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Fibroproliferative ARDS in the Era of Low-Tidal-Volume VentilationFibroproliferative ARDS FREE TO VIEW

Manu Jain, MD
Author and Funding Information

From the Division of Pulmonary Critical Care, Department of Medicine, Northwestern University.

CORRESPONDENCE TO: Manu Jain, MD, Northwestern University, 240 E Huron Ave, McGaw M-332, Chicago, IL 60611; e-mail: m-jain@northwestern.edu


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(5):1140-1142. doi:10.1378/chest.14-1210
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Though mortality in ARDS has been improving, in unselected populations, mortality may still be as high as 40%.1 Patients with ARDS infrequently die of refractory hypoxemia and more often die due to sepsis and multiorgan failure, both complications of prolonged mechanical ventilation (MV). Inability to discontinue MV likely reflects disordered lung repair which may in part be due to excessive fibroblast activation. Markers of fibroblast activation such as procollagen III2 and transforming growth factor-β are elevated early in ARDS3 and are associated with increased mortality. Factors that have contributed to better ARDS outcomes include less-injurious MV strategies, judicious fluid management, and generally improved supportive care.4,5 As more patients with ARDS are surviving their acute illness, long-term outcomes for these patients have garnered increased attention. It has been shown in multiple studies that survivors of ARDS continue to have reduced health-related quality of life (HRQoL) for years after their acute illness.6 The cause of reduced HRQoL has most often been attributed to neuromuscular and psychosocial dysfunction.6 The contributions of residual pulmonary dysfunction have received less attention and a National Institutes of Health-sponsored ARDS workshop failed to identify fibroproliferation as a significant contributor to morbidity and mortality in the era of low-tidal-volume ventilation.7

However, there is accumulating data that despite low-tidal-volume ventilation, persistent pulmonary dysfunction in survivors of ARDS is a significant contributor to reduced HRQoL. The incidence of persistent pulmonary dysfunction in survivors of ARDS depends on how it is defined. If radiologic abnormality is used as the basis of defining persistent pulmonary dysfunction, the incidence is significantly higher. CT scanning of survivors of ARDS demonstrates reticular infiltrates, often with an anterior distribution, in up to 85% of patients, which persist out to at least 5 years.8,9 If one uses physiologic assessment with pulmonary function testing to define persistent pulmonary dysfunction, the incidence is smaller though not trivial. Multiple studies have reported that while the median FVC is normal in long-term survivors of ARDS, about 25% will have values below the normal range.6 Similar findings were reported for FEV1, total lung capacity, and diffusing capacity for carbon monoxide. The data relating pulmonary dysfunction to diminished HRQoL is conflicting. Some studies have been able to demonstrate associations of decreased pulmonary function testing parameters with poorer scores on components of the Short-Form 36 as well as the St. George’s Respiratory Questionnaire10 while others have attributed much of the HRQoL changes to neuromuscular weakness.6 One study that measured respiratory muscle strength in survivors of ARDS found it to be normal.8

To improve long-term outcomes, several investigators have attempted to identify factors during the acute illness that are associated with adverse long-term outcomes. With respect to this issue, Burnham and colleagues11 publish data in this issue of CHEST (see page 1196) that supplements previous evidence linking physiologic abnormalities present on the day of ARDS onset with long-term outcomes. In a retrospective analysis of prospectively collected data from an ARDS clinical trial, they found static respiratory system compliance measured on the first day or averaged over the first 14 days of MV had an inverse correlation with the severity of reticular changes on chest high-resolution CT (HRCT) scan. HRCT scan reticular changes are thought to most often reflect areas of tissue fibrosis. This study complements data previously published by the same group in which they showed that HRCT scanning at day 14 correlated with poorer HRQoL at 6 months.12 The strengths of the present study include a prospective collection of data, an explicit protocol for low-tidal-volume MV and weaning, as well as a defined protocol for performance of HRCT scan and interpretation by blinded readers. One significant limitation of the study is that the included subjects were a “convenience cohort” that was substantially different than the cohort of patients who were eligible but were not enrolled. The excluded patients had more severe physiologic derangements, which precluded safe transport for an HRCT scan and much higher 28-day mortality. This limits generalizability of the studies’ findings and raises the question of whether a noninvasive physiologic measure that could be assessed at the bedside, such as dead-space fraction or oxygenation index, would work as well as an HRCT scan in identifying patients destined for long-term morbidity. In addition, it is not clear from this work whether compliance abnormalities measured in the first 14 days reflect pulmonary edema, an exuberant fibroproliferative response,3 or most likely a combination of both.

Nevertheless, the studies by Burnham and colleagues11,12 suggest that the severity of physiologic derangement in early ARDS impacts long-term HRQoL in survivors despite use of low-tidal-volume ventilation. Prior studies have identified speed of lung-injury resolution, duration of MV, corticosteroids, neuromuscular blocking agents, glycemic control, and sedatives as contributors to adverse long-term outcomes in survivors of ARDS. These observations highlight the importance of appropriate decision-making in the early phase of ARDS in an effort to not just improve survival for patients with ARDS but optimize HRQoL for the long-term, even in the era of low-tidal-volume ventilation. A second inference from the studies by Burnham and colleagues11,12 is that HRCT scanning may be useful in identifying patients at risk for poorer long-term HRQoL. However, at this time, identifying such patients has no obvious therapeutic implications and so it is difficult to endorse routine HRCT scanning in the management of survivors of ARDS. That would have to be reconsidered if effective interventions targeting fibroproliferation are identified in the future.

References

Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685-1693. [CrossRef] [PubMed]
 
Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med. 1995;122(1):17-23. [CrossRef] [PubMed]
 
Synenki L, Chandel NS, Budinger GR, et al. Bronchoalveolar lavage fluid from patients with acute lung injury/acute respiratory distress syndrome induces myofibroblast differentiation. Crit Care Med. 2007;35(3):842-848. [CrossRef] [PubMed]
 
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-1308. [CrossRef] [PubMed]
 
Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. [CrossRef] [PubMed]
 
Herridge MS, Tansey CM, Matté A, et al; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-1304. [CrossRef] [PubMed]
 
Spragg RG, Bernard GR, Checkley W, et al. Beyond mortality: future clinical research in acute lung injury. Am J Respir Crit Care Med. 2010;181(10):1121-1127. [CrossRef] [PubMed]
 
Masclans JR, Roca O, Muñoz X, et al. Quality of life, pulmonary function, and tomographic scan abnormalities after ARDS. Chest. 2011;139(6):1340-1346. [CrossRef] [PubMed]
 
Wilcox ME, Patsios D, Murphy G, et al. Radiologic outcomes at 5 years after severe ARDS. Chest. 2013;143(4):920-926. [CrossRef] [PubMed]
 
Heyland DK, Groll D, Caeser M. Survivors of acute respiratory distress syndrome: relationship between pulmonary dysfunction and long-term health-related quality of life. Crit Care Med. 2005;33(7):1549-1556. [CrossRef] [PubMed]
 
Burnham EL, Hyzy RC, Paine R III, et al. Detection of fibroproliferation by chest high-resolution CT scan in resolving ARDS. Chest. 2014;146(5):1196-1204.
 
Burnham EL, Hyzy RC, Paine R III, et al. Chest CT features are associated with poorer quality of life in acute lung injury survivors. Crit Care Med. 2013;41(2):445-456. [CrossRef] [PubMed]
 

Figures

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References

Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685-1693. [CrossRef] [PubMed]
 
Clark JG, Milberg JA, Steinberg KP, Hudson LD. Type III procollagen peptide in the adult respiratory distress syndrome. Association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death. Ann Intern Med. 1995;122(1):17-23. [CrossRef] [PubMed]
 
Synenki L, Chandel NS, Budinger GR, et al. Bronchoalveolar lavage fluid from patients with acute lung injury/acute respiratory distress syndrome induces myofibroblast differentiation. Crit Care Med. 2007;35(3):842-848. [CrossRef] [PubMed]
 
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342(18):1301-1308. [CrossRef] [PubMed]
 
Wiedemann HP, Wheeler AP, Bernard GR, et al; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-2575. [CrossRef] [PubMed]
 
Herridge MS, Tansey CM, Matté A, et al; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-1304. [CrossRef] [PubMed]
 
Spragg RG, Bernard GR, Checkley W, et al. Beyond mortality: future clinical research in acute lung injury. Am J Respir Crit Care Med. 2010;181(10):1121-1127. [CrossRef] [PubMed]
 
Masclans JR, Roca O, Muñoz X, et al. Quality of life, pulmonary function, and tomographic scan abnormalities after ARDS. Chest. 2011;139(6):1340-1346. [CrossRef] [PubMed]
 
Wilcox ME, Patsios D, Murphy G, et al. Radiologic outcomes at 5 years after severe ARDS. Chest. 2013;143(4):920-926. [CrossRef] [PubMed]
 
Heyland DK, Groll D, Caeser M. Survivors of acute respiratory distress syndrome: relationship between pulmonary dysfunction and long-term health-related quality of life. Crit Care Med. 2005;33(7):1549-1556. [CrossRef] [PubMed]
 
Burnham EL, Hyzy RC, Paine R III, et al. Detection of fibroproliferation by chest high-resolution CT scan in resolving ARDS. Chest. 2014;146(5):1196-1204.
 
Burnham EL, Hyzy RC, Paine R III, et al. Chest CT features are associated with poorer quality of life in acute lung injury survivors. Crit Care Med. 2013;41(2):445-456. [CrossRef] [PubMed]
 
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