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Editorial Views  |   November 2016
Early Regional Inflammation: The Seeds of Lung Injury
Author Notes
  • From the Departments of Anesthesiology and Critical Care (M.C.) and Radiology (Y.X.), University of Pennsylvania, Philadelphia, Pennsylvania.
  • Corresponding article on page 992.
    Corresponding article on page 992.×
  • Accepted for publication July 28, 2016.
    Accepted for publication July 28, 2016.×
  • Address correspondence to Dr. Cereda: maurizio.cereda@uphs.upenn.edu
Article Information
Editorial Views / Respiratory System
Editorial Views   |   November 2016
Early Regional Inflammation: The Seeds of Lung Injury
Anesthesiology 11 2016, Vol.125, 838-840. doi:10.1097/ALN.0000000000001335
Anesthesiology 11 2016, Vol.125, 838-840. doi:10.1097/ALN.0000000000001335
Image: J. P. Rathmell.
Image: J. P. Rathmell.
Image: J. P. Rathmell.
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CLINICIANS diagnose acute respiratory distress syndrome (ARDS) using consensus criteria such as the Berlin definition,1  which primarily rely on blood oxygen levels and on chest radiography to identify inflammatory lung injury. Patients who meet these criteria may benefit from low-stretch ventilation,2  prone positioning,3  muscle paralysis,4  and perhaps lung recruitment.5  Because ARDS is often underdiagnosed,6  improving its recognition and the application of evidence-based treatment should improve outcomes. Investigators, encouraged by funding agencies, are conducting research on early preemptive strategies capable of reducing ARDS incidence.7  However, there is no accepted standard for ARDS: autopsy studies show that consensus definitions have limited specificity (around 50%) when tested against histologically proven injury.8,9  This is obviously problematic when the goal is to contain lung inflammation: early therapy will have uncertain success until better markers of injury progression are available. Clinically diagnosed ARDS is the epilog of inflammatory dissemination, which sometimes starts in localized lung regions.10  We know little about this evolution. But the imaging study by Wellman et al.11  published in this issue of Anesthesiology provides some insight into the early stages of lung injury.
The authors studied sheep receiving a lipopolysaccharide infusion (a model of septic lung injury) while ventilated for 20 h. Positron emission tomography (PET) was performed at baseline and at 6 and 20 h of ventilation while lung injury progressed. By measuring distribution and cell uptake of 2-deoxy-2-[(18)F]fluoro-d-glucose—a radioactive, nonmetabolized analog of glucose—the authors measured regional metabolic activity (assumed to reflect acute inflammation) and abundance of neutrophils in pulmonary tissue. Spatially matched measurements of aeration, ventilation, and perfusion were also obtained. In a similar model, the same group previously showed that 2-deoxy-2-[(18)F]fluoro-d-glucose PET detected regional inflammatory responses to lipopolysaccharide and ventilator-induced lung stretch.12 
The long duration of the experiments and the large animal model used created fairly realistic conditions and thus meaningful results: a major improvement over the majority of experimental studies in this field, which use small animals and shorter time scales (few hours). But the work by Wellman et al.11  is remarkable also for other reasons. First, thanks to the study design, the authors were able to capture a time frame when regional inflammation was detectable but severe hypoxemia and loss of aeration (which essentially define clinical ARDS) were not. This result suggests that the trajectory of ARDS may be determined by events occurring well before pulmonary dysfunction is obvious. If this very early stage is detected, intervention may have more chances of success than anything attempted in established ARDS. Second, the earliest metabolic changes were visible in the dependent (dorsal) regions of the lungs where aeration was reduced. Later on, metabolic activity also increased in the nondependent (ventral) lung, which was more inflated. With microarray methodology, the authors showed differential gene activation in dependent versus nondependent tissue, supporting regional differences of injury mechanisms.
Early inflammation in the dorsal lung suggests that injury may originate here. There are various potential explanations for this finding, with dorsal preponderance of blood flow13,14  and unstable atelectasis (“atelectrauma”) being high on the list.15  In addition, specific ventilation was also consistently higher in dorsal (poorly aerated) versus ventral lung regions (fig. 3C in the main text of the article11 ). Specific ventilation is a measurement of alveolar gas turnover that is indirectly related to regional stretch induced by the ventilator.16  It does not necessarily coincide with pulmonary aeration: studies have shown that lung tissue with reduced, but not abolished, gas content may be hyperventilated.17,18  High specific ventilation could be a marker of gas maldistribution and of local augmentation of lung stretch.
Several mechanisms of ventilator-induced injury are relatively well understood in established ARDS, when tidal volume is concentrated in a small fraction of viable but hyperinflated “baby lung,” causing alveolar epithelial damage in these regions.19  Yet, the processes through which ventilation might cause harm in minimally diseased or in healthy lungs (e.g., during surgical anesthesia20 ) remain uncertain. The results of the study by Wellman et al.11  support a model wherein local events may trigger injury in poorly inflated lung regions when inflammation is still mild and before macroscopic hyperinflation of the “baby lung.” Systemic inflammation likely potentiates the harmful effects of mechanical ventilation, but it might not be obligatory: a previous study by the same group showed increased dorsal metabolic activity during prolonged ventilation in healthy animals.21  Nevertheless, the current study suggests important links among regional lung mechanics, metabolic activity, and gene expression, which may explain how mechanical ventilation injures patients before they have the functional and morphologic characteristics of ARDS.
It is unlikely that PET will be used on a broad clinical scale for the identification of patients at risk of ARDS. It is more plausible that targeted microarray methodology, enabled by studies such as the study by Wellman et al.,11  will yield more precise biomarkers of lung inflammation and, at some point, more personalized care. In the meantime, clinicians will have to deal with ambiguous selection criteria and inherently uncertain decision-making. But studies like this are valuable not only in their application of innovative techniques, but also in their unearthing of novel information that itself may increase the success of efforts to preempt ARDS development. If the dorsal lung is vulnerable in the early stages of lung injury, strategies could be designed to improve the alveolar microenvironment (e.g., with patient positioning) or to deliver therapeutics in a more targeted manner—approaches that could be more effective than simply using canonic low-stretch ventilation, which did not prevent inflammation from evolving to severe injury in the authors’ study. All of us interested in the prevention of ARDS should take note here: our best weapon against ARDS may not be completely protective in the earliest stages of lung injury.
Competing Interests
The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article.
References
Force, ADT, Ranieri, VM, Rubenfeld, GD, Thompson, BT, Ferguson, ND, Caldwell, E, Fan, E, Camporota, L, Slutsky, AS Acute respiratory distress syndrome: The Berlin definition.. JAMA. (2012). 307 2526–33 [PubMed]
The 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 Med. (2000). 342 1301–8 [Article] [PubMed]
Guérin, C, Reignier, J, Richard, JC, Beuret, P, Gacouin, A, Boulain, T, Mercier, E, Badet, M, Mercat, A, Baudin, O, Clavel, M, Chatellier, D, Jaber, S, Rosselli, S, Mancebo, J, Sirodot, M, Hilbert, G, Bengler, C, Richecoeur, J, Gainnier, M, Bayle, F, Bourdin, G, Leray, V, Girard, R, Baboi, L, Ayzac, L PROSEVA Study Group, Prone positioning in severe acute respiratory distress syndrome.. N Engl J Med. (2013). 368 2159–68 [Article] [PubMed]
Papazian, L, Forel, JM, Gacouin, A, Penot-Ragon, C, Perrin, G, Loundou, A, Jaber, S, Arnal, JM, Perez, D, Seghboyan, JM, Constantin, JM, Courant, P, Lefrant, JY, Guérin, C, Prat, G, Morange, S, Roch, A ACURASYS Study Investigators, Neuromuscular blockers in early acute respiratory distress syndrome.. N Engl J Med. (2010). 363 1107–16 [Article] [PubMed]
Briel, M, Meade, M, Mercat, A, Brower, RG, Talmor, D, Walter, SD, Slutsky, AS, Pullenayegum, E, Zhou, Q, Cook, D, Brochard, L, Richard, JC, Lamontagne, F, Bhatnagar, N, Stewart, TE, Guyatt, G Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-analysis.. JAMA. (2010). 303 865–73 [Article] [PubMed]
Bellani, G, Laffey, JG, Pham, T, Fan, E, Brochard, L, Esteban, A, Gattinoni, L, van Haren, F, Larsson, A, McAuley, DF, Ranieri, M, Rubenfeld, G, Thompson, BT, Wrigge, H, Slutsky, AS, Pesenti, A LUNG SAFE Investigators; ESICM Trials Group, Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.. JAMA. (2016). 315 788–800 [Article] [PubMed]
Gong, MN, Thompson, BT Acute respiratory distress syndrome: Shifting the emphasis from treatment to prevention.. Curr Opin Crit Care. (2016). 22 21–37 [Article] [PubMed]
Thille, AW, Esteban, A, Fernández-Segoviano, P, Rodriguez, JM, Aramburu, JA, Peñuelas, O, Cortés-Puch, I, Cardinal-Fernández, P, Lorente, JA, Frutos-Vivar, F Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy.. Am J Respir Crit Care Med. (2013). 187 761–7 [Article] [PubMed]
Lorente, JA, Cardinal-Fernández, P, Muñoz, D, Frutos-Vivar, F, Thille, AW, Jaramillo, C, Ballén-Barragán, A, Rodríguez, JM, Peñuelas, O, Ortiz, G, Blanco, J, Pinheiro, BV, Nin, N, del Carmen Marin, M, Esteban, A, Thompson, TB Acute respiratory distress syndrome in patients with and without diffuse alveolar damage: An autopsy study.. Intensive Care Med. (2015). 41 1921–30 [Article] [PubMed]
Cereda, M, Xin, Y, Meeder, N, Zeng, J, Jiang, Y, Hamedani, H, Profka, H, Kadlecek, S, Clapp, J, Deshpande, CG, Wu, J, Gee, JC, Kavanagh, BP, Rizi, RR Visualizing the propagation of acute lung injury.. Anesthesiology. (2016). 124 121–31 [Article] [PubMed]
Wellman, T, de Prost, N, Tucci, M, Winkler, T, Baron, RM, Filipczak, P, Raby, B, Chu, J-h, Harris, RS, Musch, G, dos Reis Falcao, LF, Capelozzi, V, Venegas, J, Vidal Melo, MF Lung metabolic activation as an early biomarker of acute respiratory distress syndrome and local gene expression heterogeneity.. Anesthesiology. (2016). 125 992–1004
Wellman, TJ, Winkler, T, Costa, EL, Musch, G, Harris, RS, Zheng, H, Venegas, JG, Vidal Melo, MF Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep.. Crit Care Med. (2014). 42 e491–500 [Article] [PubMed]
Schuster, DP, Anderson, C, Kozlowski, J, Lange, N Regional pulmonary perfusion in patients with acute pulmonary edema.. J Nucl Med. (2002). 43 863–70 [PubMed]
Broccard, AF, Hotchkiss, JR, Kuwayama, N, Olson, DA, Jamal, S, Wangensteen, DO, Marini, JJ Consequences of vascular flow on lung injury induced by mechanical ventilation.. Am J Respir Crit Care Med. (1998). 1576 Pt 1 1935–42 [Article] [PubMed]
Otto, CM, Markstaller, K, Kajikawa, O, Karmrodt, J, Syring, RS, Pfeiffer, B, Good, VP, Frevert, CW, Baumgardner, JE Spatial and temporal heterogeneity of ventilator-associated lung injury after surfactant depletion.. J Appl Physiol. (2008). 104 1485–94 [Article] [PubMed]
Wellman, TJ, Winkler, T, Costa, EL, Musch, G, Harris, RS, Venegas, JG, Melo, MF Measurement of regional specific lung volume change using respiratory-gated PET of inhaled 13N-nitrogen.. J Nucl Med. (2010). 51 646–53 [Article] [PubMed]
Bayat, S, Porra, L, Albu, G, Suhonen, H, Strengell, S, Suortti, P, Sovijärvi, A, Peták, F, Habre, W Effect of positive end-expiratory pressure on regional ventilation distribution during mechanical ventilation after surfactant depletion.. Anesthesiology. (2013). 119 89–100 [Article] [PubMed]
Cereda, M, Xin, Y, Hamedani, H, Clapp, J, Kadlecek, S, Meeder, N, Zeng, J, Profka, H, Kavanagh, BP, Rizi, RR Mild loss of lung aeration augments stretch in healthy lung regions.. J Appl Physiol. (2016). 120 444–54 [Article] [PubMed]
Tsuchida, S, Engelberts, D, Peltekova, V, Hopkins, N, Frndova, H, Babyn, P, McKerlie, C, Post, M, McLoughlin, P, Kavanagh, BP Atelectasis causes alveolar injury in nonatelectatic lung regions.. Am J Respir Crit Care Med. (2006). 174 279–89 [Article] [PubMed]
Futier, E, Constantin, JM, Paugam-Burtz, C, Pascal, J, Eurin, M, Neuschwander, A, Marret, E, Beaussier, M, Gutton, C, Lefrant, JY, Allaouchiche, B, Verzilli, D, Leone, M, De Jong, A, Bazin, JE, Pereira, B, Jaber, S IMPROVE Study Group, A trial of intraoperative low-tidal-volume ventilation in abdominal surgery.. N Engl J Med. (2013). 369 428–37 [Article] [PubMed]
Tucci, MR, Costa, EL, Wellman, TJ, Musch, G, Winkler, T, Harris, RS, Venegas, JG, Amato, MB, Vidal Melo, MF Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep.. Anesthesiology. (2013). 119 156–65 [Article] [PubMed]
Image: J. P. Rathmell.
Image: J. P. Rathmell.
Image: J. P. Rathmell.
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