Chest
Volume 137, Issue 2, February 2010, Pages 288-296
Journal home page for Chest

Original Research
Critical Care Medicine
Prognostic and Pathogenetic Value of Combining Clinical and Biochemical Indices in Patients With Acute Lung Injury

https://doi.org/10.1378/chest.09-1484Get rights and content

Background

No single clinical or biologic marker reliably predicts clinical outcomes in acute lung injury (ALI)/ARDS. We hypothesized that a combination of biologic and clinical markers would be superior to either biomarkers or clinical factors alone in predicting ALI/ARDS mortality and would provide insight into the pathogenesis of clinical ALI/ARDS.

Methods

Eight biologic markers that reflect endothelial and epithelial injury, inflammation, and coagulation (von Willebrand factor antigen, surfactant protein D [SP-D]), tumor necrosis factor receptor-1, interleukin [IL]-6, IL-8, intercellular adhesion molecule-1, protein C, plasminogen activator inhibitor-1) were measured in baseline plasma from 549 patients in the ARDSNet trial of low vs high positive end-expiratory pressure. Mortality was modeled with multivariable logistic regression. Predictors were selected using backward elimination. Comparisons between candidate models were based on the receiver operating characteristics (ROC) and tests of integrated discrimination improvement.

Results

Clinical predictors (Acute Physiology And Chronic Health Evaluation III [APACHE III], organ failures, age, underlying cause, alveolar-arterial oxygen gradient, plateau pressure) predicted mortality with an area under the ROC curve (AUC) of 0.82; a combination of eight biomarkers and the clinical predictors had an AUC of 0.85. The best performing biomarkers were the neutrophil chemotactic factor, IL-8, and SP-D, a product of alveolar type 2 cells, supporting the concept that acute inflammation and alveolar epithelial injury are important pathogenetic pathways in human ALI/ARDS.

Conclusions

A combination of biomarkers and clinical predictors is superior to clinical predictors or biomarkers alone for predicting mortality in ALI/ARDS and may be useful for stratifying patients in clinical trials. From a pathogenesis perspective, the degree of acute inflammation and alveolar epithelial injury are highly associated with the outcome of human ALI/ARDS.

Section snippets

Patients

Patients were eligible for inclusion if they participated in the NHLBI ARDS Clinical Trials Network multicenter randomized controlled trial of two different PEEP titration strategies (the ALVEOLI study).15 There were 549 patients enrolled in the clinical trial. Of these patients, 528 were included in the current study, based solely on the availability of baseline plasma samples. The study protocol was approved by the institutional review board at each hospital. Informed consent was obtained

Patient Characteristics and Baseline Clinical and Biomarker Variables

Patient characteristics are shown in Table 1. The overall mortality was 27.3% and did not differ significantly by ventilator group. In univariable analysis, patients who died had higher APACHE III scores, more organ failures at enrollment, a higher alveolar to arterial oxygen gradient, and higher plateau pressures, and were more likely to have nonpulmonary sepsis as the underlying cause of ALI/ARDS. Patients who died also had significantly fewer organ failure-free and ventilator-free days. A

Discussion

This study provides strong evidence that a combination of biologic and clinical risk factors provides a superior prognostic index for mortality in patients with early ALI/ARDS, as compared with either biologic or clinical risk factors alone. In addition, we found that two plasma biomarkers, IL-8 and SP-D, had major prognostic value when combined with clinical risk factors, suggesting the importance of acute inflammation and alveolar epithelial injury in the pathogenesis and recovery from human

Acknowledgments

Author contributions: Dr Ware: contributed to designing the study, supervising all measurements made, analyzing the results, and writing the manuscript.

Dr Koyama: contributed to biostatistical analysis and editing the manuscript.

Dr Billheimer: contributed to biostatistical analysis and editing the manuscript.

Dr Wu: contributed to biostatistical analysis.

Dr Bernard: contributed to designing the study, analyzing the results, and editing the manuscript.

Dr Thompson: contributed to designing the

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    Funding/Support: This study was supported by the National Institutes of Health [Grants HL81332, HR46059, HL74005, HL73996, HL74024, HL73994].

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

    *

    A complete list of study participants is located in the Appendix.

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