Current Opinion in Critical Care:
RESPIRATORY SYSTEM: Edited by Peolo Pelosi
The acute respiratory distress syndrome: incidence and mortality, has it changed?
Villar, Jesúsa,b,c; Sulemanji, Demetd,e; Kacmarek, Robert M.d,e
aCIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid
bResearch Unit, Hospital Universitario Dr Negrin, Las Palmas de Gran Canaria, Spain
cKeenan Research Center at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada
dDepartment of Respiratory Care, Massachusetts General Hospital
eDepartment of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence to Robert M. Kacmarek, Department of Respiratory Care, Massachusetts General Hospital, 55 Fruit Street, Warren 1225, Boston, MA 02114, USA. Tel: +1 617 7244480; fax: +1 617 7244495; e-mail: email@example.com
Purpose of review
The purpose of this review is to examine and discuss the incidence and outcome of patients with the acute respiratory distress syndrome (ARDS). This is a challenging task, as there is no specific clinical sign or diagnostic test that accurately identifies and adequately defines this syndrome.
This review will focus on published epidemiological studies reporting population-based incidence of ARDS, as defined by the American-European Consensus Conference criteria. In addition, the current outcome figures for ARDS patients reported in observational and randomized controlled trials will be reviewed. The focus will be on studies published since 2000, when the ARDSnet study on protective mechanical ventilation was published, although particular emphasis will be on those articles published in the last 24 months.
On the basis of current evidence, and despite the order of magnitude of reported European and USA incidence figures, it seems that the incidence and overall mortality of ARDS has not changed substantially since the original ARDSnet study. The current mortality of adult ARDS is still greater than 40%.
In 1967, Ashbaugh et al. described the acute respiratory distress syndrome (ARDS). From a cohort of 272 patients who were receiving respiratory support, they identified 12 patients with a syndrome similar to the infant respiratory distress syndrome, defined as sudden, catastrophic and often associated with a multiple organ system insult that led to hypoxemia, decreased respiratory system compliance and bilateral pulmonary infiltrates on chest radiograph due to noncardiogenic pulmonary oedema. The mortality rate was 58%, and on pathological examination, the lungs of the nonsurvivors were heavy with atelectasis, interstitial and alveolar oedema, and hyaline membranes. Since that time, the hallmarks of this syndrome have included a risk factor for the development of ARDS (i.e. sepsis, trauma, pneumonia), severe hypoxemia with a relatively high FiO2, decreased pulmonary compliance, bilateral pulmonary infiltrates and no clinical evidence of cardiogenic pulmonary oedema .
ARDS is caused by an insult to the alveolar-capillary membrane that results in increased permeability and subsequent interstitial and alveolar oedema. The mechanisms by which a wide variety of insults can lead to this syndrome are not completely understood. Independent of the underlying disease, the pathogenesis of ARDS is the result of two different pathways: a direct insult on lung cells and an indirect insult as a result of an acute systemic inflammatory response. The inflammatory responses to the initial direct (pulmonary) or indirect (nonpulmonary) insults are key factors in determining the development and progression of the acute lung injury (ALI) . Despite our improved understanding of the role of cellular and humoral components of the inflammatory responses in the lung, the precise sequence of events leading to lung damage is not fully understood. Like any form of inflammation, ALI during ARDS represents a complex process in which multiple cellular signalling pathways propagate or inhibit lung injury.
INCIDENCE OF ACUTE RESPIRATORY DISTRESS SYNDROME: HOW MANY CASES PER 100 000 INHABITANTS?
As it is difficult to measure changes in alveolar-capillary permeability at the bedside, diagnosis of ARDS is based on a combination of clinical, oxygenation, haemodynamic and radiographic criteria. These criteria allow the inclusion of a highly heterogeneous group of patients, as various types of lung injury can lead to a similar pulmonary response. Having a precise definition would help standardize experimental and clinical studies evaluating the natural history, incidence, treatment and outcome of ARDS. A good example of the problems inherent to a definition for ARDS is the wide disparity of its incidence. Reported data for the incidence of ARDS in the United States (USA) would suggest a figure that is greatly in excess of that expected by current clinical experience in Europe. The most common figure cited for the incidence of ARDS is 75 cases per 100 000 population per year. This is based on an American Lung Program Task Force of the National Heart and Lung Institute in 1972 . That internal report suggested that there were about 150 000 cases of ARDS per year in the USA, a value similar to the annual number of all new cases of cancer. In order to better characterize ARDS, an American-European Consensus Conference (AECC) defined ALI and ARDS as follows : acute and sudden onset of severe respiratory distress; bilateral infiltrates on frontal chest radiograph, and the absence of left atrial hypertension (a pulmonary capillary wedge pressure <18 mmHg or no clinical signs of left ventricular failure); and severe hypoxemia (assessed by the paO2/FiO2 ratio). According to these guidelines, ALI exists when the paO2/FiO2 ratio is 300 mmHg or less regardless of PEEP and FiO2, and ARDS when the paO2/FiO2 ratio is 200 mmHg or less regardless of PEEP and FiO2. Although this definition formalized the criteria for the diagnosis of ARDS, it has been challenged over the years [6▪▪].
Within the context of extreme variability among the few incidence studies on ARDS, we will only review the population-based studies performed in adults and children and published after 2000 using the AECC definition and lung protective ventilation , as there is unequivocal evidence that mechanical ventilation with tidal volume more than 9 ml/kg body weight can cause or aggravate ALI . There are only four main studies on ARDS incidence in adults [9–11,12▪] published in the last decade using the AECC definition and ventilating patients with a mean tidal volume of 9 ml/kg or less body weight (Table 1), one from the USA and three from Europe. The three European studies [9,11,12▪] reported a similar population-based incidence ranging from 5 to 7.2 new ARDS cases/100 000 population/year. This figure is markedly lower than the 33.8/100 000/year reported by Li et al. in the USA. Li et al. performed a retrospective analysis of patients admitted over an 8-year period (2001–2008) in two hospitals serving a USA county with 125 000 adults. By using what they called an ‘electronic ARDS screening tool’, they reviewed patients’ charts focusing on recorded information for qualifying chest radiographs and paO2/FiO2 ratios. They identified 514 ARDS cases over the 8 years (42 in 2008), representing an incidence of 33.8/100 000. Current clinical practice in Europe does not support such a high ARDS incidence in critically ill patients [9,13]. Differences in demographics and economical and healthcare systems might account for the order of magnitude difference between the reported incidence figures in Europe and the USA. There are also marked variations between the USA and Europe in the number of ICU beds, ICU utilization, ICU staffing and burden of disease requiring ICU admission . ICUs in the USA admit many more patients than European and Canadian ICUs . As stated by Li et al., the demographic features of their catchment area are not identical to those of the USA as a whole. In a recent retrospective analysis, Charron et al. from France reported their experience with 218 ARDS patients admitted during a 13-year period (1997–2009) in a single ICU, representing 16.7 ARDS patients admitted per year, a very similar figure to the 15 ARDS/hospital/year in the recent ALIEN study by Villar et al..
There are only four main studies reporting the population-based incidence of ARDS in children [16–18,19▪▪] published in the last decade using the AECC definition and protective mechanical ventilation (Table 2). Zimmerman et al. performed the first population-based study in the USA of children with ALI and ARDS admitted to four hospitals from a single county over a 1-year period. They identified 29 patients meeting the AECC criteria, representing an incidence of 9.5 cases/100 000/year. In their study, mean tidal volume at the onset of ARDS was 9.3 ml/kg . A prospective, multicentre study from Australia and New Zealand reported an incidence of 2.9/100 000/year  and a retrospective study in The Netherlands estimated an incidence of 2.2/100 000/year , although this study emphasized the possibility that the incidence could have been underestimated. Recently, López-Fernández et al.[19▪▪] performed the largest epidemiological study in the Western world in a catchment area of 3.8 million children. They identified 146 cases meeting the AECC definition, representing an incidence of 3.9/100 000/year. In summary, the incidence of ARDS in children is lower than that reported in adults, especially in the USA.
DYING WITH AND FROM ACUTE RESPIRATORY DISTRESS SYNDROME
Approximately 80% of all deaths in adult ARDS patients occur within 2–3 weeks after the onset of the syndrome . The exact cause of death in patients with ARDS remains elusive. No autopsy studies have yet revealed why patients with ARDS die. In most epidemiological studies using the AECC definition, the most common predictors of mortality include age, the underlying medical condition, degree of lung damage, extra-pulmonary organ dysfunction and ongoing sepsis. Only a small portion of ARDS patients die from hypoxemia. However, lung injury appears to predispose patients to the development of a systemic inflammatory response that culminates in multiple system organ dysfunctions (MSODs) .
MSOD is a cumulative sequence of organ dysfunctions in patients suffering from the same diseases often found in ARDS patients. ARDS and MSOD share a common pathophysiology; both ARDS and MSOD result from a severe uncontrolled total body inflammatory response, not necessarily involving bacteria or endotoxin, although sepsis has been generally incriminated as the primary causative condition. Organs primed by cytokines are damaged both morphologically and functionally. Experimental and clinical evidence suggest that the development of MSOD is due to alveolar epithelial-endothelial barrier disruption and the migration of cytokines produced in the lungs into the systemic circulation [21▪]. Recent experimental and clinical work demonstrates that circulating histones, which are major nuclear proteins, resulting from extensive cell death, are able to mediate distant organ damage, particularly of the lungs, and contribute to MSOD [22▪,23▪]. In light of current evidence on ventilator-induced lung injury (VILI), ventilator-induced inflammatory responses can alter cellular pathways that are important for the normal function of tissues and organs and are partially responsible for the development of sepsis or a sepsis-like syndrome even with negative blood cultures. Although it remains unclear how inflammatory mediators exert their detrimental effects on distal organs, experimental studies and clinical trials have shown that the application of protective ventilatory strategies is associated with decreased cytokine levels, decreased MSOD and decreased mortality [7,24].
Mortality rates of ARDS have been high since the syndrome was first described. Current overall mortality approximates 40–50% in all major series [11,25]. Differences in patient selection, severity of underlying disease, patient age, predisposition for ARDS, persistence of lung severity and mode of mechanical ventilation may explain the differences in mortality reported in most studies. In general, there is a discrepancy between the intuitive impression of many clinicians and the apparent pessimism in the clinical literature (Fig. 1) [6▪▪,11,12▪,26,27▪]. When pooling outcome data from published reports during 1967–1997, the overall mortality is greater than 50% . The year 1994 marked a turning point in the outcome figures for ARDS. That year, Hickling et al. from New Zealand published the results of a prospective study evaluating the outcome of 53 patients with ARDS treated with peak inspiratory pressure limitation to 30–40 cmH2O, low tidal volumes (4–7 ml/kg) and permissive hypercapnia without the use of bicarbonate to buffer acidosis. The ARDS mortality was significantly lower than predicted (26 vs. 53%). To test these findings, Amato et al. from Brazil conducted a randomized controlled trial using high PEEP and low tidal volume (≤6 ml/kg) in 53 patients with ARDS and found an absolute 33% reduction in mortality (37.9 vs. 70.8%), supporting the hypothesis that limitation of peak inspiratory pressures and limitation of lung overdistension may reduce VILI and improve outcome. From that year, almost all published studies have consistently reported a survival rate higher than 50% [25,27▪]. Phua et al. performed a systematic review of 53 observational studies and 36 randomized controlled trials and examined mortality trends before and after 1994 (when the AECC ARDS definition was published). They found that mortality decreased over time in observational studies before 1994. However, mortality did not decrease in observational studies between 1994 and 2006, with an average mortality of 44%. They also found that the presence of ARDS was not an independent predictor of mortality and that this mortality was consistently higher than that reported in randomized controlled trials (36%). In a recent nationwide cohort reviewing changes in the epidemiology and treatment of ARDS over 23 years, Sigurdsson et al.[12▪] from Iceland found that the mortality had decreased from 50% in 1988–1992 to 33% in 2006–2010.
To date, the only proven, widely accepted method of mechanical ventilation for ARDS is protective lung ventilation using a low tidal volume strategy and moderate to high levels of PEEP. There are sufficient data to conclude that patients with ARDS must be ventilated with a tidal volume of 4–8 ml/kg predicted body weight and a plateau pressure of less than 30 cmH2O. Ventilation with lower tidal volumes is now a routine strategy for treatment of ARDS and ALI, stopping investigators from performing additional trials [30▪]. In addition, using small tidal volumes in patients without ARDS is highly recommended [8,31,32], and there appears to be no evidence of harm, if clinicians address issues related to maintenance of sufficient PEEP and the respiratory acidosis that may arise. Even anaesthetized patients undergoing long-term surgery should be ventilated intraoperatively with lung protective ventilation [33▪▪].
THE FUTURE OF ACUTE RESPIRATORY DISTRESS SYNDROME
Given that severe hypoxemia is a hallmark of ARDS, it is crucial to the assessment of ARDS severity, for predicting the development and evolution in any given patient, and for assessing the response to treatment. Several investigators have examined whether various parameters of oxygenation and/or lung mechanics would be useful in predicting outcome [34,35], but predictors of death are similar to those predictive of mortality in the general ICU population . Villar et al. were the first to demonstrate a large variability in the severity of lung damage in ARDS patients and a strong correlation between oxygenation impairment and ICU outcome. As current guidelines for ARDS management do not follow a strict stratification as seen in patients with coronary artery diseases, diabetes or arterial hypertension, Villar et al. explored whether selected threshold values of respiratory, ventilation and physiological variables at the time of ARDS onset could be associated with ICU mortality, independent of the underlying disease or specific therapy. They found that a tertile stratification model was able to predict a profile at the time of ARDS onset associated with the greatest or the lowest risk for ICU death. Tertile categorization of patients based on age, plateau pressure and paO2/FiO2 detected crucial information about the patient population that was not evident when evaluating the mean values of those variables. Of note, although the mean paO2/FiO2 at study entry was similar in ICU survivors and nonsurvivors, when stratifying the values of paO2/FiO2, the tertile of paO2/FiO2 less than 112 mmHg at ARDS onset identified a group of patients with a mortality almost double that of the other two tertiles combined (47 vs. 25%). Risk stratification of ARDS could have several benefits. First, it would identify patients who should be the target of extraordinary measures in clinical trials aimed to decrease ARDS mortality. This speculation is supported by the results of two large meta-analyses of clinical trials in ALI/ARDS patients that evaluated the impact on survival of prone ventilation  and high PEEP  and the results of a recent randomized controlled trial on prone ventilation [39▪▪]. Second, risk stratification might identify patients in whom benefit from treatment may be limited or disproportional to the resources used. And third, the identification of ARDS in the lowest risk group would potentially allow healthcare cost savings through earlier discharge from the ICU.
The incidence of ARDS has not changed substantially in Europe in the last 10 years, but it is an order of magnitude lower than the reported incidence in USA. When considering epidemiological studies using the AECC definition and protective ventilation, it seems that mortality of ARDS has not changed since the original ARDSnet study, although several randomized controlled trials have reported an improvement in survival in selected ARDS patients. It is plausible that broad application of lung protective ventilation, appropriate setting of PEEP, restriction of blood transfusion and rapid management of sepsis would decrease incidence and mortality of hospital-acquired ARDS.
This study is supported in part by Instituto de Salud Carlos III, Spain (#10/0393 and CB06/06/1088).
This manuscript has been drafted, seen, reviewed and approved by all contributing authors.
Conflicts of interest
Dr Sulemanji has no conflict of interest in relation to this manuscript. Dr Villar has received research grants from Maquet. Dr Kacmarek is a consultant for Covidien/Newport and has received research grants for Covidien and Hollester. In addition, he has received honorarium from Maquet for lectures.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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In this prospective epidemiological study, the use of paO2/FiO2 calculated under a standard ventilatory setting (PEEP ≥10 cmH2O on FiO2 ≥ 0.5) within 24 h of ARDS diagnosis allowed a more clinically relevant classification into mild, moderate and severe ARDS.
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A retrospective analysis of all patients in Iceland who met the American-European consensus criteria for ARDS from 1988 to 2010.
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This is the largest study to estimate prospectively the paediatric population-based ARDS incidence and the first incidence study performed during the routine application of lung protective ventilation in children.
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A description of a novel and highly reproducible and clinically relevant double-hit animal model of ALI induced by chest trauma and polymicrobial sepsis to investigate the pathophysiology of ALI.
22▪. Abrams ST, Zhang N, Manson J, et al. Circulating histones are mediators of trauma-associated lung injury. Am J Respir Crit Care Med. 2013; 187:160–169.
The authors measured circulating histone levels in a cohort of 52 patients with severe blunt trauma. Their findings suggest that high levels of circulating histones in trauma patients may be an early biomarker for lung injury and, more importantly, may be a cause of lung injury and multiple organ dysfunctions.
23▪. Zhang H, Villar J, Slutsky AS. Circulating histones: a novel target in acute respiratory distress syndrome? Am J Respir Crit Care Med. 2013; 187:118–120.
This is an editorial to the work by Abrams et al.  proposing that therapeutic strategies targeting the effects of circulating histones provide novel potential pharmacological approaches to treat ARDS and multiple organ dysfunction.
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27▪. Villar J, Sulemanji DS, Kacmarek RM. Spiro SG, Silverstri GA, Agusti A. Acute respiratory distress syndrome. Clinical respiratory medicine. Philadelphia:Elsevier Saunders; 2012;. 454–470.
This book chapter represents the latest and most complete update on definition, pathophysiology, management, prognosis and outcome of ARDS.
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30▪. Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013; 2: CD003844
This systematic review is an update of a Cochrane review originally published in 2003 and updated in 2007. No new studies were eligible for inclusion in this update. The use of lower tidal volumes as a routine ventilatory strategy for ALI and ARDS is stopping investigators from performing additional trials.
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33▪▪. Futier E, Constantin JM, Paugam-Burtz C, et al. A trial of intraoperative low-tidal volume ventilation in abdominal surgery. N Engl J Med. 2013; 369:428–437.
This is a randomized controlled trial in 400 patients at risk of pulmonary complications after major abdominal surgery to determine whether a multifaceted strategy of lung protective ventilation during surgery could improve outcomes after abdominal surgery, as compared with the standard practice of nonprotective ventilation. This trial proved without reservation that the intraoperative use of lung protective ventilation reduces healthcare utilization after surgery.
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35. Villar J, Pérez-Méndez L, Basaldúa S, et al. A risk tertiles model for predicting mortality in patients with acute respiratory distress syndrome: age, plateau pressure, and PaO2/FiO2 at ARDS onset can predict mortality. Respir Care. 2011; 56:420–428.
36. Villar J, Pérez-Méndez L, López J, et al. An early PEEP/FiO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2007; 176:795–804.
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38. Briel M, Meade M, Mercat A, et al. Higher vs lower PEEP in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010; 303:865–873.
39▪▪. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013; 368:2159–2168.
A randomized controlled trial in 466 patients for evaluating the effects of early application of prone positioning on outcomes in severe ARDS. Early application of prolonged prone positioning significantly decreased 28-day mortality.
acute lung injury; acute respiratory distress syndrome; incidence; mortality; outcome
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