- Email: [email protected]
ARDS Have Decreased Over Time
Original Research CRITICAL CARE MEDICINE
Mortality Rates for Patients With Acute Lung Injury/ARDS Have Decreased Over Time* Massimo Zambon, MD; and Jean-Louis Vincent, MD, PhD, FCCP
Background: Over the last decade, several studies have suggested that survival rates for patients with acute lung injury (ALI) or ARDS may have improved. We performed a systematic analysis of the ALI/ARDS literature to document possible trends in mortality between 1994 and 2006. Methods: We used the Medline database to select studies with the key words “acute lung injury,” “ARDS,” “acute respiratory failure,” and “mechanical ventilation.” All studies that reported mortality rates for patients with ALI/ARDS defined according to the criteria of the American European Consensus Conference were selected. We excluded studies with < 30 patients and studies limited to specific subgroups of ARDS patients such as sepsis, trauma, burns, or transfusion-related ARDS. Results: Seventy-two studies were included in the analysis. There was a wide variation in mortality rates among the studies (15 to 72%). The overall pooled mortality rate for all studies was 43% (95% confidence interval, 40 to 46%). Metaregression analysis suggested a significant decrease in overall mortality rates of approximately 1.1%/yr over the period analyzed (1994 to 2006). The mortality reduction was also observed for hospital but not for ICU or 28-day mortality rates. Conclusions: In this literature review, the data are consistent with a reduction in mortality rates in general populations of patients with ALI/ARDS over the last 10 years. (CHEST 2008; 133:1120 –1127) Key words: acute respiratory failure; hypoxemia; literature review; outcomes Abbreviation: ALI ⫽ acute lung injury
the first description of ARDS in 1967 by S ince Ashbaugh and coworkers, many studies have 1
been performed in an attempt to develop new therapies and new ventilatory strategies that could improve outcomes for patients with acute lung injury (ALI)/ARDS. ALI and ARDS remain a major problem in the ICU; in a recent publication, the inci*From the Department of Intensive Care, Erasme Hospital, Universite´ libre de Bruxelles, Belgium. The authors received no external funding for this study and have no conflicts of interest to declare. Manuscript received August 30, 2007; revision accepted January 8, 2008. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Jean-Louis Vincent, MD, PhD, FCCP, Department of Intensive Care, Erasme Hospital, Route de Lennik, 808, 1070 Brussels, Belgium; e-mail: [email protected] DOI: 10.1378/chest.07-2134 1120
dence of ALI in the United States was reported to be 78.9/100,000 persons per year, with a mortality rate of approximately 40%.2 However, reported mortality rates vary widely. An analysis by Krafft et al3 published in 1996 concluded that the mortality rate of ARDS patients had remained constant from 1967 to 1994. In more recent years, however, some authors4,5 have suggested that survival rates may have improved, mainly as a result of the implementation of new protective ventilatory strategies. Nevertheless, although some studies6 – 8 do show decreased mortality rates compared to historical control groups, some studies9,10 still report mortality rates ⬎ 50%. Importantly, ARDS is a syndrome and not an illness, and therefore difficult to define. Nevertheless, criteria were developed to define ALI/ARDS at the American European Consensus Conference in 199411 and have been widely adopted, facilitating comparison of studies. Original Research
We were interested to see whether recent improvements in management may have resulted in improved outcomes and performed a systematic analysis of the literature about ALI/ARDS to document possible trends in mortality rates.
Materials and Methods We used the Medline database and selected studies with the key words “acute lung injury,” “ARDS,” “acute respiratory failure,” or “mechanical ventilation,” limiting the research to adult patients and to studies published in the English language. We also limited the search to studies that used the criteria defined by the American European Consensus Conference,11 so we did not include publications that appeared before 1994. The reference lists from identified articles were also reviewed to locate any articles that had been missed in the original search. We included all studies up to August 2006. From the identified studies, we selected those that included an assessment of mortality of a group of patients with ALI/ARDS. We arbitrarily decided to exclude studies that included ⬍ 30 patients. We also excluded studies that were limited to specific subgroups of ARDS patients, such as sepsis, trauma, burns or transfusion-related ARDS, because there may be different mortality rates among these subgroups.12–15 If the same group of patients was used in different publications, we analyzed only the first in chronological order. To take into account the inevitable time delays in publication, we took as the year of the study the last year of patient enrolment, whenever this was reported. We noted separately the ICU, hospital, and 28- to 30-day mortality rates. In controlled trials, we considered the mortality rate of the control group, so we excluded groups of patients whose mortality rate may have been altered because of treatment. In studies with historical cohorts, we considered the mortality rate of the most recent cohort. We attempted to compare the severity of the patient populations based on available severity scores. We also tried to analyze the differences in patient selection (inclusion/exclusion criteria) among studies, to determine how they may influence mortality rates, and analyzed separately studies without any exclusion criteria (primarily noninterventional/epidemiologic) and studies with exclusion criteria (primarily interventional) such as preexisting pulmonary disease, lung contusion, head injury, malignancy disease, hepatic disease, or other comorbidities. Statistical Analysis Separate metaanalyses16 were performed for different mortality outcomes: overall mortality, ICU mortality, hospital mortality, 28- to 30-day mortality, and mortality for the studies with and without exclusion criteria. These were performed using random-effects models on a logit of the outcome. The presence of between-studies heterogeneity was assessed using the standard 2 test (noted Q). Results were transformed to the proportion scale to ease interpretation.17 Additional metaregression analyses were performed to explore the effect of time. A mixed model, again using the logit of the outcome, was utilized for this purpose.18 Sensitivity analysis was performed to examine whether there was systematic variation in the results. Funnel plots were drawn, and their asymmetry19 was examined to assess whether publication bias was likely to be a problem, and the method of trim and fill, which assesses how many studies are likely to be missing and the potential impact of their exclusion on the analysis, was applied to both outcomes. Analyses were conducted using statiswww.chestjournal.org
tical software (Comprehensive Meta-Analysis Version 2; Biostat; Englewood NJ; and SPSS 14.0 for Windows; SPSS; Chicago, IL).
Results We identified 535 articles, of which 354 reported mortality rates for patients with ALI or ARDS. A total of 173 studies were excluded because the number of patients was ⬍ 30, and 92 studies were excluded because they treated a specific etiologic subgroup of ARDS patients, 11 studies because the same population was analyzed in another study, and 6 studies because the study period was not defined. Hence, 72 studies, including 11,426 patients, were included in the analysis (Table 1). Analysis of disease severity was not possible because of the wide variation in severity scores used in the studies. Mortality rates varied considerably among the studies, from 15 to 72% (Table 1); the overall pooled mortality rate for all studies was 43% (95% confidence interval, 39.9 to 46.1%), and the differences in pooled mortality rates over time are shown in Figure 1. There was heterogeneity between study results in the logit rate (Q ⫽ 682.0; p ⬍ 0.001, between-study variance, 0.24). Data from the other mortality analyses are provided in Table 2. When including time as a covariate in the metaregression model, there was an approximately constant linear reduction in overall mortality over the years covered by the literature (p ⫽ 0.02). The regression equation was logit(death) ⫽ 94.4689 ⫺ 0.0474 ⫻ time; when the regression line was transformed on the proportion scale, this translated into a 1.1% reduction in mortality per 1-year period over the analyzed time span. When analyzed separately, there was also a reduction in hospital mortality (slope coefficient, ⫺ 0.0621; p ⫽ 0.04), but there were no significant changes in the other mortality outcomes (Table 3). Funnel plots were constructed for all the studies included in the analysis, examining overall mortality and hospital mortality, in order to assess the degree of publication bias. For the overall mortality, the funnel plot was symmetrical, indicating that publication bias is unlikely to have had a major influence in the analysis of mortality rates (plots not shown). Discussion In a single-center study, Milberg et al86 reported no overall change in mortality rates for patients with ARDS from 1983 to 1987, a slight decline in 1988 and 1989, and a decrease to a low of 36% in 1993. In another study from the same center, Stapleton et al7 observed that mortality rates decreased in the 1980s until the mid-1990s, plateauing thereafter; there CHEST / 133 / 5 / MAY, 2008
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Table 1—The Selected Studies Source
Study Year (End of Enrollment)
Patients, No.
Mortality Rate, %
Doyle et al20 Nolan et al21 De Backer et al22 Ferring and Vincent23 Lewandowski et al24 Monchi et al25 Chastre et al26 Valta et al27 Manktelow et al28 Dellinger et al29 Gallart et al30 Zilberberg and Epstein14 Brochard et al31 Jardin et al6 Roupie et al32 Lundin et al33 Vieillard-Baron et al34 Esteban et al35 Luhr et al36 Ullrich et al37 Abraham et al38 Abel et al39 Villar et al40 Gadek et al41 ARDS Network42 Ferguson et al43 Markowicz et al44 Rocco et al45 Ware et al46 Esteban et al47 Matthay and Ware48 Brun-Bruisson et al49 Gattinoni et al50 Papazian et al51 Vincent et al52 ARDS Network53 Albertine et al54 Bersten et al55 Taylor et al56 Derdak et al57 Nuckton et al58 Rubenfeld et al2 Fialkow et al59 Estenssoro et al60 Spragg et al61 Kacmarek et al62 Villar et al63 O’Brien et al64 Ishizaka et al65 David et al66 Weinert et al67 Manzano et al68 Richard et al69 Venet et al70 Frenckner et al71 Lu et al72 ARDS Network73 Ferguson et al74 Gong et al75 Sakr et al76 Mancebo et al9 Singer et al10
1994 1994 1995 1995 1995 1995 1995 1995 1996 1996 1996 1996 1996 1996 1996 1996 1996 1996 1997 1997 1997 1997 1997 1997 1997 1998 1998 1998 1998 1998 1998 1999 1999 1999 1999 1999 1999 1999 1999 2000 2000 2000 2000 2000 2000 2000 2001 2001 2001 2001 2001 2001 2001 2002 2002 2002 2002 2002 2002 2002 2002 2003
123 32 43 129 122 259 56 59 88 54 48 81 58 37 67 87 98 79 221 84 171 78 56 76 117 467 134 65 51 231 45 401 152 49 32 429 51 148 193 73 179 1,113 30 217 224 105 45 1,488 35 42 398 61 174 125 37 108 230 41 221 393 60 49
58 (hospital) 47 (ICU) 47 (ICU) 52 (ICU) 25 (ICU) 65 (hospital) 61 (ICU) 37 (ICU) and 42 (hospital) 72 (hospital) 30 (28 d) 52 (ICU) 58 (hospital) 38 (hospital) 32 (ICU) 60 (28 d) 40 (30 d) 53 (ICU) 56 (ICU) and 66 (hospital) 41 (90 d) 20 (ICU) 28 (28 d) 34 (hospital) 43 (ICU) 25 (ICU) 34 (hospital) 60 (ICU) 58 (ICU) 38 (30 d) 51 (hospital) 52 (ICU) 54 (hospital) 46 (ICU) and 55 (hospital) 48 (ICU) 35 (ICU) 28 (28 d) 40 (hospital) 57 (hospital) 32 (28 d) 20 (28 d) 52 (30 d) 42 (hospital) 38 (hospital) 44 (ICU) and 48 (hospital) 58 (hospital) 32 (28 d) 15 (28 d) 53 (ICU) 37 (hospital) 32 (hospital) 43 (30 d) 45 (30 d) 66 (hospital) 59 (28 d) 22 (28 d) 34 (30 d) 68 (hospital) 25 (hospital) 29 (ICU) 46 (60 d) 39 (ICU) and 45 (hospital) 58 (ICU) 57 (28 d)
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Exclusion Criteria No No No Yes Yes No No No No Yes No No Yes No No Yes Yes Yes No Yes Yes No No Yes Yes No Yes No No No No Yes Yes No Yes Yes No Yes Yes Yes Yes No No No No Yes Yes No No Yes No No Yes Yes Yes No Yes Yes Yes No No Yes (Continued)
Original Research
Table 1—Continued Source
Study Year (End of Enrollment)
Patients, No.
2003 2003 2003 2003 2003 2003 2003 2003 2005 2005
40 57 200 246 30 56 30 91 68 487
Schmidt et al77 Gando et al78 Kallet et al8 Zeiher et al79 Salari et al80 Ware et al81 Vieira et al82 ARDS Network83 Gattinoni et al84 ARDS Network85
were no changes in the distribution of causes of death during the time period studied. Similar results were reported from a French center.6 However, an analysis by Krafft et al3 concluded that mortality rates had remained constant until 1994. Singlecenter studies8,45 with historical cohorts have suggested a decrease in mortality rates. Our literature review suggests that there has indeed been a reduction in mortality rates for patients with ALI/ARDS over the last decade. The reasons for this observation cannot be determined from the current study. There was a similar reduction in mortality rates in studies with or without exclusion criteria, indicating that the differences seen over time were not related simply to the large number of inclusion criteria and highly selective populations included in interventional studies. The decrease in mortality was more pronounced for hospital mortality than for ICU mortality; this finding is probably more meaningful, and makes it less likely that the
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Overall mortality, %
50 40 30 20 10 0
1994-1995 1996-1997 1998-1999 2000-2001 2002-2003 2004-2005
Year
Figure 1. Variation in overall pooled mortality rates over time in the 72 ALI/ARDS studies. www.chestjournal.org
Mortality Rate, %
Exclusion Criteria
25 (28 d) 46 (ICU) 32 (hospital) 30 (28 d) 43 (ICU) 61 (hospital) 50 (ICU) 29 (60 d) 28 (ICU) 26 (60 d)
Yes No Yes Yes Yes No No Yes Yes Yes
changes could have been due to changes in ICU discharge criteria over time. The decrease in mortality may have been a result of improvement in the specific management of patients with ALI/ARDS as well as in the general management of ICU patients. Respiratory failure is an uncommon cause of death in ALI/ARDS patients, and a large proportion of patients with ALI/ARDS die of sepsis-related multiorgan failure.23,55,60 In a monocenter study, Suchyta et al87 reported that compared to an historical cohort, a more recent cohort of patients with ARDS, which had a lower mortality rate, also had fewer nonpulmonary organ failures. Hence, the improved survival rates do not necessarily suggest that the respiratory management of these patients has improved. Many other nonpulmonary factors can be implicated, such as improved hygiene, better glucose control, more judicious use of blood transfusions, improved imaging to identify sources of sepsis, and methods to control sepsis. Interestingly, Ciesla et al88 recently showed a decreased progression from ALI to ARDS and multiple organ failure in a large cohort of trauma patients. We did not separate patients meeting the ALI criteria from those having ARDS. Although the severity of hypoxemia has some prognostic value in a few studies,89 a review90 reported that the Pao2/ fraction of inspired oxygen ratio at the onset of disease was not an independent predictor of mortality, and the initial degree of gas exchange is a poor predictor of outcome unless severe (eg, Pao2/fraction of inspired oxygen ⬍ 50).13 Indeed, the difference in outcome between ALI and ARDS is relatively limited in the studies14,36,55,65,66 that report results for both groups of patients. Our study has a number of limitations, including the heterogeneity in patient populations, in inclusion and exclusion criteria, and outcome measures. Nevertheless, to increase comparability, we limited our search to studies that used the criteria for ALI/ CHEST / 133 / 5 / MAY, 2008
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Table 2—Overall and Selected Mortality Rates in Metaregression Analysis
Mortality Overall ICU Hospital 28 to 30 d Exclusion criteria No exclusion criteria
Mortality Rate, % (95% Confidence Interval Studies, Q Using Random-Effects No. Statistic* Models) 72 28 26 19 37 35
682.0 144.4 284.7 147.6 336.0 283.3
43.0 (39.9 – 46.1) 44.3 (39.9–48.8) 48.7 (43.9–53.6) 35.5 (29.7–41.7) 36.7 (32.4–41.2) 49.9 (45.9–53.9)
time periods of 28 days or 30 days). The hospital stay following discharge from the ICU contributes 3 to 15% of the mortality in the few studies35,59 that have reported both; this could be related to factors occurring after the ICU stay, which may be independent of the ARDS diagnosis and management. Unfortunately, it was impossible to compare disease severity in the patients because of the high variability in the severity scores used in the studies, which included acute physiology and chronic health evaluation II or III, simplified acute physiology score II, and the lung injury score, among others.
*p ⬍ 0.001 for the heterogeneity test.
Conclusions ARDS published by the American-European Consensus Conference.11 Even though these have been criticized,40,91 they are widely used and provide some homogeneity by which to compare studies. The present definitions of ALI/ARDS are considered by some authors91 as arbitrary, and others92 have called for new definitions to be developed that include prognostic measures and reduce patient heterogeneity. Moreover, in a comparison of autopsy findings with clinical definitions, including the AmericanEuropean Consensus Conference definition, ARDS appeared to be underrecognized by clinicians, and the specificity of the definitions highly variable.93 A second potential limitation was that the absolute mortality rate may be affected by the type of study, with randomized clinical trials often having strict exclusion and inclusion criteria resulting in the selecting of populations of patients that may not always reflect the outcome of general ICU patients. However, to avoid this kind of “selection” bias, we separately analyzed studies with and without exclusion criteria, and noted a similar trend for both groups. Moreover, even if absolute mortality rates may be affected by this form of selection bias, trends over time may remain valid. A third limitation was that survival was assessed at different time periods (eg, at ICU discharge, hospital discharge, or at fixed
Table 3—Slope Values for Overall and Specific Mortality Outcomes Mortality
Studies, No.
Slope (SE)*
p Value
Overall ICU Hospital 28 to 30 d Exclusion criteria No exclusion criteria
72 28 26 19 37 35
⫺ 0.0474 (0.0211) ⫺ 0.0142 (0.0312) ⫺ 0.0621 (0.0336) ⫺ 0.0094 (0.0617) ⫺ 0.0360 (0.0326) ⫺ 0.0201 (0.0285)
0.024 0.649 0.040 0.877 0.270 0.480
*Metaregression analysis using the logit outcome. 1124
This literature review supports a reduction in mortality rates in the last 10 years in general populations of patients with ALI/ARDS. The same trend was observed in interventional and in epidemiologic studies.
References 1 Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2:319 –323 2 Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685– 1693 3 Krafft P, Fridrich P, Pernerstorfer T, et al. The acute respiratory distress syndrome: definitions, severity and clinical outcome: an analysis of 101 clinical investigations. Intensive Care Med 1996; 22:519 –529 4 Bernard GR. Acute respiratory distress syndrome: a historical perspective. Am J Respir Crit Care Med 2005; 172:798 – 806 5 Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007; 131:554 –562 6 Jardin F, Fellahi JL, Beauchet A, et al. Improved prognosis of acute respiratory distress syndrome 15 years on. Intensive Care Med 1999; 25:936 –941 7 Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005; 128:525– 532 8 Kallet RH, Jasmer RM, Pittet JF, et al. Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls. Crit Care Med 2005; 33:925–929 9 Mancebo J, Fernandez R, Blanch L, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 1233–1239 10 Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and ␥-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34:1033–1038 11 Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818 – 824 12 Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233–239 13 Montgomery BA, Stager MA, Carrico J, et al. Causes of Original Research
14
15 16
17 18 19 20 21 22 23 24
25 26 27 28
29
30
31
32
mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485– 491 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 Shander A, Popovsky MA. Understanding the consequences of transfusion-related acute lung injury. Chest 2005; 128: 598S– 604S Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008 –2012 Sutton AJ, Jones DR, Abrams KR, et al. Methods for meta-analysis in medical research. London, UK: John Wiley and Sons, 2000 Thompson SG, Sharp SJ. Explaining heterogeneity in metaanalysis: a comparison of methods. Stat Med 1999; 18:2693– 2708 Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ 2001; 323:101–105 Doyle LA, Szaflarski N, Modin GW, et al. Identification of patients with acute lung injury: predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818 –1824 Nolan S, Burgess K, Hopper L, et al. Acute respiratory distress syndrome in a community hospital ICU. Intensive Care Med 1997; 23:530 –538 De Backer D, Creteur J, Zhang H, et al. Lactate production by the lungs in acute lung injury. Am J Respir Crit Care Med 1997; 156:1099 –1104 Ferring M, Vincent JL. Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J 1997; 10:1297– 1300 Lewandowski K, Rossaint R, Pappert D, et al. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med 1997; 23:819 – 835 Monchi M, Bellenfant F, Cariou A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158:1076 –1081 Chastre J, Trouillet JL, Vuagnat A, et al. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1165–1172 Valta P, Uusaro A, Nunes S, et al. Acute respiratory distress syndrome: frequency, clinical course, and costs of care. Crit Care Med 1999; 27:2367–2374 Manktelow C, Bigatello LM, Hess D, et al. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1997; 87:297–307 Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26:15–23 Gallart L, Lu Q, Puybasset L, et al. Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome: the NO Almitrine Study Group. Am J Respir Crit Care Med 1998; 158:1770 –1777 Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome: the Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831–1838 Roupie E, Lepage E, Wysocki M, et al. Prevalence, etiologies and outcome of the acute respiratory distress syndrome among hypoxemic ventilated patients. Intensive Care Med 1999; 25:920 –929
www.chestjournal.org
33 Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study: the European Study Group of Inhaled Nitric Oxide. Intensive Care Med 1999; 25:911–919 34 Vieillard-Baron A, Girou E, Valente E, et al. Predictors of mortality in acute respiratory distress syndrome: focus on the role of right heart catheterization. Am J Respir Crit Care Med 2000; 161:1597–1601 35 Esteban A, Alia I, Gordo F, et al. Prospective randomized trial comparing pressure-controlled ventilation and volumecontrolled ventilation in ARDS: for the Spanish Lung Failure Collaborative Group. Chest 2000; 117:1690 –1696 36 Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland: the ARF Study Group. Am J Respir Crit Care Med 1999; 159:1849 –1861 37 Ullrich R, Lorber C, Roder G, et al. Controlled airway pressure therapy, nitric oxide inhalation, prone position, and extracorporeal membrane oxygenation (ECMO) as components of an integrated approach to ARDS. Anesthesiology 1999; 91:1577–1586 38 Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome (ARDS): a controlled, randomized, double-blind, multicenter clinical trial. Crit Care Med 1999; 27:1478 –1485 39 Abel SJ, Finney SJ, Brett SJ, et al. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax 1998; 53:292–294 40 Villar J, Perez-Mendez L, Kacmarek RM. Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med 1999; 25:930 –935 41 Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, ␥-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome: Enteral Nutrition in ARDS Study Group. Crit Care Med 1999; 27:1409 –1420 42 The ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308 43 Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:21–30 44 Markowicz P, Wolff M, Djedaini K, et al. Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome: incidence, prognosis, and risk factors; ARDS Study Group. Am J Respir Crit Care Med 2000; 161:1942–1948 45 Rocco TR Jr, Reinert SE, Cioffi W, et al. A 9-year, singleinstitution, retrospective review of death rate and prognostic factors in adult respiratory distress syndrome. Ann Surg 2001; 233:414 – 422 46 Ware LB, Conner ER, Matthay MA. von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 2001; 29:2325– 2331 47 Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002; 287:345–355 48 Matthay MA, Ware LB. Plasma protein C levels in patients with acute lung injury: prognostic significance. Crit Care Med 2004; 32:S229 –S232 49 Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care CHEST / 133 / 5 / MAY, 2008
1125
50
51
52
53 54
55
56 57
58 59
60 61
62
63
64
65
66 67
units: results from the ALIVE study. Intensive Care Med 2004; 30:51– 61 Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568 –573 Papazian L, Paladini MH, Bregeon F, et al. Is a short trial of prone positioning sufficient to predict the improvement in oxygenation in patients with acute respiratory distress syndrome? Intensive Care Med 2001; 27:1044 –1049 Vincent JL, Brase R, Dhainaut JF, et al. A multicenter, double blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Intensive Care Med 2001; 27:1578 –1583 The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000; 283:1995–2002 Albertine KH, Soulier MF, Wang Z, et al. Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 2002; 161:1783–1796 Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165:443– 448 Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004; 291:1603–1609 Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:801– 808 Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002; 346:1281–1286 Fialkow L, Vieira SR, Fernandes AK, et al. Acute lung injury and acute respiratory distress syndrome at the intensive care unit of a general university hospital in Brazil: an epidemiological study using the American-European Consensus Criteria. Intensive Care Med 2002; 28:1644 –1648 Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 2002; 30:2450 –2456 Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004; 351:884 – 892 Kacmarek RM, Wiedemann HP, Lavin PT, et al. Partial liquid ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 882– 889 Villar J, Kacmarek RM, Perez-Mendez L, et al. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006; 34:1311–1318 O’Brien JM Jr, Phillips GS, Ali NA, et al. Body mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury. Crit Care Med 2006; 34:738 –744 Ishizaka A, Matsuda T, Albertine KH, et al. Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2004; 286:L1088 –L1094 David M, Weiler N, Heinrichs W, et al. High-frequency oscillatory ventilation in adult acute respiratory distress syndrome. Intensive Care Med 2003; 29:1656 –1665 Weinert CR, Gross CR, Marinelli WA. Impact of randomized
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trial results on acute lung injury ventilator therapy in teaching hospitals. Am J Respir Crit Care Med 2003; 167:1304 –1309 Manzano F, Yuste E, Colmenero M, et al. Incidence of acute respiratory distress syndrome and its relation to age. J Crit Care 2005; 20:274 –280 Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003; 290:2713–2720 Venet C, Guyomarc’h S, Pingat J, et al. Prognostic factors in acute respiratory distress syndrome: a retrospective multivariate analysis including prone positioning in management strategy. Intensive Care Med 2003; 29:1435–1441 Frenckner B, Palmer P, Linden V. Extracorporeal respiratory support and minimally invasive ventilation in severe ARDS. Minerva Anestesiol 2002; 68:381–386 Lu Y, Song Z, Zhou X, et al. A 12-month clinical survey of incidence and outcome of acute respiratory distress syndrome in Shanghai intensive care units. Intensive Care Med 2004; 30:2197–2203 Brower RG, Lanken PN, Macintyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327–336 Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med 2004; 30:1111–1116 Gong MN, Thompson BT, Williams P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191–1198 Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005; 128:3098 –3108 Schmidt R, Luboeinski T, Markart P, et al. Alveolar antioxidant status in patients with acute respiratory distress syndrome. Eur Respir J 2004; 24:994 –999 Gando S, Kameue T, Matsuda N, et al. Systemic inflammation and disseminated intravascular coagulation in early stage of ALI and ARDS: role of neutrophil and endothelial activation. Inflammation 2004; 28:237–244 Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004; 32:1695–1702 Salari P, Mojtahedzadeh M, Najafi A, et al. Comparison of the effect of aminophylline and low PEEP vs high PEEP on EGF concentration in critically ill patients with ALI/ARDS. J Clin Pharm Ther 2005; 30:139 –144 Ware LB, Kaner RJ, Crystal RG, et al. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J 2005; 26:101– 105 Vieira SR, Nieszkowska A, Lu Q, et al. Low spatial resolution computed tomography underestimates lung overinflation resulting from positive pressure ventilation. Crit Care Med 2005; 33:741–749 Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonaryartery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213–2224 Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354:1775–1786 Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564 –2575 Milberg JA, Davis DR, Steinberg KP, et al. Improved survival Original Research
87 88
89 90
of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306 –309 Suchyta MR, Orme JF Jr, Morris AH. The changing face of organ failure in ARDS. Chest 2003; 124:1871–1879 Ciesla DJ, Moore EE, Johnson JL, et al. Decreased progression of postinjury lung dysfunction to the acute respiratory distress syndrome and multiple organ failure. Surgery 2006; 140:640 – 647 Suchyta MR, Clemmer TP, Elliot CG, et al. The adult respiratory distress syndrome: a report of survival and modifying factors. Chest 1992; 101:1074 –1079 Ware LB. Prognostic determinants of acute respiratory dis-
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tress syndrome in adults: impact on clinical trial design. Crit Care Med 2005; 33:S217–S222 91 Wood KA, Huang D, Angus DC. Improving clinical trial design in acute lung injury. Crit Care Med 2003; 31:S305– S311 92 Rice P, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: challenges in clinical trial design. Clin Chest Med 2006; 27:733–754 93 Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33:2228 –2234
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Mortality Rates for Patients With Acute Lung Injury/ARDS Have Decreased Over Time* Massimo Zambon, MD; and Jean-Louis Vincent, MD, PhD, FCCP
Background: Over the last decade, several studies have suggested that survival rates for patients with acute lung injury (ALI) or ARDS may have improved. We performed a systematic analysis of the ALI/ARDS literature to document possible trends in mortality between 1994 and 2006. Methods: We used the Medline database to select studies with the key words “acute lung injury,” “ARDS,” “acute respiratory failure,” and “mechanical ventilation.” All studies that reported mortality rates for patients with ALI/ARDS defined according to the criteria of the American European Consensus Conference were selected. We excluded studies with < 30 patients and studies limited to specific subgroups of ARDS patients such as sepsis, trauma, burns, or transfusion-related ARDS. Results: Seventy-two studies were included in the analysis. There was a wide variation in mortality rates among the studies (15 to 72%). The overall pooled mortality rate for all studies was 43% (95% confidence interval, 40 to 46%). Metaregression analysis suggested a significant decrease in overall mortality rates of approximately 1.1%/yr over the period analyzed (1994 to 2006). The mortality reduction was also observed for hospital but not for ICU or 28-day mortality rates. Conclusions: In this literature review, the data are consistent with a reduction in mortality rates in general populations of patients with ALI/ARDS over the last 10 years. (CHEST 2008; 133:1120 –1127) Key words: acute respiratory failure; hypoxemia; literature review; outcomes Abbreviation: ALI ⫽ acute lung injury
the first description of ARDS in 1967 by S ince Ashbaugh and coworkers, many studies have 1
been performed in an attempt to develop new therapies and new ventilatory strategies that could improve outcomes for patients with acute lung injury (ALI)/ARDS. ALI and ARDS remain a major problem in the ICU; in a recent publication, the inci*From the Department of Intensive Care, Erasme Hospital, Universite´ libre de Bruxelles, Belgium. The authors received no external funding for this study and have no conflicts of interest to declare. Manuscript received August 30, 2007; revision accepted January 8, 2008. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Jean-Louis Vincent, MD, PhD, FCCP, Department of Intensive Care, Erasme Hospital, Route de Lennik, 808, 1070 Brussels, Belgium; e-mail: [email protected] DOI: 10.1378/chest.07-2134 1120
dence of ALI in the United States was reported to be 78.9/100,000 persons per year, with a mortality rate of approximately 40%.2 However, reported mortality rates vary widely. An analysis by Krafft et al3 published in 1996 concluded that the mortality rate of ARDS patients had remained constant from 1967 to 1994. In more recent years, however, some authors4,5 have suggested that survival rates may have improved, mainly as a result of the implementation of new protective ventilatory strategies. Nevertheless, although some studies6 – 8 do show decreased mortality rates compared to historical control groups, some studies9,10 still report mortality rates ⬎ 50%. Importantly, ARDS is a syndrome and not an illness, and therefore difficult to define. Nevertheless, criteria were developed to define ALI/ARDS at the American European Consensus Conference in 199411 and have been widely adopted, facilitating comparison of studies. Original Research
We were interested to see whether recent improvements in management may have resulted in improved outcomes and performed a systematic analysis of the literature about ALI/ARDS to document possible trends in mortality rates.
Materials and Methods We used the Medline database and selected studies with the key words “acute lung injury,” “ARDS,” “acute respiratory failure,” or “mechanical ventilation,” limiting the research to adult patients and to studies published in the English language. We also limited the search to studies that used the criteria defined by the American European Consensus Conference,11 so we did not include publications that appeared before 1994. The reference lists from identified articles were also reviewed to locate any articles that had been missed in the original search. We included all studies up to August 2006. From the identified studies, we selected those that included an assessment of mortality of a group of patients with ALI/ARDS. We arbitrarily decided to exclude studies that included ⬍ 30 patients. We also excluded studies that were limited to specific subgroups of ARDS patients, such as sepsis, trauma, burns or transfusion-related ARDS, because there may be different mortality rates among these subgroups.12–15 If the same group of patients was used in different publications, we analyzed only the first in chronological order. To take into account the inevitable time delays in publication, we took as the year of the study the last year of patient enrolment, whenever this was reported. We noted separately the ICU, hospital, and 28- to 30-day mortality rates. In controlled trials, we considered the mortality rate of the control group, so we excluded groups of patients whose mortality rate may have been altered because of treatment. In studies with historical cohorts, we considered the mortality rate of the most recent cohort. We attempted to compare the severity of the patient populations based on available severity scores. We also tried to analyze the differences in patient selection (inclusion/exclusion criteria) among studies, to determine how they may influence mortality rates, and analyzed separately studies without any exclusion criteria (primarily noninterventional/epidemiologic) and studies with exclusion criteria (primarily interventional) such as preexisting pulmonary disease, lung contusion, head injury, malignancy disease, hepatic disease, or other comorbidities. Statistical Analysis Separate metaanalyses16 were performed for different mortality outcomes: overall mortality, ICU mortality, hospital mortality, 28- to 30-day mortality, and mortality for the studies with and without exclusion criteria. These were performed using random-effects models on a logit of the outcome. The presence of between-studies heterogeneity was assessed using the standard 2 test (noted Q). Results were transformed to the proportion scale to ease interpretation.17 Additional metaregression analyses were performed to explore the effect of time. A mixed model, again using the logit of the outcome, was utilized for this purpose.18 Sensitivity analysis was performed to examine whether there was systematic variation in the results. Funnel plots were drawn, and their asymmetry19 was examined to assess whether publication bias was likely to be a problem, and the method of trim and fill, which assesses how many studies are likely to be missing and the potential impact of their exclusion on the analysis, was applied to both outcomes. Analyses were conducted using statiswww.chestjournal.org
tical software (Comprehensive Meta-Analysis Version 2; Biostat; Englewood NJ; and SPSS 14.0 for Windows; SPSS; Chicago, IL).
Results We identified 535 articles, of which 354 reported mortality rates for patients with ALI or ARDS. A total of 173 studies were excluded because the number of patients was ⬍ 30, and 92 studies were excluded because they treated a specific etiologic subgroup of ARDS patients, 11 studies because the same population was analyzed in another study, and 6 studies because the study period was not defined. Hence, 72 studies, including 11,426 patients, were included in the analysis (Table 1). Analysis of disease severity was not possible because of the wide variation in severity scores used in the studies. Mortality rates varied considerably among the studies, from 15 to 72% (Table 1); the overall pooled mortality rate for all studies was 43% (95% confidence interval, 39.9 to 46.1%), and the differences in pooled mortality rates over time are shown in Figure 1. There was heterogeneity between study results in the logit rate (Q ⫽ 682.0; p ⬍ 0.001, between-study variance, 0.24). Data from the other mortality analyses are provided in Table 2. When including time as a covariate in the metaregression model, there was an approximately constant linear reduction in overall mortality over the years covered by the literature (p ⫽ 0.02). The regression equation was logit(death) ⫽ 94.4689 ⫺ 0.0474 ⫻ time; when the regression line was transformed on the proportion scale, this translated into a 1.1% reduction in mortality per 1-year period over the analyzed time span. When analyzed separately, there was also a reduction in hospital mortality (slope coefficient, ⫺ 0.0621; p ⫽ 0.04), but there were no significant changes in the other mortality outcomes (Table 3). Funnel plots were constructed for all the studies included in the analysis, examining overall mortality and hospital mortality, in order to assess the degree of publication bias. For the overall mortality, the funnel plot was symmetrical, indicating that publication bias is unlikely to have had a major influence in the analysis of mortality rates (plots not shown). Discussion In a single-center study, Milberg et al86 reported no overall change in mortality rates for patients with ARDS from 1983 to 1987, a slight decline in 1988 and 1989, and a decrease to a low of 36% in 1993. In another study from the same center, Stapleton et al7 observed that mortality rates decreased in the 1980s until the mid-1990s, plateauing thereafter; there CHEST / 133 / 5 / MAY, 2008
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Table 1—The Selected Studies Source
Study Year (End of Enrollment)
Patients, No.
Mortality Rate, %
Doyle et al20 Nolan et al21 De Backer et al22 Ferring and Vincent23 Lewandowski et al24 Monchi et al25 Chastre et al26 Valta et al27 Manktelow et al28 Dellinger et al29 Gallart et al30 Zilberberg and Epstein14 Brochard et al31 Jardin et al6 Roupie et al32 Lundin et al33 Vieillard-Baron et al34 Esteban et al35 Luhr et al36 Ullrich et al37 Abraham et al38 Abel et al39 Villar et al40 Gadek et al41 ARDS Network42 Ferguson et al43 Markowicz et al44 Rocco et al45 Ware et al46 Esteban et al47 Matthay and Ware48 Brun-Bruisson et al49 Gattinoni et al50 Papazian et al51 Vincent et al52 ARDS Network53 Albertine et al54 Bersten et al55 Taylor et al56 Derdak et al57 Nuckton et al58 Rubenfeld et al2 Fialkow et al59 Estenssoro et al60 Spragg et al61 Kacmarek et al62 Villar et al63 O’Brien et al64 Ishizaka et al65 David et al66 Weinert et al67 Manzano et al68 Richard et al69 Venet et al70 Frenckner et al71 Lu et al72 ARDS Network73 Ferguson et al74 Gong et al75 Sakr et al76 Mancebo et al9 Singer et al10
1994 1994 1995 1995 1995 1995 1995 1995 1996 1996 1996 1996 1996 1996 1996 1996 1996 1996 1997 1997 1997 1997 1997 1997 1997 1998 1998 1998 1998 1998 1998 1999 1999 1999 1999 1999 1999 1999 1999 2000 2000 2000 2000 2000 2000 2000 2001 2001 2001 2001 2001 2001 2001 2002 2002 2002 2002 2002 2002 2002 2002 2003
123 32 43 129 122 259 56 59 88 54 48 81 58 37 67 87 98 79 221 84 171 78 56 76 117 467 134 65 51 231 45 401 152 49 32 429 51 148 193 73 179 1,113 30 217 224 105 45 1,488 35 42 398 61 174 125 37 108 230 41 221 393 60 49
58 (hospital) 47 (ICU) 47 (ICU) 52 (ICU) 25 (ICU) 65 (hospital) 61 (ICU) 37 (ICU) and 42 (hospital) 72 (hospital) 30 (28 d) 52 (ICU) 58 (hospital) 38 (hospital) 32 (ICU) 60 (28 d) 40 (30 d) 53 (ICU) 56 (ICU) and 66 (hospital) 41 (90 d) 20 (ICU) 28 (28 d) 34 (hospital) 43 (ICU) 25 (ICU) 34 (hospital) 60 (ICU) 58 (ICU) 38 (30 d) 51 (hospital) 52 (ICU) 54 (hospital) 46 (ICU) and 55 (hospital) 48 (ICU) 35 (ICU) 28 (28 d) 40 (hospital) 57 (hospital) 32 (28 d) 20 (28 d) 52 (30 d) 42 (hospital) 38 (hospital) 44 (ICU) and 48 (hospital) 58 (hospital) 32 (28 d) 15 (28 d) 53 (ICU) 37 (hospital) 32 (hospital) 43 (30 d) 45 (30 d) 66 (hospital) 59 (28 d) 22 (28 d) 34 (30 d) 68 (hospital) 25 (hospital) 29 (ICU) 46 (60 d) 39 (ICU) and 45 (hospital) 58 (ICU) 57 (28 d)
1122
Exclusion Criteria No No No Yes Yes No No No No Yes No No Yes No No Yes Yes Yes No Yes Yes No No Yes Yes No Yes No No No No Yes Yes No Yes Yes No Yes Yes Yes Yes No No No No Yes Yes No No Yes No No Yes Yes Yes No Yes Yes Yes No No Yes (Continued)
Original Research
Table 1—Continued Source
Study Year (End of Enrollment)
Patients, No.
2003 2003 2003 2003 2003 2003 2003 2003 2005 2005
40 57 200 246 30 56 30 91 68 487
Schmidt et al77 Gando et al78 Kallet et al8 Zeiher et al79 Salari et al80 Ware et al81 Vieira et al82 ARDS Network83 Gattinoni et al84 ARDS Network85
were no changes in the distribution of causes of death during the time period studied. Similar results were reported from a French center.6 However, an analysis by Krafft et al3 concluded that mortality rates had remained constant until 1994. Singlecenter studies8,45 with historical cohorts have suggested a decrease in mortality rates. Our literature review suggests that there has indeed been a reduction in mortality rates for patients with ALI/ARDS over the last decade. The reasons for this observation cannot be determined from the current study. There was a similar reduction in mortality rates in studies with or without exclusion criteria, indicating that the differences seen over time were not related simply to the large number of inclusion criteria and highly selective populations included in interventional studies. The decrease in mortality was more pronounced for hospital mortality than for ICU mortality; this finding is probably more meaningful, and makes it less likely that the
60
Overall mortality, %
50 40 30 20 10 0
1994-1995 1996-1997 1998-1999 2000-2001 2002-2003 2004-2005
Year
Figure 1. Variation in overall pooled mortality rates over time in the 72 ALI/ARDS studies. www.chestjournal.org
Mortality Rate, %
Exclusion Criteria
25 (28 d) 46 (ICU) 32 (hospital) 30 (28 d) 43 (ICU) 61 (hospital) 50 (ICU) 29 (60 d) 28 (ICU) 26 (60 d)
Yes No Yes Yes Yes No No Yes Yes Yes
changes could have been due to changes in ICU discharge criteria over time. The decrease in mortality may have been a result of improvement in the specific management of patients with ALI/ARDS as well as in the general management of ICU patients. Respiratory failure is an uncommon cause of death in ALI/ARDS patients, and a large proportion of patients with ALI/ARDS die of sepsis-related multiorgan failure.23,55,60 In a monocenter study, Suchyta et al87 reported that compared to an historical cohort, a more recent cohort of patients with ARDS, which had a lower mortality rate, also had fewer nonpulmonary organ failures. Hence, the improved survival rates do not necessarily suggest that the respiratory management of these patients has improved. Many other nonpulmonary factors can be implicated, such as improved hygiene, better glucose control, more judicious use of blood transfusions, improved imaging to identify sources of sepsis, and methods to control sepsis. Interestingly, Ciesla et al88 recently showed a decreased progression from ALI to ARDS and multiple organ failure in a large cohort of trauma patients. We did not separate patients meeting the ALI criteria from those having ARDS. Although the severity of hypoxemia has some prognostic value in a few studies,89 a review90 reported that the Pao2/ fraction of inspired oxygen ratio at the onset of disease was not an independent predictor of mortality, and the initial degree of gas exchange is a poor predictor of outcome unless severe (eg, Pao2/fraction of inspired oxygen ⬍ 50).13 Indeed, the difference in outcome between ALI and ARDS is relatively limited in the studies14,36,55,65,66 that report results for both groups of patients. Our study has a number of limitations, including the heterogeneity in patient populations, in inclusion and exclusion criteria, and outcome measures. Nevertheless, to increase comparability, we limited our search to studies that used the criteria for ALI/ CHEST / 133 / 5 / MAY, 2008
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Table 2—Overall and Selected Mortality Rates in Metaregression Analysis
Mortality Overall ICU Hospital 28 to 30 d Exclusion criteria No exclusion criteria
Mortality Rate, % (95% Confidence Interval Studies, Q Using Random-Effects No. Statistic* Models) 72 28 26 19 37 35
682.0 144.4 284.7 147.6 336.0 283.3
43.0 (39.9 – 46.1) 44.3 (39.9–48.8) 48.7 (43.9–53.6) 35.5 (29.7–41.7) 36.7 (32.4–41.2) 49.9 (45.9–53.9)
time periods of 28 days or 30 days). The hospital stay following discharge from the ICU contributes 3 to 15% of the mortality in the few studies35,59 that have reported both; this could be related to factors occurring after the ICU stay, which may be independent of the ARDS diagnosis and management. Unfortunately, it was impossible to compare disease severity in the patients because of the high variability in the severity scores used in the studies, which included acute physiology and chronic health evaluation II or III, simplified acute physiology score II, and the lung injury score, among others.
*p ⬍ 0.001 for the heterogeneity test.
Conclusions ARDS published by the American-European Consensus Conference.11 Even though these have been criticized,40,91 they are widely used and provide some homogeneity by which to compare studies. The present definitions of ALI/ARDS are considered by some authors91 as arbitrary, and others92 have called for new definitions to be developed that include prognostic measures and reduce patient heterogeneity. Moreover, in a comparison of autopsy findings with clinical definitions, including the AmericanEuropean Consensus Conference definition, ARDS appeared to be underrecognized by clinicians, and the specificity of the definitions highly variable.93 A second potential limitation was that the absolute mortality rate may be affected by the type of study, with randomized clinical trials often having strict exclusion and inclusion criteria resulting in the selecting of populations of patients that may not always reflect the outcome of general ICU patients. However, to avoid this kind of “selection” bias, we separately analyzed studies with and without exclusion criteria, and noted a similar trend for both groups. Moreover, even if absolute mortality rates may be affected by this form of selection bias, trends over time may remain valid. A third limitation was that survival was assessed at different time periods (eg, at ICU discharge, hospital discharge, or at fixed
Table 3—Slope Values for Overall and Specific Mortality Outcomes Mortality
Studies, No.
Slope (SE)*
p Value
Overall ICU Hospital 28 to 30 d Exclusion criteria No exclusion criteria
72 28 26 19 37 35
⫺ 0.0474 (0.0211) ⫺ 0.0142 (0.0312) ⫺ 0.0621 (0.0336) ⫺ 0.0094 (0.0617) ⫺ 0.0360 (0.0326) ⫺ 0.0201 (0.0285)
0.024 0.649 0.040 0.877 0.270 0.480
*Metaregression analysis using the logit outcome. 1124
This literature review supports a reduction in mortality rates in the last 10 years in general populations of patients with ALI/ARDS. The same trend was observed in interventional and in epidemiologic studies.
References 1 Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2:319 –323 2 Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353:1685– 1693 3 Krafft P, Fridrich P, Pernerstorfer T, et al. The acute respiratory distress syndrome: definitions, severity and clinical outcome: an analysis of 101 clinical investigations. Intensive Care Med 1996; 22:519 –529 4 Bernard GR. Acute respiratory distress syndrome: a historical perspective. Am J Respir Crit Care Med 2005; 172:798 – 806 5 Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007; 131:554 –562 6 Jardin F, Fellahi JL, Beauchet A, et al. Improved prognosis of acute respiratory distress syndrome 15 years on. Intensive Care Med 1999; 25:936 –941 7 Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death in patients with ARDS. Chest 2005; 128:525– 532 8 Kallet RH, Jasmer RM, Pittet JF, et al. Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls. Crit Care Med 2005; 33:925–929 9 Mancebo J, Fernandez R, Blanch L, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 1233–1239 10 Singer P, Theilla M, Fisher H, et al. Benefit of an enteral diet enriched with eicosapentaenoic acid and ␥-linolenic acid in ventilated patients with acute lung injury. Crit Care Med 2006; 34:1033–1038 11 Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818 – 824 12 Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233–239 13 Montgomery BA, Stager MA, Carrico J, et al. Causes of Original Research
14
15 16
17 18 19 20 21 22 23 24
25 26 27 28
29
30
31
32
mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1985; 132:485– 491 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 Shander A, Popovsky MA. Understanding the consequences of transfusion-related acute lung injury. Chest 2005; 128: 598S– 604S Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283:2008 –2012 Sutton AJ, Jones DR, Abrams KR, et al. Methods for meta-analysis in medical research. London, UK: John Wiley and Sons, 2000 Thompson SG, Sharp SJ. Explaining heterogeneity in metaanalysis: a comparison of methods. Stat Med 1999; 18:2693– 2708 Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ 2001; 323:101–105 Doyle LA, Szaflarski N, Modin GW, et al. Identification of patients with acute lung injury: predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818 –1824 Nolan S, Burgess K, Hopper L, et al. Acute respiratory distress syndrome in a community hospital ICU. Intensive Care Med 1997; 23:530 –538 De Backer D, Creteur J, Zhang H, et al. Lactate production by the lungs in acute lung injury. Am J Respir Crit Care Med 1997; 156:1099 –1104 Ferring M, Vincent JL. Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J 1997; 10:1297– 1300 Lewandowski K, Rossaint R, Pappert D, et al. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med 1997; 23:819 – 835 Monchi M, Bellenfant F, Cariou A, et al. Early predictive factors of survival in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 158:1076 –1081 Chastre J, Trouillet JL, Vuagnat A, et al. Nosocomial pneumonia in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1998; 157:1165–1172 Valta P, Uusaro A, Nunes S, et al. Acute respiratory distress syndrome: frequency, clinical course, and costs of care. Crit Care Med 1999; 27:2367–2374 Manktelow C, Bigatello LM, Hess D, et al. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiology 1997; 87:297–307 Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998; 26:15–23 Gallart L, Lu Q, Puybasset L, et al. Intravenous almitrine combined with inhaled nitric oxide for acute respiratory distress syndrome: the NO Almitrine Study Group. Am J Respir Crit Care Med 1998; 158:1770 –1777 Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome: the Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831–1838 Roupie E, Lepage E, Wysocki M, et al. Prevalence, etiologies and outcome of the acute respiratory distress syndrome among hypoxemic ventilated patients. Intensive Care Med 1999; 25:920 –929
www.chestjournal.org
33 Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study: the European Study Group of Inhaled Nitric Oxide. Intensive Care Med 1999; 25:911–919 34 Vieillard-Baron A, Girou E, Valente E, et al. Predictors of mortality in acute respiratory distress syndrome: focus on the role of right heart catheterization. Am J Respir Crit Care Med 2000; 161:1597–1601 35 Esteban A, Alia I, Gordo F, et al. Prospective randomized trial comparing pressure-controlled ventilation and volumecontrolled ventilation in ARDS: for the Spanish Lung Failure Collaborative Group. Chest 2000; 117:1690 –1696 36 Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland: the ARF Study Group. Am J Respir Crit Care Med 1999; 159:1849 –1861 37 Ullrich R, Lorber C, Roder G, et al. Controlled airway pressure therapy, nitric oxide inhalation, prone position, and extracorporeal membrane oxygenation (ECMO) as components of an integrated approach to ARDS. Anesthesiology 1999; 91:1577–1586 38 Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome (ARDS): a controlled, randomized, double-blind, multicenter clinical trial. Crit Care Med 1999; 27:1478 –1485 39 Abel SJ, Finney SJ, Brett SJ, et al. Reduced mortality in association with the acute respiratory distress syndrome (ARDS). Thorax 1998; 53:292–294 40 Villar J, Perez-Mendez L, Kacmarek RM. Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med 1999; 25:930 –935 41 Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding with eicosapentaenoic acid, ␥-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome: Enteral Nutrition in ARDS Study Group. Crit Care Med 1999; 27:1409 –1420 42 The ARDS Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000; 342:1301–1308 43 Ferguson ND, Frutos-Vivar F, Esteban A, et al. Airway pressures, tidal volumes, and mortality in patients with acute respiratory distress syndrome. Crit Care Med 2005; 33:21–30 44 Markowicz P, Wolff M, Djedaini K, et al. Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome: incidence, prognosis, and risk factors; ARDS Study Group. Am J Respir Crit Care Med 2000; 161:1942–1948 45 Rocco TR Jr, Reinert SE, Cioffi W, et al. A 9-year, singleinstitution, retrospective review of death rate and prognostic factors in adult respiratory distress syndrome. Ann Surg 2001; 233:414 – 422 46 Ware LB, Conner ER, Matthay MA. von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 2001; 29:2325– 2331 47 Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study. JAMA 2002; 287:345–355 48 Matthay MA, Ware LB. Plasma protein C levels in patients with acute lung injury: prognostic significance. Crit Care Med 2004; 32:S229 –S232 49 Brun-Buisson C, Minelli C, Bertolini G, et al. Epidemiology and outcome of acute lung injury in European intensive care CHEST / 133 / 5 / MAY, 2008
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65
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units: results from the ALIVE study. Intensive Care Med 2004; 30:51– 61 Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568 –573 Papazian L, Paladini MH, Bregeon F, et al. Is a short trial of prone positioning sufficient to predict the improvement in oxygenation in patients with acute respiratory distress syndrome? Intensive Care Med 2001; 27:1044 –1049 Vincent JL, Brase R, Dhainaut JF, et al. A multicenter, double blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Intensive Care Med 2001; 27:1578 –1583 The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000; 283:1995–2002 Albertine KH, Soulier MF, Wang Z, et al. Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 2002; 161:1783–1796 Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165:443– 448 Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004; 291:1603–1609 Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med 2002; 166:801– 808 Nuckton TJ, Alonso JA, Kallet RH, et al. Pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 2002; 346:1281–1286 Fialkow L, Vieira SR, Fernandes AK, et al. Acute lung injury and acute respiratory distress syndrome at the intensive care unit of a general university hospital in Brazil: an epidemiological study using the American-European Consensus Criteria. Intensive Care Med 2002; 28:1644 –1648 Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 2002; 30:2450 –2456 Spragg RG, Lewis JF, Walmrath HD, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004; 351:884 – 892 Kacmarek RM, Wiedemann HP, Lavin PT, et al. Partial liquid ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 882– 889 Villar J, Kacmarek RM, Perez-Mendez L, et al. A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a randomized, controlled trial. Crit Care Med 2006; 34:1311–1318 O’Brien JM Jr, Phillips GS, Ali NA, et al. Body mass index is independently associated with hospital mortality in mechanically ventilated adults with acute lung injury. Crit Care Med 2006; 34:738 –744 Ishizaka A, Matsuda T, Albertine KH, et al. Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2004; 286:L1088 –L1094 David M, Weiler N, Heinrichs W, et al. High-frequency oscillatory ventilation in adult acute respiratory distress syndrome. Intensive Care Med 2003; 29:1656 –1665 Weinert CR, Gross CR, Marinelli WA. Impact of randomized
1126
68
69
70
71 72
73
74
75
76 77 78
79 80
81
82
83 84 85 86
trial results on acute lung injury ventilator therapy in teaching hospitals. Am J Respir Crit Care Med 2003; 167:1304 –1309 Manzano F, Yuste E, Colmenero M, et al. Incidence of acute respiratory distress syndrome and its relation to age. J Crit Care 2005; 20:274 –280 Richard C, Warszawski J, Anguel N, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2003; 290:2713–2720 Venet C, Guyomarc’h S, Pingat J, et al. Prognostic factors in acute respiratory distress syndrome: a retrospective multivariate analysis including prone positioning in management strategy. Intensive Care Med 2003; 29:1435–1441 Frenckner B, Palmer P, Linden V. Extracorporeal respiratory support and minimally invasive ventilation in severe ARDS. Minerva Anestesiol 2002; 68:381–386 Lu Y, Song Z, Zhou X, et al. A 12-month clinical survey of incidence and outcome of acute respiratory distress syndrome in Shanghai intensive care units. Intensive Care Med 2004; 30:2197–2203 Brower RG, Lanken PN, Macintyre N, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327–336 Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med 2004; 30:1111–1116 Gong MN, Thompson BT, Williams P, et al. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 2005; 33:1191–1198 Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balance are associated with worse outcome in acute lung injury. Chest 2005; 128:3098 –3108 Schmidt R, Luboeinski T, Markart P, et al. Alveolar antioxidant status in patients with acute respiratory distress syndrome. Eur Respir J 2004; 24:994 –999 Gando S, Kameue T, Matsuda N, et al. Systemic inflammation and disseminated intravascular coagulation in early stage of ALI and ARDS: role of neutrophil and endothelial activation. Inflammation 2004; 28:237–244 Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit Care Med 2004; 32:1695–1702 Salari P, Mojtahedzadeh M, Najafi A, et al. Comparison of the effect of aminophylline and low PEEP vs high PEEP on EGF concentration in critically ill patients with ALI/ARDS. J Clin Pharm Ther 2005; 30:139 –144 Ware LB, Kaner RJ, Crystal RG, et al. VEGF levels in the alveolar compartment do not distinguish between ARDS and hydrostatic pulmonary oedema. Eur Respir J 2005; 26:101– 105 Vieira SR, Nieszkowska A, Lu Q, et al. Low spatial resolution computed tomography underestimates lung overinflation resulting from positive pressure ventilation. Crit Care Med 2005; 33:741–749 Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonaryartery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006; 354:2213–2224 Gattinoni L, Caironi P, Cressoni M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med 2006; 354:1775–1786 Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006; 354:2564 –2575 Milberg JA, Davis DR, Steinberg KP, et al. Improved survival Original Research
87 88
89 90
of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306 –309 Suchyta MR, Orme JF Jr, Morris AH. The changing face of organ failure in ARDS. Chest 2003; 124:1871–1879 Ciesla DJ, Moore EE, Johnson JL, et al. Decreased progression of postinjury lung dysfunction to the acute respiratory distress syndrome and multiple organ failure. Surgery 2006; 140:640 – 647 Suchyta MR, Clemmer TP, Elliot CG, et al. The adult respiratory distress syndrome: a report of survival and modifying factors. Chest 1992; 101:1074 –1079 Ware LB. Prognostic determinants of acute respiratory dis-
www.chestjournal.org
tress syndrome in adults: impact on clinical trial design. Crit Care Med 2005; 33:S217–S222 91 Wood KA, Huang D, Angus DC. Improving clinical trial design in acute lung injury. Crit Care Med 2003; 31:S305– S311 92 Rice P, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: challenges in clinical trial design. Clin Chest Med 2006; 27:733–754 93 Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distress syndrome: underrecognition by clinicians and diagnostic accuracy of three clinical definitions. Crit Care Med 2005; 33:2228 –2234
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