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Epidemiology and outcome of acute respiratory failure in intensive

care unit patients


J. L. Vincent, MD, PhD, FCCM; Y. Sakr, MB, BCh, MSc; V. M. Ranieri, MD

Objectives: To summarize the prevalence of various forms of


acute respiratory failure in acutely ill patients and review the
major factors involved in the outcome of these patients.
Data Sources and Selection: MEDLINE search for published
studies reporting the prevalence or outcome for patients with
acute respiratory failure and cited reference studies and abstracts
from a recent international meeting in the intensive care medicine
field.
Data Synthesis and Extraction: From the selected articles,
information was obtained regarding the prevalence of acute respiratory failure, including acute respiratory distress syndrome
and acute lung injury as defined by the North American-European

cute lung injury (ALI) and


acute respiratory distress syndrome (ARDS) are common
conditions in critically ill patients, and they are associated with high
morbidity and mortality rates. However,
mortality is seldom related to respiratory
disease alone but, more generally, to failure of other organs. This review summarizes the prevalence of various forms of
acute respiratory failure (ARF) in acutely
ill patients and discusses the major factors involved in the mortality of these
patients. We will refer to the standard
definitions of ARDS and ALI as proposed
by the American-European Consensus
Conference (1), unless indicated otherwise.

From the Department of Intensive Care, Erasme


Hospital, Free University of Brussels, Brussels, Belgium
(JLV, YS); and the Department of Anesthesiology, University of Turin, Turin, Italy (VMR).
Presented, in part, at the Margaux Conference on
Critical Illness, Cabo da Roca in Sintra, Portugal, November 1317, 2002.
Address requests for reprints to: Jean-Louis Vincent, MD, PhD, Department of Intensive Care, Erasme
University Hospital, Route de Lennik 808, B-1070
Brussels, Belgium.
Copyright 2003 by Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000057906.89552.8F

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Consensus Conference, the outcome, and the factors influencing


mortality rates in this population of patients.
Conclusions: The prevalence of acute respiratory failure varies
according to the definition used and the population studied.
Nonsurvivors of acute respiratory distress syndrome die predominantly of respiratory failure in <20% of cases. The relatively high
mortality rates of acute lung injury/acute respiratory distress
syndrome are primarily related to the underlying disease, the
severity of the acute illness, and the degree of organ dysfunction.
(Crit Care Med 2003; 31[Suppl.]:S296 S299)
KEY WORDS: acute lung injury; acute respiratory distress syndrome; acute respiratory failure; intensive care unit

Prevalence of ARDS
Only a few studies have reported the
prevalence of ARDS in general intensive
care unit (ICU) populations. From the
large Acute Physiology and Chronic
Health Evaluation (APACHE) III database, Knaus et al. (2) reported that only
2.4% (423 of 17,440) of all ICU admissions met the diagnosis of ARDS. However, the diagnosis of ARDS was defined
retrospectively on the basis of the admission and International Classification of
Disease, 9th revision (ICD-9), discharge
and not on respiratory variables, so this
prevalence is probably an underestimation.
Two French studies reported that of
all ICU admissions, only ~7% met the
ARDS diagnosis criteria; in a single medical ICU, Monchi et al. (3) reported that
7.4% (259 of 3,511) of patients met the
ARDS criteria, and in a multicenter study
of primarily medical ICU patients, Roupie
et al. (4) reported a prevalence of 6.9%
(67 of 976). A recent multicenter Australian study (5) reported that 7.5% (148 of
1,977) of a mixed ICU population met the
ARDS criteria. A European study (ALIVE)
(6) involving 78 ICUs from nine countries, in which all patients (n 5,457)
were admitted to one of the participating
units for at least 4 hrs during a 2-month
study period, noted that 7.4% had, or
developed, ALI/ARDS (2.8% ALI and 5.3%

ARDS). This study noted considerable


variations in the occurrence of ALI/ARDS
among countries, ranging from 1.7% in
Switzerland to 19.5% in Portugal, although criteria used to define ALI and
ARDS were the same for all countries (7).
In the recent sepsis occurrence in the
acutely ill patient (SOAP) study (unpublished observations) including a total of
3,147 patients, 393 (12.5%) had ALI/
ARDS as defined by hypoxemia (PaO2/FIO2
of 300 mm Hg), bilateral chest infiltrates, and the need for mechanical ventilation in the absence of a history of
chronic obstructive pulmonary disease or
manifestations of left ventricular failure.
Several studies have tried to define the
proportion of patients with respiratory
failure that meet the ARDS criteria. In
one of the studies mentioned above,
Roupie et al. (4) found that 16% of all
mechanically ventilated patients met the
ARDS criteria. Two other French studies
(8, 9) reported prevalences of ARDS in
mechanically ventilated patients of 23%
and 15%, respectively. In a prospective
cohort study in Sweden, Denmark, and
Iceland, Luhr et al. (10) found that 18%
of a total of 1,231 patients ventilated for
24 hrs met the ARDS criteria, and in a
North American study involving a surgical population, 11% (111 of 980) of ventilated patients met the ARDS criteria. In
a large study of 5,183 patients treated
Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

using mechanical ventilation in the ICU,


Esteban et al. (11) found a low prevalence
of ARDS of 4.5%, but many of the patients included did not have any form of
respiratory failure, and 20% were ventilated in the postoperative period. Close
to 5% of the entire population did not
undergo endotracheal intubation.
Other investigators have reported the
prevalence of ARDS in specific populations. Goh et al. (12) reported a prevalence of 4.3% in pediatric patients.
Dancey et al. (13) reported a prevalence
of 40% in a population of patients with
thermal injury, and Navarrete-Navarro et
al. (14) reported a prevalence of 5.6% in a
large population involving 18,414 trauma
patients.

Mortality from ARDS


Mortality rates from ARDS are usually
cited within the range 40% to 60%the
variability in the rates quoted is related to
differences in the populations studied and
in the precise definitions used. The European ALIVE (6) study noted ICU mortality rates of 28.5% in patients with ALI
and 51.3% in patients with ARDS. In the
SOAP study (unpublished observations),
the ICU mortality of patients with ALI/
ARDS was 38.9%, vs. 15.6% for patients
without ALI or ARDS. The ICU mortality
rate for patients with ARDS was 42.2%.
Nonsurvivors of ALI/ARDS were older
(mean age, 65 yrs [range, 5173 yrs] vs.
61 yrs [range, 4372 yrs], p .036) and
more likely to be female (52.9% vs.
34.7%, p .016) than survivors. Overall
infection rates were similar (74.5% vs.
72.0%, p .580), although septic shock
was more prevalent in nonsurvivors
(55.6% vs. 32.2%, p .001).
Table 1 summarizes all the studies
found in a MEDLINE search on the mortality from ARDS in general ICU populations. Only Ullrich et al. (15) reported a
very low mortality rate of 20%. Despite
increased understanding of the pathophysiology of ARDS and apparent advances in respiratory support technology,
there has been no clear decrease in the
mortality rate of ARDS over time (16).
However, there may have been changes
in the case mix of the ARDS population,
with sicker patients being treated in our
ICUs.

Causes of Death
Most studies have indicated that nonsurvivors of ARDS usually die of nonresCrit Care Med 2003 Vol. 31, No. 4 (Suppl.)

Table 1. Reported mortality from acute respiratory distress syndrome in general intensive care unit
populations
Authors (Reference No.)

Year

No. of Patients

Mortality, %

Hudson et al. (32)


Doyle et al. (19)
Ferring & Vincent. (18)
Suchyta et al. (33)
Zilberberg & Epstein. (34)
Trouillet et al. (8)
Monchi et al. (3)
Brochard et al. (35)
Weg et al. (36)
Stewart et al. (37)
Luhr et al. (10)
Ullrich et al. (15)
Valta et al. (23)
Roupie et al. (4)
Luhr et al. (21)
Markowicz et al. (9)
NIH ARDS Network (38)
Esteban et al. (22)
Rocco et al. (20)
Gattinoni et al. (39)
Esteban et al. (11)
Bersten et al. (5)
Nuckton et al. (40)
Derdak et al. (41)

1995
1995
1997
1997
1998
1998
1998
1998
1998
1998
1999
1999
1999
1999
2000
2000
2000
2000
2001
2001
2002
2002
2002
2002

179
123
129
256
81
56
259
58
725
60
221
84
59
61
95
134
429
79
111
152
231
148
179
73

62
58
52
54
58
61
65
38
40
47
41
20
37
60
44
58
40
59
52
48
52
34
42
52

piratory causes (i.e., die with, rather than


of, ARDS). A landmark article by Montgomery et al. (17) showed that only 16%
of deaths were caused by respiratory failure. In most cases, early death (within 72
hrs) was caused by the underlying illness
or injury, whereas late death (beyond 72
hrs) was caused by sepsis. More than 10
yrs later, Ferring and Vincent (18) reported similar findings. In a series of 129
patients with ARDS, 67 (25%) died50%
of sepsis/multiple organ failure (MOF),
16% of respiratory failure, 15% of cardiac
failure/arrhythmia, 10% of neurologic
failure, and 8% of other causes. Recently,
Bersten et al. (5) reported that respiratory failure contributed to death in only
24% of ARDS patients and was the only
cause of death in 9% of patients with
ARDS.
Indeed, ARDS is a systemic disease,
and many investigators have found death
to be primarily related to the degree of
other organ dysfunction. For example, a
multivariate analysis by Doyle et al. (19)
found that MOF, liver disease, and sepsis
were the main factors contributing to
death. Likewise, Rocco et al. (20) found
that age and MOF were the most important prognostic factors, and Luhr et al.
(21) found that only age and acute physiologic scores were significantly associated with mortality. Other important
prognostic factors identified in these
studies include the development of right

ventricular dysfunction (3) and the presence of acute renal failure (22).
It is quite remarkable that the degree
of hypoxemia does not seem to be an
important prognostic factor. Luhr et al.
(10) reported that the 90-day mortality
was 41% for ARF without ALI, 42% for
ALI not fulfilling ARDS criteria, and 41%
for ARDS. In a subsequent study (21),
these investigators emphasized again that
the degree of hypoxemia was unimportant in terms of predicting mortality.
Likewise, Valta et al. (23) reported that
the PaO2/FIO2 ratio at the onset of ARDS
averaged 114 mm Hg in survivors and
109 mm Hg in nonsurvivors. Figure 1
illustrates the factors that can affect outcome after the initial insult responsible
for the development of ALI.

Placing the Focus on ARF


In view of these considerations, it may
be valuable to expand our scope to a
broader population of patients with ARF.
The Sequential Organ Failure Assessment
database of 1,449 patients, followed prospectively, indicated that 32% of all ICU
admissions met the diagnosis for ARF as
defined by a PaO2/FIO2 of 200 mm Hg
and the need for respiratory support (24).
Patients who presented with ARF were
older than other patients and were more
likely to have an infection. Of the 991
patients who were admitted to the ICU
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without ARF, 352 developed ARF during


the ICU stay. The independent risk factors for the development of ARF in the
ICU were infection, altered neurologic
status, and older age. The independent
risk factors for death were MOF, history
of hematologic malignancy, chronic renal failure or liver cirrhosis, presence of
circulatory shock at ICU admission, presence of infection, and older age (24).
Clinical and experimental evidence
suggest that mechanical ventilation by
causing stress to the alveolar wall due to
overdistension (25) or repeated recruitment/derecruitment (26)may influence
end-organ function. In a randomized,
controlled trial of 37 patients with ARDS,
mechanical ventilation was found to
cause a pulmonary and systemic rise in
inflammatory mediators (27). The use of
a less stressful lung-protective ventilator
strategy caused a reduction in the con-

centration of inflammatory mediators in


the lung and in the plasma. Mechanical
ventilation with high tidal volume and
low positive end-expiratory pressure was
associated with an increased prevalence
of MOF; the worsening of end-organ
function was significantly correlated with
the increase in plasma interleukin-6 levels (28). Recent data from Imai et al. (29)
confirm and expand these findings. In a
rabbit model of ARDS, injurious mechanical ventilation caused kidney, gut, and
liver failure through the activation of
Fas-mediated apoptosis. A protective ventilatory strategy was associated with no
distal organ failures and no apoptosis.
These observations reinforce the concept
of MOF as a determining factor influencing the outcome of patients with ARDS
and suggest that the beneficial effect on
mortality observed with low tidal volumes (30) may also be related to the
reduction in MOF.

Time Course of Respiratory


Failure

Figure 1. Schematic representation of the principal factors determining a poor outcome over
time, including the severity of the primary insult,
the host response (e.g., mediator release, immunosuppression), the effects of therapy (including
the potentially harmful effect of mechanical ventilation), and possible complications (e.g., nosocomial infections, thromboembolism, gastrointestinal bleeding).

Clearly, nonsurvivors of ARDS are


likely to develop more severe organ dysfunction toward the end of their ICU stay.
Thus, counting the number of organs
failing, or calculating an organ failure
score, is likely to yield a higher value in
the nonsurvivors than in the survivors.
However, taking the time factor into account may be important because the degree of organ dysfunction in survivors
and nonsurvivors may either separate
early on (Fig. 2A) or stay close until the
nonsurvivors abruptly decompensate and
the survivors rapidly improve (Fig. 2B).
Of course, intermediate scenarios can

he relatively high
mortality rates of
acute lung injury/

acute respiratory distress


syndrome are primarily related to the underlying disease, the severity of the
acute illness, and the degree
of organ dysfunction.

also occur. Although we stated previously


that the severity of hypoxemia has limited
prognostic value, the time course of the
PaO2/FIO2 ratio may be an important indicator. As early as 1989, Bone et al. (31)
emphasized that survivors and nonsurvivors differed in the early response of the
PaO2/FIO2 ratio to conventional therapy.
In a prospective study of 182 patients
with ARF in our institution (unpublished
observations), we separated 133 patients
who had early ARF (an onset of 48 hrs
after ICU admission) and 49 with late ARF
(an onset of 48 hrs after ICU admission). At admission, the cardiovascular
Sequential Organ Failure Assessment
score was higher in early than in late
ARF, whereas the neurologic score was
higher in late than in early ARF. In early
ARF, a high Sequential Organ Failure Assessment score and low Glasgow Coma
Score were predictors of mortality, and in
late ARF, a low Glasgow Coma Score at
48 hrs predicted mortality. These findings suggest that there may be important
differences in the epidemiology and outcome of ARF that are dependent on the
time of onset.

Conclusions

Figure 2. Schematic representation of possible time courses of organ dysfunction over time illustrating
the point that all nonsurvivors are likely to develop multiple organ failure before death. Hence, it may
be more informative to evaluate the time course rather than the maximum degree of organ dysfunction in survivors and nonsurvivors.

S298

The present overview indicates that


the relatively high mortality rates of ALI/
ARDS are primarily related to the underlying disease, the severity of the acute
illness, and the degree of organ dysfunction. Nonsurvivors of ARDS die predominantly from respiratory failure in 20%
of cases. Expanding the patient population from ARDS to ALI to ARF does not
markedly reduce the risk of morbidity
and mortality. More attention should be
Crit Care Med 2003 Vol. 31, No. 4 (Suppl.)

focused on the time course of organ dysfunction. This could allow the development of good studies that evaluate the
effects of new interventions on both mortality and morbidity.

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