Mortality in sepsis versus non-sepsis induced acute lung injury

cc8048 CCJ Research Mortality in sepsis versus non-sepsis induced acute lung injury Sevransky E Jonathan jsevran1@jhmi.edu Martin S Gregory greg.martin@emory.edu Shanholtz Carl cshanhol@medicine.umaryland.edu Mendez-Tellez A Pedro pmendez@jhmi.edu Pronovost Peter ppronovo@jhmi.edu Brower Roy rbrower@jhmi.edu Needham M Dale dale.needham@jhmi.edu

Division of Pulmonary and Critical Care, Johns Hopkins University, 5501 Hopkins Bayview Circle Baltimore, MD 21224 USA

Division of Pulmonary and Critical Care Emory University 615 Michael Street, Atlanta Georgia, 30322, USA

Division of Pulmonary and Critical Care, University of Maryland, 10 South Pine Street Baltimore MD, 21201, USA

Department of Anesthesiology and Critical Care, Johns Hopkins University, 600 North Wolfe Street Baltimore, MD, 21287, USA

Critical Care 1364-8535 2009 13 5 R150 http://ccforum.com/content/13/5/R150 10.1186/cc8048 19758459 23 5 2009 8 7 2009 20 8 2009 16 9 2009 16 9 2009 2009 Sevransky et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Sepsis-induced acute lung injury (ALI) has been reported to have a higher case fatality rate than other causes of ALI. However, differences in the severity of illness in septic vs. non-septic ALI patients might explain this finding.

Methods

520 patients enrolled in the Improving Care of ALI Patients Study (ICAP) were prospectively characterized as having sepsis or non sepsis-induced ALI. Biologically plausible risk factors for in-hospital death were considered in multiple logistic regression models to evaluate the independent association of sepsis vs. non-sepsis ALI risk factors with mortality.

Results

Patients with sepsis-induced ALI had greater illness severity and organ dysfunction (APACHE II and SOFA scores) at ALI diagnosis and higher crude in-hospital mortality rates compared with non-sepsis ALI patients. Patients with sepsis-induced ALI received similar tidal volumes, but higher levels of positive end expiratory pressure, and had a more positive net fluid balance in the first week after ALI diagnosis. In multivariable analysis, the following variables (odds ratio, 95% confidence interval) were significantly associated with hospital mortality: age (1.04, 1.02 to 1.05), admission to a medical intensive care unit (ICU) (2.76, 1.42 to 5.36), ICU length of stay prior to ALI diagnosis (1.15, 1.03 to 1.29), APACHE II (1.05, 1.02 to 1.08), SOFA at ALI diagnosis (1.17, 1.09 to 1.25), Lung Injury Score (2.33, 1.74 to 3.12) and net fluid balance in liters in the first week after ALI diagnosis (1.06, 1.03 to 1.09). Sepsis did not have a significant, independent association with mortality (1.02, 0.59 to 1.76).

Conclusions

Greater severity of illness contributes to the higher case fatality rate observed in sepsis-induced ALI. Sepsis was not independently associated with mortality in our study.

Introduction

Acute lung injury (ALI) and sepsis have a close relation in the intensive care unit (ICU) setting. Sepsis is the most frequent risk factor for the development of ALI 1. Moreover, up to 50% of patients admitted to an ICU with sepsis develop ALI 2.

Patients with sepsis-induced ALI have a higher case fatality rate than patients with other risk factors for ALI 13. However, it is unclear if the higher case fatality rate is related to patient's co-morbidities, severity of illness, or the etiology of ALI. For example, patients with trauma versus sepsis as their risk factor for ALI tend to have lower case fatality rates. However, patients with trauma-related ALI also tend to be younger, with fewer co-morbid conditions and lower severity of illness compared with patients with sepsis-induced ALI 45.

A recent study has suggested that that sepsis is not independently associated with mortality from ALI 6. Our objective is to evaluate whether a risk factor of sepsis is independently associated with mortality in a large cohort of racially diverse ALI patients. A secondary objective is to evaluate clinical and treatment characteristics in this cohort. We have previously demonstrated that in patients with sepsis-induced ALI, a pulmonary versus nonpulmonary source of infection is not independently associated with patient mortality. 7. Hence, we considered all sources of sepsis-induced ALI together in this evaluation. The purpose of this study is to examine whether the presence of sepsis as a risk factor for ALI is independently associated with mortality in a large representative multi-site cohort of ALI patients.

Materials and methods

Study population

This is a retrospective analysis of consecutive ALI patients enrolled into a multi-site prospective cohort study during a three-year period ending in October 2007 8. In this study, 12 ICUs at 4 teaching hospitals enrolled consecutive mechanically ventilated patients who met the American-European consensus criteria for ALI 9. Relevant exclusion criteria included: pre-existing illness with a life expectancy of less than six months; transfer to a study site ICU with pre-existing ALI of more than 24 hours' duration; more than five days of mechanical ventilation prior to ALI diagnosis; and limitations in ICU care (e.g. no vasopressors) at eligibility.

Primary outcome and exposure variables

The primary study outcome was in-hospital mortality. The primary exposure variable was sepsis versus non sepsis as the etiology of ALI with this classification prospectively obtained based on documentation in the medical record for the ICU physicians. Patients with pulmonary or non-pulmonary infections were classified as having sepsis. Any uncertainty in the classification of the primary exposure variable was addressed by an ICU investigator at each study site based on review of the medical record and discussion with the treating ICU physicians.

Patient demographic and severity of illness variables

Patient-related exposures of interest (independent variables) included patient demographics and several measures of severity of illness. These included: Acute Physiology and Chronic Health Evaluation (APACHE) II at ICU admission 10; lung injury severity at onset of ALI (lung injury score (LIS) calculated based on the number of affected quadrants on chest x-ray, positive end expiratory pressure (PEEP) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio 111213); and the organ failure score at onset of ALI (Sequential Organ Failure Assessment (SOFA) score) 14. Length of stay in hospital and ICU prior to ALI diagnosis was also included as an independent variable.

Race was determined by chart review and examination of the patient. We limited our analysis of race to white and black because of the low number of enrolled patients of other races. (12 of 520, including 7 Asian, 3 other and 2 unknown)

ICU management exposure variables

Data were collected on the following variables related to the ICU management of ALI patients: tidal volume at day 1 after ALI diagnosis; PEEP at day 1 after ALI diagnosis; and net fluid balance during the first seven days after ALI diagnosis 1112. Tidal volume and PEEP were abstracted from medical records using settings/measurements for 6:00 AM on the day after ALI diagnosis with tidal volume reported in ml/kg of predicted body weight as per the acute respiratory distress syndrome network calculations 1115. If tidal volume was not available at that time point, data was imputed from the earliest timepoint 12 or 24 hours before; most patients who did not have tidal volumes had been switched to a mode of ventilation (high frequency oscillatory ventilation) for which there was no PEEP available. (Imputation required for 40 patients with no data available for 6 patients; tidal volume and PEEP were generally not available because patients had been switched to high frequency oscillatory ventilation for which these ventilator settings are not available). Cumulative fluid balance was calculated during the first seven days that patients were alive and in the ICU based on the total intravenous and oral intake less the total urinary, gastrointestinal, dialysis and other fluid losses as applicable.

Statistical analysis

Continuous variables were reported as medians, categorical variables as proportions, and compared using Wilcoxin's rank sum, t-tests, and chi-squared tests, as appropriate. Biologically plausible risk factors for in-hospital death were considered in multiple logistic regression models if P < 0.1 in a univariable analysis. In the final multivariable model, we confirmed goodness of fit (using Pearsons chi-square and Hosmer-Lemeshow tests) and absence of colinearity (evaluated using variance inflation factors) between all demographic, severity of illness and ICU management exposure variables. We confirmed that there were no important statistical interactions of sepsis versus non-sepsis with clinically relevant exposure variables selected on an a priori basis by including individual multiplicative terms in the multivariable logistic regression models. All analyses were performed using Stata 10.0 software (Stata Corporation, College Station, TX, USA). A two-sided P < 0.05 was used to determine statistical significance.

Informed consent

A two-step process incorporating delirium screening was used to obtain informed consent from patients. Patients were screened daily for the presence of delirium using the validated screening tools Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). The Institutional Review Board granted a waiver of consent for collection of observational data on eligible patients. Patients were approached for consent when RASS and CAM-ICU data demonstrated resolution of delirium, and after assessment and determination of competency. The institutional review boards of Johns Hopkins University and all participating sites approved this study

Results

Of the 520 ALI patients enrolled in the study, 383 (74%) had sepsis as the primary risk factor for ALI, with 137 (24%) having other causes including 64 (12%%) with aspiration, 18 (3%) with pancreatitis, 8 (3%) with multiple transfusion, 12 (2%) with trauma, 15 (3%) with unknown causes and 7 (1%) with other causes. Patients with sepsis-induced ALI had greater severity of illness and organ dysfunction (APACHE II and SOFA scores) and higher crude in-hospital mortality rates (50 versus 33%) compared with non sepsis-induced ALI patients (Table 1). There were no significant differences in patients in age, gender or lung injury score at ALI diagnosis in patients with sepsis versus no-sepsis ALI risk factors.

Table 1

Patient demographics, clinical characteristics, and in-hospital mortality

Sepsis

n = 383*

Non-sepsis

n = 137*

P value**

Age, years

53 (43, 63)

50 (40, 64)

0.12

Female gender

47%

46%

0.78

Race/Ethnicity

Black

43%

27%

0.01

White

55%

70%

Other

Medical ICU

86%

63%

<0.0001

ICU LOS prior to ALI diagnosis

1 (0, 2)

0.84

Hospital LOS prior to ALI diagnosis

2 (1, 6)

2 (1, 5)

0.28

APACHE II score at ICU admission

28 (21, 34)

22 (17, 28)

<0.0001

SOFA at ALI diagnosis

10 (6, 13)

8 (7, 11)

<0.0001

Lung Injury Score at ALI diagnosis

2.0(1.7, 3.0)

2.0 (1.7, 2.7)

0.64

* Continuous variables are presented as median with interquartile range and categorical variables as proportions.

**Calculated using student's t-test for continuous data that appeared normally distributed, Wilcoxin rank sum for variables that did not appear normally distributed, and the chi-squared test for categorical data.

ALI = acute lung injury; APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit; LOS = length of stay; SOFA = Sequential Organ Failure Assessment.

Of the total cohort, 38% were black, 59% white and 3% other. Black patients were more likely than white patients to have sepsis (43% versus 27%) as a risk factor for ALI (P = 0.01). Demographic characteristics of white and black ALI patients can be seen in Table 2.

Table 2

Patient demographics, clinical characteristics for white and black ALI patients

White

n = 308*

Black

n = 200*

P value**

Age, years

53 (43, 63)

50 (40, 64)

0.12

Female gender

47%

46%

0.78

Sepsis

68%

81%

0.002

Medical ICU

74%

89%

<0.001

Hospital LOS prior to ALI diagnosis

3 (1, 6)

2 (1,6)

0.05

ICU LOS prior to ALI diagnosis

1 (0, 2)

0 (0, 1)

0.009

APACHE II

26 (20,33)

26 (20,34)

0.7

SOFA at ALI diagnosis

9 (7, 12)

9.5 (6, 12)

0.97

Lung Injury Score

2(1.7, 2.7)

2(1.7, 3)

0.23

Mortality in-hospital

45.5%

45.1

.93

* Continuous variables are presented as median with interquartile range and categorical variables as proportions. Does not include the 12 patients with different racial backgrounds

**Calculated using Student's t-test for continuous data that appeared normally distributed, Wilcoxin rank sum for variables that did not appear normally distributed, and the chi-squared test for categorical data.

ALI = acute lung injury; APACHE = Acute Physiology and Chronic Health Evaluation; ICU = intensive care unit; LOS = length of stay; SOFA = Sequential Organ Failure Assessment.

Patients with sepsis-induced ALI were treated in the ICU with higher PEEP on day 1 and had a greater net fluid balance in the first week after ALI diagnosis compared with non-sepsis-induced ALI (Table 3). This greater net fluid balance in the sepsis-induced ALI patients was present on days 1 to 3, but not days 4 to 7 (data not shown). Tidal volumes per kilogram of predicted body weight were similar between groups.

Table 3

Ventilation and fluid therapy in ICU

Parameter

Sepsis*

Non-Sepsis*

P value**

Tidal volume at day 1, mL/kg PBW***

6.7 (5.8, 7.9)

6.4 (4.9, 7.8)

0.16

PEEP on day 1, cmH₂0***

8 (5, 10)

5 (5, 10)

0.0004

PaO₂on day1

81 (66-107)

87 (66-125)

0.15

Cumulative fluid balance during first 7 days after ALI onset, Liters

9.8 (3.9, 17)

7.1 (1.9, 13)

0.004

* Continuous variables are presented as median with interquartile range.

**Calculated using Student's t-test for continuous data that appeared normally distributed, and the Wilcoxin rank sum for variables that did not appear normally distributed.

***For the sepsis and non-sepsis groups, data was missing, and could not be imputed, for tidal volume and PEEP for six patients, five in the sepsis group and one in the non-sepsis group.

PBW = predicted body weight; PEEP = positive end-expiratory pressure.

In univariable analysis, most of the variables with a clinically plausible association with mortality were significantly associated with mortality (Table 4). Sepsis as a risk factor for ALI was associated with mortality in univariable analysis (odds ratio, 95% confidence interval) (2.06, 1.37 to 3.09). In multivariable analysis, several variables (odds ratio, 95% confidence interval) had independent association with mortality: age (1.04, 1.02 to 1.05), admission to a medical ICU (2.76, 1.42 to 5.36) ICU length of stay prior to ALI diagnosis (1.15, 1.03 to 1.29), APACHE II at ICU admission (1.05, 1.02 to 1.08), SOFA (1.17, 1.09 to 1.25), LIS (2.33, 1.74 to 3.12)and fluid balance in the first week after ALI diagnosis (1.06, 1.03 to 1.09) were independently associated with mortality (Table 4). In this multivariable model, sepsis was not independently associated with mortality (1.02, 0.59 to 1.76).

Table 4

Exposures associated with in-hospital mortality in 520 patients with ALI

Univariable*

Multivariable*

Exposure

Odds ratio

(95% CI)

P value

Odds ratio

(95% CI)

P value

Age, years

1.03 (1.02-1.04)

<0.0001

1.04 (1.02-1.05)

<0.001

Ethnicity

0.98 (0.69-1.4)

0.93

Medical ICU

2.08 (1.32-3.30)

0.002

2.76(1.42-5.36)

0.003

ICU LOS prior to ALI diagnosis

1.09 (1.01-1.19)

0.025

1.15 (1.03-1.29)

0.014

Hospital LOS prior to ALI diagnosis

1.03 (1.01-1.06)

0.008

1.03 (0.99-1.05)

0.06

APACHE II at ICU admission

1.08 (1.06-1.11)

<0.0001

1.05 (1.02-1.08)

0.003

Lung Injury Score at ALI diagnosis

2.23 (1.77-2.81)

<0.0001

2.33 (1.74-3.12)

<0.001

SOFA at ALI diagnosis

1.26 (1.19-1.33)

<0.0001

1.17 (1.09-1.25)

<0.001

PEEP at day 1 after ALI, cmH₂0

1.14 (1.09-1.19)

<0.0001

1.04 (0.98-1.10)

0.15

Cumulative fluid balance in first 7 days after ALI diagnosis, Liters

1.06 (1.04-1.09)

<0.0001

1.06 (1.03-1.09)

<0.001

Sepsis vs. non-sepsis ALI risk factor

2.06 (1.37-3.09)

0.001

1.02 (0.59-1.76)

0.61

* Calculated using logistic regression analysis. The odds ratio indicates the increased odds of in-hospital mortality for a one unit increase in each continuous exposure variable or for sepsis vs. non-sepsis for this binary exposure variable.

ALI = acute lung injury; APACHE = Acute Physiology and Chronic Health Evaluation; CI = confidence interval; ICU = intensive care unit; LOS = length of stay; PEEP = positive end-expiratory pressure; SOFA = Sequential Organ Failure Assessment.

Discussion

In our multi-site study of 520 ALI patients, those with sepsis vs. non-sepsis-induced ALI had a significantly higher crude mortality rate. However, after adjustment for patient demographics, severity of illness and clinical factors, sepsis as a risk factor for ALI was not independently associated with mortality. These results suggest that the higher case fatality rate in patients with sepsis-induced ALI may be explained primarily by a greater severity of illness.

There are few studies that examine the attributable risk of sepsis as a predisposing factor for ALI. Cooke and colleagues examined a cohort of 1113 ALI patients admitted to hospitals in King County, Washington, USA 6. Although sepsis as an ALI risk factor was predictive of mortality in univariable analysis, it was not predictive of mortality in their multivariable model. Of note, less than 10% of the patients in their cohort were black 6 Black patients are more likely to develop sepsis, and have a higher case fatality rate from ALI 1617. Our study in a racially diverse cohort of white and black patients also found that sepsis as an ALI risk factor was not predictive of mortality. In addition, Estenssoro and colleagues examined risk factors for mortality in 217 Hispanic ALI patients 18. Although sepsis also was not independently associated with mortality, they included patients who developed sepsis after admission and thus were not specifically evaluating the association of sepsis as an ALI risk factor on in-hospital mortality 18.

Our results are also consistent with the results of Sakr and colleagues, who demonstrated that sepsis was predictive of mortality in univariate but not multivariate analysis in European ICUs 19. Of note, more than one-third of ALI patients in that cohort had mean tidal volumes greater than 8 cc/kg 19. In their model, both fluid balance over the first four days after ALI diagnosis and a composite exposure based on tidal volume, plateau pressure and PEEP were independently predictive of outcome. Consistent with their findings and those of Payen and colleagues 20, we also found that net fluid balance over the first week after ALI diagnosis was predictive of mortality.

Our study has several potential limitations. First, as an observational study, inferences from our findings are dependent on complete adjustment for all relevant confounders. As patients cannot be randomized to their risk factor for ALI, an observational study is the only way in which we can evaluate the potential independent mortality effects of sepsis-induced versus non-sepsis-induced ALI in humans. In this prospective study, we adjusted for plausible patient and treatment-related risk factors for mortality, specifically adjusting for differences in severity of illness using three different ICU measures which were not colinear, and all remained statistically associated with mortality in our final multivariable model. Second, we enrolled patients from teaching hospitals in one geographic area, and thus the results may not be generalizable to other hospitals in other regions. However, our results appear to be consistent with published studies from other regions, including academic and private hospitals as well as teaching hospitals in Argentina 618. Third, while the mortality rates for our observational trial for both sepsis and non-sepsis-induced ALI are higher than in some interventional trials, this higher mortality rate has been seen in other observational trials 21.

We cannot exclude the possibility of misclassification bias in the diagnoses of ALI and sepsis. However, our participating study sites have significant experience with these critical illnesses and have participated in many previous clinical trials enrolling patients with both sepsis and ALI. It is possible that misclassification bias remains. In such a case, this bias might be non-differential, potentially obscuring a true difference in mortality between the sepsis and non-sepsis groups. Finally, if therapies that improve patient mortality rates were delivered at a higher rate (intentionally or unintentionally) to patients with sepsis-induced or non-sepsis-induced ALI, we could miss a potential true difference in between groups for our mortality outcome. Of note, patients with sepsis-induced versus non-sepsis-induced ALI had a greater net fluid balance over the first week in the ICU, which is related to the initial resuscitation of patients with sepsis. However, while a fluid conservative strategy has been associated with increased days alive and off the ventilator, it has not been shown to influence ALI mortality rates 12.

Conclusions

Sepsis-induced ALI is not independently associated with mortality after adjustment for the greater severity of illness in these patients versus those with a non-sepsis risk factor for lung injury. In conjunction with the results from other studies, our research suggests that severity of illness, rather than the precipitating risk factor for ALI, should be considered in making treatment decisions and predicting outcome for these patients.

Key messages

• Patients with sepsis-induced ALI had greater severity of illness and higher crude in-hospital mortality rates compared with non-sepsis-induced ALI patients.

• In multivariable analysis, severity of illness measures, admission to a medical ICU and length of ICU stay prior to developing ALI were all associated with in-hospital mortality. Sepsis as a risk factor for ALI was not independently associated with mortality in a racially diverse cohort of 520 patients.

• More black patients had sepsis as a risk factor for ALI, and were more likely to be admitted to a medical ICU. Black patients had similar severity of illness scores, and crude inpatient mortality rates. Race was not independently associated with mortality rates.

Abbreviations

ALI: acute lung injury; APACHE: Acute Physiology and Chronic Health Evaluation Score; CAM-ICU: Confusion Assessment Method for the Intensive Care Unit; ICU: intensive care unit; LIS: lung injury score; PEEP: positive end-expiratory pressure; RASS: Richmond Agitation-Sedation Scale; SOFA: Sequential Organ Failure Assessment.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors made substantial contribution to the study design and methods. JES and DMN planned the study. JES performed the data analysis. JES drafted the manuscript and all other authors critically revised it for important intellectual content. All authors approved the final version of the manuscript for publication.

Acknowledgements

JES is supported by K-23 GMO7-1399-01A1. DMN is supported by a Clinician-Scientist Award from the Canadian Institutes of Health Research (CIHR). This research was supported by a NHBLI SCCOR grant in Acute Lung Injury SCCOR grant P050 HL 73994. The funding bodies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Incidence and outcomes of acute lung injury Rubenfeld GD Caldwell E Peabody E Weaver J Martin DP Neff M Stern EJ Hudson LD N Engl J Med 2005 353 1685 1693 10.1056/NEJMoa050333 16236739 Clinical risks for development of the acute respiratory distress syndrome Hudson LD Milberg JA Anardi D Maunder RJ Am J Respir Crit Care Med 1995 151 2 Pt 1 293 301 7842182 Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review Sevransky JE Levy MM Marini JJ Crit Care Med 2004 32 11 Suppl S548 53 10.1097/01.CCM.0000145947.19077.25 15542963 Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome Zilberberg MD Epstein SK Am J Respir Crit Care Med 1998 157 4 Pt 1 1159 1164 9563734 Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders Calfee CS Eisner MD Ware LB Thompson BT Parsons PE Wheeler AP Korpak A Matthay MA Acute Respiratory Distress Syndrome Network, National Heart, Lung, and Blood Institute Crit Care Med 2007 35 2243 2250 17944012 Predictors of hospital mortality in a population-based cohort of patients with acute lung injury Cooke CR Kahn JM Caldwell E Okamoto VN Heckbert SR Hudson LD Rubenfeld GD Crit Care Med 2008 36 1412 1420 10.1097/CCM.0b013e318170a375 18434894 Pulmonary vs nonpulmonary sepsis and mortality in acute lung injury Sevransky JE Martin GS Mendez-Tellez P Shanholtz C Brower R Pronovost PJ Needham DM Chest 2008 134 534 538 10.1378/chest.08-0309 18641112 Study protocol: The Improving Care of Acute Lung Injury Patients (ICAP) study Needham DM Dennison CR Dowdy DW Mendez-Tellez PA Ciesla N Desai SV Sevransky J Shanholtz C Scharfstein D Herridge MS Pronovost PJ Crit Care 2006 10 R9 10.1186/cc3948 1550857 16420652 The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination Bernard GR Artigas A Brigham KL Carlet J Falke K Hudson L Lamy M Legall JR Morris A Spragg R Am J Respir Crit Care Med 1994 149 3 Pt 1 818 824 7509706 APACHE II: a severity of disease classification system Knaus WA Draper EA Wagner DP Zimmerman JE Crit Care Med 1985 13 818 829 10.1097/00003246-198510000-00009 3928249 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network Anonymous N Engl J Med 2000 342 1301 1308 10.1056/NEJM200005043421801 10793162 Comparison of two fluid-management strategies in acute lung injury National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Wiedemann HP Wheeler AP Bernard GR Thompson BT Hayden D deBoisblanc B Connors AF Jr Hite RD Harabin AL N Engl J Med 2006 354 2564 2575 10.1056/NEJMoa062200 16714767 One-year outcomes in survivors of the acute respiratory distress syndrome Herridge MS Cheung AM Tansey CM Matte-Martyn A Diaz-Granados N Al-Saidi F Cooper AB Guest CB Mazer CD Mehta S Stewart TE Barr A Cook D Slutsky AS Canadian Critical Care Trials Group N Engl J Med 2003 348 683 693 10.1056/NEJMoa022450 12594312 Serial evaluation of the SOFA score to predict outcome in critically ill patients Ferreira FL Bota DP Bross A Melot C Vincent JL JAMA 2001 286 1754 1758 10.1001/jama.286.14.1754 11594901 Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome Brower RG Lanken PN MacIntyre N Matthay MA Morris A Ancukiewicz M Schoenfeld D Thompson BT National Heart, Lung, and Blood Institute ARDS Clinical Trials Network N Engl J Med 2004 351 327 336 10.1056/NEJMoa032193 15269312 Racial and ethnic disparities in mortality from acute lung injury Erickson SE Shlipak MG Martin GS Wheeler AP Ancukiewicz M Matthay MA Eisner MD National Institutes of Health National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network Crit Care Med 2009 37 1 6 10.1097/CCM.0b013e31819292ea 19050621 The Epidemiology of Sepsis in the United States from 1979 through 2000 Martin GS Mannino DM Eaton S Moss M N Engl J Med 2003 348 1546 1554 10.1056/NEJMoa022139 12700374 Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome Estenssoro E Dubin A Laffaire E Canales H Saenz G Moseinco M Pozo M Gomez A Baredes N Jannello G Osatnik J Crit Care Med 2002 30 2450 2456 10.1097/00003246-200211000-00008 12441753 High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury Sakr Y Vincent JL Reinhart K Groeneveld J Michalopoulos A Sprung CL Artigas A Ranieri VM Sepsis Occurence in Acutely Ill Patients Investigators Chest 2005 128 3098 3108 10.1378/chest.128.5.3098 16304249 A positive fluid balance is associated with a worse outcome in patients with acute renal failure Payen D de Pont AC Sakr Y Spies C Reinhart K Vincent JL Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators Crit Care 2008 12 R74 10.1186/cc6916 2481469 18533029 Has mortality from acute respiratory distress syndrome decreased over time?: A systematic review Phua J Badia JR Adhikari NK Friedrich JO Fowler RA Singh JM Scales DC Stather DR Li A Jones A Gattas DJ Hallett D Tomlinson G Stewart TE Ferguson ND Am J Respir Crit Care Med 2009 179 220 227 10.1164/rccm.200805-722OC 19011152