

We recommend the use of low tidal volume ventilation strategies
我们建议使用低潮气量通气策略
(i.e., PBW), compared to larger tidal volumes (traditionally used to normalize blood gases), to reduce mortality in patients with ARDS not due to COVID-19.
（即， PBW），与较大的潮气量（传统上用于标准化血气）相比，以降低非 COVID-19 相关 ARDS 患者的死亡率。
Strong recommendation based on expert opinion despite lack of statistical significance; high level of evidence.
基于专家意见的强烈推荐，尽管缺乏统计显著性；证据水平高。
This recommendation applies also to ARDS from COVID-19.
该建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症（ARDS）。
Strong recommendation; moderate level of evidence for indirectness.
强烈推荐；间接性证据的中等水平。

When considering the RCTs, it is important to underscore that Vt was reduced when airway pressure limits (as specified by protocols for the intervention and control arms of each individual trial) were reached. It is also very important to highlight that the Vt used in the control arms can no longer be considered as "conventional", and that no further trials have been conducted in this area for well over a decade. Moreover, it is unlikely that other RCTs will be conducted in the future given a general lack of equipoise in the field regarding this question.
在考虑随机对照试验（RCTs）时，重要的是要强调，当达到气道压力限制（如每个单独试验的干预组和对照组的方案所规定）时，潮气量（Vt）会减少。同样重要的是要指出，对照组使用的潮气量不再被视为“常规”，而且在这个领域已经超过十年没有进行进一步的试验。此外，考虑到在这个问题上领域内普遍缺乏平衡，未来进行其他 RCT 的可能性不大。
At present, the current approach to support patients with ARDS includes limiting Vt to PBW and maintaining plateau airway pressure (Pplat) . Although some investigators use the terms IBW and PBW interchangeably, Vt should be measured and adjusted using PBW.
目前，支持 ARDS 患者的当前方法包括将潮气量（Vt）限制在 理想体重（PBW）并维持平台气道压力（Pplat） 。尽管一些研究者将理想体重（IBW）和理想体重（PBW）交替使用，但潮气量应使用理想体重（PBW）进行测量和调整。

Similarly, it is unlikely that an RCT of low Vt ventilation in COVID-19 related ARDS will be conducted. Although patients with COVID-19 were not included in the RCTs which form the basis of these recommendations, there is biological plausibility for the use of low Vt ventilation in these patients since the underlying respiratory system mechanics are similar [101], and the physiologic mechanisms that underpin the use of low Vt ventilation in non-COVID-19 ARDS are similar. However, the rate of serious and prolonged multidimensional disability, particularly in patients with COVID-19, may be important and may be further exacerbated by the need for prolonged deep sedation with or without paralysis.
同样，进行一项关于 COVID-19 相关 ARDS 的低潮气量通气的随机对照试验（RCT）也不太可能。尽管在形成这些建议基础的 RCT 中并未纳入 COVID-19 患者，但在这些患者中使用低潮气量通气是有生物学合理性的，因为其基础的呼吸系统力学是相似的[101]，而在非 COVID-19 ARDS 中使用低潮气量通气的生理机制也是相似的。然而，严重和长期的多维残疾的发生率，特别是在 COVID-19 患者中，可能是重要的，并且可能因需要长期深度镇静（无论是否伴随麻痹）而进一步加重。

Future studies are needed to evaluate the merits of additional lung-protective strategies (e.g., limited driving pressure or plateau pressure, elastance normalized to PBW, appropriate levels of PEEP) and personalized ventilator targets, particularly the trade-off between tidal volume and respiratory rate to control the overall intensity of mechanical ventilation [102] balanced by the risks of very low tidal volumes (e.g., sedation, dyssynchrony etc.) in patients with lower lung elastance. Long-term multidimensional outcomes for patients and families should be included, and the views of patients and caregivers should be central to determining future research questions and outcomes.
未来需要研究评估额外肺保护策略的优点（例如，限制驱动压或平台压、相对于理想体重的弹性、适当的 PEEP 水平）和个性化通气目标，特别是在潮气量和呼吸频率之间的权衡，以控制机械通气的整体强度[102]，同时考虑到在肺弹性较低的患者中非常低潮气量的风险（例如，镇静、不同步等）。应包括患者和家庭的长期多维结果，患者和护理人员的观点应成为确定未来研究问题和结果的核心。
The key research questions to be addressed in future trials include investigation of: (1) the optimal manner to assess whether a given ventilator strategy is likely to worsen VILI, (2) the manner in which we determine optimal Vt (e.g., based on PBW, on driving pressure, or an alternative approach), (3) personalized lung-protective ventilatory strategies based on the physiology of individual patients, and (4) other approaches to remove if the current ventilator strategy is highly likely to worsen VILI.
未来试验中需要解决的关键研究问题包括： (1) 评估特定通气策略是否可能加重通气相关肺损伤（VILI）的最佳方法， (2) 确定最佳潮气量（Vt）的方法（例如，基于理想体重、驱动压或其他替代方法）， (3) 基于个体患者生理特征的个性化肺保护通气策略，以及 (4) 如果当前通气策略极有可能加重 VILI，去除 的其他方法。

Question 6.1: In patients with ARDS undergoing invasive mechanical ventilation, does routine PEEP titration using a higher strategy compared to a lower strategy reduce mortality?
问题 6.1：在接受侵入性机械通气的 ARDS 患者中，与较低 策略相比，常规 PEEP 调节使用较高 策略是否能降低死亡率？

In patients with ARDS, surfactant dysfunction, effects of gravity on the edematous lung, and heterogeneous injury
在急性呼吸窘迫综合症（ARDS）患者中，表面活性剂功能障碍、重力对水肿肺的影响以及异质性损伤
predispose to regional lung derecruitment with alveolar collapse and small airways closure [103]. The resulting mechanical heterogeneity of the lung, with regional differences in alveolar compliance and distension, is thought to be an important driver of ventilation-induced lung injury in ARDS [104, 105]. Positive end-expiratory pressure may offset these forces, promoting lung recruitment and attenuating mechanical heterogeneity. PEEP is also routinely applied to facilitate adequate oxygenation. Yet, excessive PEEP can exacerbate over-distension, potentially predisposing to hyperinflation lung injury and hemodynamic compromise. The following analyses evaluate randomized clinical trials for effects of various PEEP strategies on mortality, ventilator-free days, barotrauma, and hemodynamic compromise.
倾向于区域性肺部再招募不足，伴随肺泡塌陷和小气道闭合[103]。肺部的机械异质性，伴随肺泡顺应性和扩张的区域差异，被认为是急性呼吸窘迫综合症（ARDS）中通气诱导肺损伤的重要驱动因素[104, 105]。正呼气末压（PEEP）可能抵消这些力量，促进肺部再招募并减轻机械异质性。PEEP 也常规应用于促进足够的氧合。然而，过量的 PEEP 可能加剧过度扩张，潜在地导致肺过度膨胀损伤和血流动力学不稳定。以下分析评估了随机临床试验中各种 PEEP 策略对死亡率、无呼吸机天数、气压损伤和血流动力学不稳定的影响。

Three multi-center randomized clinical trials were identified that compared a higher versus lower PEEP strategy: ALVEOLI [106], LOVS [107], and EXPRESS [108]. ALVEOLI and LOVS each evaluated higher versus lower titration tables, which specified allowable combinations of PEEP and with instructions to target the lowest allowed combination. The EXPRESS trial compared PEEP titrated to achieve a plateau pressure of (herein identified as the higher-PEEP strategy) versus a minimal distension strategy with PEEP adjusted between 5 and (herein identified as the lower PEEP strategy). Four endpoints were considered in our evidence synthesis: efficacy endpoints (mortality and ventilator-free days), and safety endpoints (barotrauma and hemodynamic instability).
我们确定了三项多中心随机临床试验，比较了较高与较低 PEEP 策略：ALVEOLI [106]、LOVS [107] 和 EXPRESS [108]。ALVEOLI 和 LOVS 各自评估了较高与较低 滴定表，规定了 PEEP 和 的允许组合，并指示以目标最低允许组合为准。EXPRESS 试验 比较了 PEEP 滴定以达到 的平台压力（在此称为较高 PEEP 策略）与最小膨胀策略，PEEP 在 5 和 之间调整（在此称为较低 PEEP 策略）。在我们的证据综合中考虑了四个终点：疗效终点（死亡率和无通气天数）和安全终点（气压伤和血流动力学不稳定）。
The primary outcome for all three trials was some formulation of mortality, which was not significantly different in any of the three trials nor in the meta-analysis (pooled risk ratio for hospital mortality 0.93; 95% CI ). Ventilator-free days (VFD) was not pooled since it was only being reported in two trials, one using medians and the other mean values. VFD was not significantly different in ALVEOLI. Though VFD was not reported in LOVS, duration of mechanical ventilation among survivors was not significantly different. In EXPRESS, the higher-PEEP group had significantly more VFD than the lower PEEP group. Incidence of barotrauma did not differ significantly in any of the three trials nor in the meta-analysis (pooled RR 1.17; 95% CI ). Hemodynamic instability was not meta-analyzed due to reporting differences among trials. In ALVEOLI, hemodynamic instability was not reported directly in the primary publication. In LOVS, hemodynamics was reported as days of vasopressor use and number of vasopressors per day in use, and were comparable between groups. In EXPRESS, significantly more patients in the
所有三项试验的主要结果是某种形式的死亡率，在三项试验及荟萃分析中均没有显著差异（医院死亡率的合并风险比为 0.93；95% CI ）。由于只有两项试验报告了无呼吸机天数（VFD），一项使用中位数，另一项使用均值，因此未进行合并分析。ALVEOLI 中 VFD 没有显著差异。尽管 LOVS 中未报告 VFD，但幸存者的机械通气持续时间没有显著差异。在 EXPRESS 中，高 PEEP 组的 VFD 显著多于低 PEEP 组。三项试验及荟萃分析中气压伤的发生率没有显著差异（合并 RR 1.17；95% CI ）。由于试验间报告差异，血流动力学不进行了荟萃分析。在 ALVEOLI 中，主要出版物中未直接报告血流动力学不稳定。在 LOVS 中，血流动力学以使用血管加压药的天数和每天使用的血管加压药数量报告，组间可比。在 EXPRESS 中，显著更多的患者在
higher-PEEP group required fluid loading during the first 72 h ( 75.3 vs. ), but there was no significant difference in patients requiring vasopressor therapy.
高 PEEP 组在前 72 小时内需要液体负荷（75.3 vs. ），但需要使用血管收缩药的患者之间没有显著差异。

We are unable to make a recommendation for or against rou-
我们无法对 rou-做出推荐或反对
tine PEEP titration with a higher PEEP/FiO strategy versus a lower PEEP strategy to reduce mortality in patients with ARDS. No recommendation; high level of evidence of no effect.
在 ARDS 患者中，采用较高 PEEP/FiO 策略与较低 PEEP 策略进行 PEEP 滴定以降低死亡率。没有推荐；高水平证据表明没有效果。
This statement applies also to ARDS from COVID-19.
该声明同样适用于因 COVID-19 引起的急性呼吸窘迫综合症（ARDS）。
No recommendation; moderate level of evidence of no effect for indirectness.
没有推荐；间接性证据显示无效的证据水平适中。

Four randomized clinical trials were identified that compared a mechanics-based PEEP strategy to a standardized PEEP/FiO 2 table: EPVent [109], EPVent-2 [110], Pintado et al. [111], and ART [112]. EPVent was a single-center trial that compared PEEP titrated with an end-expiratory transpulmonary pressure (PL)/ table versus a low PEEP/FiO 2 table. EPVent-2 was a multi-center trial that compared PEEP titrated with a table versus a high table. In EPVent and EPVent-2, transpulmonary pressure was calculated as airway minus pleural pressure, the latter estimated with esophageal manometry. Pintado et al. was a single-center trial that compared PEEP titrated to achieve highest respiratory compliance (i.e., lowest driving pressure, defined as plateau pressure minus total PEEP) versus a low table. ART was a multi-center trial that compared PEEP titrated to above that which achieved highest respiratory compliance versus a low table. Notably, in ART, patients assigned to the complianceguided PEEP strategy also underwent a prolonged high-pressure recruitment maneuver of several minutes duration prior to selecting PEEP, which was thought to directly cause cardiac arrest in at least three trial participants.
识别出四项随机临床试验，比较了基于机械的 PEEP 策略与标准化的 PEEP/FiO2 表：EPVent [109]、EPVent-2 [110]、Pintado 等 [111] 和 ART [112]。EPVent 是一项单中心试验，比较了以呼气末肺内压（PL）/ 表调节的 PEEP 与低 PEEP/FiO2 表。EPVent-2 是一项多中心试验，比较了以 表调节的 PEEP 与高 表。在 EPVent 和 EPVent-2 中，肺内压计算为气道压力减去胸膜压力，后者通过食管测压估算。Pintado 等 是一项单中心试验，比较了调节 PEEP 以实现最高呼吸顺应性（即最低驱动压，定义为平台压减去总 PEEP）与低 表。ART 是一项多中心试验 ，比较了调节 PEEP 以 高于实现最高呼吸顺应性的 PEEP 与低 表。 值得注意的是，在人工呼吸治疗中，接受依从性指导的 PEEP 策略的患者在选择 PEEP 之前，还进行了持续几分钟的高压招募操作，这被认为直接导致至少三名试验参与者心脏骤停。
Mortality was not statistically significant in the EPVent, EPVent-2, or Pintado et al. trials. However, in ART, mortality was significantly higher in the mechanics-based group (RR 1.12; 95% CI 1.00-1.26). The pooled mortality in the meta-analysis was not significant with a mechanics-based PEEP strategy versus a PEEP/FiO 2 table (pooled RR 0.85 ; 95% CI 0.57-1.29).
在 EPVent、EPVent-2 或 Pintado 等试验中，死亡率没有统计学意义。然而，在 ART 中，机械基础组的死亡率显著较高（RR 1.12；95% CI 1.00-1.26）。在荟萃分析中，机械基础 PEEP 策略与 PEEP/FiO 2 表的合并死亡率没有显著性（合并 RR 0.85；95% CI 0.57-1.29）。

Barotrauma did not differ between groups in EPVent, EPVent-2, or Pintado et al. However, in ART, the incidence of barotrauma was significantly greater in the mechanics-based PEEP group (RR 3.56; 95% CI 1.647.73). In pooled analysis, there was no significant difference in barotrauma incidence (pooled RR 1.76, 95% CI ).
在 EPVent、EPVent-2 或 Pintado 等研究中，气压创伤在各组之间没有差异。然而，在 ART 中，机械基础 PEEP 组的气压创伤发生率显著更高（相对风险 3.56；95%置信区间 1.64-7.73）。在合并分析中，气压创伤发生率没有显著差异（合并相对风险 1.76，95%置信区间 ）。
The results of ventilator-free days analyses were inconclusive. The ART trial showed a statistically significant one-day reduction of VFDs, a finding that was not confirmed by EPVent-2. Our secondary analysis based on the meta-analysis of those studies using medians also provided a statistically non-significant result (Supplementary Materials).
通气机无日分析的结果不确定。ART 试验显示 VFDs 减少了一天，具有统计学意义，但 EPVent-2 并未确认这一发现。我们基于对这些研究中位数的荟萃分析的二次分析也提供了统计学上不显著的结果（补充材料）。
Hemodynamic instability was not meta-analyzed due to reporting differences among trials. EPVent did not report measures of hemodynamic instability. In EPVent2, shock-free days did not differ significantly between groups. In the trial by Pintado et al., the mechanics-based PEEP group had significantly less hemodynamic instability (hemodynamic failure-free days, defined as cardiovascular sequential organ failure assessment score ). By contrast, in ART, the mechanics-based PEEP group had significantly more hemodynamic instability (need to initiate or increase vasopressor or mean arterial pressure in the first hour).
由于试验之间的报告差异，血流动力学不稳定性未进行荟萃分析。EPVent 未报告血流动力学不稳定性的指标。在 EPVent2 中，各组之间无休克天数没有显著差异。在 Pintado 等人的试验中，基于机械的 PEEP 组的血流动力学不稳定性显著较少（血流动力学失败无天数，定义为心血管连续器官功能衰竭评估评分 ）。相反，在 ART 中，基于机械的 PEEP 组的血流动力学不稳定性显著较多（在第一小时内需要启动或增加血管收缩药或平均动脉压 ）。

We are unable to make a recommendation for or against PEEP
我们无法对 PEEP 做出推荐或反对的意见
titration guided principally by respiratory mechanics, compared to
主要通过呼吸力学指导的滴定，与之相比
PEEP titration based principally on PEEP/FiO 2 strategy, to reduce mortality in patients with ARDS.
基于 PEEP/FiO2 策略的 PEEP 滴定，旨在降低 ARDS 患者的死亡率。
No recommendation; high level of evidence of no effect.
没有推荐；没有效果的高水平证据。
This statement applies also to ARDS from COVID-19.
该声明同样适用于因 COVID-19 引起的急性呼吸窘迫综合症（ARDS）。
No recommendation; moderate level of evidence for indirectness.
没有推荐；间接性证据的中等水平。

PEEP titration is a potentially important determinant of patient outcomes in ARDS and one for which the optimal strategy remains to be defined. Trials included in the meta-analysis demonstrated both potential for benefit and harm from studied PEEP titration protocols. While some level of PEEP is thought necessary to prevent progressive derecruitment, what constitutes ideal PEEP to attenuate lung injury and avoid hyperinflation is unknown. In patients with more severe hypoxemia, previous meta-analyses showed potential survival benefit in favor of higher-PEEP levels [113, 114]. However, excessive PEEP unequivocally can cause barotrauma and hemodynamic instability (prompting additional fluid resuscitation or vasopressor escalation, with untoward consequences), though what constitutes "excessive PEEP" is not well defined.
PEEP 滴定可能是 ARDS 患者预后一个重要的决定因素，但最佳策略尚待确定。纳入荟萃分析的试验显示，所研究的 PEEP 滴定方案既有潜在的益处，也有危害。虽然认为某种水平的 PEEP 是必要的，以防止逐渐失去肺泡，但理想的 PEEP 水平以减轻肺损伤和避免过度膨胀仍不清楚。在重度低氧血症患者中，以往的荟萃分析显示，较高 PEEP 水平可能有生存益处。然而，过度 PEEP 无疑会导致气压伤和血流动力学不稳定（促使额外的液体复苏或升高血管加压药，带来不良后果），尽管“过度 PEEP”的定义并不明确。

Between-patient differences in severity and pattern of lung injury, lung and chest wall mechanics, tidal volume, positioning, spontaneous breathing effort, cardiac function, intra-vascular volume, and vascular tone all may contribute to variable effects of PEEP. The individual effect of different levels of PEEP may require studies incorporating a recruitability test pre-randomization to test the effect of PEEP in patients with higher potential for lung recruitment. Also, the hemodynamic cost of higher PEEP including the effects on the total volume of fluids administrated needs further data. Similarly, the use of esophageal pressure-guided PEEP and distending pressure will require further studies to balance dependent lung recruitment while limiting overall lung distension and stress and strain of the non-dependent lung. In the absence of these data how best to individualize PEEP in clinical practice remains unclear. Finally, the interactions between radiological distribution of opacities, recruitability, positioning and PEEP levels need to be elucidated.
患者之间在肺损伤的严重程度和模式、肺和胸壁力学、潮气量、体位、自发呼吸努力、心脏功能、血管内容量和血管张力等方面的差异，可能导致 PEEP 效果的变化。不同 PEEP 水平的个体效应可能需要在随机化前进行招募能力测试的研究，以测试在肺招募潜力较高的患者中 PEEP 的效果。此外，较高 PEEP 的血流动力学成本，包括对总输液量的影响，需要进一步的数据。同样，使用食管压力引导的 PEEP 和膨胀压力将需要进一步的研究，以平衡依赖性肺招募，同时限制整体肺膨胀以及非依赖性肺的应力和应变。在缺乏这些数据的情况下，如何在临床实践中个体化 PEEP 仍不清楚。最后，影像学上不透明度的分布、招募能力、体位和 PEEP 水平之间的相互作用需要进一步阐明。

Ventilator recruitment maneuvers, broadly defined, consist of a temporary increase in airway and transpulmonary pressure, to values higher than encountered during tidal ventilation, for the goal of promoting re-aeration of previously gasless regions, i.e., lung recruitment [115]. Because the pressure required to open collapsed lung units generally exceeds closing pressure [116-118], the transient pressure increase with an RM theoretically could be sufficient to achieve a durable increase in endexpiratory lung volume after the RM is completed. The resulting increase in end-expiratory lung volume with an RM may improve gas exchange, homogenize alveolar distension, and decrease lung stress and strain [105, 119], though occurrence and durability of these effects are variable . As a high-pressure maneuver, RMs also may risk complications related to over-distension, including barotrauma, reduced venous return, increase in pulmonary vascular resistance, right ventricular failureleading to hemodynamic collapse. Several potential strategies for performing RMs have been described and differ by duration, pressure target(s), frequency, and ventilator maneuver.
通气机招募操作，广义上定义为暂时增加气道和肺内压力，达到高于潮气通气时的值，目的是促进先前无气区域的再通气，即肺部招募[115]。由于打开塌陷肺单位所需的压力通常超过闭合压力[116-118]，因此，使用招募操作时的瞬时压力增加理论上可能足以在招募操作完成后实现呼气末肺容积的持久增加。招募操作后呼气末肺容积的增加可能改善气体交换，均匀肺泡膨胀，并减少肺部应力和应变[105, 119]，尽管这些效果的发生和持久性是可变的 。作为一种高压操作，招募操作也可能面临与过度膨胀相关的并发症风险，包括气压伤、静脉回流减少、肺血管阻力增加、右心衰竭导致血流动力学崩溃。已经描述了几种进行招募操作的潜在策略，这些策略在持续时间、压力目标、频率和通气机操作上有所不同。

The pre-requisite for RMs to be effective is the prevalence of collapsed but otherwise functional pulmonary units, i.e. units which are "empty" and gasless due to external compressive forces and/or complete gas reabsorption. Recruitment, however, is an umbrella term that includes several realities with different conceptual definitions. Indeed, recruitment has been defined as:
RMs 有效的前提是存在崩溃但仍然功能正常的肺单位，即由于外部压迫力和/或完全气体再吸收而“空”的无气单位。然而，招募是一个涵盖多个现实的总称，具有不同的概念定义。实际上，招募被定义为：

These methods provide largely different recruitment estimates, particularly the imaging-based methods vs. the P-V curve-based method [124]. However, whatever method is used, the common purpose is to achieve open stability of collapsed alveolar units and quantify the resulting anatomical or functional change. PEEP just maintains what has already been opened by a higher opening pressure. The pressures necessary to open the pulmonary units have been reported in few studies in humans with ARDS [116, 117]. The reported opening pressures, as measured by CT scans, have median values between 20 and and range from 10 to 50 , showing a near Gaussian distribution. However, only a small percentage of pulmonary units (about ) open pressures greater than -suggesting limited functional gains in applying pressures above ; such high pressures have a hemodynamic price, often paid with large amounts of fluids and with additional cardiovascular stress, morbidity and mortality. The median of closing pressures is around , but collapse of pulmonary units is already observed at pressures that may exceed .
这些方法提供了大相径庭的招募估计，特别是基于成像的方法与基于 P-V 曲线的方法 [124]。然而，无论使用哪种方法，共同的目的是实现已塌陷肺泡单元的开放稳定性，并量化由此产生的解剖或功能变化。PEEP 仅维持已通过更高开启压力打开的部分。打开肺单元所需的压力在少数关于 ARDS 的人类研究中有所报道 [116, 117]。通过 CT 扫描测得的开启压力的中位值在 20 和 之间，范围从 10 到 50 ，显示出近似高斯分布。然而，只有一小部分肺单元（约 ）的开启压力大于 ，这表明施加高于 的压力所带来的功能收益有限；如此高的压力会带来血流动力学代价，通常需要大量液体，并伴随额外的心血管压力、发病率和死亡率。关闭压力的中位数约为 ，但在可能超过 的压力下，肺单元的塌陷已经被观察到。

These observations lead to the following considerations:
这些观察导致了以下考虑：

All the above considerations and numeric indications refer to the whole respiratory system. A more exact approach would require the partitioning of lung mechanics (i.e., quantify the relative contribution of the chest wall), as the same recruitment airway pressure may have a different effect, depending on the chest wall elastance.
上述所有考虑和数值指示均涉及整个呼吸系统。更精确的方法需要对肺力学进行分区（即量化胸壁的相对贡献），因为相同的招募气道压力可能会产生不同的效果，这取决于胸壁的弹性。
The analysis evaluated randomized clinical trials that assigned patients to undergo an RM versus no RM for their effects on mortality, ventilator-free days, barotrauma, and hemodynamic instability.
该分析评估了随机临床试验，这些试验将患者分配接受 RM 与不接受 RM 对死亡率、无呼吸机天数、气压损伤和血流动力学不稳定性的影响。

A prolonged high-pressure RM was defined as a strategy intended to facilitate lung recruitment in which airway pressure of was maintained for at least one minute. Five trials were included which evaluated the effects of a prolonged high-pressure RM, versus no such maneuver, on hospital mortality. Hodgson et al. in [128] and in 2019 (PHARLAP trial, ) [129] evaluated a prolonged "staircase" RM in which PEEP was set to 20,30, and then for 2 min each, followed by a decremental PEEP titration to or until desaturation; the comparison group received no RM and a low strategy. Kung et al. [130] evaluated an RM in which PEEP was set to for two minutes followed by decremental PEEP titration until maximum compliance was identified; the comparison group received no RM and a low PEEP/ strategy. Chung et al. [131] evaluated an RM consisting of raising PEEP from 10 to in increments of , with 40 seconds at each recruitment, followed by a decremental PEEP titration; the comparison group received no RM. The ART trial [112] initially evaluated a "staircase" RM in which PEEP was set to for one minute, for one minute, and then for two minutes, followed by a decremental PEEP titration; the comparison group received no RM and a low strategy. The ART RM strategy was modified halfway through enrollment to a less aggressive RM due to three cardiac arrests attributed to the intervention. The ART trial was considered the highest quality among included trials. One additional potentially eligible trial [132] was excluded from analyses
一种延长的高压肺复张（RM）被定义为一种旨在促进肺部招募的策略，其中气道压力保持在 至少一分钟。包括五个试验，评估了延长高压 RM 与不进行此操作对医院死亡率的影响。Hodgson 等人在 [128]和 2019 年（PHARLAP 试验， ）[129]评估了一种延长的“楼梯”RM，其中 PEEP 设置为 20、30，然后为 ，每个阶段持续 2 分钟，随后进行递减 PEEP 滴定至 或直到去饱和；对照组未进行 RM，采用低 策略。Kung 等人 [130]评估了一种 RM，其中 PEEP 设置为 ，持续两分钟，然后进行递减 PEEP 滴定，直到识别出最大顺应性；对照组未进行 RM，采用低 PEEP/ 策略。Chung 等人 [131]评估了一种 RM，PEEP 从 10 提高到 ，每次增加 ，每次招募持续 40 秒，随后进行递减 PEEP 滴定；对照组未进行 RM。 ART 试验 [112]最初评估了一种“阶梯”呼吸机操作（RM），其中 PEEP 设置为 持续一分钟， 持续一分钟，然后 持续两分钟，随后进行递减 PEEP 滴定；对照组未接受 RM，而是采用低 策略。由于有三例心脏骤停与该干预相关，ART RM 策略在入组过程中被修改为一种不那么激进的 RM。ART 试验被认为是所包含试验中质量最高的。一个额外的潜在合格试验[132]被排除在分析之外
as it enrolled only burn patients with ARDS, a unique, population thought not to be generalizable. When considering the impact of the intervention on ICU mortality, five trials were included; the trial by Chung not reporting this outcome was excluded, while the trial by Huh et al. not included in the hospital mortality meta-analysis was included.
由于它仅招募了患有急性呼吸窘迫综合症（ARDS）的烧伤患者，这一独特人群被认为不可推广。在考虑干预对重症监护室（ICU）死亡率的影响时，纳入了五个试验；未报告该结果的 Chung 试验被排除，而 Huh 等人的试验虽然未纳入医院死亡率的荟萃分析，但被纳入。
The ART was the only trial meeting moderate-high quality standards and entering the primary analysis. In this study, the analysis of mortality at different time points provided non homogeneous findings (Supplementary Materials), but there was a suspicion of increased mortality at 6 months. However, combined in the metaanalysis (our secondary analysis), the intervention showed neither harmful nor beneficial effects on mortality. The analysis of heterogeneity was inconclusive.
ART 是唯一一项符合中等至高质量标准并进入主要分析的试验。在这项研究中，不同时间点的死亡率分析提供了不均匀的结果（补充材料），但在 6 个月时有增加死亡率的怀疑。然而，在荟萃分析中（我们的次要分析），干预对死亡率既没有有害也没有有益的影响。异质性分析结果不确定。