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Journal of Critical Care 29 (2014) 1011–1015

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Journal of Critical Care


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Volume of fluids administered during resuscitation for severe sepsis and septic
shock and the development of the acute respiratory distress syndrome☆

a, a a a
Dong W. Chang, MD , Richard Huynh, MD , Eric Sandoval, MD , Neung Han, MD , Clinton
c b
J. Coil, MD, MPH , Brad J. Spellberg, MD
a Divisions of Respiratory and Critical Care Physiology and Medicine, Los Angeles County Department of Health Services and Los Angeles Biomedical Research Institute at Harbor-University of
California Los Angeles Medical Center, Torrance, CA, USA
b General Internal Medicine, Los Angeles County Department of Health Services and Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center,
Torrance, CA, USA
c Department of Medicine and the Department of Emergency Medicine, Los Angeles County Department of Health Services and Los Angeles Biomedical Research Institute at Harbor-University of
California Los Angeles Medical Center, Torrance, CA, USA
article info abstract

Keywords: Purpose: The purpose of this study was to examine the association between the volume of intravenous (IV) fluids administered
Sepsis in the resuscitative phase of severe sepsis and septic shock and the development of the acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS).
Resuscitation Materials and methods: This was a retrospective cohort study of adult patients admitted with severe sepsis and septic shock at
Fluid balance
a large academic public hospital. The relationship between the volume of IV fluids administered and the development of
ARDS was examined using multivariable logistic regression analysis. Results: Among 296 patients hospitalized for severe
sepsis and septic shock, 75 (25.3%) developed ARDS. After controlling for confounding variables, there was no signi ficant
association between the volume of IV fluids administered in the first 24 hours of hospitalization and the development of ARDS
(odds ratio [OR], 1.05; 95% confidence interval [CI], 0.95-1.18). Serum albumin (OR, 0.52; 95% CI, 0.31-0.87) and Acute
Physiology and Chronic Health Evaluation II score (OR, 1.08; 95% CI, 1.04-1.13) on admission were the most informative
covariates for the development of ARDS in the regression model.

Conclusions: For patients hospitalized for severe sepsis and septic shock, fluid administration to improve end-organ perfusion
should remain the top priority in early resuscitation despite the potential risk of inducing ARDS.
© 2014 Elsevier Inc. All rights reserved.
1. Introduction that, in the resuscitative phase of
severe sepsis and septic shock,
Severe sepsis and septic shock restoring intravascular volume and
are the most severe manifestations maintaining end-organ perfusion are
of the sepsis syndrome and the top priorities. However, one
characterized by end-organ concern regarding aggressive
hypoperfu-sion and hypotension volume resuscitation is that it may
due to infection [1]. Previous increase the risk for complications
studies have shown that early goal- due to volume overload, such as the
directed resuscitation of patients acute respiratory distress syndrome
with severe sepsis and septic shock (ARDS) [3–5].
improves mortality [1,2]. One of the
key interventions in early goal- Acute respiratory distress
directed therapy is aggressive syndrome is a devastating
administra-tion of intravenous (IV) complication of sepsis that affects
fluids using physiologic targets to its clinical management and
assess for improvements in end- outcomes [6–8]. Previous studies
organ perfusion [2]. For patients have shown that interventions that
with severe sepsis or septic shock, minimize the administration of IV
the Surviving Sepsis Guidelines fluids in hemodynamically stable
recommend an initial bolus of 30 patients with ARDS decrease the
mL/kg of fluid followed by repeated duration of mechanical ventilation
fluid administration as long as there and intensive care unit (ICU) stay
are continued responses in hemody- without compromising end-organ
namic parameters [1]. The rationale perfusion [9]. As such, the fluid
for these recommendations is management strategies for ARDS
can become discordant with those of
sepsis when pulmonary edema
complicates the early resuscitative
☆ Research support: none.
phase of the sepsis syndrome.
Corresponding author. Department of
Medicine, Harbor-UCLA Medical Center, Given the increased propensity
Box 405, 1000 W. Carson St, Torrance, CA of the lungs to develop pulmonary
90509. Tel.: +1 310 222 3803; fax: +1 310 edema during sepsis, it is possible
328 9849.
that the effects of positive fluid
E-mail address: dchang@labiomed.org
(D.W. Chang). balance during fluid resuscitation in
patients admitted with severe sepsis
http:/ and septic shock may increase the
/dx.d risk for developing ARDS.
oi.org
/10.1
016/j.
jcrc.2
014.0
6.005
0883-
9441/
©
2014
Elsev
ier
Inc.
All
rights
reser
ved.
1012 D.W. Chang et al. / Journal of Critical Care 29 (2014) 1011–1015
confounding factors on the
The objective of this study was We examined the association All data were collected by relationship between primary and
explore this risk by examining the between the total volume of IV retrospective chart review by 2 of secondary predictor variables and
association between the volume of fluids administered in the first 24 the investigators (RH and NH) using the development of ARDS. The
IV fluids administered in the first 24 hours of hospitalization and the a structured data abstraction form. volume of IV fluids administered in
hours of hospitalization for severe development of ARDS within 72 Patient identifiers were removed the first 24 hours (primary variable
sepsis or septic shock and the hours of hospital admission in from aggregated data and were of interest) and the administration of
development of ARDS. We patients admitted with severe sepsis coded using a numeric identifier. an initial fluid bolus (secondary
hypothesized that increased IV fluid and septic shock. The total volume The list of numeric codes and variable) were included in all
administration is associated with a of IV fluids administered was corresponding patient identifiers was models. The administration of an
greater incidence of ARDS despite determined from nursing flow sheets maintained in a password-protected initial fluid bolus was included in
controlling for known predisposing that documented the total fluid computer by one of the investigators the multivariable models despite the
factors. intake and output for each patient. (DWC). The study was approved as lack of association in univariate
The development of ARDS was analysis because this variable was of
an exempt protocol by the John G
identified by chart review using the clinical interest as a potential risk
2. Materials and methods Wolf Institutional Review Board at
Berlin definition of ARDS [11,12]. factor for ARDS. The volume of IV
the Los Angeles Biomedical
Specifically, patients were identified fluids administered in the first 6
2.1. Study design and patients Research Institute. The need for
as having ARDS if they had bilateral hours of hospitalization (secondary
informed consent was waived.
opacities on chest radiograph, acute variable) was not included in the
This was a retrospective
onset of respiratory failure not fully multivariable models because it was
observational study of patients with
explained by cardiac failure, and
severe sepsis or septic shock 2.3. Statistical analysis collinear with the volume of IV
admitted to the emergency PaO2/FIO2 ratio less than 300 mm Hg fluids administered in the first 24
department of a large academic within 72 hours of admission for The primary analysis compared hours. We evaluated the models for
county hospital (Harbor-UCLA severe sepsis or septic shock. the volume of IV fluids adminis- multicollinearity using a correlation
Medical Center, Torrance, CA) tered in the first 24 hours of coefficient matrix of the covariates
between December 2011 and hospitalization in patients who [15]. All covariates included in the
January 2013. The cohort of patients 2.2. Risk factors for the models showed a correlation of less
developed ARDS vs those who did
development of ARDS than 0.60. The values of the
with severe sepsis and septic shock not. The Student t test was used to
was identified by retrospective chart compare the volume of fluids variables in the models are reported
The primary predictor variable as adjusted odds ratios (ORs) with
review of all patients seen in the administered to each group at 6 and
for the development of ARDS was 95% confidence intervals (CIs). A P
emergency department using the 24 hours. The secondary predictor
the volume of IV fluids (liters) value b .05 was used for statistical
clinical definition from the variables, volume of fluids
administered in the first 24 hours of significance in the model variables.
Surviving Sepsis Guidelines and the administered in the first 6 hours of
hospitalization. Secondary variables The data analysis was performed
Society of Critical Care hospitalization and the
included the administration of an using JMP version 11.0 (SAS
Medicine/European Society of administration of an initial fluid
initial fluid bolus of greater than 20 Institute, Cary, NC).
Intensive Care Medicine/American bolus, were analyzed using a t test
mL/kg and the volume of IV fluids
College of Chest Physicians 2
or χ test, as appropriate. A P value
given in the first 6 hours of
International Sepsis Definitions b .05 was used to define statistical
Conference [1,10]. Specifically, hospitalization. Additional risk
factors that were examined included significance. To control for factors
sepsis was defined as a probable and that may confound the relationship
suspected infection as documented patient demographics (age, sex,
race/ ethnicity), medical between the volume of fluids
by a physician in the medical record 3. Results
comorbidities (Charlson administered in the first 24 hours
with at least 2 manifestations of a (primary predictor variable) and the
systemic inflammatory response Comorbidity Index), presenting vital 3.1. Baseline characteristics between
signs and laboratory data (serum development of ARDS (primary
(temperature N 38.3°C or b35.6°C, the ARDS and control groups
sodium, bicarbon-ate, glomerular outcome variable), multivariable
heart rate N 90 beats per minute, logistic regression analysis was
respiratory rate N 20/min, or white filtration rate, albumin, lactate), The study cohort consisted of
medications, use of blood products, performed [13,14]. Prior to
blood cell count N 12.0 × 10 or
3 296 patients who were admitted
composite scores for severity of multivar-iable analysis, univariate
3 with severe sepsis or septic shock.
b4.0 × 10 , or normal white blood illness (Acute Physiology and analysis was performed on all
Of these, 75 patients (25.3%)
cell count with N 10% immature Chronic Health Evaluation covariates to identify those with the
developed ARDS within 72 hours of
band forms). Severe sepsis was [APACHE] II, Sequential Organ strongest association with the
hospital admission. There were
defined as sepsis with organ Failure Assessment [SOFA]), and development of ARDS. All
multiple differences in the baseline
dysfunction or tissue hypoperfusion suspected source of sepsis. covariates that were significant at a
characteristics between patients that
(systolic blood pressure b 90 mm Additional clinical outcomes that level of P b .10 were considered for
developed ARDS and those that did
Hg, mean arterial pressure b 70 mm were examined include hospital and multivariable analysis [15]. For
multivariable regres-sion analysis, 2 not develop ARDS (Table 1). The
Hg, lactate above the upper limit of ICU mortality. Laboratory studies
models were generated. First, all ARDS group was older (mean age,
normal, urine output b 30 mL/h that were not normally distributed
covariates of interest were included 71.5 vs 62.9 years; P = .004). In
despite initial fluid resuscitation, were log transformed for statistical
in a comprehensive model that addition, the ARDS group had a
creatinine N 2.0 mg/dL, bilirubin N analysis. The APACHE II and SOFA
contained any factors that showed lower proportion of Hispanic
2 mg/dL, platelet count b 100,000, scores were calculated from the
an association in the univariate patients compared to the no-ARDS
international normalized ratio N clinical data available on admission.
1.5). Septic shock was defined as analysis. Next, the same covariates group (17.3% vs 38.9%, P b .001).
sepsis-induced hypotension were included in stepwise logistic The serum
resulting in a systolic blood pressure regression analysis to generate a
less than 90 mm Hg or mean arterial parsimonious model that contained
pressure less than 70 mm Hg only the most informative
requiring vasopressor support covariates. These 2 models were
despite IV fluid administration used as complementary approaches
[1,10]. to control for the influence of
D.W. Chang et al. / Journal of Critical Care 29 (2014) 1011–1015 1013

Table 1
Baseline characteristics

Characteristic ARDS (n = 75) No ARDS (n = 221) P-value


Age (SD) 71.5 (18.7) 62.9 (18.2) .004
Female (%) 35 (46.7) 109 (49.3) .691
Race/ethnicity (%)
White 21 (28.0) 62 (28.1) .993
African American 22 (29.3) 45 (20.4) .116
Hispanic 13 (17.3) 86 (38.9) b.001
Asian 16 (21.3) 27 (12.2) .061
Other 3 (4.0) 1 (0.5) .287
Body mass index (SD) 25.6 (7.3) 26.4 (6.7) .375
Serum albumin (SD) 2.4 (0.7) 2.7 (0.7) .001
Lactate (SD) 3.8 (3.6) 2.5 (2.3) .002
APACHE II (SD) 24.1 (9.0) 18.8 (8.1) b.001
SOFA (SD) 9.5 (4.1) 5.1 (3.6) b.001
Serum sodium (SD) 137 (7.7) 134 (7.0) .009
Serum creatinine (SD) 2.3 (2.2) 2.0 (2.4) .356
Source of sepsis (%)
Pneumonia 44 (58.7) 87 (39.4) .004
GI tract 4 (5.3) 23 (10.4) .322
GU tract 14 (18.7) 56 (25.3) .29
Figure. The mean (±SE) volume of fluids administered during the first 6 and 24 hours of
Skin/soft tissue 2 (2.7) 20 (9.1) .035
hospitalization to patients who developed ARDS compared to those who did not develop ARDS.
Other 11 (14.7) 35 (15.8) .347
Comorbidities (%)
Congestive heart failure 14 (18.7) 55 (24.9) .263 the volume of fluid administered in the first 24 hours of hospitaliza-tion was
Diabetes mellitus 29 (38.7) 82 (37.1) .809 not significantly associated with the presence of ARDS (OR, 1.07; 95% CI,
Chronic kidney disease (GFR b 60) 16 (21.3) 38 (17.2) .429 0.95-1.21). The association between the volume of fluid administered and the
Tobacco use (%) 15 (20.0) 37 (16.7) .526
Medications (%)
presence of ARDS was also examined using a parsimonious model that
Statin 16 (21.3) 42 (19.0) .663 included only the most significantly associated covariates as identified by
ACE inhibitor 11 (14.7) 51 (23.1) .111 stepwise logistic regression (Table 4). This model contained serum albumin
Aspirin 18 (24.0) 47 (21.3) .624 (OR, 0.52; 95% CI, 0.31-0.87) and the APACHE II score (OR, 1.08; 95% CI,
β-Blockers 23 (30.7) 67 (30.3) .955
1.04-1.13). Like
PRBC transfusion in 1st 24 h (yes, %) 13 (17.3) 40 (18.1) .881
FFP transfusion in 1st 24 h (yes, %) 4 (5.3) 14 (6.3) .751
ICU mortality (%) 19 (25.3) 15 (6.8) b.001 Table 2
Hospital mortality (%) 29 (38.7) 30 (13.5) b.001 Univariate analysis examining the association between demographic/clinical factors and the
development of ARDS
Abbreviations: GI- gastrointestinal, GU- genitourinary, GFR- glomerular filtration rate, ACE-
angiotensin converting enzyme, PRBC- packed red blood cells, FFP- fresh frozen plasma, ICU- Variable OR 95% CI P-value
intensive care unit. Volume of IV fluids in first 24 h, 1-L increments 1.11 (1.01-1.22) .029
Initial IV fluid bolus N20 mL/kg 0.98 (0.49-1.88) .948
lactate and the APACHE II and SOFA scores were higher in the ARDS group, Age 1.03 (1.01-1.04) .004
suggesting a higher severity of illness and end-organ injury (P b .001). Female sex 0.90 (0.53-1.52) .691
Although pneumonia was the most common source of sepsis in both groups, it Race/ethnicity
White 1.00
was more frequent in the ARDS group (58.7% vs 39.4, P = African American 1.44 (0.71-2.95) .311
.004). The distribution of comorbidities between the ARDS and non-ARDS Hispanic 0.45 (0.20-0.95) .036
groups is shown in Table 1. The frequency of blood transfusions between the Asian 1.75 (0.79-3.87) .168
groups was similar. The ICU mortality (25.3% vs 6.8%, P b .001) and hospital Other 8.86 (1.07-184.44) .043
Temperature 0.92 (0.86-0.99) .032
mortality (38.7% vs 13.8%, P b .001) were higher in patients who developed
Heart rate 1.00 (0.99-1.01) .872
ARDS than in those that did not develop ARDS. Systolic blood pressure 1.00 (0.99-1.01) .938
Body mass index 0.98 (0.94-1.02) .375
Central venous pressure 1.02 (0.94-1.10) .675
3.2. Volume of fluids administered in the first 24 hours of hospitalization
Serum sodium 1.05 (1.01-1.09) .009
Serum bicarbonate 0.98 (0.94-1.02) .255
Patients who developed ARDS received more IV fluids than non-ARDS Log glomerular filtration rate 0.71 (0.52-0.95) .021
patients (Figure). There was a nonsignificant trend of increased fluid Serum albumin 0.49 (0.32-0.73) .001
administration after 6 hours of hospitalization (mean difference, 280 mL; P = . Log BNP 1.08 (0.68-1.75) .738
White blood cell count 1.00 (0.98-1.02) .996
07) in patients who developed ARDS. After 24 hours of hospitalization,
Log lactate 1.83 (1.26-2.71) .002
patients who developed ARDS received an average of 830 mL more IV fluids Use of statin 1.16 (0.59-2.17) .663
compared to the control group (P b .05). All patients received crystalloid Use of β-blocker 1.02 (0.57-1.78) .955
fluids during the initial volume resusci-tation. The urine output in the first 24 APACHE II 1.08 (1.04-1.12) b.001
hours of hospitalization was similar between the groups (1.30 L in ARDS History of congestive heart failure 0.69 (0.35-1.31) .263
History of diabetes mellitus 1.07 (0.62-1.82) .809
patients vs 1.37 L in non-ARDS patients, P = .68). To control for factors that History of chronic renal disease 1.31 (0.67-2.48) .429
can confound the association between IV fluid administration and the Charlson Comorbidity Index 1.09 (0.99-1.20) .064
development of ARDS, logistic regression analysis was performed. By Current tobacco use 1.24 (0.62-2.39) .526
univariate analysis age, temperature, serum sodium, glomerular filtration rate Source of sepsis
Pneumonia 1.00
(log), serum albumin, serum lactate (log), APACHE II score, Charlson
GI 0.34 (0.10-0.96) .041
Comorbidity Index, and source of sepsis showed an association (P b GU 0.49 (0.24-0.97) .039
Soft tissue/skin 0.20 (0.03-0.72) .011
.10) with the presence of ARDS (Table 2). These variables were included in a Other 0.62 (0.28-1.31) .215
comprehensive multivariable logistic model (Table 3). This model showed Transfusion of blood products in 1st 24 h 1.03 (0.52-1.96) .919
that, after controlling for confounding variables,
1014 D.W. Chang et al. / Journal of Critical Care 29 (2014) 1011–1015
administered during a heart failure, should not limit the
Table 3 hospitalization increases the Although these studies show the use of adequate fluid for
Multivariable logistic regression analysis likelihood of developing ARDS overall association between positive resuscitation in the early stages of
showing the relationship between the
among patients at risk. [19–21] Jia fluid balance and the development of sepsis.
volume of IV fluids in the first 24 hours of
hospitalization and the development of et al [20] retrospectively examined a ARDS, they do not address how
ARDS after controlling for confounding mixed cohort of mechanically aggressive volume resuscitation
covariates identified in univariate analysis ventilated patients in a large ICU during the early phases of sepsis
Variable database (Multi Parameter affects this risk. Theoretically, early
Intelligent Monitoring of Intensive goal-directed volume resuscitation In the multivariable logistic
Volume of IV fluids in first 24 h, 1-L increments Care Database) and showed that net can decrease the risk of ARDS by regression models, the serum
Initial IV fluid bolus of N20 mL/kg fluid balance was significantly improving end-organ perfusion, albumin and the APACHE II score
Serum albumin associated with the development of thereby reducing the physiologic were the most informative
APACHE II score, 1-point increments derangements associated with the
ARDS (OR, 1.30; 95% CI, 1.09- covariates for the development of
Age
Temperature
1.56). Plurad and colleagues [21] systemic inflammatory response ARDS. The associations between
Serum sodium found that, among patients admitted syndrome. Murphy et al [18] these variables and the development
Glomerular filtration rate (log) after trauma to surgical ICUs, fluid examined a retrospective cohort of of ARDS have been previously
Lactate (log) balance of greater than 2 L in the 212 patients hospitalized with reported in the medical literature
Charlson Comorbidity Index, 1-point increments
first 48 hours of hospitalization was ARDS secondary to septic shock [7,22–24]. Notably, a recent study
Source of sepsis
Pneumonia independently associated with and found that patients who had by Mikkelsen et al [7] identified
GI tract ARDS. volume resuscitation according to several risk factors for the
GU tract the Surviving Sepsis Guidelines had development of ARDS in patients
Skin/soft tissue Table 4 lower hospital mortality. In that presenting to the emergency
Other Stepwise multivariable logistic regression study, the survivors had a greater department with severe sepsis
analysis showing the relationship between
An adjusted OR of greater than 1 indicates
the volume of IV fluids in the first 24 hours
volume of fluids in the first 6 and 24 including baseline APACHE II
that the variable is associated with greater hours of hospitalization but had
of hospitalization and the development of score. The adjusted OR for
odds of developing ARDS.
ARDS after controlling for the most significantly less total volume by APACHE II score in that study was
informative confounding covariates day 7 and at hospital discharge. 1.06 (95% CI, 1.01-1.11), which is
Variable These results are consistent with the similar to our results. The
the comprehensive model, this
aggressive fluid management consistency of our findings with the
parsimonious model also showed Volume of IV fluids in first 24 h,
1-L increments strategy in early sepsis followed by medical literature where overlap
that the association between the
Initial IV fluid bolus of N20 mL/kg a conservative fluid management exists supports the validity of our
volume of fluids given in the first 24
Serum albumin strategy in ARDS. Although those models. In addition, the associations
hours of hospitalization and the APACHE II score, 1-point increments
findings demonstrated that adequate between serum albumin and the
presence of ARDS was not
An adjusted OR of greater than 1 indicates volume resuscitation is associated baseline APACHE II score to the
significant (OR, 1.05; 95% CI, 0.95-
that the variable is associated with greater with improved clinical outcomes in development of ARDS are
1.18). The secondary predictor odds of developing ARDS. patients with established sepsis- biologically plausible. Serum
variable, whether a fluid bolus of
related ARDS, they did not address albumin levels influence vascular
greater than 20 mL/kg was initially
whether patients who are treated for oncotic pressure and are a biomarker
administered, was also not
sepsis develop ARDS more readily of the burden of acute and chronic
significantly associated with the
as a result of aggressive volume illness. The APACHE II score is a
develop-ment of ARDS in both
resuscitation. Our study addresses multidimensional clinical marker
models (Tables 3 and 4).
this question and found no that has been shown to correlate
association between the volume of with the extent of systemic
fluids administered within the first 6 inflammation, clinical outcomes,
4. Discussion or 24 hours and the development of and the severity of acute illness in
ARDS within 72 hours of sepsis and ARDS [7,22,23,25–27].
Fluid management in severe hospitalization, irrespective of From these findings, we hypothesize
sepsis and septic shock is comorbidities or other factors. that patients with severe sepsis and
challenging, and the optimal Although the absence of a septic shock do not develop ARDS
strategy is unknown. Although there statistically significant association because they receive more IV fluids,
is general consensus that between the volume of fluids but instead receive more IV fluids in
resuscitation with IV fluids should administered in the first 24 hours the first 24 hours of hospitalization
be a first-line intervention in patients and the development of ARDS does because they have greater burden of
with severe sepsis and septic shock, not completely exclude the acute illness requiring more
recent studies have shown that possibility of an increased risk, the aggressive resuscitation and a
excessive fluid administration is adjusted OR of 1.07 and the narrow diminished hemodynamic response
associated with prolonged end-organ 95% CI suggest that, if there is an to IV fluids due to lower
dysfunction and increased mortality increased risk, the magnitude is intravascular oncotic pressure.
[16–18]. These studies support the small. Thus, our results, taken
concern among clinicians that together with the findings by There are several limitations to
aggressive volume resuscitation in Murphy et al, add support to the our study. First, the retrospective,
favorable risk-benefit profile of observational design limits our
severe sepsis and septic shock,
aggressive volume resuscitation in ability to identify causal
while initially improving end organ
the early phases of severe sepsis and relationships between the fluid
perfusion, may inadvertently expose
septic shock. Our results also management strategies and the
patients to complications from
indicate that concern regarding an development of ARDS. Second,
excessive fluid administration.
increased propensity to develop because our study was performed at
ARDS due to underlying a single, urban, public hospital, the
Previous studies have shown
comorbidities, such as congestive results may not generalize to other
that the volume of fluids
clinical environments. However, the
consistency of our findings with
other
D.W. Chang et al. / Journal of Critical Care 29 (2014) 1011–1015 1015
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possibility of a small increased risk central venous pressure are associated
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Acknowledgments
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[20] Jia X, Malhotra A, Saeed M, et al.
We thank Chi-hong Tseng, PhD, Risk factors for ARDS in patients
receiving mechanical ventilation for N
for his critical review of the
48 h. Chest 2008;133:853–61.
statistical analysis and manuscript. [21] Plurad D, Martin M, Green D, et al.
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