< 觀念剖析 >急性呼吸窘迫症候群最常見的基礎疾病是敗血症和創傷。它的特點是肺泡-毛細血管膜對水、溶質、血漿蛋白等物質通透性顯著增高，在ICUward，仍是常見棘手的問題。
< 介紹 > ARDS最早在1967年由Ashbaugh提出，稱作成人呼吸窘迫症候群(adult respiratory distress syndrome)。在1994年，國外專家開會，將ARDS的adult改為acute，即Acute respiratory distress syndrome急性呼吸窘迫症候群之意。並且制定ARDS統一標準﹕(1)急性發作；(2)氧合指數(PaO2/FiO2)≦ 200mmHg；(3)CXR呈現雙肺浸潤；(4)肺動脈楔嵌壓≦18mmHg。
< 誘發因素 >
直接肺損傷 (direct lung injury) | -- 胃內容物吸入(Inhaling vomited stomach contents from the mouth)；-- 吸入煙霧、刺激性或毒性氣體(Breathing in harmful fumes or smoke)；--需要重症監護的肺炎(pneumonia)；--近期溺水(Nearly drowning)；--使用呼吸機( Using a ventilator) |
間接肺損傷 (Indirect lung injury) | -- 嚴重敗血症 ( septicemia) ；--複合性wound：胸部頭部外傷； -脂肪栓塞 ( Fat embolism)；--胰腺炎( Pancreatitis)；-輸血過多、嚴重出血 ( Severe bleeding caused by an injury to the body or having many blood transfusions )；--心肺分流；--藥物反應( Drug reaction) |
< 發病過程 > 暴露於上述某個誘發因素後，早期肺功能表面正常的一個間期，持續數小時或者數天出現症狀，持續1-3天以上之肺順應性和功能殘氣量下降肺順應性進一步下降，VD/VT以及肺血管阻力增加多器官功能衰竭，以心、腎、肝功能不全常見發病第10~30天，進入緩慢階段，肺功能在數周或數月慢慢恢復
< ARDS病理改變 > 肺部變化源於廣泛性的肺泡-微血管受損，使得內皮細胞通透性增加，引起肺泡出血及水腫現象，最後導致肺內死腔及分流增大，肺順應性與氧合變差。 肺組織學檢查表明， ARDS 存在著急性和慢性階段，大致而言病理變化包含三期：滲出期 (exudates) 、增殖期 (proliferative) 、纖維期 (fibrosis) ：1、在早期階段，主要以肺泡Ⅰ型上皮細胞破壞為主；內皮細胞腫脹、間質水腫，伴有細支氣管和血管周圍的水腫。2、慢性階段以纖維組織增生為主，在1~2週後明顯，間質內可見漿細胞、淋巴細胞浸潤，之後可見成纖維細胞增生，常見血管內微血栓，柱狀上皮細胞覆蓋在肺泡及肺泡管表面，肺腺泡結構逐漸被束狀纖維組織所取代。目前ARDS患者死於呼吸衰竭的機率<5%，大多死於Sepsis或多重器官衰竭，死亡率約50%。肺纖維化程度決定日後患者肺功能與生活品質。
< ARDS病理改變 > 1、在出現症狀明顯的呼吸衰竭之前，病人呼吸急促而表淺(feeling like you can't get enough air into your lungs, rapid breathing, short of breath)，可以出現紫紺(a bluish color on your skin and lips)，聽診常有支氣管呼吸音(abnormal breathing sounds, such as crackling)。有時因心腎的血流灌注不足，可出現低血壓、乏力、意識改變等情況，應多加注意(Sometimes, people who have ARDS develop signs and symptoms such as low blood pressure, confusion, and extreme tiredness. This may mean that the body's organs, such as the kidneys and heart, aren't getting enough oxygen-rich blood)。2、An arterial blood gas test：提示低氧血症(A low level of oxygen in the blood may be a sign of ARDS)，PaO2下降而PaCO2正常或下降；當完全發展為ARDS時，PaO2/FiO2≦200mmHg。3、CXR：提示呈迅速進展的肺彌漫性浸潤影，常伴有特徵性肺泡充填的影像。4、血常規、血液生化、血培養、痰培養等，有助於明確感染等誘因(Blood tests, such as a complete blood count, blood chemistries, and blood cultures. These tests help find the cause of ARDS, such as an infection) 5、 Chest CT scan、心臟超音波。
< 最新動物研究進展 > 目前，對於應用正壓通氣(positive pressure ventilation) 的動物模型觀察發現：維持氣道峰壓30cmH2O 24小時，導致肺損傷，因此，提出了一個ARDS新機制：正壓通氣的動物模型中，肺內炎症因數前體合成增加，使肺表面活性物質的結構和功能發生改變。然而，當限制最大通氣量或是應用PEEP可使損傷消失
< ARDS治療 > 雖然對ARDS之生理機轉已有較深入瞭解，但治療目前尚無其他特殊方法，早期治療主要是支持治療，同時找出和處理那些潛在加重ARDS的可逆性因素與過程。主要目標是保證動脈血氧及外周組織供氧充足，同時要防止呼吸器可能造成的肺損傷加重。(1)早期應用 Steroid 藥物並不能阻止其進展或改變預後；在纖維增殖階段使用高劑量類固醇曾證實有效，但大型研究已證實，此方法無法有效降低死亡率。(2)另外，應用藥物阻斷炎症反應鏈的某些緩解或控制細胞因數的研究，結果令人失望。(3)控制飲食中的脂類或給予谷胱甘 前體可能有幫助。(4)在早期 ARDS 患者氣道內滴入表面活性物質，可能會改善氣體交換，降低整體死亡率；但用氣溶膠形式補充表面活性物質，效果不理想。目前，該類研究仍在進行中。【註】(1)盡快降低 [O2] ，以避免氧毒性。(2)設定低潮氣量(6 ml/kg)，以維持高原氣道壓力(plateau)＜30~35cmH2O，可減輕呼吸器對肺的再次損傷，降低死亡率。(3)可允許血[CO2]＞50mmHg。(4) 使用PEEP可增加功能殘留容積，改善通氣血流灌注比例(V/O)，進而增進肺部氧合(FiO)效果。(5)給予適當的tranquilizer與muscle relaxants，避免患者與呼吸器"打架"，增進患者與呼吸器之協調性。
近幾年來， ARDS 的存活率大幅提升。影響存活率的幾項因素包括：患者年齡、引起 ARDS 的基礎疾病、伴隨疾病等等 (Survival rates for ARDS vary depending on age, the underlying cause of ARDS, associated illnesses) 。
ARDS柏林定義診斷準則 內科學誌 2013：24：79-84黃健裕 李毓芹 陽光耀 ARDS舊的定義1988年3，Murray等學者曾把實質肺損傷(parenchymal lung injury)定義的組成(表一)分成1. 病程的急性或慢性、2. 肺損傷的程度(依據lung injury score計 分)、 與3. 發 生 原 因 等三部分討論。其中lung injury score (表二)是依據胸部X光、氧合能力(PaO2/FiO2 ratio)、PEEP的大小、與肺順應性的大小分別以0-4來計分，總和平均>2.5分就是ARDS。但是就此ARDS診斷定義而言仍舊沒有一被廣為接受的準則，於是經過各方的討論在1994年美國與歐洲共識會議 (The American-European Consensus Conference, AECC)上對ARDS的定義(以下簡稱AECC定義)、機轉、預後及臨床試驗加以說明與規範4,5，其重點有I. ARDS的A應該代表為acute而非adult，也就是ARDS的全名是Acute respiratory distress syndrome、II. ARDS是 一 種由發炎造成肺通透性增加所產生一連串臨床、影像與生理異常的症候群，而這現象無法單純由左心房與肺血管高壓解釋、III. 診斷須符合以下四項準則(表三)：(1) 急性發作。(2) 胸部X光為雙側浸潤。(3) 肺動脈楔壓≤ 18mmHg，無左心房高壓。(4) 氧合異常：PaO2/FiO2 ≤ 200mmHg。同時他們還定義了一個新的涵蓋範圍比較廣泛的名詞--急性肺損傷(acute lung injury, ALI)，它使用相同的診斷條件，但氧合異常比較輕微(PaO2/FiO2 ≤ 300 mmHg)、IV. 主要的危險因子可以分為直接因素與間接因素，直接因素有：吸入性肺炎、散佈性肺感染、溺水、有毒氣體吸入及肺挫傷；而間接因素有：敗血症、重度非胸原性創傷、輸血或急救復甦及體外循環等。ARDS新的定義--柏林定義(Berlin Definition) (表五)柏林定義與AECC定義一樣易於使用，並且延續以往的概念，也就是ARDS是一種急性瀰漫性的肺部炎症反應伴隨肺泡 - 毛細血管膜(alveolar capillary membrane)通透性增加所造成的水腫，臨床特點包括低氧合、低肺順應性、多生理死腔與雙側X光陰影(opacity)。而柏林定義的優點在於它不但釐清AECC定義所遇到的問題，同時也改善了ARDS死亡率的預測能力。就柏林定義診斷準則的子項，介紹如下。一、急性(acute)的定義從ARDS危險因子的暴露到症候群的產生，柏林定義對『急性』的定義為7天內。會選擇7天是因為先前已經有研究顯示21，雖然大多數患者在暴露於危險因子後72小時內會發展為ARDS，但幾乎所有患者的ARDS皆發生於危險因子暴露後的7天之內。二、胸部X光表現柏林定義雖然維持原AECC定義，ARDS的胸部X光表現須符合雙側肺陰影(opacity)，不過柏林定義明確定義這些雙側肺陰影必須無法完全以積液、肺塌陷或肺結節就可以解釋。三、氧合能力(oxygenation)的分類柏林定義依據PaO2/FiO2值，分別以300 mmHg、200 mmHg、100 mmHg三個切點，把ARDS分為輕度、中度及重度，會如此區分是因為研究顯示PaO2/FiO2值與預後有關22,23。同時取消急性肺損傷(ALI)一詞。六、常見的危險因子AECC定義曾提及ARDS的危險因子並且區分為直接性或間接性肺損傷，不過這些並沒有放在AECC診斷準則裡，再者直接性或間接性肺損傷的表現除了發炎反應、影像與對呼吸器使用的生理反應有一些不同外，大致而言是差不多。因此柏林定義除了把危險因子納入診斷準則外，這些危險因子(包含肺炎、非肺因性敗血症、吸入胃內容物、創傷、肺挫傷、胰臟炎、吸入性傷害、嚴重燒傷、非心因性休克、藥物中毒、輸血引起的肺損傷、肺血管炎及溺水等)，也不再區分直接性或間接性的傷害了。
The receptor for advanced glycation end products (RAGE) is now identified as a marker of alveolar type I cell injury. RAGE is a member of the immunoglobulin superfamily that acts as a multiligand receptor and is involved in propagating inflammatory responses. While the precise function of RAGE remains unclear, the elevated levels of RAGE, and its soluble isoform sRAGE, correlate with severity of ALI/ARDS in human and animal studies, and RAGE levels could reflect impaired alveolar fluid clearance. Frequently, the biology of RAGE coincides with settings in which ligands of the receptor accumulate, especially in a proinflammatory environment. More work is needed for us to understand the mechanisms by which RAGE is regulated during ALI/ARDS, especially with regard to the expression of its soluble forms and the involvement of its potential ligands.
DESIGN NARRATIVE: This observational prospective clinical study will describe and compare soluble forms (sRAGE, esRAGE) and ligands of RAGE (HMGB-1, S100A12, AGEs) levels in the alveolar edema fluid and in the plasma from ICU patients enrolled within the first 24 hours after onset of ALI/ARDS, and from patients under mechanical ventilation (control group). Edema fluid and plasma samples will be collected simultaneously on day 1, day 3 and day 6, in order to describe kinetics of evolution of soluble forms and ligands of RAGE levels. Undiluted pulmonary edema fluid samples will be collected in intubated patients only, and blood samples will be simultaneously gathered from indwelling arterial and central venous catheters. The concentrations of soluble forms (sRAGE, esRAGE) and ligands of RAGE (HMGB-1, S100A12, AGEs) will be measured in duplicate by ELISA.
PATHOGENESIS Lung injury is initiated by a specific insult but can be exacerbated by inappropriate mechanical ventilatory strategies (reviewed by Whitehead and Slutsky later in this series). Briefly, alveolar overdistension can generate a proinflammatory response which is exacerbated by repetitive opening and closing of alveoli as occurs through the use of inappropriately low levels of positive end expiratory pressure (PEEP). Indeed, overdistension or recurrent opening/closing of alveoli can also induce structural damage to the lung. The effect of high inspired concentrations of oxygen on the disease process is uncertain, particularly in humans. However, prolonged exposure to 100% oxygen is fatal in most animal models, producing neutrophil influx and alveolar edema that can be blocked in rodents using anti-inflammatory strategies such as inhaled low dose carbon monoxide. The main players in the inflammatory process are neutrophils and multiple mediator cascades. The fibroblast is key in the fibroproliferative response and is the target of regulators of matrix deposition. A complex interplay of regulatory cytokines counteracts the inflammatory mediators; similarly, matrix deposition is balanced by the actions of the metalloproteases. There is no uniform response to injury: some patients develop ARDS, some ALI, and some do not develop pulmonary symptoms at all. The reasons for this are not clear but may be partly genetic. There is evidence for a genetic susceptibility to sepsis and, recently, to ARDS itself.44–46
Surfactant dysfunction Inflammation leads to surfactant dysfunction in ARDS.76 Surfactant is secreted mainly by alveolar type II cells and consists of phospholipids (predominantly phosphatidylcholine) and surfactant specific proteins, SP-A, SP-B, SP-C and SP-D. The ability of surfactant to lower surface tension is critically dependent on both the phospholipid and the protein components, especially the hydrophobic proteins SP-B and SP-C. The phospholipids are stored in the lamellar bodies of type II cells and interact with surfactant proteins upon release from the cells, forming large aggregates called tubular myelin. During the normal cycle of breathing these functional large surfactant aggregates become dissipated, reducing to smaller aggregates which do not have the same surface tension lowering properties. Type II cells take up these small aggregates and recycle them into new surfactant. The hydrophilic surfactant protein SP-A, quantitatively the major surfactant protein, plays a key role in this process. The other hydrophilic surfactant protein is SP-D, which may also have a function in phospholipid recycling. SP-A and SP-D are members of the collectin family and form part of the innate immune system in the lung; interestingly, both have significant antibacterial activity and inhibit neutrophil apoptosis. Surfactant levels are dramatically decreased in the infant respiratory distress syndrome due to immaturity of the type II cells. By contrast, in ARDS surfactant deficiency is not a primary causal event; rather, the inflammatory processes lead to surfactant dysfunction as a secondary factor. Damage and loss of type II cells leads to decreased synthesis and recirculation of surfactant. This defect in turnover can lead to accumulation of small aggregates, while overall surfactant performance follows a reduction in the functional large surfactant aggregates and damage to surfactant proteins. In addition, the protein rich oedema in ARDS "contaminates" surfactant, further reducing its functional capacity. Furthermore, in lung injury the ratio of minor phospholipids to phosphatidylcholine increases, possibly indicating damage and release of cell membrane lipids. The degree to which surfactant dysfunction contributes to the pathogenesis of ARDS is currently not clear. Thorax 2002;57:540-546
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