Epidemiology of acute lung injury

Gordon D. Rubenfeld, MD, MSc

Objective: To review the epidemiology of acute lung injury (ALI)

with particular emphasis on its effect on public health.
Data Sources: Published studies on the definitions, incidence,
and outcomes of ALI.
Data Summary: ALI is a syndrome of acute hypoxemic respiratory failure that is not primarily cardiac in origin. The diagnostic
criteria for the syndrome have not been well studied for their
reliability or validity. The lack of a gold standard for the diagnosis
of ALI is a challenge to clinical investigation. Recent data on the
incidence of ALI (20 50 cases/105 person-years) indicate that it is
more common than previous estimates for the incidence of acute
respiratory distress syndrome (3 8 cases/105 person-years).
There is conflicting evidence as to whether the mortality rate in

pidemiology is the study of

the incidence and etiology of
disease. Clinical epidemiology addresses questions that
are particularly relevant to the clinicians who care for patients: for example, the accuracy of diagnostic criteria,
the effectiveness of available treatments, and the prognosis for patients.
Understanding the epidemiology of a
disease is essential for understanding
the burden of illness it places on the
population and for evaluating etiological factors that were discovered in the
laboratory. Because epidemiology assesses risks that cannot be randomized
(e.g., sepsis, tobacco smoking, particulate air pollution) and describes the
variation of disease occurrence in population, it is not an experimental science. Experimental control is provided
through study design and analysis
rather than randomization.
Studying the epidemiology of acute
lung injury (ALI) raises important challenges. ALI is operationally defined by

From the Division of Pulmonary and Critical Care

Medicine, Harborview Medical Center, University of
Washington, Seattle, WA.
Presented, in part, at the Margaux Conference on
Critical Illness, Cabo da Roca in Sintra, Portugal, November 1317, 2002.
Copyright 2003 by Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000057904.62683.2B

S276

the broader patient population with ALI is different from the

mortality rate in acute respiratory distress syndrome. Mortality
attributable to and associated with ALI in the United States is
comparable to HIV infection, breast cancer, and asthma. Morbidity
from impaired cognitive function, functional status, and psychiatric complications has been reported in survivors of ALI.
Conclusions: Recent studies of the epidemiology of ALI have
reported higher incidence rates for this syndrome than previously
described. The mortality and morbidity rates associated with ALI
are considerable, with significant impact on public health. (Crit
Care Med 2003; 31[Suppl.]:S276 S284)
KEY WORDS: acute lung injury; attributable mortality; bias; epidemiology; public health

laboratory, radiologic, and physiologic

criteria that themselves have not been
well characterized (1). There is no diagnostic test for ALI, such as troponin in
myocardial infarction, or bacterial culture in infectious diseases. Even the consensus terminology can be confusing.
The American-European Consensus Conference nomenclature uses ALI as a comprehensive term for the syndrome and
acute respiratory distress syndrome
(ARDS) to refer to a specific subset of
patients with more severe hypoxemia
(PaO2/FIO2 ratio 200) (1). Discharge diagnostic codes, which are used to study
the epidemiology of many diseases, do
not accurately identify patients with the
syndrome (2). Compared with chronic
diseases like cancer or asthma, ALI has a
short duration and high short-term mortality rate, which limits the number of
prevalent cases available for study at any
given time.
Finally, the epidemiology of critical
illness syndromes is further complicated
by two medical realities. First, for the
most part, epidemiology of these syndromes is performed in the intensive care
unit (ICU); therefore, the epidemiology is
partially determined by factors that affect
access to the ICU. Second, in nearly all
cases, mortality in the ICU reflects a decision to withdraw life support (3, 4).
Therefore, it is virtually impossible to
separate out risk factors for death from

the critical illness syndrome from factors

that predispose to the decision to withdraw life support.

Diagnosis
The general concepts behind the diagnosis of ALI are well accepted. It is a
syndrome of acute hypoxemic respiratory
failure, with a radiographic picture of
pulmonary edema that is not the result of
congestive heart failure or volume overload (5). In fact, there are only two reasons to have specific diagnostic criteria
for ALI: research and clinical care. Clinical research requires all investigators to
identify similar patients to generate reproducible science. Diagnostic criteria
for ALI are only relevant in clinical care if
the diagnosis entails either a specific
therapy or unique prognostic information.
The quality of diagnostic criteria is
judged by three measures:

Feasibility
Validity
Reliability

Feasibility. Feasibility is difficult to

quantitatively assess and depends on the
purpose of the diagnostic criteria. Feasibility usually involves tradeoffs with validity or reliability. For example, to ensure a homogeneous patient population,
the identification of ALI patients for a
Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

genetic epidemiology study may require

that all patients be evaluated with computed tomography, standardized ventilator settings, and bronchoscopy. Since
these procedures are not feasible in the
routine screening of critically ill patients,
they may be ideal for a genetic epidemiology study but impractical in defining an
ALI population for testing a clinical intervention.
Validity. Validity is defined as the ability of a test or definition to capture what
the investigator truly seeks to measure.
When a gold standard is available, criterion validity can be assessed with sensitivity, specificity, and accuracy. However,
critical illness syndromes, such as ALI,
ventilator-associated pneumonia, and
sepsis, lack accepted gold standards. This
is not a unique problem in medicine, and
reliance on syndromic criteria has not
been an insurmountable challenge to
drug development, genetic epidemiology,
or clinical care in psychiatry, rheumatology, or pulmonary medicine. When there
is no gold standard, validity can be assessed empirically by a number of criteria
(Table 1).
Predictive validity deserves special
mention. Definitions are said to have predictive validity if they identify patients
who respond to therapy or who have different outcomes. For example, cancer
staging has predictive validity because it
identifies patients with different mortality rates and those who respond to different therapeutic strategies. The systemic
inflammatory response syndromesepsissevere sepsisseptic shock categorization has predictive validity because it
identifies patients with increasing mortality rates (6).
In contrast, the distinction between

ALI, ARDS, and acute hypoxemic respiratory failure has variable predictive ability.
In a study by Luhr et al. (7, 8) of acute
respiratory failure in Scandinavia, there
was no significant difference in mortality
rate between the group of patients with
acute respiratory failure and those with
ALI. In a French multicenter study, ARDS
patients had a considerably higher mortality rate (60%) compared with acute
respiratory failure (31%) from other
causes (9). Finally, in an Australian cohort study, patients with ARDS had a
higher mortality rate than those with ALI
who did not meet the criteria for ARDS
(34% vs. 15%); however, this difference
was not statistically significant, and the
study only contained 168 patients, 20 of
whom had PaO2/FIO2 ratios between 200
and 300 (10). The study contained too few
patients (168 total and 20 with a PaO2/
FIO2 ratio between 200 and 300) to conclude much about the difference between
the patient populations defined by severity of hypoxemia.
Clinically, the most important measure of predictive validity is the ability to
predict who will benefit from a specific
therapy. To this extent, the AmericanEuropean Consensus Conference criteria
for ALI have been validated, since a randomized controlled trial that used these
criteria established the benefit of a lungprotective ventilation strategy in these
patients (11).
Reliability. Reliability is the measure
of whether the criteria, as used by different observers of the same patients
(interobserver reliability), or by the
same observer of the same patient at
different times (test-retest or intraobserver reliability), agree. Results are
presented as percentage agreement and

as a kappa statistic for binary criteria,

or as a Bland-Altman diagram for continuous variables. Kappa values range
from 0 (no agreement) to 1 (perfect
agreement). Values 0.4 generally represent poor agreement, and values 0.7
represent good agreement. Many studies of diagnostic tests, including the
interpretation of mammograms, ventilation-perfusion scans, and radiographic diagnosis of pneumonia, have
only modest reliability, with kappas of
approximately 0.5 (1214). All of the
major diagnostic criteria for ALI (hypoxemia, radiographic abnormality, and
absence of left atrial hypertension) have
been shown to have poor reliability in
their use to diagnose ALI.
Hypoxemia. Villar et al. (15) demonstrated that standardized ventilator settings can distinguish populations with
different mortality rates. Patients with
a Pa O 2 /F IO 2 150 on positive endexpiratory pressure 5 cm H2O had a
mortality rate of 22.6%, and patients
with a PaO2/FIO2 ratio 150 despite positive end-expiratory pressure 5 cm
H2O had a mortality rate of 68%. Therefore, the reliability and predictive validity of the hypoxemia criterion for ALI
are dependent on how the physician
chooses to ventilate the patient. The
PaO2/FIO2 ratio, although simple to calculate, has a complex relationship with
other measures of hypoxemia, for example, venous admixture and shunt fraction, and becomes particularly unstable
at FIO2 0.5 mmHg and PaO2 100
mmHg (16, 17). Therefore, physicianselected aspects of ventilator management, including positive end-expiratory
pressure, mean airway pressure, tidal

Table 1. Measures of validity

Validity Measure
Face validity
Content validity

Explanation
Definition appears on its face to represent the
disease
Definition contains all of the elements relevant to
the disease

Criterion validity

Definition corresponds to a gold standard

Predictive validity

Definition is able to predict something it

theoretically should be able to predict

Concurrent validity

Definition is able to distinguish between groups that

it theoretically should be able to distinguish
between

ALI Example
Patients identified by the proposed ALI definition feel
right to clinicians and other users
Proposed diagnostic criteria contain all of the elements
deemed essential to the diagnosis of ALI, usually as
assessed by a group of experts. Example: AECC criteria
for ARDS
Proposed diagnostic criteria for ALI correspond to a gold
standard
Proposed diagnostic criteria predict some outcome that is
unique to ALI (e.g., mortality, duration of mechanical
ventilation, or response to therapy)
Proposed diagnostic criteria are able to distinguish ALI
from other forms of acute hypoxemic respiratory failure

ALI, acute lung injury; AECC, American-European Consensus Conference; ARDS, acute respiratory distress syndrome.

Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

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volume, and FIO2, affect the hypoxemia

criterion of ALI diagnosis.
Chest Radiograph. Since the original
description of ARDS in 1967, the chest
radiograph has been an essential part of
its definition (5). In the initial report,
the chest radiograph was described as
presenting patchy, bilateral alveolar
infiltrates (5). Since then, a variety of
radiographic criteria have been described in ALI/ARDS, including reduction in the longitudinal pulmonary diameter (18), interstitial and alveolar
edema (19), and at least two radiographic scoring methods (20, 21). In
three studies, the radiographic diagnosis of ALI (or ARDS) has been shown to
have poor reliability (2224). This includes one study that used a group of
readers with extensive experience as
ALI-clinical investigators (24).
Left Atrial Hypertension. The American-European Consensus Conference
provides relatively little guidance on assessing clinical evidence of left atrial
hypertension. The pulmonary artery
occlusion pressure has been considered
a reasonable gold standard for this assessment. However, it too is demonstrably unreliable (25). Furthermore, the
assessment of transmural cardiac pressures reflected by the pulmonary artery
occlusion pressure in patients with ALI
and high levels of positive end-expiratory pressure is problematic. Since sepsis and trauma, the two leading risk
factors for ALI, can affect cardiac function and since the incidence of both
sepsis and congestive heart failure increases with age, excluding patients
with any evidence of left atrial hypertension will eliminate a considerable
number of patients who have mixed
cardiogenic and noncardiogenic causes
of respiratory failure (26). Natriuretic
peptides, which appear to be elevated in
patients with congestive heart failure,
may be helpful in operationalizing the
left atrial hypertension criterion; however, the characteristics of this test in
broad populations of patients at risk for
both ALI and congestive heart failure
have not been established (27).
Clinical Investigation When Diagnostic Criteria Are Unreliable. There are
three options for clinical investigation
when the diagnostic criteria are unreliable:

Protocolization
Adjudication
Sensitivity analysis

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Rigid protocols to refine the definitions of ALI can be developed for use in
clinical research to improve reliability
(28).
Adjudication by committee can improve the reliability of assessment by using multiple observers. If the adjudicators have expertise, they also can provide
face validity of the assessments. To prevent bias, it is essential that the adjudicators are blinded to any predictor or
outcome variables.
Sensitivity analysis is a powerful technique for assessing the effect of diagnostic criteria on the results of a study. Analyses are repeated by using different
assumptions about the patient population. Results that are insensitive to varying criteria are robust to concerns about
reliability. Although sensitivity analysis
does not provide the correct answer in
the face of varying results, it does provide
a range of results. Cook et al. (29, 30)
used combinations of these techniques to
evaluate the effect of gastrointestinal
bleeding prophylaxis on ventilatorassociated pneumonia.
Reliable diagnostic criteria are essential for reproducible clinical investigation. In the absence of a gold standard,
reliable disease definitions and measures
are essential for identifying biomarkers
and performing translational research.
This is particularly true in the field of
genetic epidemiology: Use of standardized, reproducible [case definitions] with
strict requirements for training, certification, and quality control is a fundamental
principle of population-based research
that needs to be translated to genetic
epidemiologic studies (31).
Other fields that study syndromically
defined diseases have invested considerable effort to empirically describe the reliability and validity of their evaluation
tools. In an informal MEDLINE search,
we found 500 articles that described the
reliability or validity of measures in
schizophrenia, 200 in depression, and
70 in asthma. There were only eight that
described the reliability of measures in
ALI: three on the chest radiograph, two
on pressure-volume curves, and three on
lung water measurements. Neither pressure-volume curves nor lung water measurements are part of the current consensus diagnostic criteria.

Incidence
Understanding the incidence of disease helps to place that disease in the

context of others. This is important for

estimating the burden on society and to
establish funding priorities. Knowledge
of the variation in incidence over time
provides tracking data on the efficacy of
measures to reduce the incidence of the
disease. Ecological studies of factors associated with increased incidence can
generate hypotheses about risk factors for
the disease. These data are available from
population-based studies on the incidence and outcome of cardiovascular,
pulmonary, infectious, and neoplastic
diseases. In the United States, the National Center for Health Statistics maintains data on the incidence and mortality
rate of hundreds of diseases (32). Similarly, the Surveillance, Epidemiology,
and End Results Program of the National
Cancer Institute maintains high-quality
data on cancer incidence and survival
from selected areas across the United
States (33). Data of similar quality are not
readily available for sepsis, ALI, or multiple organ failure.
Incidence is the number of new cases
divided by the population at risk. Prevalence is the number of existing cases in
the population under study at a given
time. The distinction between prevalence
and incidence is important in chronic
diseases, where the duration of illness
can lead to a large number of prevalent
cases compared with incident cases, but
is of less interest in acute diseases with
high short-term mortality rates. Incidence and prevalence must be defined in
terms of the denominator population under study. Two denominators have been
used to study ALI incidence: patients who
are admitted to the ICU, and the entire
population who receive their care at the
study hospitals. The population denominator is the most useful for calculating
the disease burden on society.
Adult respiratory distress syndrome
(sic) is listed as a rare disease on the
National Organization for Rare Disorders
website (34). If true, this would not put
ALI high on the list of pharmaceutical or
government research priorities. Starting
with an expert panel estimate in 1972,
there have been a number of studies of
the incidence of ALI or ARDS (35). Because of variations in methods, observation periods, and ALI or ARDS definitions, it is difficult to compare the values
obtained. Table 2 presents data from selected studies of the incidence of ALI.
These studies place the incidence of
ALI at 20 50 cases/105 person-years, with
approximately 18% to 25% of cases meetCrit Care Med 2003 Vol. 31, No. 4 (Suppl.)

Table 2. Selected incidence studies for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Study Location
(Sample Time of Study) (Reference)
Grand Canaria (19831985) (51)

Utah (12 mos, 19891990) (52)

Berlin (8 wks in 1991) (19)

Definition
1. Risk
2. PaO2 55 on FIO2 0.5 with PEEP 5 and no
improvement in 24 hrs and also PaO2/FIO2
150
3. Bilateral infiltrates
4. No clinical left atrial hypertension
1. PaO2/PaO2 0.2
2. Bilateral infiltrates
3. No clinical evidence of left atrial hypertension
4. Static thoracic compliance 50 mL/cm H2O
Severe lung injury: Murray-Matthay score 2.5

Sweden, Denmark, Iceland (8 wks in

1997) (18)

AECC criteria

Australia (8 wks in 1999) (10)

AECC criteria

United States (38)

Extrapolation from ARDS Network screening data

using AECC criteria
ICD-9 codes and mortality rates

United States (50)

Incidence
1.5 per 105 person-years for PaO2/FIO2 110
3.5 per 105 person-years for PaO2/FIO2 50
10.6 per 105 person-years for acute respiratory failure
4.88.3 per 105 person-years for ARDS

3.0 per 105 person-years for severe lung injury

88.6 per 105 person-years for acute respiratory failure
17.9 per 105 person-years for ALI 13.5 per 105 personyears for ARDS
76.8 per 105 person-years for acute respiratory failure
34 per 105 person-years for ALI
28 per 105 person-years for ALI
2287 per 105 person-years for ALI
1726 per 105 person-years for ARDS

PEEP, positive end-expiratory pressure; AECC, American-European Consensus Conference; ICD, International Classification of Disease.

ing the ALI (PaO2/FIO2, 200 300), but not

ARDS, hypoxemia criterion (see Table 2).
Twenty-eight day mortality rates are approximately 35%. These incidence rates
may significantly underestimate the incidence of ALI, at least in the United States.
Current evidence suggests that 383,000
patients with severe sepsis are cared for
in ICUs, and that approximately 30% of
these patients will develop ARDS (36, 37).
Assuming that there are no other causes
of ARDS, and ignoring patients with
milder hypoxemia who meet ALI criteria,
these data suggest that at least 115,000
people per year in the United States (54
cases/105 person-years) will have ARDS
from severe sepsis alone. Extrapolating
from registry data on patients identified
with ALI at each of the sites in the multiple-center ARDS Network, Goss et al.
(38) estimated that, even under the conservative assumption that ALI cases are
only cared for in ICUs with more than ten
beds and residency programs, the incidence of ALI in the United States is 2252
cases/105 person-years.
The variation in the results of these
studies may reflect differences in methods, case ascertainment, or quality control. However, it is equally likely that
these studies reflect true variation in the
incidence of ALI. Regional differences in
smoking, use of motor vehicles, population density, respiratory infections, and
genetic factors all might influence geographic variability in the incidence of ALI
(39, 40).
Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

An interesting and unexplored source

of variation is the effect of healthcare
resource use on ALI incidence. Even
within the United States, there is wide
variability in the ratio of hospital beds,
ICU beds, emergency medical response
time, and other medical resources. These
may influence the observed incidence of
ALI in two ways. First, to be diagnosed
with ALI, patients must survive long
enough to be admitted to an ICU, there
must be an ICU bed to be admitted to, a
physician must decide to admit the patient to the ICU, and the patient must
have an arterial blood gas and chest radiograph. Limited access to ICU care, implicit or explicit restriction of intensive
care, or differences in emergency medical
response time may reduce the number of
observed cases of ALI. Second, specific
medical and surgical decisions may affect
the number of cases of ALI. For example,
organ and bone marrow transplantation,
coronary bypass grafting, and intensive
chemotherapy all are associated with ALI,
and countries that provide greater access
to these treatments may have more cases
of lung injury. Resuscitation practices
may increase or decrease the incidence of
ALI (41, 42).

Attributable and Associated

Mortality Rate
Attributable mortality rate is relatively
easy to define mathematically: It is the
difference in mortality rate between those

patients with a disease or exposure and

those without. Practically, however, it is
difficult to attribute a given death to a
specific disease (43, 44). Suppose a 68-yrold alcoholic man is severely injured in a
motor vehicle crash and develops ALI.
After 14 days of multiple organ failure,
including acute renal failure, ALI, and
delirium, life-sustaining treatment is
withdrawn at the request of the patients
family. Is the patients death attributable
to alcoholism, motor vehicle trauma,
ARDS, multiple organ failure, or the decision to withdraw medical therapy?
To address these complexities, it is
helpful to think of attributable mortality
rate in two categories: deaths associated
with the disease, and deaths caused by
the disease that could be prevented by
some therapy or intervention. The former
is much easier to calculate, although the
latter is more important for public health
purposes.
Attributable Short-Term Mortality
Rate. The calculation of mortality rates
attributed to various diseases and reported in cause-of-death tables is based
on death records and generally reflects
deaths associated with the disease. Attributable mortality rate associated with ALI
can be calculated by multiplying the incidence rate by the mortality rate.
In 2000, the adult population of the
United States (15 yrs old) was 214 million. Although the preceding discussion
indicates that the incidence of ALI in the
United States has not been described, it is
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reasonable, based on the studies cited

previously, to estimate it at 20 50 cases/
105 person-years, or 43,000 107,000 cases/year. If we assume the mortality rate of
approximately 40% observed in recent
studies of acute respiratory failure,
17,000 43,000 deaths per year are associated with ALI. It is important to place
these numbers into the context of other
diseases with an important public health
impact (Table 3). This places deaths associated with ALI in the range of other
diseases with significant public health
impact such as breast cancer, HIV infection, and asthma.
Identifying the independent or causal
contribution of ALI to mortality rate is
much more difficult. Two options exist.
By examining observational epidemiologic data, one can try to control for
other factors associated with mortality
rate and estimate the independent effect
of ALI on mortality rate. This is an important analysis, because it is possible
that ALI is merely a marker of illness
severity and on its own contributes little
to mortality rate. Studies to identify the
independent effect of ALI on mortality
rate are difficult to perform, because they
require the identification of a cohort of
critically ill patients, only a minority of
whom will develop lung injury, whom the
investigator must then follow to compare
mortality rates.
Hudson et al. (45) attempted to control for this by the epidemiologic technique of restriction. By comparing patients with ARDS to those at similar risk
who did not develop ARDS, the authors
showed that ARDS increased the mortality rate by an average of 3.3-fold in all risk
conditions. The relative risks for death
attributed to ARDS ranged from 1.4 in
sepsis to 4.3 in trauma and 8.6 in drug
overdose. The authors further controlled

for Acute Physiology and Chronic Health

Evaluation score in the septic patients
and injury severity in the trauma patients, without a significant effect on the
attributable mortality rate.
More compelling evidence of the attributable and preventable deaths in ALI
would be to show a reduction in mortality
rate from an effective intervention to prevent ALI, or to prevent death after ALI.
No interventions have been shown to prevent ALI; however, recent data from two
studies suggest that a ventilator strategy
can reduce mortality rate in ALI by a
mortality difference of 8.8% to 33% (46,
11). In light of the findings in Table 3,
these data can be analyzed to estimate
that 3,800 35,000 deaths annually could
be prevented in the United States by implementing lung-protective ventilation in
ALI, depending on its incidence and the
benefits of lung-protective ventilation beyond the clinical trial population.
Change in Mortality Rate Over Time.
Several investigators have observed a reduction in mortality rates for ALI or
ARDS over time, from 60% in the
1980s to 40% in the 1990s (47 49).
These studies are consistent with the current epidemiologic cohorts, which show a
mortality rate of 40% in ALI. An analysis of death records from the United
States showed an almost 15% reduction
in deaths attributed to ARDS from 1989
to 1996 (50). In the available studies, the
authors have attempted to exclude
changes in the population or severity of
illness as explanations for the reduced
mortality rates. None have been able to
convincingly attribute the reduced mortality rates to specific therapeutic innovations or changes in ventilatory strategy.
Attributable Long-Term Mortality
Rate. There is growing interest in the

Table 3. Attributable mortality for acute lung injury (ALI), acute respiratory failure, and comparison
diseases

Disease

Attributable Mortality Rate

(Deaths Per Year)

ALIa
Acute respiratory failureb
Acute myocardial infarctionc
Breast cancerc
HIV diseasec
Asthmac

17,00043,000
60,000120,000
199,454
41,528
14,802
4,657

a
Assumes incidence range 20 50 per 105 person-years, mortality rate of 40%, and U.S. 2000 census
population of 215 million 15 yrs old; bassumes incidence range 70 140 per 105 person-years,
mortality rate of 40%, and U.S. 2000 census population of 215 million 15 yrs old; cbased on U.S. 1999
death certificate data (56).

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effects of critical illness syndromes on

long-term outcomes. The methodological
challenges are similar to those encountered in establishing attributable shortterm mortality rates. Separating the independent and causal effects of ALI on
long-term mortality rate from the effects
of the risk factors that cause or are associated with ALI is a challenge.
Because sepsis is the principal risk factor for ALI, it is reasonable to examine
the data on the long-term effects of sepsis
on mortality rates. Quartin et al. (51)
showed that, even after controlling for
age and comorbidity by using International Classification of Diseases (ICD)-9
diagnostic codes, patients with sepsis
have a higher mortality rate than controls. Among patients who survived for a
year, those who had an episode of sepsis
had an approximately 1.5 times greater
rate of death than similar patients without an episode of sepsis. The median survival of patients who survived for 30 days
was reduced from 6.24 to 2.35 yrs. Concerns about this study relate to the quality of the ICD-9 coding of comorbidities
and the possibility that patients who have
been admitted to hospital for a severe
illness, such as sepsis, have more comorbidities coded than controls.
A number of studies have followed ALI
and ARDS patients beyond hospital discharge to explore their long-term survival. For example, a study of relatively
young (mean age 48 yrs) and previously
healthy ARDS patients showed that survivors of ARDS continued to accrue mortality from day 28 after ARDS until about
day 180, when the mortality rate stabilized (52). However, these data cannot be
used to assess attributable mortality rate
of ARDS, since they only include patients
with the disease.
Only one study has compared longterm survival in ARDS patients and controls. Davidson et al. (53) looked at the
effect of ARDS on long-term survival in
patients who survived to hospital discharge and compared it with controls
matched on the severity of sepsis or
trauma. Patients with sepsis had reduced
long-term survival compared with patients with trauma, regardless of the
presence of ARDS; however, when the
analysis was restricted to patients who
survived to hospital discharge, there was
no independent effect of ARDS on longterm mortality rate. Importantly, this
study found that 80% of all deaths occurred in the hospital, 77% occurred by
Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

day 30 after ARDS onset, and 89% occurred by day 100 after ARDS onset.
This study was limited by two factors:
a) It was relatively small, and important
effects of ARDS on long-term mortality
rate therefore may have been missed; and
b) the authors could not completely exclude the possibility that the controls had
some mild component of ALI. Nevertheless, the best current evidence suggests
that ARDS (no studies have been done on
ALI) does not independently worsen longterm survival in patients who survive to
hospital discharge.

Attributable and Associated

Morbidity Rates
If, as recent clinical evidence suggests,
mortality rate after ALI is declining, and
may, in some subgroups, be as low as
20%, then the morbidity incurred by survivors of ALI becomes an increasingly significant clinical issue. We can estimate
this burden by calculating the number of
ALI 5-yr survivors in the U.S. health care
system. Assuming that there are 107,000
cases of ALI per year (see Table 3), that
70% of patients with ALI survive their
acute illness, and that all patients with
trauma-associated ALI and 50% of those
with sepsis-associated ALI survive for 5
yrs, then there are 280,000 ALI survivors in the United States. This conservative estimate excludes all survivors whose
ALI occurred 5 yrs ago.
As the acute care of critically ill patients improves, it is important to address
the healthcare sequelae that are being
created. Although information concerning the late outcomes of critical illness is
growing, this is an evolving field with
relatively few data, particularly regarding
mechanisms and treatments. The same
methodological limitations apply to identifying the attributable effect of ALI on
morbidity rate as were noted for its effect
on mortality rate.
Attributable Effects of Acute Lung Injury on Functional Status. For the purposes of this discussion, functional status
refers to objective and physiologic measures of performance after an episode of
ALI. This includes pulmonary function,
gas exchange, exercise tolerance, and
cognitive performance.
A number of investigators have studied pulmonary function in ALI survivors.
Pulmonary function appears to be severely abnormal within 1 month of ALI
onset. The abnormalities are primarily
restrictive, although obstructive abnorCrit Care Med 2003 Vol. 31, No. 4 (Suppl.)

malities also have been reported (54).

This is followed by a period, from 3
months to 6 months, of rapid improvement in pulmonary function. After approximately 6 months, most of the improvement that will occur has occurred.
The majority of patients are left with little
measurable pulmonary dysfunction, except for a reduced diffusion capacity for
carbon monoxide. A minority have a persistent severe restrictive defect.
These physiologic data are corroborated by similar changes in radiographic
studies (55, 56). Although it seems reasonable to assume that pulmonary function abnormalities are attributable to the
parenchyma and vascular pathology of
ALI, no studies have tested this hypothesis by comparing pulmonary function in
ALI patients with a similar control group.
It is possible that diffusion abnormalities
and restrictive disease in ALI survivors
are due to the combination of a slowly
resolving endothelial injury and critical
illness polyneuropathy that are sequelae
of systemic inflammation and have nothing to do with lung injury.
A growing body of literature demonstrates acute cognitive impairment in
critically ill patients (57). However, the
mechanism, persistence, and relationship
to ALI, hypoxemia, or duration of mechanical ventilation are unclear. At 1 yr,
the majority of ALI survivors have impaired memory, attention, and concentration and/or decreased mental processing speed (58). The extent to which these
cognitive abnormalities are attributable
to ALI or to the risk conditions is unknown, but they reflect significant morbidity in these patients.
Attributable Effects of Acute Lung Injury on Psychiatric Outcomes and Quality of Life. To an ALI survivor, quality of
life is as important as any specific physical or functional variable. Potential problems were initially anecdotal, as clinicians saw ALI survivors in follow-up and
heard them describe depression and difficulties at work or with relationships.
Subsequently, these outcomes have been
more formally studied by means of standardized questionnaires and tools.
Hopkins et al. (58) interviewed ALI
survivors by using the Medical Outcomes
Study 36-item, short-form health survey
(SF-36). At 1 yr, ALI survivors showed
continued poor scores in the following
domains of the SF-36: role emotional,
mental health, bodily pain, and general
health. Davidson et al. (59) evaluated
quality of life measures in ALI survivors

compared with matched critically ill controls who had not developed ALI and
found worse results for the ALI survivors
in the areas of physical functioning, general health, and vitality at an average of 2
yrs after hospitalization. Although the degree of impairment was not as profound
as for patients with other severe lung
diseases, many of these patients still
found it difficult to function fully and
return to work.
In most studies and clinical reports,
patients have described feelings of fatigue, memory loss, depression, and fear
of relapse. During the first 15 months
after ALI, Weinert et al. (60) found that
75% of survivors had scores on a depression scale that qualified for the diagnosis of depression. In addition, another
study revealed that more than one half of
a cohort of critically ill patients transferred to a long-term acute care facility
were prescribed an antidepressant (61).
Although posttraumatic stress disorder is historically studied in people who
have suffered trauma or war experiences,
it is also an important mental health assessment in critically ill patients. Many
clinicians have questioned whether patients suffered from memories of their
ICU experience, but, apart from anecdotes, few data are available.
Schelling et al. (62) studied this issue
by using tools such as the SF-36 and the
posttraumatic stress syndrome ten-question inventory. Of 80 patients studied, one
third showed evidence of posttraumatic
stress disorder at approximately 4 yrs
posthospitalization. These important outcomes should be incorporated into future
clinical trials of ALI and studied among
current survivors of ALI.
The current literature on attributable
morbidity is principally limited by the
lack of an appropriate control group to
assess the independent and potentially
causal contribution of ALI, or its therapy,
to morbid outcomes. Future studies, particularly intervention studies with
health-related quality of life outcomes,
are essential for better understanding of
this area (63, 64).

Prognosis
There are several reasons to identify
factors associated with death in ALI:

To uncover potential etiologies

To develop severity-of-illness scores
To inform clinical decision making
S281

he mortality and
morbidity rates associated

with

acute lung injury are considerable, with significant impact on public health.

Although investigators frequently seek

to answer all of these questions, each goal
places different requirements on the
analysis and interpretation of data.
Causal factors are never established solely
by epidemiologic observation and must
be supported by laboratory or, ideally,
experimental verification. Eliminating
confounding variables to measure an unbiased effect of exposure is the primary
goal of studies that seek to establish a
causal factor. Frequently, investigators
use multivariate modeling, and particularly stepwise regression modeling, to
identify independent risk factors for
mortality.
Despite its popularity, stepwise regression, where a computer algorithm selects
covariates on the basis of their statistical
significance, is notoriously error prone at
producing unbiased estimates of an exposures effects (65).
A better approach is hierarchical modeling, where the investigator explicitly
tests a specific causal hypothesis. Severityof-illness models are used as confounder
scores in clinical research. Their purpose
is not to make predictions in individual
cases but to be used as a research tool to
control for differences in likelihood of
death between populations. For example,
to answer the question of whether ICUs
that care for more patients with ALI have
lower mortality rates, an investigator
would need to control for differences in
severity of illness between the ICUs.
Although a generic ICU severity-ofillness score like the Acute Physiology
and Chronic Health Evaluation or the
mortality prediction model could be
used, an ALI-specific severity-of-illness
model might be more sensitive to differences between ICUs. The value of the
model is not in the estimate of an individual variables effect but the overall
ability of the model to predict death assessed by its discrimination and calibration (66). Finally, identifying predictive
S282

models or variables that are useful at the

bedside requires that they be sufficiently
accurate for the decision and that they
generalize to the patient population in
which they are being applied (67, 68).
Three recent multiple-center studies
have evaluated patients with ALI or ARDS
outside of clinical trial populations to explore prognostic variables. A Scandinavian study found that age, acute physiology, PaO2/FIO2 ratio, and chronic liver
disease were statistically significant predictors of mortality rate (7, 8). An Australian study found that age, Acute Physiology and Chronic Health Evaluation II
score, PaO2/FIO2 ratio, number of radiographic quadrants involved, and organ
failure were significantly associated with
mortality rate (10). Finally, a French cohort found that acute physiology, PaO2/
FIO2 ratio, septic shock, and immunosuppression as a comorbidity were significantly associated with mortality rate (9).
Two series of predominantly medical ICU
patients showed a higher mortality rate
(58%) from ALI than reported in general
series of ALI patients, suggesting that the
medical population of ALI patients is at
greater risk of death. Mortality rate in
these series was associated with comorbidities such as cirrhosis, cancer, and HIV
infection (69, 70).

Conclusion
Epidemiology provides an important
clinical background to understanding the
significance of disease. ALI, when studied
with rigorous methods, appears to be
more common than was indicated by previous estimates of the incidence of ARDS.
This syndrome has a significant effect on
public health (71).
Epidemiology alone cannot identify
causal factors but can be used to verify
mechanisms generated in the laboratory.
There are important research questions
that do not fall under the umbrella of
traditional epidemiology. Health services
research, where the research questions
involve interaction between clinicians,
clinical practice, the health system, and
human disease, is just beginning in ALI.
The implementation of lung-protective
ventilation techniques, practice variation
in the management of ALI, and the effect
of ICU structure and volume on ALI and
mechanical ventilation outcomes are all
important health services research questions that are waiting to be addressed.

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