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Is the Mortality Higher in the Pulmonary vs the Extrapulmonary ARDS?*: A Metaanalysis FREE TO VIEW

Ritesh Agarwal, DM, FCCP; Rajagopala Srinivas, MD; Alok Nath, MD; Surinder K. Jindal, MD, FCCP
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*From the Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Correspondence to: Surinder K. Jindal, FCCP, Professor and Head, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh 160012, India; e-mail: skjindal@indiachest.org



Chest. 2008;133(6):1463-1473. doi:10.1378/chest.07-2182
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Background and aim: ARDS can occur from the following two pathogenetic pathways: a direct pulmonary injury (ARDSp); and an indirect injury (ARDSexp). The predisposing clinical factor can influence the pathogenesis and clinical outcome of ARDS. This metaanalysis was aimed at evaluating whether there is any difference in mortality between the two groups.

Methods: We searched the MEDLINE, EMBASE, and CINAHL databases for relevant studies published from 1987 to 2007, and included studies that have reported mortality in the two groups of ARDS. We calculated the odds ratio (OR) and 95% confidence interval (CI) to assess mortality in patients with ARDSp vs patients with ARDSexp and pooled the results using three different statistical models.

Results: Our search yielded 34 studies. In all, the studies involved 4,311 patients with 2,330 patients in the ARDSp group and 1,981 patients in the ARDSexp group. The OR of mortality in ARDSp group compared to the ARDSexp group was 1.11 (95% CI, 0.88 to 1.39), as determined by the random-effects model; 1.04 (95% CI, 0.92 to 1.18), as determined by the fixed-effects model; and 1.04 (95% CI, 0.92 to 1.18), as determined by the exact method, indicating that mortality is similar in the two groups. The mortality was no different whether the studies were classified as prospective (OR, 1.15; 95% CI, 0.87 to 1.51) or retrospective (OR, 1.01; 95% CI, 0.61 to 1.69); small (OR, 1.11; 95% CI, 0.77 to 1.60) or large (OR, 1.1; 95% CI, 0.82 to 1.49); or observational (OR, 1.10; 95% CI, 0.82 to 1.49) or interventional (OR, 0.97; 95% CI, 0.79 to 1.19). There was methodological and statistical heterogeneity (I2, 50.9%; 95% CI, 21.3 to 66.2%; χ2 statistic, 67.22; p = 0.0004).

Conclusions: The results of this study suggest that there is no difference in mortality between these two groups. Further studies should focus on specific etiologies within the subgroups rather than focusing on the broader division of ARDSp and ARDSexp.

Figures in this Article

ARDS is a clinical syndrome that is characterized by inflammatory pulmonary edema, severe hypoxemia, and diffuse endothelial and epithelial injury.1Progress in the understanding of the pathogenesis of this entity and the role of mechanical ventilation in the perpetuation of tissue injury2has led to a shift in the aim of mechanical ventilation to protection of the lung from ventilator-induced lung injury. To this end, there has been a search for pathogenetic subgroups that might respond differently to mechanical ventilation, adjunctive maneuvers, and pharmacologic interventions. Gattinoni et al3 in 1998 proposed the distinction between pulmonary ARDS (ARDSp) and extrapulmonary ARDS (ARDSexp). This division of ARDS into pulmonary and extrapulmonary origins can have significant clinical implications, as patients might respond differently to various treatments including mechanical ventilation.315 Thus, the predisposing clinical risk factor also has the potential to influence the major clinical outcome (ie, mortality). However, additional data16 have failed to show any reproducible distinction. The point that is still unclear is whether there is any difference at all between the two groups in terms of mortality, with or without any specific intervention; and, few studies have actually reported mortality-specific outcomes between the two groups.

In a retrospective analysis16 of 180 patients, we have shown that the underlying cause of ARDS does not affect the length of ICU stay or of survival in the hospital. The aim of this metaanalysis was to generate a large database, thereby reducing sample size and geographic variations to analyze for possible differences in mortality between the two groups of ARDS patients. In this analysis, mortality rates are specifically targeted because, irrespective of changes in parameters like lung injury scores and gas exchange, what really makes a difference is the ultimate hospital survival rate.10

Search Strategy and Selection Criteria

To identify studies for inclusion in this review, all of the authors independently searched the computer databases MEDLINE, EMBASE, and CINAHL for relevant studies published from January 1987 to June 2007 using the following free text terms: “pulmonary and extrapulmonary ARDS,” “pulmonary and extrapulmonary ARDS,” “primary and secondary ARDS,” “primary and secondary ARDS,” “direct and indirect ARDS,” “direct and indirect ARDS,” “pulmonary and extrapulmonary ALI [acute lung injury],” “pulmonary and extrapulmonary acute lung injury,” “primary and secondary ALI,” “primary and secondary acute lung injury,” “direct and indirect ALI,” “direct and indirect acute lung injury,” “recruitment maneuvers,” “ali,” “ards,” “acute lung injury,” and “acute respiratory distress syndrome.” The search was limited to adults (ie, those persons ≥19 years of age), English language, clinical trial, randomized controlled trial, and humans. Bibliographies of all selected articles and review articles that included information on ARDS and ALI were reviewed. In addition, we reviewed our personal files.

Data Abstraction

The abstracts of the studies were independently reviewed by two authors (R.A. and R.S.), without blinding to study the details. Any disagreement was resolved by discussion between the authors. We included studies that had described the mortality data on pulmonary and extrapulmonary ARDS separately. Data were recorded on a standard data extraction form. The following items were extracted: (1) publication details (title; authors; and other citation details including geographic locale); (2) details of the criteria used for the diagnosis of lung injury; (3) the number of patients with pulmonary and extrapulmonary ARDS and mortality in the respective groups (specific details on the number of patients with pneumonia and aspiration in the pulmonary group, and sepsis and nonpulmonary trauma in the extrapulmonary group, were also extracted); and (4) the use of any specific intervention in a particular study.

Due to the limitations associated with retrospective studies, and the occurrence of errors associated with the classification of ARDS using information retrieved retrospectively from databases, we further divided the studies into prospective and retrospective studies. As there may be limitations associated with small numbers of patients, we arbitrarily divided the studies into small studies (ie, ≤ 100 patients) and large studies (ie, > 100 patients). Furthermore, as any intervention might adversely affect the outcome, we again classified the studies as observational or interventional to look for any differences in outcome between the two groups.

Determination of the Pooled Treatment Effect

Two statistical software packages (StatsDirect, version 2.6.2 for MS Windows; StatsDirect Ltd; Cheshire, UK [http://www.statsdirect.com]; and RevMan, version 4.2.10 for MS Windows; The Nordic Cochrane Centre of The Cochrane Collaboration; Copenhagen, Denmark) were used to perform the statistical analysis. We calculated the odds ratio (OR) and 95% confidence intervals (CIs) to assess the mortality from ARDS in the ARDSp group compared to the ARDSexp group. The results from individual studies were pooled using the fixed-effects model of Mantel and Haenszel,17the random-effects model of DerSimonian and Laird,18and the partial polynomial multiplication algorithm, the exact method of Martin and Austin.19

Assessment of Heterogeneity

The impact of heterogeneity on the pooled estimates of the individual outcomes of the metaanalysis was assessed using the χ2 test and/or the I2 test (measuring the extent of inconsistency among the results of the studies, which were interpreted as the approximate proportion of total variation in study estimates that is due to heterogeneity rather than sampling error). An I2 value > 40% indicates significant heterogeneity. As the χ2 test has a low sensitivity for detecting heterogeneity, a p value of < 0.1 was considered to be significant for the presence of statistical heterogeneity.20 Institutional review board clearance was not required for this study as this was a metaanalysis of published studies.

Our initial data search yielded a total of 788 citations (Fig 1 ). We excluded 754 articles because they did not meet our inclusion criteria. Thirty-four studies3,7,9,1113,16,2147 were identified that had reported mortality separately for ARDSp and ARDSexp (Table 1 ). These studies were from around the globe (Table 1). Only nine studies,3,7,1113,16,2930,47 dealt primarily with the ARDSp and ARDSexp categories. The other references were studies involving ARDS patients that evaluated different aspects of the disease but reported mortality separately for ARDSp and ARDSexp groups. Of the studies evaluated, 4 studies16,23,30,47 were retrospective and the remaining 30 studies3,7,9,1113,2122,2429,3146 were prospective (Table 1). Twenty-two studies,3,7,9,11,13,2122,24,2629,31,3435,3840,44,4647 had < 100 patients in each study, whereas the remaining 12 studies16,23,25,30,3233,3637,4143,45 each had > 100 patients. In all, the studies involved 4,311 patients with 2,330 patients belonging to the ARDSp group and 1,981 patients belonging to the ARDSexp groups. The OR of mortality in the ARDSp group compared to the ARDSexp group was 1.11 (95% CI, 0.88 to 1.39) as determined by the random-effects model; 1.04 (95% CI, 0.92 to 1.18), as determined by the fixed-effects model; and 1.04 (95% CI, 0.92 to 1.18), as determined by the exact method, indicating that mortality is similar in the two groups.

The OR for mortality in the ARDSp group compared to the ARDSexp group was not different whether the studies were classified as retrospective (total, 1,386 patients; ARDSp group, 733 patients; ARDSexp group, 653 patients; OR, 1.01; 95% CI, 0.61 to 1.69) or prospective (total, 2,925 patients; ARDSp group, 1,597 patients; ARDSexp group, 1,328 patients; OR, 1.15; 95% CI, 0.87 to 1.51) [Fig 2 ]; small (total, 654 patients; ARDSp group, 381 patients; ARDSexp group, 273 patients; OR, 1.11; 95% CI, 0.77 to 1.60) and large (total, 3,657 patients; ARDSp group, 1,949 patients; ARDSexp group, 1,708 patients; OR, 1.10; 95% CI, 0.82 to 1.49) [Fig 3 ]; or interventional (total, 1,769 patients; ARDSp group, 996 patients; ARDSexp group, 773 patients; OR, 0.97; 95% CI, 0.79 to 1.19) and observational (total, 2,542 patients; ARDSp group, 1,334 patients; ARDSexp group, 1,208 patients; OR, 1.31; 95% CI, 0.93 to 1.86) [Fig 4 ]. There was methodological heterogeneity (Table 1) and statistical heterogeneity (I2, 50.9%; 95% CI, 21.3 to 66.2%; χ2 statistic, 67.22; p = 0.0004).

ARDS is a heterogeneous syndrome with high morbidity and mortality.16,33 Despite immense advances in the understanding of the pathogenesis and management of this entity, the only mortality-reducing intervention is the reduction in iatrogenic injury from mechanical ventilation.10 It is in this context that the further identification of different pathogenetic subsets is imperative so that appropriate directed therapies are tested and instituted. The reported differences between ARDSp and ARDSexp groups have stimulated investigation in this regard.

While studies aimed at arbitrarily dichotomizing a heterogeneous entity in search of possible differences in physiologic variables are laudable, only those distinctive subgroups with consistent pathophysiologic and mortality differences, with or without specific directed therapeutic interventions, are likely to be clinically relevant. Furthermore, a large study10 of ARDS patients has exemplified the fact that the normalization of physiologic variables does not correlate with mortality reduction, and the use of surrogate markers to separate purported subgroups may lead to conflicting results, as has been observed.3,15 Thus, hospital mortality rate was used as the only outcome variable in this analysis because the change in other physiologic parameters like lung injury scores and gas exchange does not correlate with actual hospital survival.10

In particular, sepsis4850 and aspiration pneumonia5152 have been associated with the highest mortality, whereas patients with lung injury resulting from major trauma have a lower risk of death. Also, direct lung injury has been associated with greater mortality.23 Given the lack of difference in mortality between the ARDSp and ARDSexp groups, we concluded that these are large heterogeneous subgroups and that the possible differences in mortality achieved with the current approaches to ARDS treatment may be masked due to variable effects on individual etiologic entities. Studies directed at possible differences in respiratory mechanics of individual etiologic subgroups, especially groups of patients with trauma-related and sepsis-related ARDS, are urgently needed to understand the observed differences in mortality and to direct specific ventilatory strategies.

In this analysis, we found no difference in mortality between the two subgroups despite stratifying by either the prospective or retrospective nature of studies, or whether they had small or large sample sizes. Patients reported in small trials on specific interventions may not represent the disease spectrum that is observed clinically. To overcome this limitation, stratification determined on the basis of the size of the study cohort was performed to reduce any bias due to sample size. We also stratified studies based on the temporal nature of data collection because of the reported difficulties in the classification of ARDSp and ARDSexp groups. In a recent retrospective analysis,47 the authors were unable to classify 37% of their patients despite analysis by three expert investigators. In our previous study,16 13.9% of patients were excluded due to classification difficulties. Furthermore, reported differences in the ease of classification might be simplistic. In the original cohort of nine patients with ARDSexp in the study by Gattinoni et al,3 30% (three of nine patients) had positive airway culture findings; the absence of blood culture positivity in pneumonia, given its poor sensitivity, does not negate the presence of bacteremia and indirect injury. Finally, to investigate the impact of any intervention on outcome, we divided the studies into interventional or observational and found no differences.

We used three different statistical models for summarizing the ORs1719 to avoid any statistical bias that can confound the results. The ORs derived from three different statistical techniques were very similar, indicating the robustness of the results. There can be variation in the results and their interpretation if different statistical models are used.53The choice of a random-effects model vs the fixed-effects model is based on the recognition of heterogeneity, and in the presence of significant heterogeneity a random-effects model is used.54 However, the problem lies with the recognition of heterogeneity in a trial. Any kind of variability among studies in a systematic review may be termed heterogeneity. Variability in the participants, interventions, and outcomes studied is described as clinical heterogeneity, variability in trial design and quality is described as methodological heterogeneity, and variability in the treatment effects being evaluated in the different trials is known as statistical heterogeneity. Ideally, a metaanalysis should only be considered when a group of trials is sufficiently homogeneous in terms of participants, interventions, and outcomes. Such a situation is utopian. In fact, one can argue that, since clinical and methodological diversity always occur in a metaanalysis, statistical heterogeneity is inevitable. Thus, the test for heterogeneity is irrelevant to the choice of analysis; heterogeneity will always exist whether or not we happen to be able to detect it using a statistical test.,54 Apart from the conventional techniques of fixed-effects and random-effects metaanalysis, we also used a partial polynomial multiplication algorithm in this study19; because the method is exact, the sparseness of individual studies, which was seen in this analysis, is not an issue.

The original separation of ARDSp and ARDSexp patients has failed to yield consistent results in terms of radiologic appearances,7,5556 respiratory mechanics,3,28,47,56 response to specific therapies,1112,2930,5659 and, most importantly, the hospital survival according to this metaanalysis. In fact, the cornerstone of this classification, namely, the correlation between ARDSp and consolidation, and ARDSexp with diffuse ground-glassing, and collapse, has been challenged by several authors.28,55 Of note, the concept of predominant collapse in ARDSexp patients and the relevance of the recruitment and prevention of atelectrauma itself have been challenged.60It seems likely that both consolidation and collapse exist in varying combinations in both ARDSp and ARDSexp patients, and the observed results of mechanics, the response to therapy with positive end-expiratory pressure, prone position, and pharmacotherapy would depend on the dominant morphology.61 Differences in the methodology of the quantification of recruitment might have also contributed to the observed paradoxical results. Gattinoni et al3 had suggested that recruitment is greater in ARDSexp patients because of predominant collapse (compared to ARDSp patients, who predominantly have consolidation) by using the quasistatic technique for measuring recruitment. However, in a series reported in 2006, the same group15 found that patients with ARDSp had a higher percentage of recruitable lung than patients with ARDSexp when using CT scans of the whole lung to quantify recruitment. In contrast, Thille et al47 have demonstrated that the quasistatic compliance method is inappropriate for measuring recruitment in ARDSp and ARDSexp patients by using the pressure-volume curve method.

The limitations of this metaanalysis include the fact that specific maneuvers employed in many studies may have themselves contributed to mortality. Further, many of the physiologic studies included in this metaanalysis were neither prospective randomized controlled trials nor were powered for mortality. But, given the large amount of patient data in the current analysis, these reasons seem unlikely. The different management strategies used across various centers may also have contributed to mortality. The results of this study show significant statistical and methodological heterogeneity. The following are the possible reasons for this heterogeneity. First is the difference in sample size and the nature of the clinical trials (eg, prospective, retrospective, and physiologic). The other causes are the variation of the patients with respect to their baseline characteristics such as age and severity of the underlying illness. Finally, the management protocols and logistics that affect patient management may vary from center to center, contributing to clinical heterogeneity. We did try to correct for this heterogeneity by trying to perform a subgroup analysis and metaregression, but as the data available from different studies were sparse, this was not accomplished. We have also tried to overcome this limitation by using three different statistical methods. Although the presence of heterogeneity makes the results less robust than would otherwise be the case, this weakness also simulates the real-life situation that exists at different centers. The strength of the metaanalysis includes a systematic approach and the fact that a large data set of patients across the globe were included in the analysis, which helps in the widespread generalization of the results.

In conclusion, within the limitations of this analysis, the results of this systematic review suggest that there is no difference in mortality due to lung injury caused by pulmonary or extrapulmonary etiologies. Therefore, it is imperative at this time to understand that, as of now, the differences among radiologic appearances, respiratory mechanics, and response to specific therapies cannot be extrapolated to the ultimate outcome (ie, mortality). Further studies should specifically focus on specific subsets of these subgroups such as sepsis-related or trauma-related lung injury rather than the broad categories of pulmonary and extrapulmonary lung injury.

Abbreviations: ALI = acute lung injury; ARDSexp = extrapulmonary ARDS; ARDSp = pulmonary ARDS; CI = confidence interval; OR = odds ratio

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Flow diagram showing the trial selection process for this metaanalysis.Grahic Jump Location
Table Graphic Jump Location
Table 1. Studies Describing Mortality in Pulmonary vs Extrapulmonary ARDS*
Table Graphic Jump Location
Table 1A. Continued
Table Graphic Jump Location
Table 1B. Continued
* 

RCT = randomized controlled trial; NA = not available; Vt = tidal volume; Fio2 = fraction of inspired oxygen; AECC = American European Consensus Conference; HFOV = high-frequency oscillatory ventilation; LIS = lung injury score; NO = nitric oxide; PEEP = positive end-expiratory pressure; IQR = interquartile range.

 

Values are given as the mean (SD), unless otherwise stated.

 

Values are given as the simplified acute physiology score (SAPS).

§ 

Values are given as the acute physiology and chronic health evaluation (APACHE) III score.

 

Values are given as the SAPS II.

 

Values are given as the APACHE II score.

# 

Values are given as the sequential organ failure assessment score.

Figure Jump LinkFigure 2. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the prospective or retrospective nature of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location
Figure Jump LinkFigure 3. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the sample sizes of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location
Figure Jump LinkFigure 4. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the observational or interventional nature of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location
Ashbaugh, DG, Bigelow, DB, Petty, TL, et al (1967) Acute respiratory distress in adults.Lancet2,319-323. [PubMed]
 
Dreyfuss, D, Saumon, G Ventilator induced lung injury: lessons from experimental studies.Am J Respir Crit Care Med1998;157,294-323. [PubMed]
 
Gattinoni, L, Pelosi, P, Suter, PM, et al Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?Am J Respir Crit Care Med1998;158,3-11. [PubMed]
 
Amato, MB, Barbas, CS, Medeiros, DM, et al Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.N Engl J Med1998;338,347-354. [PubMed] [CrossRef]
 
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 Med1998;158,1831-1838. [PubMed]
 
Brower, RG, Shanholtz, CB, Fessler, HE, et al Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.Crit Care Med1999;27,1492-1498. [PubMed]
 
Goodman, LR, Fumagalli, R, Tagliabue, P, et al Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations.Radiology1999;213,545-552. [PubMed]
 
Ranieri, VM, Suter, PM, Tortorella, C, et al Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.JAMA1999;282,54-61. [PubMed]
 
Pelosi, P, Cadringher, P, Bottino, N, et al Sigh in acute respiratory distress syndrome.Am J Respir Crit Care Med1999;159,872-880. [PubMed]
 
Acute Respiratory Distress Syndrome 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 Med2000;342,1301-1308. [PubMed]
 
Lim, CM, Kim, EK, Lee, JS, et al Comparison of the response to the prone position between pulmonary and extrapulmonary acute respiratory distress syndrome.Intensive Care Med2001;27,477-485. [PubMed]
 
Rialp, G, Betbese, AJ, Perez-Marquez, M, et al Short-term effects of inhaled nitric oxide and prone position in pulmonary and extrapulmonary acute respiratory distress syndrome.Am J Respir Crit Care Med2001;164,243-249. [PubMed]
 
Suntharalingam, G, Regan, K, Keogh, BF, et al Influence of direct and indirect etiology on acute outcome and 6-month functional recovery in acute respiratory distress syndrome.Crit Care Med2001;29,562-566. [PubMed]
 
Negri, EM, Hoelz, C, Barbas, CS, et al Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS: an autopsy study of collagen-elastic system fibers.Pathol Res Pract2002;198,355-361. [PubMed]
 
Gattinoni, L, Caironi, P, Cressoni, M, et al Lung recruitment in patients with the acute respiratory distress syndrome.N Engl J Med2006;354,1775-1786. [PubMed]
 
Agarwal, R, Aggarwal, AN, Gupta, D, et al Etiology and outcomes of pulmonary and extrapulmonary acute lung injury/ARDS in a respiratory ICU in North India.Chest2006;130,724-729. [PubMed]
 
Mantel, N, Haenszel, W Statistical aspects of the analysis of data from retrospective studies of disease.J Natl Cancer Inst1959;22,719-748. [PubMed]
 
DerSimonian, R, Laird, N Meta-analysis in clinical trials.Control Clin Trials1986;7,177-188. [PubMed]
 
Martin, DO, Austin, H An exact method for meta-analysis of case-control and follow-up studies.Epidemiology2000;11,255-260. [PubMed]
 
Lau, J, Ioannidis, JP, Schmid, CH Quantitative synthesis in systematic reviews.Ann Intern Med1997;127,820-826. [PubMed]
 
Servillo, G, Svantesson, C, Beydon, L, et al Pressure-volume curves in acute respiratory failure: automated low flow inflation versus occlusion.Am J Respir Crit Care Med1997;155,1629-1636. [PubMed]
 
Michael, JR, Barton, RG, Saffle, JR, et al Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.Am J Respir Crit Care Med1998;157,1372-1380. [PubMed]
 
Monchi, M, Bellenfant, F, Cariou, A, et al Early predictive factors of survival in the acute respiratory distress syndrome: a multivariate analysis.Am J Respir Crit Care Med1998;158,1076-1081. [PubMed]
 
Papazian, L, Bregeon, F, Gaillat, F, et al Respective and combined effects of prone position and inhaled nitric oxide in patients with acute respiratory distress syndrome.Am J Respir Crit Care Med1998;157,580-585. [PubMed]
 
Squara, P, Dhainaut, JF, Artigas, A, et al Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study.Intensive Care Med1998;24,1018-1028. [PubMed]
 
Jardin, F, Fellahi, JL, Beauchet, A, et al Improved prognosis of acute respiratory distress syndrome 15 years on.Intensive Care Med1999;25,936-941. [PubMed]
 
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 Med1999;25,930-935. [PubMed]
 
Rouby, JJ, Puybasset, L, Cluzel, P, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: II. Physiological correlations and definition of an ARDS Severity Score: CT Scan ARDS Study Group.Intensive Care Med2000;26,1046-1056. [PubMed]
 
Domenighetti, G, Stricker, H, Waldispuehl, B Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response.Crit Care Med2001;29,57-62. [PubMed]
 
Eisner, MD, Thompson, T, Hudson, LD, et al Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.Am J Respir Crit Care Med2001;164,231-236. [PubMed]
 
Sitbon, P, Teboul, JL, Duranteau, J, et al Effects of tidal volume reduction in acute respiratory distress syndrome on gastric mucosal perfusion.Intensive Care Med2001;27,911-915. [PubMed]
 
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 Med2002;165,443-448. [PubMed]
 
Estenssoro, E, Dubin, A, Laffaire, E, et al Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome.Crit Care Med2002;30,2450-2456. [PubMed]
 
Albaiceta, GM, Taboada, F, Parra, D, et al Differences in the deflation limb of the pressure-volume curves in acute respiratory distress syndrome from pulmonary and extrapulmonary origin.Intensive Care Med2003;29,1943-1949. [PubMed]
 
Dyhr, T, Bonde, J, Larsson, A Lung recruitment manoeuvres are effective in regaining lung volume and oxygenation after open endotracheal suctioning in acute respiratory distress syndrome.Crit Care2003;7,55-62. [PubMed]
 
Herridge, MS, Cheung, AM, Tansey, CM, et al One-year outcomes in survivors of the acute respiratory distress syndrome.N Engl J Med2003;348,683-693. [PubMed]
 
Hughes, M, MacKirdy, FN, Ross, J, et al Acute respiratory distress syndrome: an audit of incidence and outcome in Scottish intensive care units.Anaesthesia2003;58,838-845. [PubMed]
 
Pelosi, P, Bottino, N, Chiumello, D, et al Sigh in supine and prone position during acute respiratory distress syndrome.Am J Respir Crit Care Med2003;167,521-527. [PubMed]
 
Pestana, D, Hernandez-Gancedo, C, Royo, C, et al Adjusting positive end-expiratory pressure and tidal volume in acute respiratory distress syndrome according to the pressure-volume curve.Acta Anaesthesiol Scand2003;47,326-334. [PubMed]
 
Albaiceta, GM, Taboada, F, Parra, D, et al Tomographic study of the inflection points of the pressure-volume curve in acute lung injury.Am J Respir Crit Care Med2004;170,1066-1072. [PubMed]
 
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 Med2004;30,2197-2203. [PubMed]
 
Moran, JL, Solomon, PJ, Fox, V, et al Modelling thirty-day mortality in the acute respiratory distress syndrome (ARDS) in an adult ICU.Anaesth Intensive Care2004;32,317-329. [PubMed]
 
Gong, MN, Zhou, W, Williams, PL, et al -308GA and TNFB polymorphisms in acute respiratory distress syndrome.Eur Respir J2005;26,382-389. [PubMed]
 
Patroniti, N, Bellani, G, Maggioni, E, et al Measurement of pulmonary edema in patients with acute respiratory distress syndrome.Crit Care Med2005;33,2547-2554. [PubMed]
 
Kacmarek, RM, Wiedemann, HP, Lavin, PT, et al Partial liquid ventilation in adult patients with acute respiratory distress syndrome.Am J Respir Crit Care Med2006;173,882-889. [PubMed]
 
Pachl, J, Roubik, K, Waldauf, P, et al Normocapnic high-frequency oscillatory ventilation affects differently extrapulmonary and pulmonary forms of acute respiratory distress syndrome in adults.Physiol Res2006;55,15-24. [PubMed]
 
Thille, AW, Richard, JC, Maggiore, SM, et al Alveolar recruitment in pulmonary and extrapulmonary acute respiratory distress syndrome: comparison using pressure-volume curve or static compliance.Anesthesiology2007;106,212-217. [PubMed]
 
Milberg, JA, Davis, DR, Steinberg, KP, et al Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993.JAMA1995;273,306-309. [PubMed]
 
Doyle, RL, Szaflarski, N, Modin, GW, et al Identification of patients with acute lung injury: predictors of mortality.Am J Respir Crit Care Med1995;152,1818-1824. [PubMed]
 
Zilberberg, MD, Epstein, SK Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome.Am J Respir Crit Care Med1998;157,1159-1164. [PubMed]
 
Hudson, LD, Milberg, JA, Anardi, D, et al Clinical risks for development of the acute respiratory distress syndrome.Am J Respir Crit Care Med1995;151,293-301. [PubMed]
 
Fowler, AA, Hamman, RF, Good, JT, et al Adult respiratory distress syndrome: risk with common predispositions.Ann Intern Med1983;98,593-597. [PubMed]
 
Agarwal, R, Nath, A Activated protein C in sepsis: down but not out, yet.Crit Care2006;10,416. [PubMed]
 
Deeks, JJ, Higgins, JPT, Altman, DG Analysing and presenting results. Alderson, P Green, S Higgins, JPT eds.Cochrane reviewers’ handbook 4.2.2, updated March 20042004,68-139 John Wiley & Sons. Chichester, UK:
 
Desai, SR, Wells, AU, Suntharalingam, G, et al Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study.Radiology2001;218,689-693. [PubMed]
 
Puybasset, L, Gusman, P, Muller, JC, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: III. Consequences for the effects of positive end-expiratory pressure: CT Scan ARDS Study Group; Adult Respiratory Distress Syndrome.Intensive Care Med2000;26,1215-1227. [PubMed]
 
Estenssoro, E, Dubin, A, Laffaire, E, et al Impact of positive end-expiratory pressure on the definition of acute respiratory distress syndrome.Intensive Care Med2003;29,1936-1942. [PubMed]
 
Pelosi, P, Brazzi, L, Gattinoni, L Prone position in acute respiratory distress syndrome.Eur Respir J2002;20,1017-1028. [PubMed]
 
Gerlach, H, Keh, D, Semmerow, A, et al Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study.Am J Respir Crit Care Med2003;167,1008-1015. [PubMed]
 
Hubmayr, RD Perspective on lung injury and recruitment: a skeptical look at the opening and collapse story.Am J Respir Crit Care Med2002;165,1647-1653. [PubMed]
 
Puybasset, L, Cluzel, P, Gusman, P, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: I. Consequences for lung morphology: CT Scan ARDS Study Group.Intensive Care Med2000;26,857-869. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Flow diagram showing the trial selection process for this metaanalysis.Grahic Jump Location
Figure Jump LinkFigure 2. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the prospective or retrospective nature of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location
Figure Jump LinkFigure 3. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the sample sizes of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location
Figure Jump LinkFigure 4. Forest plot showing mortality in the ARDSp vs the ARDSexp groups stratified by the observational or interventional nature of the studies. The mortality was similar in the two groups. Values are given as the OR (95% CI), as determined by the random-effects model.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Studies Describing Mortality in Pulmonary vs Extrapulmonary ARDS*
Table Graphic Jump Location
Table 1A. Continued
Table Graphic Jump Location
Table 1B. Continued
* 

RCT = randomized controlled trial; NA = not available; Vt = tidal volume; Fio2 = fraction of inspired oxygen; AECC = American European Consensus Conference; HFOV = high-frequency oscillatory ventilation; LIS = lung injury score; NO = nitric oxide; PEEP = positive end-expiratory pressure; IQR = interquartile range.

 

Values are given as the mean (SD), unless otherwise stated.

 

Values are given as the simplified acute physiology score (SAPS).

§ 

Values are given as the acute physiology and chronic health evaluation (APACHE) III score.

 

Values are given as the SAPS II.

 

Values are given as the APACHE II score.

# 

Values are given as the sequential organ failure assessment score.

References

Ashbaugh, DG, Bigelow, DB, Petty, TL, et al (1967) Acute respiratory distress in adults.Lancet2,319-323. [PubMed]
 
Dreyfuss, D, Saumon, G Ventilator induced lung injury: lessons from experimental studies.Am J Respir Crit Care Med1998;157,294-323. [PubMed]
 
Gattinoni, L, Pelosi, P, Suter, PM, et al Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease: different syndromes?Am J Respir Crit Care Med1998;158,3-11. [PubMed]
 
Amato, MB, Barbas, CS, Medeiros, DM, et al Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome.N Engl J Med1998;338,347-354. [PubMed] [CrossRef]
 
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 Med1998;158,1831-1838. [PubMed]
 
Brower, RG, Shanholtz, CB, Fessler, HE, et al Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients.Crit Care Med1999;27,1492-1498. [PubMed]
 
Goodman, LR, Fumagalli, R, Tagliabue, P, et al Adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: CT, clinical, and functional correlations.Radiology1999;213,545-552. [PubMed]
 
Ranieri, VM, Suter, PM, Tortorella, C, et al Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.JAMA1999;282,54-61. [PubMed]
 
Pelosi, P, Cadringher, P, Bottino, N, et al Sigh in acute respiratory distress syndrome.Am J Respir Crit Care Med1999;159,872-880. [PubMed]
 
Acute Respiratory Distress Syndrome 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 Med2000;342,1301-1308. [PubMed]
 
Lim, CM, Kim, EK, Lee, JS, et al Comparison of the response to the prone position between pulmonary and extrapulmonary acute respiratory distress syndrome.Intensive Care Med2001;27,477-485. [PubMed]
 
Rialp, G, Betbese, AJ, Perez-Marquez, M, et al Short-term effects of inhaled nitric oxide and prone position in pulmonary and extrapulmonary acute respiratory distress syndrome.Am J Respir Crit Care Med2001;164,243-249. [PubMed]
 
Suntharalingam, G, Regan, K, Keogh, BF, et al Influence of direct and indirect etiology on acute outcome and 6-month functional recovery in acute respiratory distress syndrome.Crit Care Med2001;29,562-566. [PubMed]
 
Negri, EM, Hoelz, C, Barbas, CS, et al Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS: an autopsy study of collagen-elastic system fibers.Pathol Res Pract2002;198,355-361. [PubMed]
 
Gattinoni, L, Caironi, P, Cressoni, M, et al Lung recruitment in patients with the acute respiratory distress syndrome.N Engl J Med2006;354,1775-1786. [PubMed]
 
Agarwal, R, Aggarwal, AN, Gupta, D, et al Etiology and outcomes of pulmonary and extrapulmonary acute lung injury/ARDS in a respiratory ICU in North India.Chest2006;130,724-729. [PubMed]
 
Mantel, N, Haenszel, W Statistical aspects of the analysis of data from retrospective studies of disease.J Natl Cancer Inst1959;22,719-748. [PubMed]
 
DerSimonian, R, Laird, N Meta-analysis in clinical trials.Control Clin Trials1986;7,177-188. [PubMed]
 
Martin, DO, Austin, H An exact method for meta-analysis of case-control and follow-up studies.Epidemiology2000;11,255-260. [PubMed]
 
Lau, J, Ioannidis, JP, Schmid, CH Quantitative synthesis in systematic reviews.Ann Intern Med1997;127,820-826. [PubMed]
 
Servillo, G, Svantesson, C, Beydon, L, et al Pressure-volume curves in acute respiratory failure: automated low flow inflation versus occlusion.Am J Respir Crit Care Med1997;155,1629-1636. [PubMed]
 
Michael, JR, Barton, RG, Saffle, JR, et al Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.Am J Respir Crit Care Med1998;157,1372-1380. [PubMed]
 
Monchi, M, Bellenfant, F, Cariou, A, et al Early predictive factors of survival in the acute respiratory distress syndrome: a multivariate analysis.Am J Respir Crit Care Med1998;158,1076-1081. [PubMed]
 
Papazian, L, Bregeon, F, Gaillat, F, et al Respective and combined effects of prone position and inhaled nitric oxide in patients with acute respiratory distress syndrome.Am J Respir Crit Care Med1998;157,580-585. [PubMed]
 
Squara, P, Dhainaut, JF, Artigas, A, et al Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study.Intensive Care Med1998;24,1018-1028. [PubMed]
 
Jardin, F, Fellahi, JL, Beauchet, A, et al Improved prognosis of acute respiratory distress syndrome 15 years on.Intensive Care Med1999;25,936-941. [PubMed]
 
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 Med1999;25,930-935. [PubMed]
 
Rouby, JJ, Puybasset, L, Cluzel, P, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: II. Physiological correlations and definition of an ARDS Severity Score: CT Scan ARDS Study Group.Intensive Care Med2000;26,1046-1056. [PubMed]
 
Domenighetti, G, Stricker, H, Waldispuehl, B Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response.Crit Care Med2001;29,57-62. [PubMed]
 
Eisner, MD, Thompson, T, Hudson, LD, et al Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.Am J Respir Crit Care Med2001;164,231-236. [PubMed]
 
Sitbon, P, Teboul, JL, Duranteau, J, et al Effects of tidal volume reduction in acute respiratory distress syndrome on gastric mucosal perfusion.Intensive Care Med2001;27,911-915. [PubMed]
 
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 Med2002;165,443-448. [PubMed]
 
Estenssoro, E, Dubin, A, Laffaire, E, et al Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome.Crit Care Med2002;30,2450-2456. [PubMed]
 
Albaiceta, GM, Taboada, F, Parra, D, et al Differences in the deflation limb of the pressure-volume curves in acute respiratory distress syndrome from pulmonary and extrapulmonary origin.Intensive Care Med2003;29,1943-1949. [PubMed]
 
Dyhr, T, Bonde, J, Larsson, A Lung recruitment manoeuvres are effective in regaining lung volume and oxygenation after open endotracheal suctioning in acute respiratory distress syndrome.Crit Care2003;7,55-62. [PubMed]
 
Herridge, MS, Cheung, AM, Tansey, CM, et al One-year outcomes in survivors of the acute respiratory distress syndrome.N Engl J Med2003;348,683-693. [PubMed]
 
Hughes, M, MacKirdy, FN, Ross, J, et al Acute respiratory distress syndrome: an audit of incidence and outcome in Scottish intensive care units.Anaesthesia2003;58,838-845. [PubMed]
 
Pelosi, P, Bottino, N, Chiumello, D, et al Sigh in supine and prone position during acute respiratory distress syndrome.Am J Respir Crit Care Med2003;167,521-527. [PubMed]
 
Pestana, D, Hernandez-Gancedo, C, Royo, C, et al Adjusting positive end-expiratory pressure and tidal volume in acute respiratory distress syndrome according to the pressure-volume curve.Acta Anaesthesiol Scand2003;47,326-334. [PubMed]
 
Albaiceta, GM, Taboada, F, Parra, D, et al Tomographic study of the inflection points of the pressure-volume curve in acute lung injury.Am J Respir Crit Care Med2004;170,1066-1072. [PubMed]
 
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 Med2004;30,2197-2203. [PubMed]
 
Moran, JL, Solomon, PJ, Fox, V, et al Modelling thirty-day mortality in the acute respiratory distress syndrome (ARDS) in an adult ICU.Anaesth Intensive Care2004;32,317-329. [PubMed]
 
Gong, MN, Zhou, W, Williams, PL, et al -308GA and TNFB polymorphisms in acute respiratory distress syndrome.Eur Respir J2005;26,382-389. [PubMed]
 
Patroniti, N, Bellani, G, Maggioni, E, et al Measurement of pulmonary edema in patients with acute respiratory distress syndrome.Crit Care Med2005;33,2547-2554. [PubMed]
 
Kacmarek, RM, Wiedemann, HP, Lavin, PT, et al Partial liquid ventilation in adult patients with acute respiratory distress syndrome.Am J Respir Crit Care Med2006;173,882-889. [PubMed]
 
Pachl, J, Roubik, K, Waldauf, P, et al Normocapnic high-frequency oscillatory ventilation affects differently extrapulmonary and pulmonary forms of acute respiratory distress syndrome in adults.Physiol Res2006;55,15-24. [PubMed]
 
Thille, AW, Richard, JC, Maggiore, SM, et al Alveolar recruitment in pulmonary and extrapulmonary acute respiratory distress syndrome: comparison using pressure-volume curve or static compliance.Anesthesiology2007;106,212-217. [PubMed]
 
Milberg, JA, Davis, DR, Steinberg, KP, et al Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993.JAMA1995;273,306-309. [PubMed]
 
Doyle, RL, Szaflarski, N, Modin, GW, et al Identification of patients with acute lung injury: predictors of mortality.Am J Respir Crit Care Med1995;152,1818-1824. [PubMed]
 
Zilberberg, MD, Epstein, SK Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome.Am J Respir Crit Care Med1998;157,1159-1164. [PubMed]
 
Hudson, LD, Milberg, JA, Anardi, D, et al Clinical risks for development of the acute respiratory distress syndrome.Am J Respir Crit Care Med1995;151,293-301. [PubMed]
 
Fowler, AA, Hamman, RF, Good, JT, et al Adult respiratory distress syndrome: risk with common predispositions.Ann Intern Med1983;98,593-597. [PubMed]
 
Agarwal, R, Nath, A Activated protein C in sepsis: down but not out, yet.Crit Care2006;10,416. [PubMed]
 
Deeks, JJ, Higgins, JPT, Altman, DG Analysing and presenting results. Alderson, P Green, S Higgins, JPT eds.Cochrane reviewers’ handbook 4.2.2, updated March 20042004,68-139 John Wiley & Sons. Chichester, UK:
 
Desai, SR, Wells, AU, Suntharalingam, G, et al Acute respiratory distress syndrome caused by pulmonary and extrapulmonary injury: a comparative CT study.Radiology2001;218,689-693. [PubMed]
 
Puybasset, L, Gusman, P, Muller, JC, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: III. Consequences for the effects of positive end-expiratory pressure: CT Scan ARDS Study Group; Adult Respiratory Distress Syndrome.Intensive Care Med2000;26,1215-1227. [PubMed]
 
Estenssoro, E, Dubin, A, Laffaire, E, et al Impact of positive end-expiratory pressure on the definition of acute respiratory distress syndrome.Intensive Care Med2003;29,1936-1942. [PubMed]
 
Pelosi, P, Brazzi, L, Gattinoni, L Prone position in acute respiratory distress syndrome.Eur Respir J2002;20,1017-1028. [PubMed]
 
Gerlach, H, Keh, D, Semmerow, A, et al Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study.Am J Respir Crit Care Med2003;167,1008-1015. [PubMed]
 
Hubmayr, RD Perspective on lung injury and recruitment: a skeptical look at the opening and collapse story.Am J Respir Crit Care Med2002;165,1647-1653. [PubMed]
 
Puybasset, L, Cluzel, P, Gusman, P, et al Regional distribution of gas and tissue in acute respiratory distress syndrome: I. Consequences for lung morphology: CT Scan ARDS Study Group.Intensive Care Med2000;26,857-869. [PubMed]
 
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