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Isn’t it time to abandon ARDS? The COVID-19 lesson
Critical Care ( IF 8.8 ) Pub Date : 2021-09-06 , DOI: 10.1186/s13054-021-03748-6
L Gattinoni _{1,

2} , J J Marini _{1,

2}

Affiliation

In 1967, Ashbaugh et al. [1] reported 12 patients having respiratory failure of different origins who presented a set of similar features. According to current parlance, those elements might constitute a phenotype: (1) hypoxemia refractory to oxygen administration; (2) low respiratory system compliance; (3) bilateral x-ray infiltrates; and for non-survivors, heavy lungs at autopsy. This collection of characteristics, manifesting itself as respiratory difficulty, was called the adult respiratory distress ‘syndrome’ (ARDS) by analogy with similar features observed in premature neonates with surfactant deficiency, termed infant respiratory distress syndrome. (syndrome = symptoms which run together).

The logic behind ‘ARDS’ was that appropriate treatment, primarily of hypoxemia, was similar across patients, regardless of causal etiology (i.e., disease). Some authors [2] questioned the wisdom of lumping together as a unique syndrome such sharply different diseases. The term ‘ARDS’, however, rapidly gained traction and transformed into “Acute” instead of “Adult” Respiratory Distress. ARDS rapidly became the signature “disorder” of the newly fledged discipline of intensive care [3].

Because lungs and clinical manifestations of ‘ARDS’ looked superficially similar regardless of etiology, it was reasoned that the respiratory treatment should be essentially the same. Quite quickly this became the universally accepted approach. One clear advantage of lumping together different diseases into a single entity was that large, randomized trials of treatment became feasible. Indeed, since the number of trial patients required to show significant clinical differences of 5–6% for key variables might require more than two thousand patients, the need to adopt definitions broad enough to allow enrolment of a sufficient number of patients became evident. We believe that this has been a main driver for modifications to the ARDS definition that occurred over subsequent decades. The refractory hypoxemia of Ashbaugh’s original definition of ARDS became first PaO₂/FiO₂ ratio 300 mmHg and then 200, and the core feature of low compliance was excluded from later definitions on the questionable basis that measures of respiratory mechanics add little predictive value [4]. Such definitional simplification facilitated study enrollment. For many clinicians, each definitional refinement solidified ‘ARDS’ as a descriptor of a distinct “disease-like” entity. As an example, in a widely quoted paper we find: “the rate of clinician recognition of ARDS was low, with 40% of all cases not being diagnosed” [5]. Which diagnosis? The Ashbaugh? The Chicago? The Berlin? Does it really matter [6]?

Considering ARDS as a ‘disease’ with specific treatment had some advantages; through randomized trials using the broadened ARDS definition, we confirmed that gentle treatment of the lung is the most efficacious approach to this respiratory syndrome. We should not forget, however, that all knowledge from randomized trials has derived primarily from ARDS populations with bacterial pneumonia and septic abdominal disease [7]. Other causes for ARDS are rather sparsely represented. Meanwhile, physiological and pathophysiological studies dissect differences among ARDS populations with distinguishable characteristics and treatment responses, beginning with pulmonary and extra-pulmonary [8]. Indeed, there is now progressive pressure towards ‘personalizing’ medicine, a process which, in a sense, is exactly the opposite from the lumping used to define a syndrome. Against this framework, COVID-19 pneumonia abruptly appeared and changed our lives. Did also it change our thinking?

As many COVID-19 patients present to the hospital with acute bilateral lung opacities the label of “ARDS” has been reflexively assigned and standard treatments for ARDS applied, in line with guidelines of the panels representing the National Institutes of Health and the Surviving Sepsis Campaign [9]. The recommended ‘lung protective’ strategy (low tidal volume and PEEP guided by published PaO₂/FiO₂ tables) led to the early use of PEEP levels exceeding 14 cmH₂O [10]. However, front-line physicians treating these patients soon recognized that regardless of the severity of hypoxemia, the early stage COVID-ARDS lungs were unusually compliant and gas filled. At the same time, the prerequisites for PEEP to work, i.e., lung collapse and recruitability of functional units, were marginal, and unlike traditional ARDS, hypoxemia at COVID’s early stage was due primarily to impaired perfusion regulation, rather than true shunt. Moreover, in patients who failed to improve, compliance impressively deteriorated and pathophysiologic mechanisms dramatically changed. These findings introduced a question that initiated hot debate: Are treatment guidelines derived from studies of patients with ARDS caused by bacterial pneumonia and sepsis (which are characterized by recruitable ‘baby’ lungs) well suited to COVID-caused ARDS distinguished by unrecruitable and mechanically evolving ‘adult’ lungs? The answer is important; respiratory treatment likely plays a key role in determining outcome, as the reported ICU mortality rates for the same disease significantly varied between different ICUs [11, 12].

COVID-19 has clearly taught us that this “atypical” form of ARDS requires different treatment than “typical” ARDS. Similar reasoning could be applied for the pulmonary versus extra-pulmonary or for the inflammatory versus non-inflammatory phenotypes. This progressive migration towards “personalized” medicine implies the loss of the primary therapeutic advantage that initially led to lumping that justifies a uniform approach.

At this stage, two different scenarios are possible to accommodate the discordant and inconvenient COVID-19 observations: (1) modify, rearrange, and rethink the ARDS definition; or (2) abandon the ARDS term as understood in its present form (Table 1). In support of the first option, it has been proposed to expand the ARDS definition by modifying the radiological criterion to include ultrasound imaging, the gas-exchange criterion to allow pulse oximetry [13], and the oxygenation support criterion to recognize the use of high-flow oxygen and moderate PEEP [14]. It is difficult for us to understand the advantages of this ‘ultra-lumping’ approach [15]. If that course is taken, nearly all forms of respiratory distress will be diagnosed as ‘ARDS’. Why should we do this if appropriate management should be different? It seems more logical simply to label the diseases as they are: for example, pneumococcal respiratory distress, herpes respiratory distress, pancreatitis respiratory distress, etc. This de-lumping’ approach would push our thinking towards truly personalized medicine, realizing that not only the etiological treatment but also the appropriate respiratory approach might well be different in different situations and at different stages of the disease process.

Table 1 Keeping and abandoning ARDS: advantages and disadvatages

Full size table

Not applicable.

1.
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967;2(7511):319–23.
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4.
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Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E, Oczkowski S, Levy MM, Derde L, Dzierba A, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med. 2020;48(6):e440–69.
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Matthay MA, Thompson BT, Ware LB. The Berlin definition of acute respiratory distress syndrome: should patients receiving high-flow nasal oxygen be included? Lancet Respir Med. 2021.
15.
Brown SM, Peltan ID, Barkauskas C, Rogers AJ, Kan V, Gelijns A, Thompson BT. What does "ARDS" mean during the COVID-19 pandemic? Ann Am Thorac Soc. 2021.

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Department of Anesthesiology, Medical University of Göttingen, Robert Koch Straße 40, 37075, Göttingen, Germany
L. Gattinoni & J. J. Marini
Department of Pulmonary and Critical Care Medicine, University of Minnesota and Regions Hospital, St. Paul, MN, USA
L. Gattinoni & J. J. Marini

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Gattinoni, L., Marini, J.J. Isn’t it time to abandon ARDS? The COVID-19 lesson. Crit Care 25, 326 (2021). https://doi.org/10.1186/s13054-021-03748-6

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Received: 18 August 2021
Accepted: 25 August 2021
Published: 06 September 2021
DOI: https://doi.org/10.1186/s13054-021-03748-6

中文翻译：

是不是该放弃ARDS了？COVID-19 课程

1967 年，Ashbaugh 等人。[1] 报告了 12 名不同来源的呼吸衰竭患者，他们表现出一组相似的特征。根据目前的说法，这些元素可能构成一种表型：（1）对氧气管理难治的低氧血症；(2)呼吸系统顺应性低；(3)双侧X线浸润；对于非幸存者，尸检时肺部沉重。这一系列表现为呼吸困难的特征被称为成人呼吸窘迫“综合征”(ARDS)，类似于在表面活性剂缺乏的早产新生儿中观察到的类似特征，称为婴儿呼吸窘迫综合征。（综合症 = 一起出现的症状）。

“ARDS”背后的逻辑是，无论病因（即疾病）如何，患者之间的适当治疗（主要是低氧血症）是相似的。一些作者 [2] 质疑将如此截然不同的疾病作为一种独特的综合征混为一谈是否明智。然而，“ARDS”一词迅速受到关注并转变为“急性”而非“成人”呼吸窘迫。ARDS 迅速成为新兴的重症监护学科的标志性“疾病”[3]。

由于无论病因如何，“ARDS”的肺部和临床表现在表面上看起来都相似，因此有理由认为呼吸治疗应该基本相同。很快，这成为普遍接受的方法。将不同的疾病归为一个单一实体的一个明显优势是大型随机治疗试验变得可行。事实上，由于需要显示关键变量 5-6% 的显着临床差异的试验患者数量可能需要超过 2000 名患者，因此需要采用足够广泛的定义以允许招募足够数量的患者。我们认为，这一直是随后几十年发生的 ARDS 定义修改的主要驱动因素。₂ /FiO ₂比率为 300 mmHg 然后为 200，并且基于呼吸力学测量几乎没有预测价值的问题，后来的定义排除了低依从性的核心特征 [4]。这种定义简化促进了研究注册。对于许多临床医生来说，每一次定义的改进都将“ARDS”固化为一个独特的“疾病样”实体的描述词。例如，在一篇被广泛引用的论文中，我们发现：“临床医生对 ARDS 的识别率很低，所有病例中有 40% 未被确诊”[5]。哪个诊断？阿什堡？芝加哥？柏林？真的重要吗[6]？

将 ARDS 视为一种需要特殊治疗的“疾病”有一些优势；通过使用扩大的 ARDS 定义的随机试验，我们证实对肺进行温和治疗是治疗这种呼吸综合征最有效的方法。然而，我们不应忘记，来自随机试验的所有知识主要来自患有细菌性肺炎和败血性腹部疾病的 ARDS 人群 [7]。ARDS 的其他原因很少被提及。同时，生理学和病理生理学研究剖析了具有可区分特征和治疗反应的 ARDS 人群之间的差异，从肺和肺外开始 [8]。事实上，现在对“个性化”医学的压力越来越大，从某种意义上说，这个过程与用于定义综合征的集总正好相反。在此框架下，COVID-19 肺炎突然出现并改变了我们的生活。是否也改变了我们的想法？

由于许多 COVID-19 患者因急性双侧肺混浊就诊，因此根据代表美国国立卫生研究院和败血症幸存运动的专家组的指导方针，反射性地分配了“ARDS”的标签并应用了 ARDS 的标准治疗[9]。推荐的“肺保护”策略（低潮气量和 PEEP 由已发布的 PaO ₂ /FiO ₂表指导）导致早期使用超过 14 cmH ₂ O的 PEEP 水平[10]。然而，治疗这些患者的一线医生很快意识到，无论低氧血症的严重程度如何，早期 COVID-ARDS 肺都异常顺应且充满气体。同时，PEEP 起作用的先决条件，即肺塌陷和肺复张能力功能性的单位，是边缘的，并且与传统的 ARDS 不同，COVID 早期的低氧血症主要是由于灌注调节受损，而不是真正的分流。此外，在未能改善的患者中，依从性显着恶化，病理生理机制发生了巨大变化。这些发现提出了一个引发热议的问题：源自对细菌性肺炎和败血症（其特征是可再生的“婴儿”肺）引起的 ARDS 患者的研究的治疗指南是否非常适合 COVID 引起的 ARDS，其特点是不可招募和机械演变“成人”肺？答案很重要；呼吸治疗可能在决定结果方面起着关键作用，因为报告的同一疾病的 ICU 死亡率在不同 ICU 之间存在显着差异 [11, 12]。

COVID-19 清楚地告诉我们，这种“非典型”ARDS 形式需要与“典型”ARDS 不同的治疗方法。类似的推理可以应用于肺与肺外或炎症与非炎症表型。这种向“个性化”医学的逐步迁移意味着失去最初导致统一方法合理化的主要治疗优势。

在这个阶段，有两种不同的场景可以适应不一致和不方便的 COVID-19 观察：（1）修改、重新排列和重新思考 ARDS 的定义；或 (2) 放弃 ARDS 术语的现有形式（表 1）。为支持第一种选择，有人提议通过修改放射学标准来扩展 ARDS 定义以包括超声成像、气体交换标准以允许脉搏血氧饱和度测定 [13] 以及氧合支持标准以识别使用高- 流动氧气和适度的 PEEP [14]。我们很难理解这种“超集总”方法的优势 [15]。如果采取该课程，几乎所有形式的呼吸窘迫都会被诊断为“ARDS”。如果适当的管理应该不同，我们为什么要这样做？简单地给疾病贴上标签似乎更合乎逻辑：例如，肺炎球菌呼吸窘迫、疱疹性呼吸窘迫、胰腺炎呼吸窘迫等。这种去集结的方法将推动我们思考真正的个性化医疗，意识到不仅在不同情况下和疾病过程的不同阶段，病因治疗以及适当的呼吸方法可能会有所不同。

表1 保留和放弃ARDS：优点和缺点

全尺寸表

不适用。

1.
Ashbaugh DG、Bigelow DB、Petty TL、Levine BE。成人急性呼吸窘迫。柳叶刀。1967；2（7511）：319-23。
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默里 JF。社论：成人呼吸窘迫综合征（愿它安息）。Am Rev Respir Dis。1975;111(6):716-8。
CAS PubMed 谷歌学术
3.
Gattinoni L, Quintel M. 五十年的 ARDS 研究为什么急性呼吸窘迫综合征对重症监护如此重要？Am J Respir Crit Care Med。2016;194(9):1051-2。
文章谷歌学术
4.
Ranieri VM、Rubenfeld GD、Thompson BT、Ferguson ND、Caldwell E、Fan E、Camporota L、Slutsky AS。急性呼吸窘迫综合征：柏林定义。杂志。2012;307(23):2526-33。
考研谷歌学术
5.
Bellani G、Laffey JG、Pham T、Fan E、Brochard L、Esteban A、Gattinoni L、Van Haren FMP、Larsson A、McAuley DF 等。50 个国家重症监护病房急性呼吸窘迫综合征患者的流行病学、护理模式和死亡率。JAMA J Am Med Assoc。2016;315(8):788-800。
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7.
急性呼吸窘迫综合征 N，布劳尔 RG，马赛马，莫里斯 A，舍恩费尔德 D，汤普森 BT，惠勒 A。与传统潮气量相比，用于急性肺损伤和急性呼吸窘迫综合征的潮气量较低的通气。N Engl J Med。2000;342(18):1301-8。
文章谷歌学术
8.
Pelosi P、D'Onofrio D、Chiumello D、Paolo S、Chiara G、Capelozzi VL、Barbas CS、Chiaranda M、Gattinoni L。肺和肺外急性呼吸窘迫综合征是不同的。欧洲呼吸杂志增刊。2003 年。
9.
Alhazzani W、Moller MH、Arabi YM、Loeb M、Gong MN、Fan E、Oczkowski S、Levy MM、Derde L、Dzierba A 等。败血症幸存运动：2019 年冠状病毒病 (COVID-19) 重症成人管理指南。暴击护理医学。2020;48(6):e440-69。
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Riviello ED、Kiviri W、Twagirumugabe T、Mueller A、Banner-Goodspeed VM、警官 L、Novack V、Mutumwinka M、Talmor DS、Fowler RA。使用柏林定义的基加利修改版的急性呼吸窘迫综合征的医院发病率和结果。Am J Respir Crit Care Med。2016;193(1):52-9。
文章谷歌学术
14.
Matthay MA、汤普森 BT、Ware LB。急性呼吸窘迫综合征的柏林定义：是否应包括接受高流量鼻氧的患者？柳叶刀呼吸医学。2021。
15.
Brown SM、Peltan ID、Barkauskas C、Rogers AJ、Kan V、Gelijns A、Thompson BT。在 COVID-19 大流行期间，“ARDS”是什么意思？Ann Am Thorac Soc。2021。

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