The acute respiratory distress syndrome.docx

1、The acute respiratory distress syndromeReview seriesThe acute respiratory distress syndromeMichael A. Matthay,1 Lorraine B. Ware,2 and Guy A. Zimmerman31Cardiovascular Research Institute and Departments of Medicine and Anesthesia, UCSF, San Francisco, California, USA.2Division of Allergy, Pulmonary

2、and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.3Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, Utah, USA.The acute respiratory distress syndrome (ARDS) is an important cause of acute

3、respiratory failure that is often asso- ciated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arteria

4、l hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved su

5、r- vival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.IntroductionSince the original description of the acute respiratory distress syn- drome (ARDS) in 1967, considerable progre

6、ss has been made in understanding the pathogenesis and pathophysiology of acute lung injury (ALI) (14). The likelihood of survival is determined by the severity of lung injury, the extent of nonpulmonary organ dysfunction, preexisting medical conditions, and the quality of supportive care. Because A

7、RDS is a complex syndrome with a broad clinical phenotype, it has been challenging to translate the results of cell and animal studies to pharmacologic therapies that reduce mortality in humans. Nevertheless, laboratory-based inves- tigations have produced valuable insights into the mechanisms respo

8、nsible for the pathogenesis and resolution of lung injury, and preclinical studies paved the way for important improvements in supportive care. Two of these therapies, lung-protective ventila- tion and fluid-conservative management, have reduced mortality and morbidity, respectively. This review of

9、ARDS will focus on some of these issues, including new insights into the molecular mechanisms of lung injury and repair.Definitions, epidemiology, incidence, and mortality Criteria for the diagnosis of ARDS have evolved. The original description emphasized rapidly progressive respiratory failure fro

10、m noncardiogenic pulmonary edema, requiring mechanical ventilation because of severe arterial hypoxemia and difficulty breathing (5). In 1988, a 4-point scoring system provided a quan- titative assessment of lung injury severity based on the degree of hypoxemia, the level of positive end-expiratory

11、pressure (PEEP), static respiratory compliance, and the extent of radiographic infiltrates (6), and this scoring system has been useful for research and clinical trials. In 1994, a consensus conference recommended simplified criteria: arterial hypoxemia with PaO2/FiO2 ratio less than 300 mmHg and le

12、ss than 200 mmHg to define ALI and ARDS, respectively, and bilateral radiographic opacities without evidence of left atrial hypertension (7). These criteria have been widely utilized, although some investigators believe that the defi- nitions should specify the level of PEEP and/or the fraction of i

13、nspired oxygen. A recent report what is now called the Berlin definition recommends use of three categories of ARDS, basedon the degree of hypoxemia: mild (200 mmHg PaO2/FiO2 300 mmHg), moderate (100 mmHg PaO2/FiO2 200 mmHg), and severe (PaO2/FiO2 100 mmHg) (8). Whether stratification of patients ba

14、sed on these descriptions will advance the efficacy of clinical detection and of charting the natural history of ARDS remains to be determined.Most investigations have focused on ALI and/or ARDS patients who are already mechanically ventilated. Recently, progress has been made in diagnosing ALI in s

15、pontaneously breathing patients who have bilateral pulmonary infiltrates and arterial hypoxemia and in whom intravascular volume overload and congestive heart failure are excluded (9, 10). This approach facilitates patient identification and testing of new therapies prior to the need for mechanical

16、ventilation. Figure 1 provides a clinical vignette describing early recognition of ALI.Bacterial or viral pneumonia is the most common cause of ALI and ARDS (1). Sepsis due to nonpulmonary infections, aspira- tion of gastric contents, and major trauma with shock also com- monly precipitate the injur

17、y. Less commonly, acute pancrea- titis, transfusions, drug reactions, and fungal and parasitic lung infections are linked to ALI and ARDS. The coexistence of two or more of these risk factors can enhance the likelihood of develop- ing ALI or ARDS (1).A prospective epidemiologic study in 19992000 est

18、imated an annual incidence of ALI and ARDS of 190,000 adult patients in the United States (11). There is a substantial incidence of ALI and ARDS in children as well (12, 13). Data from 20012008 indicate that the incidence of ALI and/or ARDS in hospitalized adults has declined, perhaps secondary to m

19、ore widespread use of lung-pro- tective ventilation, reductions in nosocomial infections, and more conservative use of blood products (14, 15).Severe arterial hypoxemia (PaO2/FiO2 0.60) are associated with higher mortality (16), as are shock, liver dysfunction, acute kid- ney injury, age over 60 yea

20、rs, and higher severity of illness scores (1719). Based on the NIH Heart, Lung and Blood Institute (NHLBI) ARDS Network trials, 60-day mortality has declined from 36% in 19961997 to 26% in 20042005 (20). The most recent ARDS Network clinical trials reported a 60-day mortality of 22% in adult patient

21、s despite higher APACHE III scores and aConflict of interest: The authors have declared that no conflict of interest exists.Citation for this article: J Clin Invest. 2012;122(8):27312740. doi:10.1172/JCI60331.higher incidence of shock at enrollment compared with a prior trial in 2006 (Figure 2 and r

22、ef. 4).Figure 1Chest radiograph of a patient with influenza-related pneumonia that illustrates early ALI, which progressed over 48 hours to more classic ALI that required positive-pressure ventilation. (A) Anterior-posterior portable chest radiograph of a previously healthy 41-year-old man who prese

23、nted to the emergency department with a 2-day history of myalgias and fever, a productive cough, and shortness of breath. Chest auscultation revealed rales and rhonchi posteriorly in both lung fields. The chest radiograph demonstrates patchy infiltrates in the right lower lung field and also in the

24、left lower lung field. (B) Anterior-posterior chest radiograph 48 hours after the chest radiograph in A, 1 hour after endotracheal intubation (arrow) and initiation of positive-pressure ventilation using the ARDS Network lung-protective ventilation protocol (97). There was marked progression of the

25、bilateral radiographic infiltrates, with dense consolidation in the right upper, right lower, and left lower lung zones. The patients hypoxemia steadily worsened during the 48 hours following his initial presentation, accompanied by an increase in respiratory rate to 40 breaths/minute. Diagnostic ev

26、aluation confirmed H1N1 influenza infection. All cultures for bacteria were negative. Recent clinical investigation indicates that it is possible in some patients to diagnose ALI in an early phase (9), as shown in A, well before the progression of acute respiratory failure to the need for mechanical

27、 ventilation, as illustrated in B. Earlier diagnosis of ALI could facilitate testing of therapeutic strategies that may have time- dependent efficacy prior to the development of established ALI that requires intubation and mechanical ventilation.Environmental and genetic influencesEnvironmental and

28、genetic factors that contribute to susceptibil- ity and severity of ALI and ARDS have emerged as a major research focus. Chronic alcohol abuse increases the risk of ALI and ARDS(21) and multiple organ failure in septic shock (22). Both active and passive cigarette smoke exposure, as quantified by pl

29、asma lev- els of cotinine, have been independently associated with the devel- opment of ALI after severe blunt trauma (23). The mechanisms may include priming effects of cigarette smoke exposure on the lung endothelium, alveolar epithelium, or inflammatory cells.Variants in more than 25 genes have b

30、een associated with devel- oping ALI and/or ARDS and with clinical outcomes (24) including common variants of genes that regulate inflammation, coagula- tion, endothelial cell function, reactive oxygen radical generation, and apoptosis (2529) all processes that are important in lung injury and repai

31、r (2, 30, 31). For example, the Fas pathway modu- lates apoptosis, inflammation, and epithelial cell injury; in a can- didate gene study, common genetic variants in Fas were associated with susceptibility to developing clinical lung injury (27). African Americans with ALI have a higher risk of death

32、 compared with white patients. A candidate gene study identified a functional T-46C polymorphism (rs2814778) in the promoter region of the Duffy antigen/receptor for chemokines (DARC) gene that was associated with a 17% increase in 60-day mortality in African- American patients enrolled in ARDS Network clinical trials. Plas- ma interleukin-8 levels were increased in those individuals with the DARC polymorphism, supporting one mechanism contribut- ing to a worse clinical outcome (29).Genetic polymorphisms that predispose individuals to