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(Chest. 1999;116:74S-82S.)
© 1999 American College of Chest Physicians

Epidemiology of Acute Lung Injury and ARDS*

Leonard D. Hudson, MD, FCCP and Kenneth P. Steinberg, MD, FCCP

* From the Department of Pulmonary and Critical Care Medicine (Drs. Hudson and Steinberg), Harborview Medical Center, University of Washington School of Medicine (Dr. Steinberg), Seattle, WA.

Correspondence to: Leonard D. Hudson, MD, FCCP, Harborview Medical Center, 325 Ninth Ave., Box 359762, Seattle, WA 98104-2499


   Introduction
TOP
 Introduction
Incidence
 Risk Factors
 Course of ARDS
 Outcomes
 References
 
ARDS and acute lung injury (ALI) are terms used to reflect what we think is a relatively specific form of pathologic injury to the lung but occurring from a wide diversity of causes or associated conditions. The assumption underlying use of these terms is that the abnormality reflects diffuse alveolar damage, involving both the endothelial and epithelial layers. This damage is characterized pathophysiologically by a breakdown in the barrier and gas exchange functions in the lung. Initially this results in flooding of the alveolar spaces with protein-rich edema fluid resulting in severe gas exchange abnormalities. If the process is sustained, fibroproliferation occurs with collagen deposition and lung remodeling. Since pathology specimens are rarely available and no practical methods exist to measure the barrier function or endothelial and epithelial injuries, we are left with definitions using surrogates or clinical reflections of these processes. Thus, we have defined ARDS and ALI in terms of their associated gas exchange abnormalities and radiologic manifestations. The specific definitions used have enormous effects on the outcomes of epidemiologic studies. Therefore, whenever epidemiologic data are evaluated, the specific definitions used must be kept in mind.

The current definitions most widely used are those developed by the American-European Consensus Conference (AECC) on ARDS, published in 1994.1 This international group of experts simplified previous definitions for ease of wide application and limited the criteria for ARDS to (1) an oxygenation abnormality, a PaO2/fraction of inspired oxygen (FIO2) <= 200; and (2) a chest radiograph criterion, bilateral infiltrates compatible with pulmonary edema. This definition also contained a single exclusion factor in an attempt to rule out cardiogenic pulmonary edema as the major cause of the clinical picture, defined as a pulmonary artery wedge pressure >= 18 mm Hg if a pulmonary artery catheter was in place or no clinical evidence of increased left atrial pressure if no wedge pressure measurements were available. In an attempt to define a milder form of injury, the term ALI was coined with the same criteria as ARDS except that the PaO2/FIO2 ratio was <= 300. Since these definitions only became available in 1994, many of the epidemiologic studies have used various definitions, which could lead to differing results.


   Incidence
TOP
 Introduction
 Incidence
Risk Factors
 Course of ARDS
 Outcomes
 References
 
The incidences of ARDS and ALI are not clear. A National Institutes of Health panel in 1972 estimated the incidence of ARDS to be 150,000 cases per year in the United States, an incidence of approximately 75/100,000 population per year.2 This number has been widely used since that time without confirmation from epidemiologic studies. Recent prospective studies have found a much lower incidence of ARDS ranging from 1.5 to 8.4 cases per 100,000 population per year.3 4 5 The method to perform an appropriate incidence study is difficult, requiring a known population base and identification of all patients with the disease or syndrome. A study from the Canary Islands likely captured all cases of ARDS and found an incidence of 1.5 to 3.5/100,000 population.3 However, these investigators used severe oxygenation criteria for ARDS, a PaO2/FIO2 <= 110, resulting in the 1.5/100,000/yr figure, or a PaO2/FIO2 <= 150, resulting in an incidence of 3.5/100,000. The generalizability of this population to other more urban populations has been questioned. A study from Utah used International Classification of Diseases, ninth revision (ICD-9) coding to identify patients and found an incidence of 4.8 to 8.3/100,000 population/year.4 These investigators also used a severe oxygenation criterion of a PaO2/PAO2 <= 0.2, which is equivalent to a PaO2/FIO2 of approximately <= 110 at sea level. Also, some of the assumptions using ICD-9 coding and incomplete sampling of all hospitals can be questioned. A study from Berlin, Germany, identified patients over a short period using a lung injury score (LIS) of >= 2.5 to identify ARDS, finding an incidence of 3.0/100,000 population per year.5 If an LIS of >1.75 was used to include milder forms of lung injury, the resulting incidence was 17.1/100,000/yr. All of these studies were performed before the AECC definitions were developed. Data on the incidence of either ARDS or ALI using AECC criteria have not yet been published (to our knowledge), although a multicenter study from France using a single point in time prevalence determination method has been performed.

In ongoing studies of ALI and ARDS at Harborview Medical Center, University of Washington, in Seattle, WA, we have identified in a 1-year period (1997) an incidence of ARDS by AECC criteria for residents of King County of 12.6/100,000/yr, a single hospital value that is higher than the upper limit of the range determined by any of the previous studies using more severe criteria. The single hospital incidence of ALI for King County residents at Harborview Medical Center was 18.9/100,000/yr; therefore, we think that the incidence of ARDS and especially ALI by AECC criteria is likely to be considerably higher than the recent prospective studies would indicate. However, this remains to be confirmed.


   Risk Factors
TOP
 Introduction
 Incidence
 Risk Factors
Course of ARDS
 Outcomes
 References
 
Incidence of ARDS Associated With Clinical Risk Factors
Risk factors or etiologic factors are either conditions that are associated with ARDS or markers that occur in conditions known to be associated with ARDS. These associated conditions can be either direct (primary)—ie, resulting in direct injury to the lung—or indirect (secondary)—ie, a result of extrapulmonary illness or injury that injures the lungs through activation of systemic inflammation, presumably related in part to elevated blood cytokine levels and other biochemical and cellular mediators. Understanding the importance of various risk factors includes knowing the incidence of ARDS or ALI associated with the particular risk factor but also knowing the prevalence of that particular risk factor in the general population at risk.

Attempts to identify patients at risk for ALI have included identification of clinical conditions or associated findings and also biochemical measurements in the blood or BAL fluid. Obviously, obtaining BAL fluid in all patients at potential risk for ARDS in order to identify those with early or mild injury, which would be more likely to progress to a full-blown clinical picture of ARDS, is not a particularly practical approach to identifying patients at significant risk and is limited essentially to research studies. Measurement of blood biochemical markers, including the cytokines reputedly associated with indirect lung injury, has not been particularly successful. In general, these studies have found that although the finding of elevated levels of cytokines may be necessary for indirect injury (ie, they are specific), they are not adequate in and of themselves to cause injury (ie, they are not particularly sensitive). Thus, a number of patients with either sepsis or trauma have elevated cytokine levels but do not go on to develop ARDS. If any particular level of a specific cytokine is used, there is poor separation between patients who go on to develop ARDS and those who do not. Clinical markers or predictors of ALI are easier to identify and at least as successful in predicting the development of ALI. Thus, only the studies of clinical risk factors predicting ARDS will be reviewed here.

To our knowledge, only three prospective studies have identified clinical risk conditions for ARDS and then measured the subsequent development of ARDS, allowing a calculation of ARDS incidence associated with a particular risk factor.6 7 8 All were based on data collected in the early 1980s. This needs to be kept in mind in reviewing these studies since some clinical practices—for example, clinical indications for administering blood transfusions in trauma patients—may have changed since the data were collected. Two of these studies were performed at Harborview Medical Center in Seattle, WA,6 7 and the other was performed in Denver, CO, at the University of Colorado Medical Center.8 The study designs had differing aims: in the Seattle studies, attempting to identify patients at high risk for ARDS for use in clinical trials, and in the Denver study, attempting to capture all patients at risk for ARDS. When considered together, these studies give us a better picture of ARDS incidence.

An initial small study in Seattle was done preliminary to a clinical trial of early application of positive end-expiratory pressure.6 Exclusion criteria were relatively liberal,7 excluding any patients who might have increased risk from positive end-expiratory pressure application. Thus, only approximately half of the patients who ultimately developed ARDS during the study period were identified by the risk factors (ie, approximately half of the ARDS cases were "missed"). Subsequently, based on these data, the inclusion criteria were refined, the exclusion criteria were limited, and a subsequent larger study was carried out.

The results of the second Seattle study and the Denver study are shown in Table 1 . The study by Fowler et al8 included patients with bacteremia defined as having two positive blood cultures, a definition that was associated with a 4.2% incidence of ARDS. In the Seattle study, a definition of sepsis syndrome was used. This definition was developed prior to the American College of Chest Physicians-Society of Critical Care Medicine (ACCP-SCCM) Consensus Conference that developed sepsis definitions.9 A definition of severe sepsis was similar to that subsequently developed by ACCP-SCCM in that it had elements indicating (1) systemic inflammatory response syndrome (although the elements had more severe requirements than the ACCP-SCCM definition of systemic inflammatory response syndrome), and (2) "deleterious systemic response" or organ failure component, which required evidence suggesting hypotension and hypoprofusion—ie, septic shock. This definition of sepsis syndrome was associated with a 42% incidence of development of ARDS.


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  		Table 1. Frequency of ARDS After Clinical Risk

 
The Seattle study included three markers of severe trauma, including multiple transfusions for emergency resuscitation (15 U within a 24-h period), multiple bone fractures or an unstable pelvic fracture, and lung contusion. Of these, the category of multiple transfusions was associated with the highest incidence of ARDS—35%. Of interest, multiple transfusions were also associated with a 35% incidence of ARDS when they occurred in medicine service patients without trauma. Long bone fractures were associated with the lowest incidence of ARDS of these three—11%—whereas the incidence associated with lung contusion was intermediate—22%. Patients with trauma, including any or a combination of these three definitions, had an overall ARDS incidence of 25.5%. Both studies used the same definition of aspiration of gastric contents—ie, either witnessed aspiration or suctioning gastric contents from the trachea and both found this to be associated with a moderate incidence of ARDS (36% and 22%). The highest incidence of ARDS was associated with sepsis syndrome in the Seattle study and aspiration of gastric contents in the Denver study.

The Denver study included the category of "ICU pneumonia" (a patient with pneumonia admitted to the ICU), which was associated with an incidence of 11.9%. The Seattle study did not include pneumonia. Both studies missed approximately 22% of patients developing ARDS during the study period and pneumonia did not appear to be a prominent diagnosis in the "missed" patients in the Seattle study. This raises the hypothesis that patients with severe pneumonia who are likely to develop the diffuse lung injury of ARDS are also likely to have the elements meeting criteria for sepsis syndrome or severe sepsis.

To our knowledge, no study has prospectively studied risk factors for their association with ALI or ARDS using the AECC definitions. Using these newer definitions with less rigorous radiographic criteria than used in the two previous studies may change the number of patients with severe (bilateral) pneumonia who would be classified as having ARDS. Other issues that limit the usefulness of these studies are the changes in our practices since these studies were carried out, such as a decreased use of blood products in resuscitation of trauma patients and the use of a cell-saver device in the operating room.

Prevalence of ARDS Associated With Clinical Risk Factors
Most ARDS series from around the globe indicate that severe sepsis is the most common risk condition predisposing to ARDS. The prevalence of any given risk condition will vary considerably by both geography and special clinical populations seen at a given institution. However, in general, sepsis is the most common, with aspiration of gastric contents being relatively common, and trauma, less common but still important. Diffuse pneumonia also appears to be a relatively common risk condition. The specific infections related to severe sepsis vary considerably by geographic area. For example, leptospirosis is a common cause of ARDS in Brazil10 and also in Thailand, India, and other tropical countries but not in the United States or western Europe.

Other Factors That Affect ARDS Development
ARDS appears to be more common with increasing age in patients with similar underlying risk conditions.7 11 Gender appears to have no effect on the likelihood of developing ARDS given similar risk conditions.7 11 One study has found that chronic alcoholism carries an increased risk of development of ARDS, given similar risk conditions.12


   Course of ARDS
TOP
 Introduction
 Incidence
 Risk Factors
 Course of ARDS
Outcomes
 References
 
The onset of identification of the risk factors to the onset of meeting the criteria for ARDS was studied by both the Denver and Seattle studies described above with similar findings,7 8 and results from the Seattle study are shown in Figure 1 . When sepsis syndrome is first identified (all criteria are met), approximately 20% of all patients have already developed ARDS. Only a small percent of trauma patients meet the criteria of ARDS at the onset of trauma, probably since the trauma event is well characterized in time, whereas the inflammatory process has been ongoing for some time before severe sepsis criteria are met. Including the three categories of sepsis, trauma and other causes—primarily aspiration of gastric contents, approximately 50% of patients who will eventually develop ARDS do so by 24 h after the onset of their risk event. Approximately 85% will have developed ARDS by 72 h, with the remaining patients who ultimately develop ARDS doing so over the next several days. These patients may simply have delayed lung injury related to systemic inflammation, may have onset of a second risk factor during this time, for example sepsis complicating trauma, or this delay may reflect worsening lung injury developing in mechanically ventilated patients related to ventilator-induced lung injury.



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  		Figure 1. The time from onset of the clinical risk to onset of ARDS in all patients who eventually developed ARDS is displayed. Reprinted with permission from Hudson et al.7

 
The patient's course after the onset of ALI is quite variable. During the first week, patients are both dying and improving and no longer requiring mechanical ventilation. The course has been described graphically by Sloane et al13 in a multicenter-based study based in Philadelphia, PA (Fig 2) .



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  		Figure 2. The course of ARDS is displayed by percent of patients still receiving mechanical ventilation in the hospital, still in the hospital but not receiving mechanical ventilation, and discharged to home. Reprinted with permission from Sloane et al.13

 

   Outcomes
TOP
 Introduction
 Incidence
 Risk Factors
 Course of ARDS
 Outcomes
References
 
Mortality
Factors associated with mortality include risk factor and age. Sepsis as a risk for ARDS is generally associated with a considerably higher mortality than most other common risks, including trauma and aspiration of gastric contents.7 Older patients, often studied as patients > 65 years of age, compared with younger patients have an increased mortality rate as determined in several studies.7 11 14 15 None of these studies considered comorbidities in a multivariant analysis so the effect of age independent from comorbidities is not clear. Suchyta et al14 found fewer organ failures in the older compared with younger patients, leading them to speculate as to whether "age bias" led to a higher rate of withdrawal of life support in older patients. Mortality rate is similar in men and women.7

The severity of ARDS at the time of first diagnosis as measured by oxygenation abnormality (PaO2/FIO2) has generally not been associated with differing outcomes except at the very extremes of abnormalities. These findings suggest no difference in outcome between the AECC definitions of ALI vs ARDS. Zilberberg and Epstein16 found similar mortality in patients with PaO2/FIO2 ratios of < 300 compared with < 200 at the time of first recognition of ALI. Doyle et al17 found similar mortality rates in patients with PaO2/FIO2 < 300 compared with < 150. Earlier, Bone et al18 had found that PaO2/FIO2 ratio at the time of onset of identifying patients with ARDS did not affect outcome; improvement in PaO2/FIO2, however, occurred over the first few days in ultimate survivors but did occur in those who eventually died. Krafft et al,19 in a meta-analysis of 102 publications on ARDS, found no correlation between PaO2/FIO2 and mortality. Subsequently, we have confirmed that oxygenation by AECC criteria for ALI and ARDS does not affect outcome, nor does a more stringent chest radiograph interpretation requiring significant infiltrates filling most of at least three quadrants of the lung fields on frontal chest radiograph compared with a definition requiring only bilateral infiltrates.20

Certain variables reflecting differing pathophysiology have been shown to be associated with differing outcome. For example, patients with higher compared with lower BAL levels of procollagen peptide III, a breakdown product of procollagen generally believed to reflect the intensity of the fibrotic process, were associated with significantly higher mortality.21 A higher concentration of neutrophils in BAL fluid initially and persistence of neutrophils as the predominant cell in the BAL fluid over time has been associated with higher mortality rates.22 23

A study by Montgomery et al,24 published in 1985, found that patients dying after ARDS onset died without their ARDS having resolved, but appeared to die primarily of multiple organ failure and sepsis rather than a respiratory death—ie, due to hypoxia or uncontrollable respiratory acidosis. Suchyta et al14 found a higher proportion of deaths related to respiratory causes. We have performed subsequent analyses using the same definitions and approaches in the Montgomery et al24 study and, although our mortality rate is lower in later years, patients appear to be proportionally dying of the same causes with sepsis and multiple organ failure still being the leading "cause" of death.25 In a study from Brussels, Belgium, Ferring and Vincent26 have also confirmed that sepsis/multiple organ failure is the most common cause of death in patients with ARDS.

There is a debate as to whether fatality rates in patients with ARDS have decreased over time. Suchyta et al14 first reported that patients meeting extracorporeal membrane oxygenation study criteria for ARDS—ie, very severe criteria that had been associated with a 90% mortality in the early 1970s, had had a substantial reduction in mortality by the early 1990s to approximately 50%. Subsequently, we examined outcome in our cohort of patients in whom we had prospectively identified the presence and outcome of ARDS since the early 1980s, using the same definition since that time.27 Through most of the 1980s, mortality was in the range of 60% or higher. A gradual reduction in mortality rate began in approximately 1989 until mortality was in the 30 to 40% range by 1994. This mortality has persisted since that time in our patients (Fig 3) . These data were adjusted for age, risk factor, and gender; APACHE (acute physiology and chronic health evaluation) II scores were similar in the years for which they were available (1981 to 1982, 1990, and 1993) and injury severity scores were similar over time in trauma victims. We also found that mortality had improved in all age groups, including in patients >65 years, although their mortality was still higher than younger patients.28 In a subsequent study by Abel et al,29 mortality was shown to have decreased from approximately 60 to 30% when the years 1990 to 1993 were compared with 1993 to 1996. The prevalence of sepsis and multiple organ failure was unchanged in the two cohorts and age and APACHE II scores were also not different. Krafft et al19 have published a meta-analysis of 102 studies of ARDS plotting mortality against year of publication. They found no reduction in mortality over time. There was a wide range in mortality throughout the entire time that they examined in the studies they included. They concluded that there was no evidence for a reduction in mortality in later years.



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  		Figure 3. Mortality in patients with ARDS prospectively identified at Harborview Medical Center is shown over time. Data through 1994 were reported by Milberg et al.27 Data were adjusted for age, gender, and risk factor. This plot through 1998 shows that mortality has remained between 30% and 40% from 1994 through 1998. The same definition for ARDS was used during this entire time. In the published study, APACHE II scores were similar for patients with sepsis in ARDS at three selected time periods throughout the study and injury severity scores were similar for trauma patients. Reprinted with permission from Milberg et al.27

 
Pulmonary Function in Survivors of ARDS
Several studies have examined pulmonary function in survivors of ARDS.30 31 32 33 34 35 Most of these have studied patients at varying times over the course following discontinuation of mechanical ventilation.30 31 32 33 34 McHugh et al35 studied patients at set time points following discontinuation of mechanical ventilation (Fig 4) . Pulmonary function testing performed within 2 weeks of extubation showed significant restrictive impairments and abnormalities in diffusing capacity. Substantial improvement occurred by 3 months with further improvement at 6 months following extubation. No further improvement occurred at 1 year. Patients either returned to the normal range of pulmonary function or had mild-to-moderate restrictive impairment with abnormal diffusing capacity. Duration of time receiving mechanical ventilation or severity of illness as measured by a cumulative LIS (addition of LISs daily for the period of time receiving mechanical ventilation) was associated with more severe restrictive impairments. This study is consistent qualitatively with most other studies. Most studies have shown improvement over time, but with many patients having persistent mild-to-moderate restrictive impairment.30 31 32 33 34 In the McHugh et al35 study, in a 1-year period, no patients had severe restrictive impairment; however, other studies have the occasional subject who continues to have severe restrictive impairment34 and we have had that anecdotal clinical experience as well, although this occurrence is infrequent. Some earlier studies suggested that mild reversible airflow obstruction developed in some patients following ARDS.36 37 This was not found in the study by McHugh et al35 in which the investigators attempted to study all survivors (although some were missed) rather than selection of survivors with known symptoms or impairment, suggesting that if this does occur, it is unusual.



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  		Figure 4. Pulmonary function is shown as percent of predicted measured within 2 weeks of extubation following ARDS and at 3, 6, and 12 months. There is improvement to 6 months in lung volumes and diffusing capacity with no further improvement at 12 months. Reprinted with permission from McHugh et al.35

 
Quality of Life in Survivors of ARDS
Quality of life in survivors of ARDS was first measured in a systematic way by McHugh et al35 using an instrument called the Sickness Impact Profile (SIP). This instrument had previously been used in large studies of patients with COPD38 39 as well as in a variety of other medical conditions. Health-related quality of life was markedly abnormal when measured within the 2 weeks following extubation but progressively improved to the 1-year time point, the last interval studied, following extubation. At that time, there was a mild-to-moderate decrement in health-related quality of life as measured by the SIP. The mean value for SIP was approximately 10 with high values being more abnormal and a normal population having an SIP of <= 3.5. For comparison, hypoxemic COPD patients in the Nocturnal Oxygen Therapy Trial had a mean SIP of approximately 2538 and less severely hypoxemic COPD patients in the Intermittent Positive Pressure Breathing Trial had a mean SIP of 18.39 Other investigators have subsequently confirmed abnormality in health-related quality of life using other instruments.40 41 42 Abnormalities were found in multiple domains of quality of life in all studies. Hopkins et al40 found significant neuropsychological deficits in ARDS survivors. They presented evidence for more severe or protracted hypoxemia in patients with greater abnormalities on neuropsychological testing as opposed to those with less severe or no abnormalities.

A recent study examined whether impairment in health-related quality of life was related to the development of ARDS or was associated with the clinical critical illness (risk factor or condition) associated with ARDS. Davidson et al43 compared quality of life in survivors of ARDS associated with sepsis or trauma to comparison or control groups of patients with severe sepsis or trauma who did not develop ARDS. Patients with severe sepsis were matched to patients with ARDS related to sepsis by APACHE III scores and trauma control subjects were matched to ARDS patients associated with trauma by injury severity scores. Decrements in health-related quality of life were identified by both generic and respiratory-specific instruments in ARDS survivors compared with published normal data. Perhaps more importantly, ARDS survivors had more impaired health-related quality of life than the two control groups, survivors of severe sepsis and trauma without ARDS (Fig 5) . Thus, it appears that ARDS confers an additional burden of morbidity following hospital discharge than that associated with the underlying illnesses or injuries predisposing to ARDS.



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  		Figure 5. Health-related quality of life in three domains as measured by the Short Form 36 generic health-related quality of life instrument and compared with published normal values. Patients with sepsis and trauma with ARDS are compared to matched sepsis and trauma patients without ARDS. The function in each domain was significantly more impaired in ARDS survivors than in matched sepsis and trauma control subjects. Sepsis control subjects were matched by APACHE III scores to ARDS patients with sepsis. Trauma control subjects were matched by injury severity scores to ARDS patients with trauma. Reprinted with permission from Davidson et al.43

 


   References
TOP
 Introduction
 Incidence
 Risk Factors
 Course of ARDS
 Outcomes
 References
 

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