ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies ESICM 急性呼吸窘迫综合征指南:定义、表型和呼吸支持策略
Giacomo Grasselli 1, , Carolyn S. Calfee , Luigi Camporota , Daniele Poole , Marcelo B. P. Amato , 贾科莫·格拉塞利 1, , 卡罗琳·S·卡尔菲 , 卢伊吉·坎波罗塔 , 达尼埃尔·普尔 , 马塞洛·B·P·阿马托 ,Massimo Antonelli , Yaseen M. Arabi , Francesca Baroncelli , Jeremy R. Beitler , Giacomo Bellani , 马西莫·安东内利 ,亚辛·阿拉比 ,弗朗西斯卡·巴罗切利 ,杰里米·R·贝特勒 ,贾科莫·贝拉尼 ,Geoff Bellingan , Bronagh Blackwood , Lieuwe D. J. Bos , Laurent Brochard , Daniel Brodie , 杰夫·贝林根 ,布朗娜·布莱克伍德 ,利乌韦·D·J·博斯 ,洛朗·布罗查德 ,丹尼尔·布罗迪 ,Karen E. A. Burns , Alain Combes , Sonia D’Arrigo , Daniel De Backer , Alexandre Demoule , 凯伦·E·A·伯恩斯 ,阿兰·孔布 ,索尼娅·达里戈 ,丹尼尔·德·巴克 ,亚历山大·德穆尔 ,Sharon Einav , Eddy Fan , Niall D. Ferguson , Jean-Pierre Frat , Luciano Gattinoni , 香农·艾纳夫 , 艾迪·范 , 尼尔·D·弗格森 , 让-皮埃尔·弗拉特 , 卢西亚诺·加蒂诺尼 Claude Guérin , Margaret S. Herridge , Carol Hodgson , Catherine L. Hough , Samir Jaber , 克劳德·盖兰 , 玛格丽特·S·赫里奇 , 卡罗尔·霍奇森 , 凯瑟琳·L·霍夫 , 萨米尔·贾贝尔 Nicole P. Juffermans , Christian Karagiannidis , Jozef Kesecioglu , Arthur Kwizera , John G. Laffey , 妮可·P·尤弗曼斯 ,克里斯蒂安·卡拉基安尼迪斯 ,约瑟夫·凯塞乔格鲁 ,阿瑟·库维泽拉 ,约翰·G·拉菲 ,Jordi Mancebo , Michael A. Matthay , Daniel F. McAuley , Alain Mercat , Nuala J. Meyer , Marc Moss , 乔尔迪·曼塞博 , 迈克尔·A·马塔伊 , 丹尼尔·F·麦考利 , 阿兰·梅尔卡特 , 努阿拉·J·迈耶 , 马克·莫斯 ,Laveena Munshi , Sheila N. Myatra , Michelle Ng Gong , Laurent Papazian , Bhakti K. Patel , 拉维娜·穆恩希 ,希拉·N·米亚特拉 ,米歇尔·吴·龚 ,洛朗·帕帕齐安 ,巴克提·K·帕特尔 ,Mariangela Pellegrini , Anders Perner , Antonio Pesenti , Lise Piquilloud , Haibo Qiu , Marco V. Ranier , 玛丽安吉拉·佩莱格里尼 ,安德斯·佩尔纳 ,安东尼奥·佩森蒂 ,莉丝·皮基卢 ,邱海波 ,马尔科·V·拉尼尔 ,Elisabeth Riviello , Arthur S. Slutsky , Renee D. Stapleton , Charlotte Summers , Taylor B. Thompson , 伊丽莎白·里维耶洛 ,亚瑟·S·斯卢茨基 ,瑞妮·D·斯塔普尔顿 ,夏洛特·萨默斯 ,泰勒·B·汤普森 ,Carmen S. Valente Barbas , Jesús Villar 24,75,76, Lorraine B. Ware , Björn Weiss , Fernando G. Zampieri , 卡门·S·瓦伦特·巴尔巴斯 ,赫苏斯·比利亚尔 24,75,76,洛雷恩·B·韦尔 ,比约恩·韦斯 ,费尔南多·G·赞皮耶里 ,Elie Azoulay and Maurizio Cecconi on behalf of the European Society of Intensive Care Medicine 埃利·阿祖莱 和 毛里齐奥·切科尼 代表欧洲重症医学会Taskforce on ARDS ARDS 工作组
(c) 2023 The Author(s) (c) 2023 作者(s)
Abstract 摘要
The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 这些指南的目的是更新 2017 年欧洲重症医学学会(ESICM)的临床实践指南(CPG)。该 CPG 的范围仅限于成人患者以及针对急性呼吸窘迫综合症(ARDS)不同方面的非药物呼吸支持策略,包括因 2019 冠状病毒病(COVID-19)引起的 ARDS。这些指南由一国际临床专家小组、一名方法学家和患者代表代表 ESICM 制定。审查遵循了系统评价和荟萃分析的优先报告项目(PRISMA)声明的建议。我们采用了推荐评估、发展和评价的分级(GRADE)方法来评估证据的确定性、分级推荐以及根据 EQUATOR(提升健康研究的质量和透明度)网络指南报告每项研究的质量。该 CPG 涉及
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
Introduction 介绍
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。
Methods 方法
Topic and panel composition 主题和小组组成
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。
Research question selection and literature search 研究问题选择与文献检索
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。
Formulation of recommendations and consensus methodology 建议和共识方法的制定
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。
Domain 1: ARDS definition 领域 1:ARDS 定义
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。
Domain 2: ARDS phenotyping 领域 2:ARDS 表型分析
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]。
Question 2.1: How do we define an ARDS sub-phenotype? 问题 2.1:我们如何定义 ARDS 亚表型?
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。
Question 2.2: How do we identify or operationalize an ARDS sub-phenotype? 问题 2.2:我们如何识别或操作化 ARDS 亚表型?
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]。
Does sub-phenotyping alter patient response to PEEP interventions in ARDS? 亚表型是否会改变 ARDS 患者对 PEEP 干预的反应?
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。
Does sub-phenotyping alter patient response to fluid strategies in ARDS? 亚表型是否会改变 ARDS 患者对液体策略的反应?
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。
Question 2.4: How does sub-phenotyping relate to patient outcome (prognostic enrichment)? 问题 2.4:亚表型与患者结果(预后丰富性)之间有什么关系?
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)
Systemic inflammatory response gauged by plasma proteins (higher mortality in hyper-inflammatory than in hypo-inflammatory) [31, 34]; 通过血浆蛋白评估的全身性炎症反应(高炎症状态下的死亡率高于低炎症状态)[31, 34];
Lung radiographic morphology (higher mortality in non-focal than in focal) [38]; 肺部放射学形态(非局灶性比局灶性死亡率更高)[38];
Recruitability (higher mortality in recruitable than in non-recruitable) ; 可招募性(可招募者的死亡率高于不可招募者) ;
Clinical features (higher mortality with more organ failure and/or comorbidities and/or acidosis) [47]; 临床特征(更高的死亡率伴随更多的器官衰竭和/或合并症和/或酸中毒)[47];
Longitudinal changes in respiratory parameters (higher mortality in upwards trajectory of ventilatory ratio and mechanical power than in steady trajectory) [45] 呼吸参数的纵向变化(通气比和机械功率上升轨迹的死亡率高于稳定轨迹)[45]
Question 2.5: What are the research questions related to the use of sub-phenotyping for future trials? 问题 2.5:与未来试验中使用亚表型相关的研究问题是什么?
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。
Domain 3: High-flow nasal oxygen 领域 3:高流量鼻氧气
Abstract 摘要
Question 3.1: In non-mechanically ventilated patients with acute hypoxemic respiratory failure not due to cardiogenic pulmonary edema or acute exacerbation of chronic obstructive pulmonary disease (COPD), does HFNO compared to conventional oxygen therapy (COT) reduce mortality or intubation? 问题 3.1:在非机械通气的急性缺氧性呼吸衰竭患者中,如果不是由于心源性肺水肿或慢性阻塞性肺疾病(COPD)的急性加重,HFNO 与常规氧疗(COT)相比,是否能降低死亡率或插管率?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 3.1 推荐 3.1
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。
Expert opinion on clinical application 临床应用的专家意见
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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?
Background 背景
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 。
Summary of the evidence 证据摘要
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 )。
Recommendation 3.2 推荐 3.2
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。
Expert opinion on clinical application 临床应用的专家意见
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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。
Domain 4: CPAP/NIV 领域 4:CPAP/NIV
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?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 4.1 推荐 4.1
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 4.2 推荐 4.2
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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。
Question 4.3: In patients with AHRF, does NIV as compared to CPAP reduce mortality or intubation? 问题 4.3:在急性呼吸衰竭患者中,与 CPAP 相比,非侵入性通气(NIV)是否能降低死亡率或插管率?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 4.3 推荐 4.3
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。
Expert opinion on clinical application 临床应用的专家意见
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 5.1 推荐 5.1
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。
Expert opinion on clinical application 临床应用的专家意见
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。
Unresolved questions and research gaps 未解决的问题和研究空白
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。
Domain 6: PEEP and recruitment maneuvers 领域 6:PEEP 和招募手段
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?
Background 背景
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。
Summary of the evidence 证据摘要
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。
Recommendation 6.1 推荐 6.1
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。
Question 6.2: In patients with ARDS undergoing invasive mechanical ventilation, does routine PEEP titration based principally on respiratory mechanics compared to PEEP titration based principally on a standardized PEEP/FiO 2 table reduce mortality? 问题 6.2:在接受侵入性机械通气的 ARDS 患者中,基于呼吸力学的常规 PEEP 调整与基于标准化 PEEP/FiO2 表的 PEEP 调整相比,是否能降低死亡率?
Summary of the evidence 证据摘要
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 )。
Recommendation 6.2 推荐 6.2
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。
Expert opinion on clinical application: PEEP titration in ARDS 临床应用的专家意见:ARDS 中的 PEEP 滴定
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。
Unresolved questions and research gaps: PEEP titration in ARDS 未解决的问题和研究空白:ARDS 中的 PEEP 滴定
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。
Question 6.3: In patients with ARDS undergoing invasive mechanical ventilation, does use of prolonged high-pressure recruitment maneuvers, compared to not using prolonged high-pressure RMs, reduce mortality? 问题 6.3:在接受侵入性机械通气的 ARDS 患者中,与不使用持续高压招募手段相比,使用持续高压招募手段是否能降低死亡率?
Background 背景
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。
Pathophysiological considerations 病理生理学考虑
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:
Re-aeration of previously gasless pulmonary units (CT scan) [120]; 重新通气之前无气体的肺单位(CT 扫描)[120];
Re-aeration of previously gasless and poorly aerated pulmonary units (CT scan) [121]; 重新通气之前无气体且通气不良的肺单位(CT 扫描)[121];
Difference between expected respiratory compliance vs measured after PEEP increased (double pressurevolume, P-V curves) [122]; 期望的呼吸顺应性与 PEEP 增加后测得的呼吸顺应性之间的差异(双压力-体积曲线,P-V 曲线)[122];
Modifications of different lung ultrasound score (LUS) entities, assessed by a semi-quantitative score [123]. 不同肺部超声评分(LUS)实体的修改,通过半定量评分进行评估[123]。
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:
If the plateau pressure is maintained at , a portion of the pulmonary units opened during recruitment maneuvers at pressures higher than the plateau pressure will unavoidably collapse again. This process is associated with deterioration in gas exchange and possible atelectrauma until their collapse is fully established. To keep the lung fully open after recruitment at a pressure of , PEEP values greater than are necessary[125, 126]. 如果将平台压力维持在 ,在高于平台压力的压力下,通过招募手段打开的部分肺单位将不可避免地再次塌陷。这个过程与气体交换的恶化和可能的肺不张损伤相关,直到它们的塌陷完全建立。在以 的压力进行招募后,为了保持肺部完全开放,需要大于 的 PEEP 值[125, 126]。
During ultra-protective lung ventilation, a Pplat lower than may encourage progressive lung collapse of the units previously opened by RM performed at pressures greater than . 在超保护性肺通气期间,Pplat 低于 可能会促使之前在压力大于 下通过 RM 打开的肺单位逐渐塌陷。
In physiological studies, intermittent 'sighs' have been shown to counteract the lung collapse occurring in lung-protective strategies [127]. 在生理研究中,间歇性的“叹息”已被证明可以对抗在肺保护策略中发生的肺部塌陷[127]。
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。
Summary of the evidence 证据摘要
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。
The analysis of barotrauma, instead, showed an outlier position of the ART trial, with a clear harmful effect (RR 3.56, 95% CI 1.64-7.73), quite different from the other trials combined in a separate meta-analysis (RR 0.60, 95% CI 0.25-1.41) (see Supplementary Materials). This finding strongly supported our recommendation against the use of recruitment high-pressure recruitment maneuvers. 气压损伤的分析显示,ART 试验的结果明显偏离,具有明显的有害效应(RR 3.56,95% CI 1.64-7.73),与在单独的荟萃分析中结合的其他试验(RR 0.60,95% CI 0.25-1.41)截然不同(见补充材料)。这一发现强烈支持我们反对使用高压招募手法的建议。
VFDs were reported by three trials [112, 129, 130]. We based our primary analysis on the ART trial [112] which showed a significant reduction in the mean number of VFD in the intervention arm, given that the other two trials reported medians and interquartile ranges and thus could not be meta-analyzed with the ART trial. 有三项试验报告了 VFD [112, 129, 130]。我们将主要分析基于 ART 试验 [112],该试验显示干预组的 VFD 平均数量显著减少,而其他两项试验报告的是中位数和四分位数范围,因此无法与 ART 试验进行荟萃分析。
Recommendation 6.3 推荐 6.3
We recommend against use of prolonged high-pressure 我们建议避免长时间使用高压
recruitment maneuvers (defined as airway pressure maintained for at least one minute) to reduce mortality of patients with ARDS. 招募手段(定义为气道压力维持在 至少一分钟)以降低 ARDS 患者的死亡率。
Strong recommendation; moderate level of evidence against. 强烈推荐;中等水平的反对证据。
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; low level of evidence against for indirectness. 强烈推荐;间接性证据水平低。
Question 6.4: In patients with ARDS undergoing invasive mechanical ventilation, does routine use of brief high-pressure recruitment maneuvers, compared to no use of brief high-pressure recruitment maneuvers, reduce mortality? 问题 6.4:在接受侵入性机械通气的 ARDS 患者中,与不使用短暂高压招募手法相比,常规使用短暂高压招募手法是否能降低死亡率?
Summary of the evidence 证据摘要
A brief high-pressure RM was defined as a strategy intended to facilitate lung recruitment in which airway pressure of was maintained for less than one minute. Three trials were included in analyses. Kacmarek et al. [133] compared a series of two brief RMs (transient increase in PEEP to ) interspersed with a decremental PEEP trial versus no RM with a low PEEP/FiO 2 table. LOVS [107] utilized a single brief RM ( breath hold for 40 seconds; subsequent RMs allowed for ventilator circuit disconnect) with a high table compared to no RM with a low PEEP/FiO 2 table. Xi et al. [134] compared a brief RM ( breath hold for 40 seconds) repeated every 8 hours for up to five days versus no RM. The trial by Xi et al. did not standardize PEEP in either group, and was thus considered separately. 简短的高压呼吸机复苏(RM)被定义为一种旨在促进肺部复张的策略,其中气道压力保持在 ,持续时间少于一分钟。分析中包括了三项试验。Kacmarek 等人 [133] 比较了一系列两次简短的 RM(PEEP 暂时增加至 )与低 PEEP/FiO2 表的无 RM 试验交替进行。LOVS [107] 使用了一次简短的 RM( 屏气 40 秒;后续 RM 允许断开呼吸机回路),与低 PEEP/FiO2 表的无 RM 进行比较。Xi 等人[134] 比较了一次简短的 RM( 屏气 40 秒),每 8 小时重复一次,持续最多五天,与无 RM 进行比较。Xi 等人的试验在任何组中都没有标准化 PEEP,因此被单独考虑。
Mortality did not differ significantly between treatment groups in any of the three trials individually, nor in metaanalysis pooling the two trials with standardized PEEP (pooled RR 0.89; 95% CI 0.77-1.04). VFDs did not differ significantly between treatment groups in Kacmarek et al. or Xi et al. VFD was not reported in LOVS. 在三个试验中,治疗组之间的死亡率没有显著差异,也在对两个使用标准化 PEEP 的试验进行的荟萃分析中(合并相对风险 0.89;95%置信区间 0.77-1.04)。在 Kacmarek 等和 Xi 等的研究中,治疗组之间的 VFD 没有显著差异。在 LOVS 中未报告 VFD。
Barotrauma did not differ significantly between treatment groups in any of the three trials individually, nor in meta-analysis pooling the two trials with standardized PEEP (pooled RR 1.14; 95% CI 0.81-1.62). 在三个试验中,治疗组之间的气压创伤没有显著差异,进行标准化 PEEP 的两个试验的荟萃分析也没有显著差异(合并相对风险 1.14;95%置信区间 0.81-1.62)。
Considering hemodynamic instability, in Kacmarek et al. there was no significant difference in incidence of hypotension, arrhythmia, or cardiac arrest. In LOVS, hemodynamics was reported as days of vasopressor use and number of vasopressors per day in use and were comparable between groups. Hemodynamic effects were not well characterized in Xi et al. 考虑到血流动力学不稳定,Kacmarek 等人的研究中低血压、心律失常或心脏骤停的发生率没有显著差异。在 LOVS 中,血流动力学被报告为使用血管收缩药的天数和每天使用的血管收缩药数量,且在各组之间是可比的。Xi 等人的研究中血流动力学效应没有得到很好的表征。
Absence of evidence in favor or against the use of recruitment maneuvers, the potential safety issues led to a weak recommendation against their routine use. 由于缺乏支持或反对使用招募手段的证据,以及潜在的安全问题,导致对其常规使用提出了弱推荐。
Recommendation 6.4 推荐 6.4
We suggest against routine use of brief high-pressure recruitment maneuvers (defined as airway pressure maintained for less than one minute) to reduce mortality in patients with ARDS. 我们建议不要常规使用短时间高压招募手段(定义为气道压力维持在 以下一分钟)来降低 ARDS 患者的死亡率。
Weak recommendation; high level of evidence of no effect. 弱推荐;没有效果的高水平证据。
This suggestion 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)。
Weak recommendation; moderate level of evidence of no effect for indirectness. 弱推荐;间接性无效的证据水平适中。
Expert opinion on clinical application of recruitment maneuvers 专家对招募手段临床应用的意见
Hypotension and desaturation are the most common adverse events described during or immediately after an RM, each occurring in roughly of patients undergoing an RM [119]. Bradycardia, presumably vagally mediated, also may occur [135]. Clinical trial data indicate prolonged high-pressure RMs increase risks, leading not only to hemodynamic instability but increased risk of barotrauma and cardiac arrest [112]. These clinically 低血压和脱饱和是进行或紧接着进行 RM 时最常见的不良事件,每种情况大约发生在 的 RM 患者中[119]。心动过缓,可能是迷走神经介导的,也可能发生[135]。临床试验数据表明,持续的高压 RM 增加风险,不仅导致血流动力学不稳定,还增加气压损伤和心脏骤停的风险[112]。这些临床上
important risks outweigh potential benefits and led to the recommendation against their use. 重要风险超过潜在好处,因此建议不使用它们。
Brief high-pressure RMs also may produce transient, potentially reversible hypotension and bradycardia [115, 135] which can result from acute right heart failure. Existing data do not support routine use of brief RMs, likely because lung mechanical effects from briefly raising airway pressure are transient unless accompanied by other maneuvers to prevent progressive collapse [136]. Nevertheless, brief RMs may have a limited role in attempt to reverse hypoxemia in situations where desaturation is likely caused by derecruitment, for example after ventilator disconnect, suctioning, bronchoscopy or patient repositioning. If performed, brief high-pressure RMs should only be done with a plan to abort the maneuver immediately if cardiovascular instability ensues. 短暂的高压呼吸机复苏(RMs)也可能导致短暂的、潜在可逆的低血压和心动过缓,这可能是由急性右心衰竭引起的。现有数据不支持常规使用短暂的 RMs,这可能是因为短时间内提高气道压力所产生的肺机械效应是短暂的,除非伴随其他措施以防止逐渐塌陷。然而,短暂的 RMs 在试图逆转低氧血症的情况下可能有有限的作用,例如在通气机断开、吸痰、支气管镜检查或患者重新定位后,如果进行短暂的高压 RMs,应该有计划立即中止该操作,以防出现心血管不稳定。
Unresolved questions and research gaps 未解决的问题和研究空白
Brief recruitment maneuvers in the form of "sigh" breaths, performed periodically one or more times every few minutes, may prevent progressive derecruitment that can occur with low airway pressure, low tidal volume ventilation [127, 137]. Whether such periodic maneuvers attenuate ventilation-induced lung injury or pose safety risks, how often they might need to be performed to afford such lung protection (if any), and in whom they might afford benefit based on potential for lung recruitment all warrant further investigation. 定期进行“叹气”式的简短招募动作,每几分钟一次或多次,可能会防止在低气道压力和低潮气量通气下发生的逐渐失招募[127, 137]。这些周期性动作是否能减轻通气引起的肺损伤或带来安全风险,以及为了提供这种肺保护(如果有的话)需要多频繁进行这些动作,和在何种情况下可能带来益处,基于肺招募的潜力,都需要进一步研究。
Domain 7: Prone positioning 领域 7:俯卧位
Question 7.1: In intubated patients with ARDS, does prone position compared to supine position reduce mortality? 问题 7.1:在插管的 ARDS 患者中,与仰卧位相比,俯卧位是否能降低死亡率?
Background 背景
Prone position was proposed for patients with acute hypoxemic respiratory failure and ARDS in the 1970s. Physiological benefits include improvement of oxygenation, better homogenization of lung stress, and decreased right ventricular strain. Over the years, several trials were conducted comparing prone to supine position, with improved designs on the basis of the critical analysis of previous ones [138-144]. Thus, progressively more hypoxemic patients were selected, the duration of prone ventilation cycles increased, and protective ventilation was combined with pronation. In 2013, the PROSEVA trial demonstrated a clear protective effect of prone ventilation in patients with moderate-to-severe ARDS [9]. In 2017, the ESICM and the American Thoracic Society (ATS) provided recommendations for the use of prone ventilation in ARDS [13] based on both aggregated and individual patient data meta-analysis 俯卧位在 1970 年代被提议用于急性低氧性呼吸衰竭和急性呼吸窘迫综合症(ARDS)患者。生理益处包括改善氧合、肺部应力的更好均匀化以及右心室负担的减少。多年来,进行了几项比较俯卧位与仰卧位的试验,基于对之前试验的关键分析进行了改进设计。因此,逐渐选择了更多低氧血症患者,俯卧通气周期的持续时间增加,并且保护性通气与俯卧位结合在一起。2013 年,PROSEVA 试验证明了俯卧通气在中度至重度 ARDS 患者中的明显保护作用。2017 年,欧洲重症监护医学会(ESICM)和美国胸科学会(ATS)基于汇总和个体患者数据的荟萃分析,提供了在 ARDS 中使用俯卧通气的建议。
[10] that included the largest four trials [138, 139, 143, 144]. In the aggregated data meta-analysis, the overall result was non-significant; however, in studies that used duration of proning longer than twelve hours or included patients with , a statistically significant mortality reduction was found. The individual patient meta-analysis [10] identified a survival benefit in patients with . However, this subgroup analysis did not allow any definitive conclusion since the benefits of randomization are not maintained in subgroups (and only one study stratified patients according to the degree of hypoxemia [144]). In general, subgroup analyses in meta-analysis have an exploratory nature, and results should be interpreted cautiously. There were no RCTs identified specifically addressing proning of mechanically ventilated patients in COVID-19. [10] 包括了最大的四个试验 [138, 139, 143, 144]。在汇总数据的荟萃分析中,整体结果并不显著;然而,在使用俯卧位超过十二小时或包括患者 的研究中,发现了统计学上显著的死亡率降低。个体患者的荟萃分析 [10] 确定了 患者的生存获益。然而,这一亚组分析并未得出任何明确的结论,因为随机化的好处在亚组中并未保持(且仅有一项研究根据低氧血症的程度对患者进行了分层 [144])。一般来说,荟萃分析中的亚组分析具有探索性,结果应谨慎解读。没有识别出专门针对 COVID-19 中机械通气患者俯卧位的随机对照试验。
Summary of the evidence 证据摘要
We based our analysis on the eight trials selected in the previous 2017 guidelines since no further trials on this topic have been conducted since. However, we excluded the 2004 trial that was not restricted to ARDS [139]. Meta-analysis was conducted for the outcome of shortterm mortality, defined as either at 28 days or in the ICU, and separately for 90 -days mortality. 我们基于 2017 年指南中选择的八项试验进行分析,因为自那时以来没有进行进一步的相关试验。然而,我们排除了 2004 年的试验,因为该试验并不局限于 ARDS [139]。我们对短期死亡率的结果进行了荟萃分析,短期死亡率定义为 28 天内或在 ICU 内的死亡率,并单独分析了 90 天的死亡率。
Relevant clinical heterogeneity was found among the studies in terms of modality of ventilation, dose of daily prone ventilation, patient selection, and timing of application of prone positioning. 在研究中发现相关的临床异质性,包括通气方式、每日俯卧通气的剂量、患者选择和俯卧位应用的时机。
Short-term mortality did not differ between prone and supine position (RR 0.79 95% CI [0.61-1.03]). In the subgroup of the first five trials, the short-term mortality did not differ between supine and prone positioning ( 0.91 [0.77-1.08]). However, the short-term mortality was significantly lower in the prone positioning group of the PROSEVA trial ( , with a statistically significant interaction test (supplement materials). 短期死亡率在俯卧位和仰卧位之间没有差异(RR 0.79 95% CI [0.61-1.03])。在前五个试验的亚组中,仰卧位和俯卧位之间的短期死亡率没有差异(0.91 [0.77-1.08])。然而,在 PROSEVA 试验的俯卧位组中,短期死亡率显著较低( ),并且有统计学显著的交互作用检验(补充材料)。
Longer-term mortality did not differ between prone and supine position ( 0.81 [0.64-1.02]). In the subgroup of the first five trials the longer-term mortality did not differ ( 0.93 [0.79-1.09]). 90-days mortality was significantly improved by proning in the PROSEVA trial ( . In this case as well the interaction test turned out to be statistically significant. The unique findings of the PROSEVA trial were further highlighted by a cumulative meta-analysis that investigated the results of meta-analyses carried over time (Supplementary Materials). Further, the analysis of heterogeneity performed using the double-p plot approach [145], identified the PROSEVA trial as a clear outlier. 长期死亡率在俯卧位和仰卧位之间没有差异(0.81 [0.64-1.02])。在前五个试验的亚组中,长期死亡率也没有差异(0.93 [0.79-1.09])。在 PROSEVA 试验中,90 天死亡率通过俯卧位显著改善( )。在这种情况下,交互作用检验也显示出统计学意义。PROSEVA 试验的独特发现通过一项累积的荟萃分析得到了进一步强调,该分析调查了随时间推移的荟萃分析结果(补充材料)。此外,使用双 P 图方法进行的异质性分析[145],将 PROSEVA 试验识别为明显的异常值。
Our primary analysis was thus based on the individual evaluation of findings from the PROSEVA trial. The secondary analysis included, instead, all the trials. 我们的主要分析基于对 PROSEVA 试验结果的个体评估。相反,次要分析包括所有试验。
Recommendation 7.1 推荐 7.1
We recommend using prone position as compared to supine position for patients with moderate-severe ARDS (defined as and , despite optimization of ventilation settings) to reduce mortality. 我们建议对于中重度急性呼吸窘迫综合症(定义为 和 ,尽管通气设置已优化)患者,使用俯卧位而非仰卧位,以降低死亡率。
Strong recommendation, high level of evidence in favor. 强烈推荐,证据水平高。
This recommendation applies also to ARDS from COVID-19. Strong recommendation; moderate level of evidence in favor for indirectness. 该建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。强烈推荐;间接证据的支持程度为中等。
Expert opinion on clinical application 临床应用的专家意见
The overall risk-benefit balance favors prone position used according to the PROSEVA trial criteria, particularly given that its application is feasible in most ICUs with adequately skilled and staffed caregivers when paying careful attention to the risk of pressure-related skin complications. 整体风险收益平衡支持根据 PROSEVA 试验标准使用俯卧位,特别是考虑到在大多数具备足够技能和人员的 ICU 中应用是可行的,同时需仔细关注与压力相关的皮肤并发症风险。
Unresolved questions and research gaps 未解决的问题和研究空白
It is unlikely that a trial comparing prone to supine will be conducted in moderate-severe COVID-related ARDS given the lack of equipoise in the field at present. A trial is ongoing in France in adult intubated patients with mild to moderate ARDS (NCT05056090). 在目前该领域缺乏平衡的情况下,比较俯卧位与仰卧位的试验在中重度 COVID 相关 ARDS 中不太可能进行。法国正在对轻度至中度 ARDS 的成年插管患者进行一项试验(NCT05056090)。
Question 7.2: In patients with moderate-severe ARDS, when should prone positioning be started to reduce mortality? 问题 7.2:在中度至重度 ARDS 患者中,何时应开始俯卧位以降低死亡率?
Background 背景
No specific trial was designed to explore the role of predetermined criteria in the decision to start prone position. Therefore, the evidence used for this question is the same as that for previous the question. 没有专门的试验设计来探讨预定标准在决定开始俯卧位中的作用。因此,用于这个问题的证据与之前问题的证据相同。
Recommendation 7.2 推荐 7.2
We recommend starting prone position in patients with ARDS receiving invasive mechanical ventilation early after intubation, after a period of stabilization during which low tidal volume is applied and PEEP adjusted and at the end of which the remains ; and proning should be applied for prolonged sessions ( 16 consecutive hours or more) to reduce mortality. 我们建议在接受侵入性机械通气的 ARDS 患者中,在插管后经过一段稳定期(期间应用低潮气量并调整 PEEP)后,开始采用俯卧位,此时 保持在 ;并且应进行长时间(连续 16 小时或更长时间)的俯卧位,以降低死亡率。
Strong recommendation; high level of evidence in favor. 强烈推荐;有很高的证据支持。
This recommendation applies also to ARDS from COVID-19. Strong recommendation; moderate level of evidence in favor for indirectness. 该建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。强烈推荐;间接证据的支持程度为中等。
Expert opinion on clinical application 临床应用的专家意见
The current recommendation is based on the evidence obtained from one trial (PROSEVA). The stabilization period before proning should take into account the time to optimize the ventilator settings and hemodynamics. Continuing prone position even if there is no significant initial improvement in oxygenation is based on the potential of prone position to protect the lung by homogenization of lung stress and potentially improving trajectory of recovery. 当前的建议基于一项试验(PROSEVA)获得的证据。在俯卧位之前的稳定期应考虑优化呼吸机设置和血流动力学所需的时间。即使在氧合没有显著初步改善的情况下继续保持俯卧位,基于俯卧位可能通过均匀肺部压力来保护肺部,并可能改善恢复轨迹。
Unresolved questions and research gaps 未解决的问题和研究空白
There is no trial comparing different durations of prone position and no trial testing strategies other than oxygenation to determine when to cease proning sessions. The difference in ratio between prone and subsequent supine position could be used to guide when to cease prone position. Moreover, using respiratory mechanics, e.g., keeping driving pressure within safe ranges, in addition to oxygenation and/or markers of dead-space ventilation, may be taken into account in the decision to stop the sessions. The effect of prolonged sessions of proning in patients showing minimal improvement in gas exchange should be further evaluated. 目前没有试验比较不同俯卧位持续时间,也没有试验测试除氧合以外的策略来确定何时停止俯卧位。俯卧位与随后的仰卧位之间的 比率差异可以用来指导何时停止俯卧位。此外,除了氧合和/或死腔通气的标志外,使用呼吸力学,例如保持驱动压在安全范围内,也可能在决定停止会话时被考虑在内。对于在气体交换方面显示出最小改善的患者,俯卧位的延长会话效果应进一步评估。
Question 7.3: In non intubated patients with AHRF, does awake prone positioning (APP) as compared to supine positioning reduce intubation or mortality? 问题 7.3:在非插管的急性呼吸衰竭患者中,与仰卧位相比,清醒俯卧位(APP)是否能减少插管或死亡率?
Background 背景
During the recent COVID-19 pandemic, with the spread of non-invasive respiratory support strategies in the wards and ICUs, so-called "awake proning" in nonmechanically ventilated patients was often performed and became the focus of several clinical trials [146]. Indeed, all the high-quality evidence from RCTs derived from studies enrolling only COVID-19 patients. 在最近的 COVID-19 大流行期间,随着非侵入性呼吸支持策略在病房和 ICU 中的推广,所谓的“清醒俯卧位”在未接受机械通气的患者中经常被实施,并成为多个临床试验的焦点[146]。实际上,所有来自 RCT 的高质量证据均来源于仅招募 COVID-19 患者的研究。
Summary of the evidence 证据摘要
Three trials comparing APP to a control group in the supine position, all in COVID-19 patients [147-149], were included in the meta-analysis. One of the studies was a meta-trial including six randomized controlled trials conducted in six different countries (Canada, France, Ireland, Mexico, Spain, United States of America) harmonizing the protocols and combining the data [147]. Most patients enrolled in all three trials were treated with HFNO. Specifically, the proportion of patients treated with HFNO at time of inclusion was APP vs control in the meta-trial [147], 86.1% APP vs control in the Swedish study [148], and APP vs control in the third study [149]. The corresponding rates 在这项荟萃分析中,纳入了三项比较 APP 与对照组在仰卧位的试验,所有试验均在 COVID-19 患者中进行[147-149]。其中一项研究是一个荟萃试验,包括在六个不同国家(加拿大、法国、爱尔兰、墨西哥、西班牙、美国)进行的六项随机对照试验,统一了协议并合并了数据[147]。所有三项试验中大多数患者均接受了 HFNO 治疗。具体而言,在纳入时接受 HFNO 治疗的患者比例为 APP 对 对照在荟萃试验中[147],在瑞典研究中为 86.1% APP 对 对照[148],在第三项研究中为 APP 对 对照[149]。相应的比例
of non-invasive ventilation were vs [147], vs [148], and vs [149]. 非侵入性通气的比较为 对 [147], 对 [148],以及 对 [149]。
In the primary analysis, the meta-trial was split into its six individual components and, therefore, performed the meta-analysis over eight trials. Furthermore, the trial performed in Mexico was removed from the meta-trial because it was associated with a significant reduction in intubation rate compared to the five other trials; also, it provided a twofold higher duration of APP than the other trials, and it behaved as an outlier on a plot that highlighted the inconsistency across the studies in the metatrial. Therefore, the primary analysis was done on two subgroups: one with seven trials and one with Mexico trial only. 在初步分析中,元试验被分为六个独立组成部分,因此对八个试验进行了元分析。此外,墨西哥进行的试验被从元试验中移除,因为与其他五个试验相比,它与插管率显著降低相关;此外,它提供的 APP 持续时间是其他试验的两倍,并且在突出显示元试验中研究不一致性的图表上表现为异常值。因此,初步分析是在两个子组上进行的:一个包含七个试验,另一个仅包含墨西哥试验。
The main outcome of the meta-trial was a composite endpoint including mortality and intubation at 28 days. To be reliable, the elements of a composite outcome needs to fulfill three conditions: have similar clinical relevance, occur with the same frequency, and should be affected similarly by the trailed intervention. The composite endpoint selected in the trials included in our review did not meet these criteria and, hence, we investigated separately intubation and mortality, which were at either 28 or 30 days. 这项元试验的主要结果是一个复合终点,包括 28 天内的死亡率和插管率。为了可靠,复合结果的元素需要满足三个条件:具有相似的临床相关性、以相同的频率发生,并且应受到试验干预的类似影响。我们回顾中纳入的试验所选择的复合终点未能满足这些标准,因此我们分别调查了插管和死亡率,这些数据是在 28 天或 30 天时收集的。
APP significantly reduced the risk of intubation in both the primary analysis, focused on five trials with the lower level of bias, and the secondary analysis including all 8 studies (RR and , respectively). In the subgroup of seven trials, the intubation rate did not differ between APP and control groups ( 0.89 [0.77-1.04]); in contrast, the trial in Mexico reported a significantly lower risk of intubation in APP (0.7 [0.54 ). Although the interaction test was statistically non-significant, a careful the analysis of heterogeneity revealed the trial in Mexico to be an outlier and APP had no overall effect on mortality. APP 显著降低了插管风险,在主要分析中,专注于五项偏倚水平较低的试验,以及包括所有 8 项研究的次要分析中(RR 和 ,分别)。在七项试验的亚组中,APP 组和对照组的插管率没有差异(0.89 [0.77-1.04]);相比之下,墨西哥的试验报告了 APP 插管风险显著降低(0.7 [0.54 )。尽管交互检验在统计上不显著,但对异质性的仔细分析显示墨西哥的试验是一个异常值,APP 对死亡率没有整体影响。
Recommendation 7.3 推荐 7.3
We suggest awake prone positioning as compared to supine 我们建议采用俯卧位,而不是仰卧位
positioning for non-intubated patients with COVID-19-related 非插管 COVID-19 相关患者的定位
AHRF to reduce intubation. AHRF 减少插管。
Weak recommendation; low level of evidence in favor. 弱推荐;支持的证据水平低。
We are unable to make a recommendation for or against APP 我们无法对 APP 做出推荐或反对的意见
for non-intubated patients with COVID-19-related AHRF to reduce mortality. 对于非插管的 COVID-19 相关急性呼吸衰竭患者,以降低死亡率。
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。
We are unable to make a recommendation for or against APP 我们无法对 APP 做出推荐或反对的意见
for patients with AHRF not due to COVID-19. 对于非因 COVID-19 引起的急性呼吸衰竭患者。
No recommendation; no evidence. 没有推荐;没有证据。
Expert opinion on clinical application 临床应用的专家意见
APP can be considered in patients with AHRF due to COVID-19. Close monitoring is required to avoid delaying intubation and to regularly assess and manage comfort and tolerance. APP 可以考虑用于因 COVID-19 导致的急性呼吸衰竭患者。需要密切监测,以避免延迟插管,并定期评估和管理舒适度和耐受性。
Unresolved questions and research gaps 未解决的问题和研究空白
More data are needed on the effect of APP in nonCOVID-19 patients with AHRF. Selecting the adequate outcome is an issue, as a composite score has some limitations; mortality is likely the most relevant outcome. Other issues with APP that need clarification include the location (ICU vs non-ICU), the optimal respiratory support (HFNO, CPAP, NIV) and the impact of APP on inspiratory effort, work of breathing and potential lung injury. 需要更多关于 APP 在非 COVID-19 患者中急性呼吸衰竭(AHRF)影响的数据。选择适当的结果是一个问题,因为复合评分有一些局限性;死亡率可能是最相关的结果。关于 APP 的其他问题需要澄清,包括位置(ICU 与非 ICU)、最佳呼吸支持(HFNO、CPAP、NIV)以及 APP 对吸气努力、呼吸工作和潜在肺损伤的影响。
Question 8.1: Does the routine use of a continuous infusion of neuromuscular blocking agents (NMBA) in patients with moderate-to-severe ARDS not due to COVID-19 or moderate-to-severe ARDS due to COVID-19 reduce mortality? 问题 8.1:在非 COVID-19 引起的中重度 ARDS 患者或因 COVID-19 引起的中重度 ARDS 患者中,常规使用神经肌肉阻滞剂(NMBA)的持续输注是否能降低死亡率?
Background 背景
The administration of NMBA to mechanically ventilated patients with ARDS reduces the work of breathing and patient-ventilator asynchronyand may affect outcome [150]. However, prolonged use of NMBA is also associated with neuromuscular weakness and requires deep sedation, which itself can result in adverse outcomes [151, 152]. More than a decade ago, the ACURASYS trial reported that the early administration of a infusion of NMBA in patients with moderate-to-severe ARDS with PEEP resulted in lower mortality than a strategy of deep sedation without routine NMBA use, after an adjusted analysis [153]. Three other smaller trials with similar inclusion criteria and treatment protocols showed benefit with routine NMBA use [154-156]. However, ICU practices have evolved since these trials, with emphasis on lighter sedation and earlier return to spontaneous breathing. 对机械通气的急性呼吸窘迫综合症(ARDS)患者使用神经肌肉阻滞剂(NMBA)可以减少呼吸工作量和患者与呼吸机之间的不协调,并可能影响结果。然而,长期使用 NMBA 也与神经肌肉无力相关,并需要深度镇静,而深度镇静本身可能导致不良结果。十多年前,ACURASYS 试验报告称,在中度至重度 ARDS 患者中,早期给予 NMBA 输注的策略与不常规使用 NMBA 的深度镇静策略相比,经过调整分析后,死亡率更低。其他三项具有类似纳入标准和治疗方案的小型试验显示常规使用 NMBA 有益。然而,自这些试验以来,重症监护室的实践已经演变,更加注重轻度镇静和更早恢复自发呼吸。
In the recent ROSE trial, which randomized patients with moderate-to-severe ARDS to a 48 h continuous infusion of NMBA with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group), there was no significant difference in mortality at 90 days [157]. There has been an increased use of NMBA infusions in patients with COVID-19 ARDS who are mechanically ventilated, most commonly to abolish vigorous spontaneous efforts and decrease the generation of high transpulmonary pressures that could aggravate self-inflicted lung 在最近的 ROSE 试验中,将中度至重度 ARDS 患者随机分为干预组(接受 48 小时连续 NMBA 输注和深度镇静)和对照组(接受常规护理,不常规使用神经肌肉阻滞剂,镇静目标较轻),在 90 天的死亡率上没有显著差异[157]。在机械通气的 COVID-19 ARDS 患者中,NMBA 输注的使用有所增加,主要是为了消除剧烈的自发呼吸努力,并减少可能加重自我造成肺损伤的高肺内压的产生。
injury or asynchronies [158]. However, randomized trials on NMBA use in patients with COVID-19 are lacking. Given that the ROSE trial excluded a significant number of patients already receiving NMBA, the benefit of early continuous NMBA remains unclear. 伤害或不同步[158]。然而,关于在 COVID-19 患者中使用神经肌肉阻滞剂(NMBA)的随机试验仍然缺乏。考虑到 ROSE 试验排除了大量已经接受 NMBA 治疗的患者,早期持续使用 NMBA 的益处仍不明确。
Summary of the evidence 证据摘要
Two studies provided different results, for the 90-days outcome with the ACURASYS trial reporting a protective effect [153], and the latest ROSE trial demonstrating a non-significant result [157]. The ACURASYS trial sample size calculation was based on the expectation of a large mortality reduction (15%). The reduction found was not statistically significant . The power for the observed delta was , and 842 patients would have been required assuming a power of given the same difference. The ROSE trial assumed an mortality reduction, and under the assumption of a power, the randomization of about 1400 patients was planned. A meta-analysis of the two studies found an overall non-significant result, with a heterogeneity estimate that was high ( ), although the imprecision was such that we could not rule out either low or high heterogeneity. The evaluation of overall evidence was moderate against (according to the GRADE after rating down for imprecision), and according to the risk of biases (RoB) 2 assessment tool, there was an overall low risk of bias. 两项研究提供了不同的结果,ACURASYS 试验报告了 90 天结果的保护效应[153],而最新的 ROSE 试验则显示出非显著结果[157]。ACURASYS 试验的样本量计算是基于对大幅降低死亡率(15%)的预期。发现的 降低在统计上并不显著 。观察到的差异的效能为 ,假设相同的差异,需要 842 名患者以达到 的效能。ROSE 试验假设了 的死亡率降低,并在假设 的效能下,计划随机分配约 1400 名患者。对这两项研究的荟萃分析发现总体结果非显著,异质性估计较高( ),尽管不确定性使我们无法排除低或高异质性。根据 GRADE 评估整体证据的质量为中等(因不确定性而降低评分),根据偏倚风险(RoB)2 评估工具,整体偏倚风险较低。
When analyzing the 28-days or ICU mortality, five trials were included [153-157]. Of these, three reported 28-days mortality, and two ICU mortality [153, 157]. Meta-analysis identified no significant mortality reduction in the NMBA group compared to no NMBA, with a 0.80 relative risk ( CI ), value 0.086 . 在分析 28 天或 ICU 死亡率时,纳入了五项试验[153-157]。其中三项报告了 28 天死亡率,两个报告了 ICU 死亡率[153, 157]。荟萃分析显示,NMBA 组与无 NMBA 组相比,死亡率没有显著降低,相对风险为 0.80( CI ), 值为 0.086。
There were several differences between the two larger studies [153, 157] highlighted. Prone ventilation was less common in the ROSE trial compared to the ACURASYS trial ( 15.8 vs. ). The sedation targets for controls were lighter in the ROSE trial, possibly related to a lower number of serious cardiovascular events ( 14 vs. 4, intervention arm vs. controls) and mortality in the control arm. Higher PEEP strategies were used in the ROSE trial, with an unclear effect on mortality. It is also interesting that the mortality in the intervention arm in the ROSE study was not different from those the control arm in the ROSE and ACURASYS trials. There are two potential explanations for this finding. First, it is possible that patients had the same severity in the two trials, but the intervention overall was not effective in the ROSE trial because the interventions were substantially different, e.g., same pharmacological approach but different ventilatory approach such as PEEP protocols or ventilation in the prone position. Alternatively, it may have been that patients were less severely ill in the ACURASYS trial, but sedation was heavier in the control group (compared to the ROSE trial) causing higher mortality rates. 在这两项较大研究[153, 157]中突出显示了几个差异。与 ACURASYS 试验相比,ROSE 试验中的俯卧通气较少(15.8 vs. )。ROSE 试验中对照组的镇静目标较轻,这可能与对照组中严重心血管事件(14 vs. 4,干预组与对照组)和死亡率较低有关。ROSE 试验中使用了更高的 PEEP 策略,但对死亡率的影响不明确。值得注意的是,ROSE 研究中干预组的死亡率与 ROSE 和 ACURASYS 试验中的对照组没有差异。对此发现有两个可能的解释。首先,可能两项试验中的患者严重程度相同,但由于干预措施有显著不同,ROSE 试验中的干预总体上并不有效,例如相同的药物治疗方法但不同的通气方法,如 PEEP 方案或俯卧通气。 或者,ACURASYS 试验中的患者可能病情较轻,但对照组的镇静程度较重(与 ROSE 试验相比),导致更高的死亡率。
There were no randomized controlled trials in patients with ARDS due to COVID-19. Only indirect evidence from non-COVID studies was available. 由于 COVID-19 引起的急性呼吸窘迫综合症(ARDS)患者中没有随机对照试验。仅有来自非 COVID 研究的间接证据可用。
Recommendation 8.1 推荐 8.1
We recommend against the routine use of continuous infusions of NMBA to reduce mortality in patients with moderate-to-severe ARDS not due to COVID-19. 我们不建议在非 COVID-19 引起的中度至重度 ARDS 患者中常规使用 NMBA 的持续输注来降低死亡率。
Strong recommendation, moderate level of evidence. 强烈推荐,适度的证据水平。
We are unable to make a recommendation for or against the routine use of continuous infusions of NMBA to reduce mortality in patients with moderate-to-severe ARDS due to COVID-19. No recommendation; no evidence. 我们无法对常规使用 NMBA 持续输注以降低中度至重度 COVID-19 相关 ARDS 患者的死亡率提出支持或反对的建议。没有建议;没有证据。
Expert opinion on clinical application 临床应用的专家意见
In the ACURASYS trial, the use of prone ventilation without neuromuscular blockade was associated with deeper sedation targets, which may have contributed to the increased mortality in the control arm [153]. A clear protective effect for pneumothorax was found in the NMBA group compared to controls in the four studies included [153-155, 157]. This finding may support the use of NMBA in those patients at risk of developing a pneumothorax. 在 ACURASYS 试验中,使用俯卧通气而不使用神经肌肉阻滞剂与更深的镇静目标相关,这可能导致对照组的死亡率增加[153]。在四项纳入的研究中,NMBA 组与对照组相比,发现了对气胸的明显保护作用[153-155, 157]。这一发现可能支持在有气胸风险的患者中使用 NMBA。
Unresolved questions and research gaps 未解决的问题和研究空白
Future research should prioritize other outcomes including successful extubation, re-intubation, paralysis recall, ICU acquired weakness and health-related quality of life and the specific role on NMBA in prone position. Another important area of research is the recognition of poor patient-ventilator interaction in invasively ventilated ARDS patients, as this has potential effects on clinical outcomes and may represent a possible indication for the administration of NMBA. The views of patients and caregivers should be central to determining future research questions and outcomes. 未来的研究应优先考虑其他结果,包括成功拔管、再插管、麻痹回忆、ICU 获得性虚弱、与健康相关的生活质量以及 NMBA 在俯卧位中的具体作用。另一个重要的研究领域是识别侵入性通气的 ARDS 患者中不良的患者-呼吸机互动,因为这可能对临床结果产生影响,并可能代表施用 NMBA 的一个潜在指征。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。
Domain 9: Extracorporeal life support 领域 9:体外生命支持
Question 9.1: In adult patients with severe acute respiratory distress syndrome (ARDS) or COVID-19 does veno-venous extracorporeal membrane oxygenation (VV-ECMO) compared with conventional ventilation improve outcomes? 问题 9.1:在患有严重急性呼吸窘迫综合症(ARDS)或 COVID-19 的成人患者中,静脉-静脉体外膜氧合(VV-ECMO)与常规通气相比是否改善了预后?
Background 背景
VV-ECMO is used to support or replace gas exchange. During ECMO, blood is passed through a "membrane lung" which facilitates exchange of oxygen and carbon VV-ECMO 用于支持或替代气体交换。在 ECMO 过程中,血液通过“膜肺”进行循环,促进氧气和二氧化碳的交换。
dioxide by diffusion. Technological improvements have led to improved gas exchange and reduced complications [159]. ECMO has been used for patients with severe ARDS including more recently patients with COVID-19. High-volume expert centers report better outcomes with ECMO [160]. It is likely that an overall package of care delivered alongside the use of ECMO, including lung-protective ventilation and prone positioning, is required to achieve improved outcomes in patients receiving ECMO. 通过扩散的二氧化碳。技术改进导致气体交换改善和并发症减少[159]。ECMO 已被用于严重 ARDS 患者,包括最近的 COVID-19 患者。高容量专家中心报告使用 ECMO 的结果更好[160]。很可能,在使用 ECMO 的同时,需要提供整体护理方案,包括肺保护通气和俯卧位,以实现接受 ECMO 患者的改善结果。
Summary of the evidence 证据摘要
Two randomized controlled trials informed the basis of these recommendations. The CESAR trial included 180 patients, and the EOLIA trial included 249 patients with ARDS [161]. The EOLIA inclusion criteria were as follows: a for hours, or a of for hours, or a pH of with a of for hours, with the respiratory rate increased to 35 breaths per minute and mechanical ventilation settings adjusted to keep a plateau pressure of . 两项随机对照试验为这些建议提供了依据。CESAR 试验包括 180 名患者,EOLIA 试验包括 249 名 ARDS 患者[161]。EOLIA 的纳入标准如下: 持续 小时,或 持续 小时,或 pH 值为 且 为 持续 小时,呼吸频率增加到每分钟 35 次,机械通气设置调整以保持 的峰值压力。
These studies included patients with severe ARDS of any etiology (average values were approximately 75 mmHg ), though both were conducted prior to the COVID-19 pandemic. The EOLIA and CESAR trials were considered clinically sufficiently homogenous to be meta-analytically combined. According to the RoB2 tool, there was a high risk of bias with the CESAR trial, as about one-quarter of patient in the intervention arm did not receive ECMO. 这些研究包括任何病因导致的重度 ARDS 患者(平均 值约为 75 mmHg),尽管这两项研究均在 COVID-19 大流行之前进行。EOLIA 和 CESAR 试验被认为在临床上足够同质,可以进行荟萃分析。根据 RoB2 工具,CESAR 试验存在高风险偏倚,因为约四分之一的干预组患者没有接受 ECMO。
Meta-analysis identified a significant decrease in 60-day mortality in patients receiving VV-ECMO compared to conventional mechanical ventilation (RR 0.72; 95% CI ; moderate confidence). The protective effect was consistent across the 90-days mortality outcomes as well as a composite outcome of mortality and therapeutic failure at 60 days. Observational studies, including a posthoc Bayesian analysis of the EOLIA study [163], mostly confirmed a protective effect of ECMO [163-171]. However, the very low evidence that they provided did not substantially affect the moderate quality of evidence provided by the meta-analysis of the two randomized trials. The observational studies were not combined in a metaanalysis due to methodological limitations. 荟萃分析发现,与常规机械通气相比,接受 VV-ECMO 的患者在 60 天死亡率上显著降低(相对风险 0.72;95%置信区间 ;中等信心)。这种保护作用在 90 天死亡率结果以及 60 天死亡和治疗失败的综合结果中是一致的。观察性研究,包括 EOLIA 研究的事后贝叶斯分析[163],大多确认了 ECMO 的保护作用[163-171]。然而,它们提供的证据非常有限,并未实质性影响两项随机试验的荟萃分析所提供的中等质量证据。由于方法学限制,观察性研究未在荟萃分析中合并。
There were no randomized controlled trials in patients with COVID-19. The evidence for ECMO in COVID-19 was assessed as weak in favor, being downgraded due to the indirectness of the available RCT evidence. Observational studies in COVID-19 mostly showed a protective effect of ECMO in short-term survival [167, 169-171]. We did not combine the observational studies in a metaanalysis due to methodological limitations. 在 COVID-19 患者中没有随机对照试验。关于 ECMO 在 COVID-19 中的证据被评估为支持性较弱,由于现有 RCT 证据的间接性而被降级。COVID-19 的观察性研究大多显示 ECMO 对短期生存有保护作用[167, 169-171]。由于方法学限制,我们没有将观察性研究合并进行荟萃分析。
The use of ECMO is associated with the risk of serious bleeding. In the EOLIA trial, higher rates of bleeding events leading to blood transfusion (46 vs. 28%) and of severe thrombocytopenia ( 27 vs. ) in the intervention arm were reported. However, less ischemic strokes (5% absolute risk reduction; CI, ) and no differences in hemorrhagic strokes was found [162]. ECMO 的使用与严重出血的风险相关。在 EOLIA 试验中,干预组报告了更高的导致输血的出血事件发生率(46%对 28%)和严重血小板减少症的发生率(27%对 )。然而,缺血性中风的发生率较低(绝对风险降低 5%; CI, ),且出血性中风没有差异[162]。
Recommendation 9.1 推荐 9.1
We recommend that patients with severe ARDS not due to COVID- 我们建议非因 COVID-19 引起的重症 ARDS 患者
19 as defined by the EOLIA trial eligibility criteria, should be treated with ECMO in an ECMO center which meets defined organizational standards, adhering to a management strategy similar to that used in the EOLIA trial. 根据 EOLIA 试验的资格标准,19 岁及以上的患者应在符合规定组织标准的 ECMO 中心接受 ECMO 治疗,遵循与 EOLIA 试验中使用的管理策略类似的管理策略。
Strong recommendation, moderate level of evidence in favor 强烈推荐,适度的证据支持
This recommendation applies also to patients with severe ARDS due to COVID-19. 该建议同样适用于因 COVID-19 导致的重度急性呼吸窘迫综合症(ARDS)患者。
Strong recommendation; low level of evidence in favor for indirectness. 强烈推荐;间接性证据水平低。
Expert opinion on clinical application 临床应用的专家意见
A network of ECMO centers with expertise in this technique is likely to be required to effectively provide ECMO. With centralization of patients from non-ECMO centers, an ECMO team with capacity to transfer patients on ECMO (mobile ECMO) is required. Resources and skills to deliver such a service are required. 一个拥有这种技术专长的 ECMO 中心网络可能是有效提供 ECMO 所必需的。随着非 ECMO 中心患者的集中,需要一个能够转运 ECMO 患者的 ECMO 团队(移动 ECMO)。提供此类服务所需的资源和技能是必不可少的。
It is unlikely that an RCT of ECMO in severe ARDS due to COVID-19 will be conducted. In patients with ARDS due to COVID, early mortality up to 90-days was similar to non-COVID ARDS patients when ECMO was initiated in experienced centers. Although patients with COVID will not have been included in the RCTs which form the basis of these recommendations, there is biological plausibility that ARDS due to non-COVID and COVID should have similar outcomes with ECMO. However, the rate of serious and prolonged multidimensional disability, particularly in patients with COVID-19 may be significant, although specific attribution to ECMO rather than severe ARDS is unknown. 在严重的 COVID-19 相关 ARDS 中进行 ECMO 的随机对照试验(RCT)不太可能。在 COVID 引起的 ARDS 患者中,当在经验丰富的中心启动 ECMO 时,早期死亡率(高达 90 天)与非 COVID ARDS 患者相似。尽管 COVID 患者未被纳入形成这些建议基础的 RCT,但非 COVID 和 COVID 引起的 ARDS 在 ECMO 下应有相似结果的生物学合理性。然而,COVID-19 患者中严重和长期多维残疾的发生率可能显著,尽管具体归因于 ECMO 而非严重 ARDS 尚不清楚。
Unresolved questions and research gaps 未解决的问题和研究空白
Future research should additionally prioritize long-term multidimensional outcomes for patients and families and ascertain ECMO-specific morbidities. The views of patients and carers should be central to determining future research questions and outcomes. 未来的研究还应优先考虑患者和家庭的长期多维结果,并确定 ECMO 特有的发病率。患者和照顾者的观点应成为确定未来研究问题和结果的核心。
Table 2 Summary of recommendations 表 2 建议摘要
HIGH FLOW NASAL OXYGEN 高流量鼻氧气
Q1 In non-mechanically ventilated patients with acute hypoxemic respiratory failure (AHRF) not due to cardiogenic pulmonary edema or acute exacerbation of chronic obstructive pulmonary disease (COPD), does high flow nasal oxygen (HFNO) compared to conventional oxygen therapy (COT) reduce mortality or intubation? 在非机械通气的急性缺氧性呼吸衰竭(AHRF)患者中,如果不是由于心源性肺水肿或慢性阻塞性肺疾病(COPD)的急性加重,高流量鼻氧(HFNO)与常规氧疗(COT)相比,是否能降低死亡率或插管率?
1 We recommend that non-mechanically ventilated patients with AHRF not due to cardiogenic pulmonary edema or acute exacerbation of COPD receive HFNO as compared to COT to reduce the risk of intubation. 我们建议非机械通气的急性呼吸衰竭患者(不因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),而不是常规氧疗(COT),以降低插管风险。
2 This recommendation applies also to AHRF from coronavirus 2019 (COVID-19) 此建议同样适用于 2019 冠状病毒病(COVID-19)相关的 AHRF
OW LEVEL OF EVIDENCE 证据的 OW 级别
3 We are unable to make a recommendation for or against the use of HFNO over COT to reduce mortality. 我们无法对使用高流量鼻氧(HFNO)或常规氧疗(COT)来降低死亡率提出推荐。
4 This recommendation applies also to AHRF from COVID-19. 此建议同样适用于因 COVID-19 而产生的 AHRF。
Q2 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 (NIV) reduce mortality or intubation? 在非机械通气的急性呼吸衰竭患者中,如果不是由于心源性肺水肿或慢性阻塞性肺病急性加重,HFNO 与非侵入性通气(NIV)相比,是否能降低死亡率或插管率?
1 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 AHRF not due to cardiogenic pulmonary edema or acute exacerbation of COPD. 我们无法对 HFNO 与持续正压通气(CPAP)/非侵入性通气(NIV)在减少未选择的急性呼吸衰竭(AHRF)患者的插管或死亡率方面的使用做出推荐,无论是支持还是反对,这些患者并非因心源性肺水肿或慢性阻塞性肺病(COPD)急性加重而导致。
2 We suggest that CPAP/NIV can be considered instead of HFNO to reduce the risk of intubation in AHRF due to COVID-19. 我们建议可以考虑使用 CPAP/NIV 来替代 HFNO,以降低因 COVID-19 引起的急性呼吸衰竭(AHRF)中插管的风险。
MODERATE LEVEL OF EVIDENCE 中等证据水平
3 No recommendation can be made for whether CPAP/NIV can decrease mortality compared to HFNO in COVID-19. 无法推荐 CPAP/NIV 与 HFNO 相比在 COVID-19 中是否能降低死亡率。
MODERATE LEVEL OF EVIDENCE FOR MORTALITY LOW LEVEL OF EVIDENCE FOR INTUBATION 中等水平的死亡证据,低水平的插管证据
Q1 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 COT reduce mortality or intubation? 在非机械通气的急性呼吸衰竭患者中,如果不是由于心源性肺水肿、肥胖低通气或慢性阻塞性肺病急性加重,CPAP/NIV 与常规氧疗相比,是否能降低死亡率或插管率?
1 We are unable to make a recommendation for or against the use of CPAP/NIV compared to COT 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 COT 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。
2 We suggest the use of CPAP over COT to reduce the risk of intubation in patients with AHRF due to COVID-19. 我们建议在因 COVID-19 引起的急性呼吸衰竭患者中使用 CPAP 而不是 COT,以降低插管的风险。
3 We are unable to make a recommendation for or against the use of CPAP over COT to reduce mortality in AHRF due to COVID-19. 我们无法对使用 CPAP 或 COT 在减少因 COVID-19 引起的急性呼吸衰竭(AHRF)死亡率方面做出推荐。
HIGH LEVEL OF EVIDENCE FOR MORTALITY MODERATE LEVEL OF EVIDENCE FOR INTUBATION 高水平的死亡证据,中等水平的插管证据
LOW LEVEL OF EVIDENCE 低水平证据
MODERATE LEVEL OF EVIDENCE 中等证据水平
Table 2 (continued) 表 2(续)
POSITIVE END-EXPIRATORY PRESSURE AND RECRUITMENT MANEUVERS 正压呼气末压力和招募手法
Q1
在接受侵入性机械通气的急性呼吸窘迫综合症(ARDS)患者中,常规使用较高的呼气末正压(PEEP)进行 PEEP 滴定是否有效?
策略相比于较低的 策略如何降低死亡率?
In patients with ARDS undergoing invasive mechanical ventilation, does
routine positive end-expiratory pressure (PEEP) titration using a higher PEEP/
strategy compared to a lower strategy reduce mortality?
1
我们无法对常规 PEEP 滴定提出推荐或反对意见
具有更高的 策略与较低的 减少急性呼吸窘迫综合症(ARDS)患者死亡率的策略。
We are unable to make a recommendation for or against routine PEEP titration
with a higher strategy versus a lower strategy to reduce
mortality in patients with ARDS.
3 high LeVEL Of EVIDENCE 3 级高证据水平
2
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)。
MODERATE LEVEL Of EVIDENCE 中等证据水平
Q2
在接受侵入性机械通气的 ARDS 患者中,基于呼吸力学的常规 PEEP 调节与其他方法相比如何?
基于标准化的 PEEP 滴定 表格能降低死亡率吗?
In patients with ARDS undergoing invasive mechanical ventilation, does
routine PEEP titration based principally on respiratory mechanics compared
to PEEP titration based principally on a standardized table reduce
mortality?
1
我们无法对主要基于呼吸力学的 PEEP 滴定提出支持或反对的建议,与主要基于其他因素的 PEEP 滴定相比
在 PEEP/FiO 策略,以减少 ARDS 患者的死亡率。
We are unable to make a recommendation for or against PEEP titration guided
principally by respiratory mechanics, compared to PEEP titration based principally
on PEEP/FiO strategy, to reduce mortality in patients with ARDS.
HIGH LEVEL OF EVIDENCE 高水平证据
2
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)。
MODERATE LEVEL Of eVIdence 中等证据水平
Table 2 (continued) 表 2(续)
(a3 In patients with ARDS undergoing invasive mechanical ventilation, does use of prolonged high-pressure recruitment maneuvers (RMs), compared to not using prolonged high-pressure RMs, reduce mortality? 在接受侵入性机械通气的 ARDS 患者中,与不使用持续高压招募手法(RMs)相比,使用持续高压招募手法是否能降低死亡率?
1 We recommend against use of prolonged high-pressure RMs (defined as airway pressure maintained for at least one minute) to reduce mortality of patients with ARDS. 我们不建议使用持续高压呼吸机(定义为气道压力维持在 至少一分钟)来降低 ARDS 患者的死亡率。
2 This recommendation applies also to ARDS from COVID-19. 此建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。
Q4 In patients with ARDS undergoing invasive mechanical ventilation, does routine use of brief high-pressure RMs, compared to no use of brief highpressure RMs, reduce mortality? 在接受侵入性机械通气的 ARDS 患者中,与不使用短暂高压复张(RMs)相比,常规使用短暂高压复张是否能降低死亡率?
1 We suggest against routine use of brief high-pressure RMs (defined as airway pressure maintained for less than one minute) to reduce mortality in patients with ARDS. 我们建议不要常规使用短时间高压呼吸机(定义为气道压力维持在 以下一分钟)来降低 ARDS 患者的死亡率。
2 This suggestion applies also to ARDS from COVID-19. 此建议同样适用于 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。
PRONE POSITIONING 俯卧位
Q1 In intubated patients with ARDS, does prone position compared to supine position reduce mortality? 在插管的 ARDS 患者中,与仰卧位相比,俯卧位是否能降低死亡率?
1 We recommend using prone position as compared to supine position for patients with moderate-severe ARDS (defined as and , despite optimization of ventilation settings) to reduce mortality. 我们建议对于中重度 ARDS 患者(定义为 和 ,尽管通气设置已优化),使用俯卧位而不是仰卧位,以降低死亡率。
2 This recommendation applies also to ARDS from COVID-19. 此建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。
@2 In patients with moderate-severe ARDS, when should prone positioning be started to reduce mortality? 在中重度 ARDS 患者中,何时应开始俯卧位以降低死亡率?
(1) We recommend starting prone position in patients with ARDS receiving invasive mechanical ventilation early after intubation, after a period of stabilization during which low tidal volume is applied and PEEP adjusted and at the end of which the remains ; and proning should be applied for prolonged sessions ( 16 consecutive hours or more) to reduce mortality. 我们建议在接受侵入性机械通气的 ARDS 患者中,在插管后经过一段稳定期(期间应用低潮气量并调整 PEEP)后,开始采用俯卧位,并且在此期间 保持 ;俯卧位应持续应用较长时间(连续 16 小时或更长)以降低死亡率。
2 This recommendation applies also to ARDS from COVID-19. 此建议同样适用于因 COVID-19 引起的急性呼吸窘迫综合症(ARDS)。
MODERATE LEVEL OF EVIDENCE 中等证据水平
HIGH LEVEL OF EVIDENCE MODERATE LEVEL OF EVIDENCE HIGH LEVEL OF EVIDENCE 高水平证据 中等水平证据 高水平证据
Table 2 (continued) 表 2(续)
a3
In non intubated patients with AHRF, does awake prone positioning (APP) as compared to supine positioning reduce intubation or mortality? 在未插管的急性呼吸衰竭患者中,清醒俯卧位(APP)与仰卧位相比,是否能减少插管或死亡率?
1 We suggest awake prone positioning as compared to supine positioning for nonintubated patients with COVID-19-related AHRF to reduce intubation. 我们建议对非插管的 COVID-19 相关急性呼吸衰竭患者采用清醒俯卧位,而不是仰卧位,以减少插管。
2 We are unable to make a recommendation for or against APP for non-intubated patients with COVID-19-related AHRF to reduce mortality. 我们无法对非插管的 COVID-19 相关 AHRF 患者使用 APP 进行推荐或反对,以降低死亡率。
3 We are unable to make a recommendation for patients with AHRF failure not due to COVID-19. 我们无法对因非 COVID-19 导致的 AHRF 失败患者提出建议。
NEUROMUSCULAR BLOCKING AGENTS 神经肌肉阻滞剂
Q1 Does the routine use of a continuous infusion of neuromuscular blocking agents (NMBA) in patients with moderate to severe ARDS not due to COVID-19 or moderate to severe ARDS due to COVID-19 reduce mortality? Q1 在非 COVID-19 引起的中度至重度 ARDS 患者或因 COVID-19 引起的中度至重度 ARDS 患者中,常规使用神经肌肉阻滞剂(NMBA)的持续输注是否能降低死亡率?
1 We recommend against the routine use of continuous infusions of NMBA to reduce mortality in patients with moderate to severe ARDS not due to COVID-19. 我们不建议在非 COVID-19 引起的中度至重度 ARDS 患者中常规使用 NMBA 的持续输注以降低死亡率。
2 We are unable to make a recommendation for or against the routine use of continuous infusions of NMBA to reduce mortality in patients with moderate to severe ARDS due to COVID-19. 我们无法对常规使用 NMBA 持续输注以降低中重度 COVID-19 相关 ARDS 患者的死亡率提出支持或反对的建议。
EXTRACORPOREAL LIFE SUPPORT 体外生命支持
Q1 In adult patients with severe ARDS or COVID-19 does veno-venous extracorporeal membrane oxygenation (VV-ECMO) compared with conventional ventilation improve outcomes? 在严重急性呼吸窘迫综合症(ARDS)或 COVID-19 的成人患者中,静脉-静脉体外膜氧合(VV-ECMO)与常规通气相比是否改善了预后?
1 We recommend that patients with severe ARDS not due to COVID-19 as defined by the EOLIA trial eligibility criteria, should be treated with ECMO in an ECMO centre which meets defined organisational standards, adhering to a management strategy similar to that used in the EOLIA trial. 我们建议,符合 EOLIA 试验资格标准的非 COVID-19 引起的重度 ARDS 患者,应在符合规定组织标准的 ECMO 中心接受 ECMO 治疗,遵循与 EOLIA 试验中使用的管理策略相似的管理方案。
2 This recommendation applies also to severe ARDS from COVID-19. 此建议同样适用于因 COVID-19 引起的重症急性呼吸窘迫综合症(ARDS)。
Q2 In adult patients with ARDS, does extracorporeal carbon dioxide removal compared with conventional ventilation improve outcomes? 在患有急性呼吸窘迫综合症(ARDS)的成人患者中,体外二氧化碳去除 与常规通气相比,是否改善了预后?
1 We recommend against the use of for the treatment of ARDS not due to COVID-19 to prevent mortality outside of randomized controlled trials. 我们建议不要在随机对照试验之外使用 来治疗非 COVID-19 引起的急性呼吸窘迫综合症,以防止死亡。
2 This recommendation applies also to severe ARDS from COVID-19 此建议同样适用于因 COVID-19 引起的重度 ARDS
Table 3 Comparison between 2017 and 2023 ARDS guidelines 表 3 2017 年与 2023 年 ARDS 指南的比较
Question 9.2: In adult patients with ARDS, does extracorporeal carbon dioxide removal compared with conventional ventilation improve outcomes? 问题 9.2:在患有急性呼吸窘迫综合症(ARDS)的成人患者中,体外二氧化碳去除 与常规通气相比,是否改善预后?
Background 背景
aims to remove carbon dioxide via an extracorporeal circuit. uses lower extracorporeal blood flow rates (typically between 200 and ) compared to ECMO because the blood flow rates needed to remove are much lower than required to achieve adequate oxygenation. Although is often defined based on the flow rate through the extracorporeal circuit, it has been suggested that should be defined based on the clinician's intended use [172]. The primary aim of in ARDS is to facilitate a reduction in injurious mechanical ventilation. 旨在通过体外循环去除二氧化碳。与 ECMO 相比, 使用较低的体外血流速率(通常在 200 和 之间),因为去除 所需的血流速率远低于实现足够氧合所需的血流速率。尽管 通常是根据体外循环的流量来定义的,但有人建议 应根据临床医生的预期用途来定义[172]。在 ARDS 中, 的主要目标是促进减少有害的机械通气。
Summary of the evidence 证据摘要
Two RCTs formed the basis of these recommendations. The Xtravent trial included 79 patients with ARDS with 这两项随机对照试验(RCT)构成了这些建议的基础。Xtravent 试验包括 79 名患有急性呼吸窘迫综合症(ARDS)的患者。 who received removal using a "pumpless" arterio-venous (approximately ) approach [173]. The REST trial included 412 hypoxemic patients who received removal using a veno-venous low flow (approximately ) approach. The majority of patients had ARDS (approximately 60%) [174]. The Xtravent and REST trials were considered clinically sufficiently homogenous to be meta-analytically combined. There were methodological concerns with the Xtravent trial and some methodological concerns for the REST trial according to the RoB2 assessment. When considering ventilator-free days, methodological concerns were recognized due to lack of blinding. 接受了 移除,采用“无泵”动静脉(大约 )的方法 [173]。REST 试验包括 412 名缺氧患者 ,他们接受了 移除,采用静静脉低流量(大约 )的方法。大多数患者患有 ARDS(大约 60%) [174]。Xtravent 和 REST 试验被认为在临床上足够同质,可以进行荟萃分析。根据 RoB2 评估,Xtravent 试验存在方法学问题,REST 试验也存在一些方法学问题。在考虑无通气天数时,由于缺乏盲法,识别出方法学问题。
In meta-analysis of these 2 trials, did not reduce mortality (RR ; high confidence). Patients receiving had fewer ventilator-free days to day 28 (mean difference - 1.21; CI -3.77 to 1.34 ; moderate confidence). There were no randomized controlled trials in patients with COVID-19. Evidence was considered applicable to COVID patients although this was not directly investigated and therefore the evidence was downgraded due to the indirectness of the available RCT evidence. The REST trial reported increased serious side-effects attributable to with nine patients ( ) having a cerebral hemorrhage and six patients (3%) having extracranial bleeding compared to none and one ( ), respectively, in the control arm [174]. 在这两项试验的荟萃分析中, 并未降低死亡率(RR ;高可信度)。接受 的患者在第 28 天前的无呼吸机天数较少(平均差异-1.21; CI -3.77 至 1.34;中等可信度)。在 COVID-19 患者中没有随机对照试验。尽管没有直接调查,但证据被认为适用于 COVID 患者,因此由于现有 RCT 证据的间接性,证据被降级。REST 试验报告了与 相关的严重副作用增加,九名患者( )发生脑出血,六名患者(3%)发生颅外出血,而对照组分别为零和一( )。
Recommendation 9.2 推荐 9.2
We recommend against the use of for the treatment of 我们不建议使用 来治疗
ARDS not due to COVID-19 to prevent mortality outside of rand- ARDS 不是由于 COVID-19 引起的,以防止随机之外的死亡率
omized controlled trials. 随机对照试验。
Strong recommendation, high level of evidence of no effect. 强烈推荐,证据水平高,表明没有效果。
This recommendation applies also to patients with severe ARDS due 该建议同样适用于因严重 ARDS 而导致的患者
to COVID-19. 至 COVID-19。
Strong recommendation; moderate level of evidence of no effect for 强烈推荐;中等水平的证据表明没有效果
indirectness. 间接性。
Recommendation 9.2 推荐 9.2
We recommend against the use of for the treatment of 我们不建议使用 来治疗
ARDS not due to COVID-19 to prevent mortality outside of randomized controlled trials. ARDS 不是由于 COVID-19 引起的,以防止在随机对照试验之外的死亡率。
Strong recommendation, high level of evidence of no effect. 强烈推荐,证据水平高,表明没有效果。
This recommendation applies also to patients with severe ARDS due to COVID-19. 该建议同样适用于因 COVID-19 导致的重度急性呼吸窘迫综合症(ARDS)患者。
Strong recommendation; moderate level of evidence of no effect for indirectness. 强烈推荐;间接性证据的无效性中等水平。
Expert opinion on clinical application 临床应用的专家意见
The Xtravent trial had blood flows of 1-2 L/min and the REST trial of approximately . A lower blood flow rate of approximately 500 mL (or approximately removal) may be insufficient to achieve a sufficient reduction in injurious ventilation. The resource requirement for in the REST trial (blood flow ) was estimated to be comparable to that of CRRT; however, with higher blood flows the delivery of requires competencies similar to ECMO centers. Xtravent 试验的血流量为 1-2 L/min,而 REST 试验约为 。约 500 mL(或约 去除)的较低血流速率可能不足以实现对有害通气的足够减少。REST 试验中 的资源需求(血流 )估计与 CRRT 相当;然而,随着血流量的增加, 的输送需要与 ECMO 中心相似的能力。
Unresolved questions and research gaps 未解决的问题和研究空白
Although current evidence is against the effectiveness of , uncertainty about the role of remains. Further research is needed to identify if a specific population of ARDS patients may respond to . In addition, the technique may be device-dependent for both efficacy and safety. Ongoing randomized controlled trials may provide further evidence in this field. When these trials conclude, the ARDS ESICM guidelines group will review and update the current recommendation. Future research should additionally prioritize long-term multidimensional outcomes for patients and families and ascertain specific morbidity. The views of patients and carers should be central to determining future research questions and outcomes. 尽管目前的证据反对 的有效性,但关于 的作用仍然存在不确定性。需要进一步研究以确定是否有特定的 ARDS 患者群体可能对 产生反应。此外,该技术的有效性和安全性可能依赖于设备。正在进行的随机对照试验可能会在这一领域提供更多证据。当这些试验结束时,ARDS ESICM 指南小组将审查并更新当前的建议。未来的研究还应优先考虑患者和家庭的长期多维结果,并确定 的特定发病率。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。
Conclusions 结论
In conclusion, these guidelines present 21 evidence-based recommendations (summarized in Table 2) including definition, phenotyping and the respiratory management of ARDS. A summary table comparing the changes in scope and recommendations compared with the 2017 ARDS guidelines are presented in Table 3. Finally, research priorities are identified for future studies. 总之,这些指南提出了 21 条基于证据的建议(见表 2),包括 ARDS 的定义、表型和呼吸管理。表 3 中列出了与 2017 年 ARDS 指南相比的范围和建议变化的总结表。最后,确定了未来研究的优先事项。
Supplementary Information 补充信息
The online version contains Supplementary Materials available at https://doi. org/10.1007/s00134-023-07050-7. 在线版本包含可在 https://doi. org/10.1007/s00134-023-07050-7 获取的补充材料。
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Acknowledgments 致谢
We acknowledge the following patients and family representatives who contributed to the formulation of the PICO questions, the outcomes and the research gaps.: Daniel Bertin (Switzerland), Phillys Kay (USA), Eileen Rubin (USA), Sylvie Debigare (Canada), Kai Hughes (UK), Callum Ross (UK), Michael Bainbridge (UK), Pijush K. Roy (India). We are grateful to Guy Francois and the ESICM Research Office for their invaluable and continuous support. We thank Luigi Vivona and Amedeo Guzzardella for their technical assistance. 我们感谢以下患者和家庭代表,他们为 PICO 问题、结果和研究空白的制定做出了贡献:Daniel Bertin(瑞士)、Phillys Kay(美国)、Eileen Rubin(美国)、Sylvie Debigare(加拿大)、Kai Hughes(英国)、Callum Ross(英国)、Michael Bainbridge(英国)、Pijush K. Roy(印度)。我们对 Guy Francois 和 ESICM 研究办公室的宝贵和持续支持表示感谢。我们感谢 Luigi Vivona 和 Amedeo Guzzardella 的技术支持。
Funding 资金
This work was supported by the European Society of Intensive Care Medicine. 这项工作得到了欧洲重症医学会的支持。
Data availability 数据可用性
Not applicable. 不适用。
Declarations 声明
Conflicts of interest 利益冲突
GG received funding from Fischer&Paykel, MSD, Pfizer, and received fees from Getinge, Draeger Medical, Cook, MundiPharma, Fischer&Paykel, Pfizer. CSC received funding from National Institute of Health, Roche Genen Tech, Quantum Leap Health Care Collaborative and received fees from Cellenkos, Vasomune, NGM Bio, Gen1e Life Sciences. LC received fees from Draeger Medical, Hamilton, Medtronic. MA received funding from GE, Toray and received fees from Fischer&Paykel, Menarini, Pfizer. YMA is a Board member of International Severe Acute Respiratory and emerging Infection Consortium (ISARIC); is Co-Chair of International Study Steering Committee of O2CoV2 Study of World Health Organization and is PI of Helmet-COVID trial. JRB received funding from National Institute of Health, Quantum Leap Health Care Collaborative, Sedana Medical and received fees from Biomark Pharmaceutics. GB received royalties from Flowmeter Spa and received fees from Flowmeter Spa, Draeger Medical, Getinge. LDJB received funding from Amsterdam UMC, Longfonds, European Respiratory Society, Innovative Medicine Intiative, Santhera, ZonMW, and received fees from AstraZeneca, Bayer, Novartis, Santhera, Sobi, Scailyte. LB received funding from Draeger Medical, Medtronic, Stimit, Vitalair and received fees from Fischer&Paykel and received equipments from Fischer&Paykel, Sentec. DB is Extracorporeal Life Support Organization President-elect and member board of directors and Chair Executive Committee of ECMONet. He is in the Data Safety Monitoring Board of ECMO-Rehab Study, was in the Advisory Boards for Livanova, Abiomed, Xenios, Medtronic, Inspira, Cellenkos and received funding from Livanova and received fees from Livanova, Abiomed, Xenios, Inspira, Medtronic, Cellenkos. KEAB is President of Canadian Critical Care Society, Past-Chair of Women in Critical Care of the American Thoracic Society and ex-officio member of Canadian Critical Care Trials Group Executive; she received fees from Fischer&Paykel. AC received fees from Getinge, Baxter, Fresenius. AD received funding from Philips, French Ministry of Health, Respinor, Lungpacer, Assistance publique - Hôpitaux de Paris, and received fees from Lungpacer, Respinor, Lowenstein, Tribunal administrative de Cergy, Liberate Medical, GG 获得了 Fischer&Paykel、MSD、Pfizer 的资金,并从 Getinge、Draeger Medical、Cook、MundiPharma、Fischer&Paykel、Pfizer 收取了费用。CSC 获得了国家卫生研究院、罗氏基因科技、Quantum Leap 健康护理合作的资金,并从 Cellenkos、Vasomune、NGM Bio、Gen1e 生命科学收取了费用。LC 从 Draeger Medical、Hamilton、Medtronic 收取了费用。MA 获得了 GE、Toray 的资金,并从 Fischer&Paykel、Menarini、Pfizer 收取了费用。YMA 是国际严重急性呼吸综合症和新兴感染联盟(ISARIC)的董事会成员;是世界卫生组织 O2CoV2 研究国际研究指导委员会的共同主席,并且是 Helmet-COVID 试验的首席研究员。JRB 获得了国家卫生研究院、Quantum Leap 健康护理合作、Sedana Medical 的资金,并从 Biomark 制药收取了费用。GB 从 Flowmeter Spa 获得了版税,并从 Flowmeter Spa、Draeger Medical、Getinge 收取了费用。LDJB 获得了阿姆斯特丹大学医学中心、Longfonds、欧洲呼吸学会、创新医学倡议、Santhera、ZonMW 的资金,并从阿斯利康、拜耳、诺华、Santhera、Sobi、Scailyte 收取了费用。 LB 从德尔格医疗、迈特瑞、Stimit、Vitalair 获得资金,并从 Fischer&Paykel 收取费用,获得 Fischer&Paykel 和 Sentec 的设备。DB 是体外生命支持组织的当选主席,董事会成员及 ECMONet 执行委员会主席。他是 ECMO-Rehab 研究的数据安全监测委员会成员,曾在 Livanova、Abiomed、Xenios、迈特瑞、Inspira、Cellenkos 的顾问委员会中任职,并从 Livanova 获得资金,从 Livanova、Abiomed、Xenios、Inspira、迈特瑞、Cellenkos 收取费用。KEAB 是加拿大重症监护学会的主席,美国胸科学会重症监护女性委员会的前主席,加拿大重症监护试验组执行委员会的法定成员;她从 Fischer&Paykel 收取费用。AC 从 Getinge、Baxter、Fresenius 收取费用。AD 获得了来自飞利浦、法国卫生部、Respinor、Lungpacer、巴黎公共医院的资金,并从 Lungpacer、Respinor、Lowenstein、Cergy 行政法庭、Liberate Medical 收取了费用
Fischer&Paykel, Getinge, Agence Européenne Informatique, Astra, Baxter, Mindray. SE is member of American Society of Anesthesiology (Data Use Committee) and member of American Society of Anesthesiology (Perioperative Resuscitation and Life Support Committee); she is Data Safety Monitoring Board for the COVID-High Trial; she received fees from Oridion, Zoll, Medtronic, Fischer&Paykel and received equipments from Medtronic, Diasorin, Eli-Lilly, Eisai. EF received fees from Alung Technologies, Baxter, Inspira, Vasomune, Aerogen, GE. NDF is in the Advisory Board of NIH, MHRC Australia, Sedana Medical; he received funding from CIHR, received fees from Xenios. J-PF received funding from Fischer&Paykel, and received fees from Fischer&Paykel, SOS Oxygène. LG received funding from , Estor, and received fees from SIDAM, Grifols, Advitos, Apheretica, Estor, GE. MSH is the Committee of Canadian Critical Care Trials Group and in the Committee of Women in Critical Care of the American Thoracic Society; she received funding from Canadian Institute of Health Research and received support for travel from ESICM, ISICEM. CH leads the National ECMO Registry in Australia (EXCEL Registry) and sits in International ECMO Network Executive and Scientific Committee and is member of Research Committee for ELSO; she received funding from National Health and Medical Research Council, Medical Research Future Fund, AND received support for travel from Fischer&Paykel. CLH is in the Advisory Board of Quantum Health and received funding from National Institute of Health, American Lung Association. SJ received fees from Fischer&Paykel, Draeger Medical, Medtronic, Mindray, Baxter, Fresenius. CK is the Governmental Commission COVID-19 and Hospital Restructuring; he is in the Advisory Board of Bayer and Xenios; he received fees from Bayer, Xenios. AK received funding from Wellcome Trust, and received fees from Clinton Health Access Initiative; received equipments from Fischer&Paykel, and received support for travel from ESICM. JGL received funding from Science Foundation Ireland, Health Research Board Ireland, and received fees from Baxter. MAM received funding from National Institute of Health, Department of Defense, Roche-Genentech, and received fees from Novartis, Gilead Pharmaceuticals, Johnson and Johnson Pharmaceuticals, Cellenkos. DFMA is in the Data Safety Monitoring Board of VIr Biotechnology Inc and of Faron Pharmaceuticals; he is Co-director of Research for the Intensive Care Society and is Director of EME Program of MR-NIHR; he received funding from NIHR, Wellcome Trust, Innovate UK, MRC, Northern Ireland HSC R&D Division, Randox, Novavax, and received royalties from Queen's University Belfast; he received fees from Bayer, GlaxoSmithKline, Boehringer Ingelhelm, Novartis, Eli-Lilly, Sobi. AM is Past- President of the Franch Society of Intensive Care; he received funding from Air Liquide Medical Systems, Fischer&Paykel, and received fees from Bayer, Air Liquide Medical Systems, Fischer&Paykel, Getinge, Covidien, Draeger Medical. NJM is in the Data Safety Monitoring Board of Caviards and NIH Spiromics and Source Studies; he received funding from National Institute of Health, Quantum Leap Health Care Collaborative, and received fees from Endpoint Health Inc, NYU Langone Medical Center, and received support for travel from Intensive Care Society. MM is in the Advisory Board of an NIH Sponsored Trial, and received funding from National Institute of Health. LM was in the Ontario COVID-19 Science Advisory Table, is in the American Thoracic Society Mechanical Ventilation Guidelines Committee and in the ESICM Guidelines Committee; she is Section Editor of Intensive Care Medicine; she received funding from Leukemia and Lymphoma Society of Canada, H Barrie Fairley Scholarship. SNM is President Elect of Indian Society of intensive Care Medicine; is Chair of Intensive Care Section of WFSA; she is member of the ESICM fluid Guidelines Committee. MNG is member of Data Safety Monitoring Board of Regeneron and EMORY; she is Chair of ATS Critical Care Assembly; she received funding from NHLBI, CDC, and received fees from New York Medical College, and received support for travel from ATS. LP is Data Safety Monitoring Board of SESAR; he received fees from Air Liquide Medical Systems, and received support for travel from Lowenstein. BKP received funding from National Institute of Health,Walder Foundation and University of Chicago and received fees from Merk, CHEST Foundation, Subpoena. AP is in Advisory Board of MEGA-ROX and UK-ROX Trails; he received funding from Novo Nordisc Foundation SYGEFORSIKRINGEN Pfizer, and received fees from Novartis. LP received fees from Lowenstein, Lungpacer, Getinge, Hamilton, Fischer&Paykel, GE, Air Liquide Medical Systems, and received support for travel from Getinge, Hamilton, Fischer&Paykel, GE, Air Liquide Medical Systems, and received equipments from Draeger Medical, Getinge. ER received funding from Wellcome Trust, and received equipments from Fischer&Paykel. ASS is Chair of Scientific Committee of ECMONet and he participated on DSMB for Gala Therapeutics; he received fees from Altimmune, Apeiron, Baxter, Cellenkos, Constant Therapeutics, Diffusion Pharmaceuticals, Edesa, Exvastat, Faron, GSK, Fischer&Paykel、Getinge、欧洲计算机机构、阿斯利康、百特、迈瑞。SE 是美国麻醉学会(数据使用委员会)的成员,也是美国麻醉学会(围手术期复苏与生命支持委员会)的成员;她是 COVID-High 试验的数据安全监测委员会成员;她收到了 Oridion、Zoll、美敦力、Fischer&Paykel 的费用,并从美敦力、Diasorin、礼来、卫材获得了设备。EF 收到了 Alung Technologies、百特、Inspira、Vasomune、Aerogen、GE 的费用。NDF 是 NIH、MHRC 澳大利亚、Sedana Medical 的顾问委员会成员;他获得了 CIHR 的资助,并收到了 Xenios 的费用。J-PF 获得了 Fischer&Paykel 的资助,并收到了 Fischer&Paykel、SOS Oxygène 的费用。LG 获得了 、Estor 的资助,并收到了 SIDAM、Grifols、Advitos、Apheretica、Estor、GE 的费用。MSH 是加拿大重症监护试验小组的委员会成员,也是美国胸科学会重症监护女性委员会的成员;她获得了加拿大健康研究所的资助,并从 ESICM、ISICEM 获得了旅行支持。 CH 领导澳大利亚国家 ECMO 注册(EXCEL 注册),并担任国际 ECMO 网络执行委员会和科学委员会成员,同时也是 ELSO 研究委员会的成员;她获得了国家健康与医学研究委员会、医学研究未来基金的资助,并获得了 Fischer&Paykel 的旅行支持。CLH 在 Quantum Health 的顾问委员会中,并获得了国家卫生研究院和美国肺协会的资助。SJ 从 Fischer&Paykel、德尔格医疗、美敦力、迈瑞、百特、费森尤斯获得了费用。CK 是政府委员会 COVID-19 和医院重组的成员;他在拜耳和 Xenios 的顾问委员会中;他从拜耳和 Xenios 获得了费用。AK 获得了威康信托的资助,并从克林顿健康访问倡议获得了费用;从 Fischer&Paykel 获得了设备,并从 ESICM 获得了旅行支持。JGL 获得了爱尔兰科学基金会、爱尔兰健康研究委员会的资助,并从百特获得了费用。 MAM 获得了来自国家卫生研究院、国防部、罗氏-基因泰克的资金,并从诺华、吉利德制药、强生制药、Cellenkos 收取了费用。DFMA 是 VIr 生物技术公司和 Faron 制药公司的数据安全监测委员会成员;他是重症监护学会的研究联合主任,并且是 MR-NIHR 的 EME 项目主任;他获得了来自 NIHR、威康信托、创新英国、医学研究委员会、北爱尔兰 HSC 研发部门、Randox、Novavax 的资金,并从贝尔法斯特女王大学获得了版税;他从拜耳、葛兰素史克、勃林格殷格翰、诺华、礼来、Sobi 收取了费用。AM 是法国重症监护学会的前任会长;他获得了来自空气液化医疗系统、Fischer&Paykel 的资金,并从拜耳、空气液化医疗系统、Fischer&Paykel、Getinge、Covidien、德尔格医疗收取了费用。 NJM 在 Caviards 和 NIH Spiromics 及 Source Studies 的数据安全监测委员会中;他获得了国家卫生研究院、Quantum Leap 健康护理合作组织的资助,并从 Endpoint Health Inc、NYU Langone 医学中心获得了费用,同时还获得了重症监护学会的旅行支持。MM 在一个 NIH 赞助的试验的顾问委员会中,并获得了国家卫生研究院的资助。LM 曾在安大略省 COVID-19 科学顾问小组中,现为美国胸科学会机械通气指南委员会和 ESICM 指南委员会的成员;她是《重症医学》期刊的版块编辑;她获得了加拿大白血病和淋巴瘤协会和 H Barrie Fairley 奖学金的资助。SNM 是印度重症医学会的当选会长;是 WFSA 重症监护部分的主席;她是 ESICM 液体指南委员会的成员。MNG 是 Regeneron 和 EMORY 的数据安全监测委员会成员;她是 ATS 重症护理委员会的主席;她获得了 NHLBI、CDC 的资助,并从纽约医科大学获得了费用,同时还获得了 ATS 的旅行支持。 LP 是 SESAR 的数据安全监测委员会成员;他从空气液化医疗系统收取了费用,并从 Lowenstein 获得了旅行支持。BKP 获得了国家卫生研究院、Walder 基金会和芝加哥大学的资助,并从 Merk、CHEST 基金会和 Subpoena 收取了费用。AP 是 MEGA-ROX 和 UK-ROX 试验的顾问委员会成员;他获得了 Novo Nordisc 基金会、SYGEFORSIKRINGEN 和辉瑞的资助,并从诺华收取了费用。LP 从 Lowenstein、Lungpacer、Getinge、Hamilton、Fischer&Paykel、GE 和空气液化医疗系统收取了费用,并从 Getinge、Hamilton、Fischer&Paykel、GE 和空气液化医疗系统获得了旅行支持,并从德尔格医疗和 Getinge 获得了设备。ER 获得了威康信托的资助,并从 Fischer&Paykel 获得了设备。ASS 是 ECMONet 科学委员会的主席,他参与了 Gala Therapeutics 的 DSMB;他收到了来自 Altimmune、Apeiron、Baxter、Cellenkos、Constant Therapeutics、Diffusion Pharmaceuticals、Edesa、Exvastat、Faron 和 GSK 的费用
Krypton, SafeBVM, SaNOtize, Stimit, Thornhill Scientific, and received equipments from Thornhill Scientific. RDS was member of ATS Board of directors and is member of DSMBs of RCTs in North America and received funding from National Institute of Health, and received support for travel from National Institute of Health, ATS. CS received funding from NIHR, Wellcome Trust,UK Research and Innovation and received fees from GlaxoSmithKline, Abbvie, RocheSanofi-Pasteur. TBT received funding from Department of Defense, National Heart, Lung and Blood Instituite and received fees from Bayer, Novartis, Genentech. CSVB is Scientific Director of Brazilian Association of Critical Care Medicine. JV received funding from Instituto de Salud Carlos III, Madrid, Spain (CB06/06/1088, PI19/00141), The European Regional Development Funds, and Fundación Canaria Instituto de Investigatión Sanitaria de Canarias, Spain (PIFIISC21-36). LBW is the Chair of the American Thoracic Society Awards Committee and is in the DSMB of CHILL Study and SIGNET Study; he received funding from National Institute of Health, Genentech, Boehringer Ingelheim and received fees from Santhera, Global Blood Therapeutics, Boehringer Ingelheim, Merck, Citius, Foresee Pharmaceuticals. BW is member of ESICM NEXT Committee; he received fees from Orion Pharma LTD, Dr. F. Koehler Chemie and received support for travel from Teladoc Health. FGZ received fees from Bactiguard. EA received funding from MSD, GE, Alexion, Pfizer, received fees from Pfizer, Alexion, Mindray, Sanofi and received equipments from Pfizer. The remaining Authors have disclosed that they do not have any potential conflicts of interest. 氪、SafeBVM、SaNOtize、Stimit、Thornhill Scientific,并从 Thornhill Scientific 收到了设备。RDS 是 ATS 董事会成员,并且是北美 RCT 的 DSMBS 成员,获得了国家卫生研究院的资助,并获得了国家卫生研究院和 ATS 的旅行支持。CS 获得了 NIHR、威康信托、英国研究与创新的资助,并从葛兰素史克、艾伯维、罗氏和赛诺菲-巴斯德收取了费用。TBT 获得了国防部、国家心脏、肺和血液研究所的资助,并从拜耳、诺华、基因泰克收取了费用。CSVB 是巴西重症医学协会的科学主任。JV 获得了西班牙马德里卡洛斯三世健康研究所(CB06/06/1088,PI19/00141)、欧洲区域发展基金和西班牙加那利群岛卫生研究所基金会(PIFIISC21-36)的资助。 LBW 是美国胸科学会奖项委员会的主席,并且是 CHILL 研究和 SIGNET 研究的独立数据监测委员会成员;他获得了来自国家卫生研究院、基因泰克、勃林格殷格翰的资助,并从 Santhera、全球血液治疗公司、勃林格殷格翰、默克、Citius、Foresee 制药公司收取了费用。BW 是 ESICM NEXT 委员会的成员;他从 Orion Pharma LTD、Dr. F. Koehler Chemie 收取了费用,并从 Teladoc Health 获得了旅行支持。FGZ 从 Bactiguard 收取了费用。EA 获得了来自 MSD、GE、Alexion、辉瑞的资助,从辉瑞、Alexion、迈瑞、赛诺菲收取了费用,并从辉瑞获得了设备。其余作者已披露他们没有任何潜在的利益冲突。
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Received: 12 January 2023 Accepted: 24 March 2023 收到:2023 年 1 月 12 日 接受:2023 年 3 月 24 日
Published: 16 June 2023 发布:2023 年 6 月 16 日
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*Correspondence: giacomo.grasselli@unimi.it *通讯: giacomo.grasselli@unimi.it Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy Full author information is available at the end of the article 意大利米兰,卡格兰达医院大医院麻醉、重症监护和急救科,IRCCS 基金会。完整的作者信息在文章末尾提供
Giacomo Grasselli, Carolyn S. Calfee and Luigi Camporota contributed equally and should be all considered first authors. 贾科莫·格拉塞利、卡罗琳·S·卡尔菲和路易吉·坎波罗塔贡献相同,均应视为第一作者。
Jordi Mancebo deceased on August 2022. 乔尔迪·曼塞博于 2022 年 8 月去世。
Author details 作者详情 Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. 意大利米兰,卡格兰达医院大医院麻醉、重症监护和急救科。 意大利米兰,米兰大学病理生理学与移植系。 美国加利福尼亚州旧金山,加州大学旧金山分校医学系肺部、重症监护、过敏与睡眠医学部。 Department of Adult Critical Care, Guy's and St Thomas' NHS Foundation Trust, London, UK. Centre for Human and Applied Physiological Sciences, King's College London, London, UK. Operative Unit of Anesthesia and Intensive Care, S. Martino Hospital, Belluno, Italy. Hospital das Clinicas, Universidade de São Paulo, São Paulo, Brazil. Department of Anesthesiology Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Università Cattolica del Sacro Cuore, Rome, Italy. Intensive Care Department, Ministry of the National Guard - Health Affairs, Riyadh, Kingdom of Saudi Arabia. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Kingdom of Saudi Arabia. King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia. 伦敦,英国,盖伊和圣托马斯 NHS 基金信托成人重症监护部。 伦敦国王学院人类与应用生理科学中心,伦敦,英国。 意大利贝卢诺 S.马尔蒂诺医院麻醉与重症监护手术单位。 巴西圣保罗大学临床医院,圣保罗,巴西。 意大利罗马 A.杰梅利大学医院麻醉重症监护与急救医学系。 意大利罗马天主教圣心大学。 沙特阿拉伯利雅得国家卫队卫生事务部重症监护部。 沙特阿拉伯利雅得国王沙特阿卜杜勒阿齐兹健康科学大学。 沙特阿拉伯利雅得国王阿卜杜拉国际医学研究中心。 Department of Anesthesia and Intensive Care, San Giovanni Bosco Hospital, Torino, Italy. Center for Acute Respiratory Failure and Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University, New York, NY, USA. 意大利都灵圣乔瓦尼·博斯科医院麻醉与重症监护科。 美国纽约哥伦比亚大学急性呼吸衰竭中心及肺病、过敏与重症医学科。 Centre for Medical Sciences - CISMed, University of Trento, Trento, Italy. 特伦托大学医学科学中心 - CISMed,意大利特伦托。 Department of Anesthesia and Intensive Care, Santa Chiara Hospital, APSS Trento, Trento, Italy. Intensive Care Medicine, University College London, NIHR University College London Hospitals Biomedical Research Centre, London, UK. Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK. Intensive Care, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands. Keenan Research Center, Li Ka Shing Knowledge Institute, Unity Health Toronto, Toronto, Canada. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada. Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. Department of Medicine, Division of Critical Care, Unity Health Toronto - Saint Michael's Hospital, Toronto, Canada. Li Ka Shing Knowledge Institute, St Michael's 意大利特伦托,APSS 特伦托,圣基亚拉医院麻醉与重症监护科。 英国伦敦大学学院重症医学,NIHR 伦敦大学学院医院生物医学研究中心。 英国贝尔法斯特女王大学威康-沃尔夫森实验医学研究所。 荷兰阿姆斯特丹大学医学中心重症监护,阿姆斯特丹大学,阿姆斯特丹。 加拿大多伦多,李嘉诚知识学院基南研究中心,统一健康多伦多。 加拿大多伦多,大学的重症医学跨部门分部。 美国马里兰州巴尔的摩,约翰霍普金斯大学医学院内科。 加拿大多伦多,统一健康多伦多-圣迈克尔医院内科,重症监护科。 圣迈克尔医院李嘉诚知识学院。