Acute Lung Injury in the Medical ICU

Comorbid Conditions, Age, Etiology, and Hospital Outcome

MARYA D. ZILBERBERG and SCOTT K. EPSTEIN
Department of Medicine, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine,
Boston, Massachusetts

The independent effects of chronic disease, age, severity of illness, lung injury score (LIS) and etiol-
ogy, and preceding nonpulmonary organ-system dysfunction (OSD) on the outcome of acute lung in-
jury (ALI) have not been examined in an exclusively medical-intensive-care-unit (MICU) population.
Therefore, 107 consecutive MICU patients with ALI (76% with acute respiratory distress syndrome
[ARDS]) were prospectively investigated. The impact of comorbidities, age . 65 yr, acute physiology
score (APS), LIS, etiology of ALI, and OSD on hospital survival were studied. The overall mortality was
62 of 107 patients (58%), including 47 (58%) with ARDS. With univariate analysis, age . 65 yr, organ
transplantation, human immunodeficiency virus (HIV) infection, active malignancy, chronic steroid
use, and a septic or aspiration-related etiology of ALI were associated with a > 1.2-fold greater rela-
tive risk (RR) of hospital mortality. With multiple logistic regression, independent predictors of hospi-
tal death were age . 65 yr, organ transplantation, HIV infection, cirrhosis, active malignancy, and
sepsis. APS, LIS, aspiration-related etiology of ALI, preceding OSD, and other comorbidities were not
independently predictive of hospital death. Multivariate analysis of the ARDS cohort showed similar
results, although cirrhosis and malignancy did not reach statistical significance. We conclude that co-
morbid conditions, older age, and sepsis etiology are independent predictors of hospital death in ex-
clusively MICU patients with ALI (76% of whom satisfied criteria for ARDS). These factors should be
considered in analyzing studies of new therapies and interpreting trends in mortality for ALI and
ARDS. Zilberberg MD, Epstein SK. Acute lung injury in the medical ICU: comorbid conditions,
age, etiology, and hospital outcome. AM J RESPIR CRIT CARE MED 1998;157:1159–1164.

Since its identification in 1967 by Ashbaugh and colleagues,
many investigators have examined the features that affect the
outcome of acute lung injury (ALI) and acute respiratory dis-
tress syndrome (ARDS) (1). Univariate analyses have identi-
fied multiple factors that are associated with increased mortal-
ity rates for ALI and ARDS, including sepsis syndrome
preceding (2, 3) or following ARDS (4, 5); Acute Physiology
and Chronic Health Evaluation II (APACHE II) score (5, 6);
preceding (2, 7, 8) or subsequent organ failure (5, 7, 9); older
age (5, 8, 10–13); or the presence of comorbid or chronic con-
ditions, such as cirrhosis (2, 14); human immunodeficiency vi-
rus (HIV) infection (5, 15); organ transplantation (2, 16); and
active malignancy (2, 5). In contrast, few multivariate analyses
of factors associated with increased mortality in ALI or
ARDS are available, and these have included either a mixed
patient population (e.g., combining medical and surgical pa-
tients) or have analyzed only a portion of the important
univariate predictors previously identified (2, 3, 6, 17). A pri-
ori identification of populations at high risk for in-hospital
mortality will have important implications for interpreting
(Received in original form April 17, 1997 and in revised form December 9, 1997)
Correspondence and requests for reprints should be addressed to Scott K. Ep-
stein, M.D., Pulmonary and Critical Care Division, Box 369, New England Medi-
cal Center, 750 Washington Street, Boston, MA 02111.
Am J Respir Crit Care Med Vol 157. pp 1159–1164, 1998
mortality statistics provided by studies of new therapeutic
strategies for ALI and ARDS. In addition, all factors that af-
fect mortality must be considered in evaluating trends in ALI
and ARDS outcome (11, 18, 19). To fully interpret analyses of
such data the prevalence of important comorbid conditions
and how they change over time must be known. To identify
conditions present at the onset of respiratory failure that con-
tribute independently to mortality, we conducted an exclusive
study of medical-intensive-care-unit (MICU) patients with
ALI and ARDS (20).
METHODS
Study Population
Over a 36-mo period, 107 consecutive patients meeting criteria for
ALI (see the subsequent discussion) were recruited from the MICU of
the New England Medical Center, the principal teaching hospital of
Tufts University School of Medicine and a major tertiary-care referral
center in Boston, Massachusetts. These patients represented 22% of
all patients mechanically ventilated within this period. All of the pa-
tients were exclusively medical; with the exception of a single patient
with ARDS secondary to fat emboli following an orthopedic proce-
dure, there were no cases of major trauma or postoperative acute lung
injury. In addition, no patient received nitric oxide (NO), surfactant,
or other experimental pharmacologic intervention for either ALI and
ARDS or for sepsis. Patients were admitted to the MICU from three
sources: transfer from a floor bed, direct admission from the emer-
gency department (ED), and transfer from an outside hospital. Candi-
1160 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 157 1998

dates for the study were prospectively identified by a daily review of
all ventilated patients in the 10-bed MICU.
Criteria for Diagnosis of ALI and ARDS
The criteria for diagnosis of ALI and ARDS as set by the North
American/European Consensus Conference were used and were as
follows: acute onset of lung injury, diffuse bilateral infiltrates seen
upon chest radiography, PaO2/FIO2 , 200 mm Hg for ARDS and PaO2/
FIO2 , 300 mm Hg for ALI, pulmonary artery occlusion pressure
(PAOP) , 19 mm Hg, or no clinical evidence of congestive heart fail-
ure (CHF) (20).
Data Collection
At the onset of mechanical ventilation, the history and physical, labo-
ratory, and roentgenographic data and hemodynamic and ventilatory
variables were recorded, and the presence of comorbid conditions
(see the subsequent discussion) was noted. The APACHE II score
and acute physiology score (APS) were calculated within 6 h of initia-
tion of mechanical ventilation (21). On the basis of the data available
in the first 24 h of mechanical ventilation, an LIS was calculated (22).
Physiologic and laboratory characteristics prior to the initiation of me-
chanical ventilation were measured to determine the development of
nonpulmonary organ-system dysfunction (ODS) between the time of
hospital admission and the onset of mechanical ventilation. A cause
for ALI or ARDS was assigned, using prospectively defined criteria
(see the subsequent discussion). All patient screening, data collection,
and chest-radiograph interpretation were performed by the investi-
gators.
Definitions
On the basis of a review of previously published univariate analyses,
comorbid conditions most likely to affect mortality were prospectively
selected and defined as “primary” chronic diseases or comorbidities
as follows:
Malignancy: Active, untreated, or undergoing current treatment (pa-
tients having received a bone-marrow transplant for their malig-
nancy were excluded from this category).
Cirrhosis: Biopsy-proven or with evidence of portal hypertension,
such as variceal bleeding, ascites, or encephalopathy in the appro-
priate clinical setting.
HIV infection: Serologic evidence of infection with or without previ-
ous acquired immune deficiency syndrome (AIDS)-defining ill-
ness.
Organ transplantation: A history of bone marrow, liver, or kidney
transplantation.
We also identified the presence of other potentially important chronic
conditions, as follows:
Chronic obstructive pulmonary disease (COPD): A known history of
obstructive lung disease or obstructive defect on pulmonary func-
tion studies.
Alcohol abuse: Current active use of alcohol.
Intravenous drug use (IVDU): Current active use of intravenous
drugs.
Chronic steroid use: Current use of corticosteroids for > 2 weeks and
dose > 20 mg/d.
Diabetes mellitus: A history of diabetes requiring chronic therapy
with insulin or an oral hypoglycemic agent.
The impact of age on outcome was determined by categorizing pa-
tients by age, using a threshold age of 65 yr. Preceding nonpulmonary
OSD was defined as such dysfunction developing after admission to
the hospital and persisting through the time of initiation of mechani-
cal ventilation, in a specific organ system, as follows:
Hepatic dysfunction: Total serum bilirubin . 2.0 mg/dl, along with a
prothrombin time . 3 s longer than the control value.
Renal dysfunction: Serum creatinine . 2.0 mg/dl.
Hematologic dysfunction: A platelet count of , 75,000/mm3, total
white blood cell (WBC) count , 1,000 cells/mm3, or evidence of
disseminated intravascular coagulation (DIC).
Neurologic dysfunction: Obtundation not attributable to a sedative
drug effect or a primary central nervous system (CNS) event, such
as seizures, hemorrhage, or acute cerebrovascular accident.
Gastrointestinal dysfunction: Ileus lasting . 24 h or hemorrhage re-
quiring transfusions (23).
Risk Factors for ALI/ARDS
For each case, an etiology of ALI and ARDS was prospectively de-
fined. Sepsis was defined as present if at least three of the following
criteria were satisfied: rectal temperature . 398 C or , 358 C; unex-
plained hypotension with a systolic blood pressure , 90 mm Hg for at
least 2 h in the absence of dehydration; hemorrhage or cardiac failure;
leukocytosis manifested by an increase of at least 3,000/mm3 in one
day or . 20% bands; positive blood culture; and systemic vascular re-
sistance , 800 dynes/s/cm5 in the absence of chronic liver disease (7).
Aspiration of gastric contents was said to be present if it was docu-
mented by direct observation by medical personnel or if gastric con-
tents were suctioned from the endotracheal tube (9). The presence of
pneumonia was defined from the radiographic presence of new infil-
trate(s), coupled with identification of at least one pathogen in a spu-
tum specimen or bronchoalveolar lavage fluid (BALF) culture and
clinical evidence of infection (7). Patients meeting the criteria for both
sepsis and pneumonia were classified as having sepsis and were ex-
cluded from the pneumonia category. Patients who met the criteria
for ALI or ARDS in the setting of other clinical conditions, including
drug overdose (24), hypertransfusion (17), pancreatitis (7), and fat
embolism (24), or when no definite etiology could be identified, were
classified as having another condition.

TABLE 1
PATIENT CHARACTERISTICS COMPARING SURVIVORS WITH NONSURVIVORS

All Patients ARDS

(n 5 107) (n 5 81)

Survivors Nonsurvivors Survivors Nonsurvivors

(n 5 45) (n 5 62) p Value (n 5 34) (n 5 47) p Value

Age, yr 47 6 2 53 6 2 , 0.05 46 6 3 53 6 3 , 0.05

Women/men 18/27 24/38 . 0.2 11/23 20/27 . 0.2
APS* 13 6 1 14 6 1 . 0.2 13 6 1 15 6 1 0.2
APACHE II Score 17 6 1 20 6 1 0.05 17 6 1 21 6 1 , 0.05
PaO2/FIO2† 151 6 12 150 6 12 . 0.2 114 6 6 107 6 5 . 0.2
Lung injury score‡ 2.6 6 0.1 2.6 6 0.1 . 0.2 2.8 6 0.1 2.8 6 0.1 . 0.2
Primary comorbidity present (%)§ 17 (38) 47 (76) , 0.0001 14 (41) 35 (74) , 0.01

Data are expressed as mean 6 SEM.

* APS 5 acute physiology score.
†
PaO2/FIO2: interquartile range 87 to 189 for all patients, 82 to 139 for ARDS.
‡
Lung injury score: interquartile range 2.3 to 3.0 for all patients and the ARDS.
§
Primary comorbidities, including cirrhosis, human immunodeficiency virus (HIV) infection, active malignancy, and organ transplanta-
tion.
Zilberberg and Epstein: Acute Lung Injury in the ICU 1161

Figure 1. Clinical conditions associated with acute lung injury in
107 medical-intensive-care-unit patients.
Relative risk (RR) and 95% confidence intervals (CIs) were deter-
mined. Our goal was to ascertain whether factors previously found to
be associated with increased mortality in lung injury in univariate
analyses would continue to have an independent effect after control-
ling for other important variables. Therefore, to ascertain which fac-
tors contributed independently to mortality, we constructed a multi-
ple-logistic-regression model. This was done in a forward, stepwise
manner, with hospital death as the dependent variable and the pro-
spectively identified independent variables including older age (. 65
yr), individual primary comorbidities, septic and gastric aspiration-re-
lated etiologies of lung injury, APACHE II score or APS, LIS, and
development of nonpulmonary OSD prior to the onset of mechanical
ventilation. Another analysis was then done, using the other (“nonpri-
mary”) comorbidities as additional independent variables. These analy-
ses were then repeated in the cohort of patients meeting criteria for
ARDS. All statistical analysis was done with SPSS v.6.1 software (SPSS,
Inc., Chicago, IL).

Statistical Analysis
The principal outcome studied was hospital survival. Survivors and
nonsurvivors were compared through Student’s t test for continuous
variables and a chi-square test with two-tailed Fisher’s exact test for
dichotomous variables. Univariate analysis was done by comparing
the mortality rates in the presence and absence of a comorbid condi-
tion, previous nonpulmonary OSD, APACHE II score . 20, APS
. 15, LIS . 2.5, and the individual risk factors for ALI and ARDS.
RESULTS
Of the 107 patients enrolled in the study, there were 65 men
and 42 women, aged 51 6 2 yr (mean 6 SEM; range: 20 to 73
yr) (Table 1). A prospectively defined primary comorbid con-
dition was often present, including cirrhosis (n 5 21; 20%),
HIV infection (n 5 11; 10%), active malignancy (n 5 26; 24%),
and organ transplantation (n 5 10; 9%). Of the 10 transplant
patients, nine had received a bone-marrow and one a kidney

TABLE 2
UNIVARIATE ANALYSIS OF FACTORS INFLUENCING MORTALITY IN ALL PATIENTS
WITH ACUTE LUNG INJURY AND THOSE WITH ARDS

All ARDS
(n 5 107) (n 5 81)

Mortality Mortality
(%)* RR† 95% CI‡ p Value (%)* RR† 95% CI‡ p Value

Age . 65 yr 23/31 (74) 1.45 1.07–1.96 , 0.05 18/23 (78) 1.56 1.12–2.17 0.02
Comorbidities§
Malignancy 19/26 (73) 1.37 1.01–1.89 0.07 15/22 (68) 1.25 0.87–1.82 . 0.2
Cirrhosis 14/21 (67) 1.19 0.83–1.71 . 0.2 8/12 (67) 1.18 0.75–1.85 . 0.2
HIV 9/11 (82) 1.49 1.06–2.08 0.11 5/7 (71) 1.27 0.76–2.08 . 0.2
Transplant 9/10 (90) 1.65 1.25–2.17 , 0.05 9/10 (90) 1.69 1.25–2.27 , 0.05
COPD 7/15 (47) 0.78 0.44–1.37 . 0.2 5/12 (42) 0.68 0.34–1.37 0.2
Steroids 15/21 (71) 1.30 0.93–1.82 0.2 13/17 (76) 1.45 1.01–2.04 0.08
Alcohol 11/24 (46) 0.75 0.47–1.19 0.2 8/18 (44) 0.72 0.41–1.25 0.2
Drugs 4/6 (67) 1.16 0.64–2.08 . 0.2 2/4 (50) 0.85 0.32–2.33 . 0.2
Diabetes 5/9 (56) 0.95 0.52–1.75 . 0.2 3/4 (75) 1.32 0.72–2.38 . 0.2
Any 56/91 (62) 1.67 0.85–3.12 0.07 42/68 (62) 1.61 0.79–3.22 0.1
Preceding organ dysfunction
Neurologic 7/16 (44) 0.72 0.40–1.30 0.2 6/11 (55) 0.93 0.52–1.67 . 0.2
Hematologic 14/24 (58) 1.01 0.68–1.49 . 0.2 12/17 (70) 1.30 0.88–1.89 0.2
Renal 14/23 (61) 1.06 0.73–1.56 . 0.2 11/17 (65) 1.15 0.76–1.72 . 0.2
Gastrointestinal 14/18 (78) 1.45 1.05–1.96 0.06 9/12 (75) 1.37 0.93–2.00 0.2
Liver 4/8 (50) 0.85 0.42–1.75 . 0.2 3/7 (43) 0.72 0.30–1.72 . 0.2
Any 31/50 (62) 1.14 0.83–1.56 . 0.2 23/35 (66) 1.27 0.88–1.82 0.2
Risk factors for ALI/ARDS
Sepsis 23/33 (70) 1.33 0.97–1.81 0.1 19/23 (83) 1.72 1.23–2.38 , 0.05
Aspiration 8/10 (80) 1.43 1.01–2.04 0.2 5/7 (71) 1.27 0.76–2.08 . 0.2
Pneumonia 21/43 (49) 0.76 0.54–1.09 0.1 15/35 (43) 0.62 0.40–0.94 , 0.05
Other 10/21 (48) 0.79 0.49–1.27 . 0.2 9/17 (53) 0.89 0.55–1.45 . 0.2
APS . 15¶ 26/43 (60) 1.08 0.78–1.49 . 0.2 22/34 (65) 1.22 0.85–1.75 . 0.2
APACHE II . 20 24/41 (58) 1.02 0.63–1.67 . 0.2 20/31 (65) 1.19 0.83–1.72 . 0.2
LIS . 2.5i 34/58 (59) 1.05 0.77–1.45 . 0.2 32/56 (57) 0.98 0.65–1.47 . 0.2

Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease; HIV 5 human immunodeficiency virus.
* Ratio of patients with the condition who died divided by the total number with the condition.
†
RR, relative risk.
‡
95% CI, 95% confidence interval.
§
See METHODS section for definition of comorbidities, preceding organ dysfunction, and risk factors.
¶
APS, acute physiology score.
i
LIS, lung injury score (21).
1162 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
transplant. The most prevalent predisposing conditions for
ALI and ARDS were pneumonia, sepsis, and aspiration of
gastric contents (Figure 1). A similar distribution of comorbid
conditions and etiologies was found in the 81 (76%) patients
meeting the criteria for ARDS (Table 2).
Sixty-two (58%) of the 107 patients, including 47 (58%) of
the 81 patients with ARDS, died in the hospital. Mortality was
greater among patients with sepsis or gastric aspiration than
among those with pneumonia or other causes of ARDS (p ,
0.05) (Figure 2, Table 2). When survivors were compared with
nonsurvivors, the latter were slightly older and had a higher
APACHE II score, whereas there was no difference in gen-
der, APS, PaO2/FIO2, or LIS (Table 1). A comorbid condition
or age . 65 yr was twice as likely to be present in the nonsur-
vivors as in the survivors.
In the univariate analysis, all of the primary chronic condi-
tions under investigation, except cirrhosis, were associated
with at least a 1.2-fold greater RR of dying in the hospital, al-
though statistical significance at the p , 0.05 level was
achieved only for organ transplantation (Table 2). The pres-
ence of any one of these underlying comorbidities was associ-
ated with an increased mortality (Table 1). For the other
chronic conditions, only steroid use approached statistical sig-
nificance for the ARDS cohort (Table 2). Patients over the
age of 65 yr were 1.45 times (1.56 times for the ARDS group)
as likely to die as those 65 yr of age or younger. The presence
of both older age and a primary comorbidity increased the RR
of dying among all patients to 5.0 (95% CI: 2.0 to 12.5; p ,
0.0001), and in the ARDS group to 7.1 (95% CI: 1.9 to 25.0; p ,
0.0001). Among patients < 65 yr old who did not have a pri-
mary comorbidity, 84% and 90%, respectively, of those with
ALI and ARDS survived, as compared with only 20% and
25% of those with ALI and ARDS, respectively, who were
older than 65 yr and who had a primary comorbidity. Both
septic and aspiration-related etiologies were associated with
an increased RR of death during hospitalization, with only the
former in the ARDS cohort reaching statistical significance
(Table 2). The RR of dying in the hospital in the presence of
any preceding nonpulmonary OSD, APACHE II score . 20,
APS . 15, or LIS . 2.5 was not increased.
With multiple logistic regression, cirrhosis, HIV infection,
active malignancy, organ transplantation, age . 65 yr, and
sepsis were all independent predictors of hospital death in pa-
Figure 2. Mortality based on the etiology of acute lung injury in
107 medical intensive care unit patients.
VOL 157 1998
tients with ALI, whereas in the ARDS cohort, cirrhosis and
active malignancy failed to achieve statistical significance (Ta-
ble 3). Nonpulmonary OSD developing between hospital ad-
mission and the onset of mechanical ventilation, aspiration of
gastric contents as an etiology, APACHE II score or APS, and
LIS measured during the first 24 h of ALI/ARDS were not
found to be independently associated with increased mortality
in either group. This was the case whether the APS and LIS
were analyzed as continuous variables or whether threshold
values were used. When the regression analysis was reconfig-
ured to exclude age and comorbid conditions, the APACHE
II score became an independent predictor of mortality. In con-
trast (under the same conditions), when the APS was substi-
tuted for the APACHE II score, it was not an independent
predictor of outcome.
When other widely prevalent comorbidities, including
COPD, steroid use, alcohol or intravenous drug abuse, and di-
abetes mellitus were analyzed with respect to their impact on
mortality, none reached statistical significance in either the
univariate or the multivariate analysis (Tables 2 and 3).
DISCUSSION
The principal findings of this study were that comorbid condi-
tions, age . 65 yr, and sepsis are important independent pre-
dictors of hospital death in MICU patients with ALI, 75% of
whom satisfied the criteria for ARDS. In contrast, after con-
trolling for these independent predictors, severity of illness,
severity of lung injury, gastric aspiration as an etiology of ALI,
and preceding nonpulmonary OSD were not independently
predictive of outcome.
A number of studies, using univariate analyses, have identi-
fied conditions associated with increased mortality in ALI and
ARDS. These conditions include older age (3, 5, 10–13, 17);
cirrhosis (2, 14); HIV infection (15); bone-marrow and solid-
organ transplantation (2, 16); active malignancy (2, 5); and eti-
ology of lung injury (6, 10, 11, 17, 25, 26). By finding mortality
rates of > 67% for cirrhosis, active malignancy, HIV infection,
organ transplantation, sepsis, and gastric aspiration, our
univariate analysis done exclusively with MICU patients is in
general agreement with the majority of the studies cited ear-
lier of mixed-patient (i.e., combined medical and surgical) or
single-disease populations.
TABLE 3
MULTIVARIATE ANALYSIS OF RISK FACTORS ASSOCIATED WITH
INCREASED MORTALITY IN ACUTE LUNG INJURY AND ARDS*
All Patients† ARDS‡
(n 5 107) (n 5 81)
Coefficient p Value Coefficient p Value
Age . 65 yr 1.98 (0.58) , 0.001 1.89 (0.62) , 0.01
Cirrhosis 1.75 (0.60) , 0.01 — 0.1
HIV 2.75 (0.91) , 0.01 1.75 (0.96) , 0.05
Malignancy 1.60 (0.60) , 0.01 — 0.5
Transplant 3.67 (1.16) , 0.001 2.80 (1.10) , 0.01
Sepsis 1.02 (0.52) , 0.05 1.98 (0.66) , 0.01
Definition of abbreviations: APACHE 5 Acute Physiology and Chronic Health Evalua-
tion; COPD 5 chronic obstructive pulmonary disease; LIS 5 lung injury score.
* Multiple logistic regression analysis was used, with hospital death as the dependent
variable.
†
Variables not achieving statistical significance: COPD, diabetes, drugs, alcohol,
chronic steroid use, acute physiology or APACHE II score, LIS . 2.5, preceding organ
dysfunction, gastric aspiration or pneumonia etiology.
‡
Variables not achieving statistical significance: cirrhosis, malignancy, COPD, diabe-
tes, drugs, alcohol, chronic steroid use, acute physiology or APACHE II score, LIS . 2.5,
preceding organ dysfunction, gastric aspiration or pneumonia etiology. Coefficient is
the logistic regression coefficient and SE (parentheses).
Zilberberg and Epstein: Acute Lung Injury in the ICU
Previous investigators have demonstrated that nonpulmo-
nary OSD following the onset of ARDS has a profound nega-
tive impact on survival (5, 7–10). Recently, Doyle and cowork-
ers found preceding organ dysfunction in 21% of medical and
surgical ALI patients, and its presence was associated with an
88% mortality rate (2). Although our criteria for OSD were
similar, we used the interval from hospital admission to the
onset of mechanical ventilation, rather than to ICU admission,
as the period for occurrence of such dysfunction. Although
nonpulmonary OSD was identified in 46% of our MICU pa-
tients, the associated mortality rate, in contrast to that in pre-
vious studies, was not increased with univariate analysis.
There are several reasons why preceding nonpulmonary OSD
may not be associated with increased mortality. First, al-
though our criteria were similar to those of other investiga-
tors, the low threshold values (i.e., creatinine . 2.0 mg/dl, bi-
lirubin . 2.0 mg/dl, etc.) set in our study raise the possibility
that although organ dysfunction was present, it was milder
than in previous studies. The potential impact of this is sup-
ported by studies showing that a multiorgan-system-dysfunc-
tion score, with increasing points given for increasing dysfunc-
tion, more accurately predicts outcome than does a single
threshold value (27). Second, because mortality rates differ
for individual organ failures, different distributions of OSDs
in different studies may affect their combined influence on
mortality. Moreover, preceding OSD may be more important
in surgical ICU patients, a group excluded from our analysis.
Measures of lung injury severity and of severity of illness
have variable success in predicting ARDS-associated out-
come. A number of reports have found a direct association be-
tween poor oxygenation and mortality (3, 10, 12, 25), whereas
other studies have failed to identify a correlation (2, 5). When
tested prospectively, increasing severity of lung injury (using
LIS score), measured at 24 h, 48 h, and 72 h, was not associ-
ated with increased mortality (2). Our findings confirm that
survival in MICU patients is independent of the LIS deter-
mined within the first 24 h of mechanical ventilation. Simi-
larly, although some have found that APACHE scores predict
outcome for ARDS (4, 6), this has not been confirmed by
other investigators (28–30). APACHE II score was only an in-
dependent predictor when age . 65 yr and comorbid condi-
tions were excluded from our multivariate model. In contrast,
when the acute physiology component is substituted for the
APACHE II score, it is not an independent predictor, irre-
spective of whether age and comorbidities are included in the
model. In other words, it is the contribution of age and certain
comorbidities, rather than the acute physiology component,
that make the APACHE II score a predictor of outcome. One
potential limitation of our APACHE II-score analysis is that
we used data for the first 6 h of mechanical ventilation rather
than for the first 24 h of ICU stay. We believe the impact of
this to be minor, because 75% of our patients were intubated
on the first ICU day (91% within the first 3 d), and the
APACHE II score measured after the first day in mechani-
cally ventilated patients appears to be an accurate predictor of
outcome (31). It is also possible that our study population size
did not provide sufficient statistical power to show an inde-
pendent effect of acute physiologic derangement, given the
very strong effect of comorbidity.
Although numerous univariate analyses of factors associ-
ated with increased mortality rates for ALI and ARDS have
been published, few studies have used multivariate techniques
to identify truly independent predictors of mortality. More-
over, for the most part, the investigations using univariate
analyses have focused exclusively on physiologic variables (8)
or have used parameters present several days after the onset
1163
of ARDS (3, 6). When comorbidities have been included, the
roles of individual conditions have not always been specified
(6). The most complete multivariate analysis to date is that
done by Doyle and colleagues, who examined 123 patients
with ALI (2). Their use of multiple logistic regression showed
cirrhosis, sepsis, and preceding OSD, but not LIS (determined
on Days 1, 2, and 3) to be independently associated with in-
creased hospital mortality. Our findings confirm both the in-
dependent effects of cirrhosis and sepsis on ALI outcome, and
the failure of the 24-h LIS to predict hospital mortality. In
contrast, we identified additional independent factors govern-
ing ALI outcome, including organ transplantation (primarily
bone-marrow transplantation), HIV infection, and the pres-
ence of active malignancy. In further distinction to Doyle and
colleagues, we did not find that preceding OSD achieved sta-
tistical significance in the multivariate model. Although simi-
larities between the studies exist, including overall mortality
rate, average age, and the percentage of patients with sepsis as
the cause for ALI and ARDS, important differences are present.
Most significantly, we studied only MICU patients, rather than
a mixed medical-surgical ICU population. We also controlled
for age and generalized severity of illness (APS), finding the
former, but not the latter, to be an important independent pre-
dictor of hospital outcome. Interestingly, Doyle and colleagues
found no difference in mortality in comparing patients on the
basis of a PaO2/FIO2 threshold value of 150. Similarly, we found
the same 58% mortality among patients with ARDS and those
with ALI but without ARDS with the use of a PaO2/FIO2 thresh-
old of 200. Unfortunately, the small number of patients in the
latter group and large number of independent variables stud-
ied precluded analysis with multiple logistic regression.
The findings of the current study have several important
clinical implications. First, we have identified factors present
at the onset of respiratory failure, including age . 65 yr and a
number of comorbid conditions, that should be considered to
ensure balanced assignment of patients in investigations of
new therapies for lung injury. Failure to account for these fac-
tors may lead to erroneous conclusions about the efficacy or
lack of efficacy of the therapeutic modality under investiga-
tion. For example, a number of recent studies, although noting
exclusion criteria, have not specified the proportions or alloca-
tion of patients with cirrhosis, active malignancy, HIV infec-
tion and organ transplantation (19, 32–34). Given the high
mortality associated with these conditions, failure to account
for their presence may be important when their prevalence is
high and/or study size is small (35). Similar considerations ex-
ist in interpreting studies that analyze time trends in mortality.
Although such analyses show reductions in mortality after
controlling for age and etiology, they do not consider possible
changes in the prevalence of comorbid conditions (11). On the
basis of earlier published univariate analyses showing poor
outcome for ALI and ARDS, one might anticipate an increase
in the proportion of patients with cirrhosis, HIV infection, or-
gan transplantation, and active malignancy opting to forego
mechanical ventilation. If this proves true, then recent im-
provement in mortality rates may in part reflect decreases in
the prevalence of these conditions among patients with ALI
and ARDS. As in recent studies of new therapies for ALI and
ARDS (19, 32) and those showing a decrease in mortality over
time (11), our mortality rate, in the absence of a chronic con-
dition, was only 35% (only 16% when age < 65 yr). Con-
versely, recent advances in the management of patients with
ALI and ARDS would appear even more impressive if de-
creased mortality trends occurred in the setting of increasing
prevalence of these conditions. Additionally, it has been sug-
gested that gender affects the outcome of mechanical ventila-
1164 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
tion, with women having a higher mortality (36). In contrast,
among MICU patients with acute lung injury, we found mor-
tality in men and women to be similar.
In conclusion, using multivariate techniques, we found that
independent predictors of hospital mortality in exclusively
MICU patients with ALI (75% of whom satisfied the criteria
for ARDS) include cirrhosis, the presence of HIV, active ma-
lignancy, organ transplantation, age . 65 yr, and sepsis as a
cause of ALI. Preceding nonpulmonary OSD, APS, LIS, aspi-
ration as the etiology, and other chronic diseases were not
found to be independent predictors of hospital mortality.
These factors must be considered when analyzing results of
trials of new treatment modalities for lung injury. Addition-
ally, these factors, and their changing prevalence, must be
taken into account when interpreting trends in ALI and
ARDS mortality.
References
1. Ashbaugh, D. G., D. B. Bigelow, T. L. Petty, and B. E. Levine. 1967.
Acute respiratory distress in adults. Lancet 2:319–323.
2. Doyle, R. L., N. Szaflarski, G. W. Modin, J. P. Weiner-Kronish, and
M. A. Matthay. 1995. Identification of patients with acute lung injury:
predictors of mortality. Am. J. Respir. Crit. Care Med. 152:1818–1824.
3. Maunder, R. J., P. S. Kublis, D. M. Anardi, and L. D. Hudson. 1989. De-
terminants of survival in the adult respiratory distress syndrome
(ARDS) (abstract). Am. Rev. Respir. Dis. 139:A220.
4. Montgomery, B., M. A. Stager, C. J. Carrico, and L. D. Hudson. 1985.
Causes of mortality in patients with adult respiratory distress syn-
drome. Am. Rev. Respir. Dis. 132:485–489.
5. Suchyta, M. R., T. P. Clemmer, C. G. Elliott, J. F. Orme, Jr., and L. K.
Weaver. 1992. The adult respiratory distress syndrome: a report of
survival and modifying factors. Chest 101:1074–1079.
6. Knaus, W. A. 1991. Prognostic factors in the intensive care unit with spe-
cial emphasis on acute respiratory failure. In W. Zapol and F. Le-
Maire, editors. Adult Respiratory Distress Syndrome. Marcel Dekker,
New York. 91–104.
7. Bell, R. C., J. J. Coalson, J. D. Smith, and W. G. Johanson. 1983. Multi-
ple organ system failure and infection in adult respiratory distress syn-
drome. Ann. Intern. Med. 99:293–298.
8. Fowler, A. A., R. F. Hamman, G. O. Zerbe, K. N. Benson, and T. M.
Hyers. 1985. Adult respiratory distress syndrome: prognosis after on-
set. Am. Rev. Respir. Dis. 132:472–478.
9. Pepe, P. E., R. T. Plotkin, D. Holtman-Reus, L. D. Hudson, and C. J.
Carrico. 1982. Clinical predictors of the adult respiratory distress syn-
drome. Am. J. Surg. 144:124–131.
10. Artigas, A., J. Carlet, J. R. LeGall, C. L. Chastang, L. Blanch, and R.
Fernandez. 1991. Clinical presentation, prognostic factors, and out-
come of ARDS in the European Collaborative Study (1985–1987): a
preliminary report. In W. Zapol and F. Lemaire, editors. Adult Respi-
ratory Distress Syndrome. Marcel Dekker, New York. 1–22.
11. Milberg, J. A., D. R. Davis, K. P. Steinberg, and L. D. Hudson. 1995. Im-
proved survival of patients with acute respiratory distress syndrome
(ARDS): 1983–1993. J.A.M.A. 273:306–309.
12. Sloane, P. J., M. H. Gee, J. E. Gottlieb, K. H. Albertine, S. P. Peters,
J. R. Burns, G. Machiedo, and J. E. Fish. 1992. A multicenter registry
of patients with acute respiratory distress syndrome: physiology and
outcome. Am. Rev. Respir. Dis. 146:419–426.
13. Gee, M. H., J. E. Gottlieb, K. H. Albertine, J. M. Kubis, S. P. Peters, and
J. E. Fish. 1990. Physiology of aging related to outcome in the adult
respiratory distress syndrome. J. Appl. Physiol. 69:822–829.
14. Matuschak, G. M., J. Rinaldo, M. R. Pinsky, J. S. Gavaler, and D. H.
Van Thiel. 1987. Effect of end-stage liver failure on the incidence and
resolution of the adult respiratory distress syndrome. J. Crit. Care 2:
162–173.
15. Torres, A., M. El-Ebiary, R. Marrades, J.-M. Miro, J.-M. Gatell, J. M.
Sanchez-Nieto, A. Xaubet, C. Augusti, and R. Rodriguez-Roisin. 1995.
Aetiology and prognostic factors of patients with AIDS presenting
life-threatening acute respiratory failure. Eur. Respir. J. 8:1922–1928.
16. Rubenfeld, G. D., and S. W. Crawford. 1996. Withdrawing life support
from mechanically ventilated recipients of bone marrow transplants: a
case for evidence-based guidelines. Ann. Intern. Med. 125:625–633.
VOL 157 1998
17. Fowler, A. A., R. F. Hamman, J. T. Good, K. N. Benson, M. Baird, D. J.
Eberle, T. L. Petty, and T. M. Hyers. 1983. Adult respiratory distress
syndrome: risk with common predispositions. Ann. Intern. Med. 98:593–
597.
18. Schuster, D. P. 1995. What is acute lung injury? What is ARDS? Chest
107:1721–1726.
19. Anzueto, A., R. P. Baughman, K. K. Guntupalli, J. G. Weg, H. P. Wiede-
mann, A. A. Raventos, F. Lemaire, W. Long, D. S. Zaccardelli, E. N.
Pattishall, and the Exosurf Acute Respiratory Distress Syndrome
Sepsis Study Group. 1996. Aerosolized surfactant in adults with sep-
sis-induced acute respiratory distress syndrome. N. Engl. J. Med.
334:1417–1421.
20. Bernard, G. R., A. Artigas, K. L. Brigham, J. Carlet, K. Falke, L. Hud-
son, M. Lamy, J. R. LeGall, A. Morris, R. Spragg, and the Consensus
Committee. 1994. The American-European consensus conference on
ARDS: definitions, mechanisms, relevant outcomes, and clinical trial
coordination. Am. J. Respir. Crit. Care Med. 149:818–824.
21. Knaus, W. A., E. A. Draper, D. P. Wagner, and J. E. Zimmerman. 1985.
APACHE II: a severity of disease classification system. Crit. Care
Med. 13:818–829.
22. Murray, J. F., M. A. Matthay, J. M. Luce, and M. R. Flick. 1988. An ex-
panded definition of the adult respiratory distress syndrome. Am.
Rev. Respir. Dis. 138:720–723.
23. Rubin, D. B., J. P. Weiner-Kronish, J. F. Murray, J. Turner, J. M. Luce,
A. B. Montgomery, J. D. Marks, and M. A. Matthay. 1990. Elevated
von Willebrand factor antigen is an early plasma predictor of acute
lung injury in non-pulmonary sepsis syndrome. J. Clin. Invest. 86:474–
480.
24. Pepe, P. E. 1986. The clinical entity of adult respiratory distress syn-
drome: definition, prediction, and prognosis. Crit. Care Clin. 2:377–403.
25. Zapol, W. M., M. J. Frikker, H. Pontopiddan, R. S. Wilson, and K. E.
Lynch. 1991. The adult respiratory distress syndrome at Massachu-
setts General Hospital: etiology, progression, and survival rates 1978-
1988. In W. Zapol and F. LeMaire, editors. Adult Respiratory Dis-
tress Syndrome. Marcel Dekker, New York. 367–380.
26. Hudson, L. D., J. A. Milberg, D. Anardi, and R. J. Maunder. 1995. Clini-
cal risks for development of the acute respiratory distress syndrome.
Am. J. Respir. Crit. Care Med. 151:293–301.
27. Marshall, J. C., D. J. Cook, N. V. Christou, G. R. Bernard, C. L. Sprung,
and W. J. Sibbald. 1995. Multiple Organ Dysfunction Score: a reliable
descriptor of a complex clinical outcome. Crit. Care Med. 23:1638–
1652.
28. Suchyta, M. R., T. P. Clemmer, J. F. Orme, A. H. Morris, and C. G. El-
liott. 1991. Increased survival of ARDS patients with severe hypox-
emia (ECMO criteria). Chest 99:951–955.
29. Turner, J. S., P. D. Potgeiter, and D. M. Linton. 1989. Systems for scor-
ing severity of illness in intensive care. S. Afr. Med. J. 76:17–20.
30. Turner, J. S., and P. D. Potgeiter. 1996. Severity scoring. In T. Evans and
C. Haslett, editors. ARDS: Acute Respiratory Distress Syndrome.
Chapman and Hall, London. 381–391.
31. Knaus, W. A. 1989. Prognosis with mechanical ventilation: the influence
of disease, severity of disease, age and chronic health status on sur-
vival from an acute illness. Am. Rev. Respir. Dis. 140:S8–S13.
32. Amato, M. B. P., C. S. V. Barbas, D. M. Medeiros, G. dP. P. Schettino,
G. L. Filho, R. A. Kairalla, D. Deheinzelin, C. Moraise, E.dO.
Fernandes, T. Y. Takagaki, and C. R. R. de Carvalho. 1995. Beneficial
effects of the “open lung approach” with low distending pressures in
the acute respiratory distress syndrome: a prospective randomized
study on mechanical ventilation. Am. J. Respir. Crit. Care Med. 152:
1835–1846.
33. Bernard, G. R., J. M. Luce, C. L. Sprung, J. E. Rinaldo, R. M. Tate, W. J.
Sibbald, K. Kariman, S. Higging, R. Bradley, C. A. Metz, T. R. Harris,
and K. L. Brigham. 1987. High-dose corticosteroids in patients with
the adult respiratory distress syndrome. N. Engl. J. Med. 317:1565–
1570.
34. Bone, R. C., G. Slotman, R. Maunder, H. Silverman, T. M. Hyers, M. D.
Kerstein, J. J. Ursprung, and the Prostaglandin E1 Study Group. 1989.
Randomized double-blind, multicenter study of prostaglandin E 1 in
patients with the adult respiratory distress syndrome. Chest 96:114-
119.
35. Bailar, J. C., and F. Mosteller. 1992. Medical Uses of Statistics, 2nd ed.
NEJM Books. Waltham, MA.
36. Kollef, M. H., J. D. O’Brien, and P. Silver. 1997. The impact of gender
on outcome from mechanical ventilation. Chest 111:434–441.