Logo of ajrccmIssue Featuring ArticlePublisher's Version of ArticleSubmissionsAmerican Thoracic SocietyAmerican Thoracic SocietyAmerican Journal of Respiratory and Critical Care Medicine
Am J Respir Crit Care Med. May 1, 2011; 183(9): 1193–1199.
Published online Jan 21, 2011. doi:  10.1164/rccm.201008-1318OC
PMCID: PMC3114052

Lung Regional Metabolic Activity and Gas Volume Changes Induced by Tidal Ventilation in Patients with Acute Lung Injury


Rationale: During acute lung injury (ALI), mechanical ventilation can aggravate inflammation by promoting alveolar distension and cyclic recruitment–derecruitment. As an estimate of the intensity of inflammation, metabolic activity can be measured by positron emission tomography imaging of [18F]fluoro-2-deoxy-D-glucose.

Objectives: To assess the relationship between gas volume changes induced by tidal ventilation and pulmonary metabolic activity in patients with ALI.

Methods: In 13 mechanically ventilated patients with ALI and relatively high positive end-expiratory pressure, we performed a positron emission tomography scan of the chest and three computed tomography scans: at mean airway pressure, end-expiration, and end-inspiration. Metabolic activity was measured from the [18F]fluoro-2-deoxy-D-glucose uptake rate. The computed tomography scans were used to classify lung regions as derecruited throughout the respiratory cycle, undergoing recruitment–derecruitment, and normally aerated.

Measurements and Main Results: Metabolic activity of normally aerated lung was positively correlated both with plateau pressure, showing a pronounced increase above 26 to 27 cm H2O, and with regional Vt normalized by end-expiratory lung gas volume. This relationship did not appear to be caused by a higher underlying parenchymal metabolic activity in patients with higher plateau pressure. Regions undergoing cyclic recruitment–derecruitment did not have higher metabolic activity than those collapsed throughout the respiratory cycle.

Conclusions: In patients with ALI managed with relatively high end-expiratory pressure, metabolic activity of aerated regions was associated with both plateau pressure and regional Vt normalized by end-expiratory lung gas volume, whereas no association was found between cyclic recruitment–derecruitment and increased metabolic activity.

Keywords: acute lung injury, respiration, artificial, tomography, X-ray computed, positron emission tomography


Scientific Knowledge on the Subject

Mechanical ventilation is a potential powerful inflammatory stimulus during acute lung injury because it can promote cyclic alveolar recruitment–derecruitment and overdistension. Positron emission tomography can be used to monitor regional inflammation as reflected by local metabolic activity in vivo.

What This Study Adds to the Field

Metabolic activity of normally aerated lung regions was correlated with plateau pressure and with regional Vt normalized by end-expiratory gas volume. This correlation appeared to be due, at least in part, to the effect of mechanical ventilation per se.

We reported (1) that positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (18FDG) shows diffuse increase in metabolic activity in the lungs of patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In keeping with previous evidence, we interpreted the increased metabolic activity as indicating the presence of an inflammatory process (25). The cross-registration of dynamic PET images with computed tomography (CT) scans allowed us to show that the increased metabolic activity was not confined to regions with abnormal density but also involved normally aerated regions (1, 6).

Mechanical ventilation can be a powerful inflammatory stimulus and ventilator-induced lung injury (VILI) has been the object of extensive research. Two main mechanisms have been advocated for VILI, the first being the cyclic recruitment and derecruitment of alveolar units (sometimes referred to as “atelectrauma”) (7, 8) and the second being the (over)distension of aerated alveolar units (9, 10). Most of the data on VILI derive from animal studies, which mimic the clinical condition only to a limited extent (11). However, data obtained in patients with ALI/ARDS suggest that mechanical ventilation can, in fact, promote lung inflammation (12). The reduction of Vt from 12 to 6 ml/kg resulted in a decreased mortality rate (13) and further reduction of Vt caused a decrease in the levels of inflammatory cytokines in bronchoalveolar lavage fluid (14). At the same time, in humans, the relative contribution of “atelectrauma” versus alveolar overdistention in clinical VILI is unclear and data directly relating regional distension induced by mechanical ventilation and regional inflammation are lacking.

CT allows measurement of regional aeration and of its changes induced by mechanical ventilation (1517). PET can detect the presence of metabolically active inflammatory cells, including neutrophils (2, 3, 5, 1822), which have been shown to be primary effectors of VILI (3, 9, 10, 2325). By combining PET with CT scans obtained at end-expiration and end-inspiration in patients with ALI/ARDS, we analyzed the association between regional gas volume changes induced by mechanical ventilation and metabolic activity as a measurement of inflammation, arising from the same regions.

Specifically, we assessed if regions undergoing intratidal recruitment–derecruitment had increased metabolic activity compared with regions that remained derecruited throughout the respiratory cycle. In addition, we assessed the relationship of regional metabolic activity with plateau pressure and regional volume expansion in areas of normally or poorly aerated lung.

Part of the results have been previously reported in form of an abstract (26).


Additional details are provided in the online supplement.

Investigational Protocol

The protocol was approved by our institution's ethical committee; informed consent was obtained according to the committee recommendations. Inclusion criteria were: diagnosis of ALI/ARDS with a positive end-expiratory pressure (PEEP) of at least 8 cm H2O and planned thorax CT by the clinicians caring for the patient. Exclusion criteria are specified in the online supplement. Seven of the 13 patients enrolled are part of the population included in a previous report (1). Before transport we recorded arterial blood gases and hemodynamic and respiratory parameters. The latter were unmodified from those set clinically in the days before the study. Nutrition and any glucose-containing intravenous infusion (and insulin therapy) were stopped at least 6 to 8 hours before the PET study. Blood glucose was tested to confirm a level between 80 and 140 mg/dl.

During transport from the intensive care unit to the PET/CT facility, and throughout the study, patients were sedated, paralyzed, and continuously monitored; ventilated by a high-performance mechanical ventilator; and clinical care was provided by a physician and a nurse uninvolved in the study procedures. Ventilatory settings, sedation, paralysis, and fluid therapy were maintained constant throughout the study period, unless clinically required.

Imaging Protocol

Using a PET/CT tomograph with an eight-slice CT (Discovery ST; GE Healthcare, Milwaukee, WI), we imaged a section of thorax 15 cm long on the longitudinal axis (kept constant throughout the protocol). The first CT scan (CTFUSION) was obtained at mean airway pressure to optimize cross-registration with PET. A bolus of 18FDG (approximately 300 MBq) was injected intravenously, and PET images were acquired with the following protocol: 12 × 10 second frames (12 × 10″), 10 × 30″, 8 × 300″, 1 × 600″.

We also acquired a CT scan at end-expiration (PEEP, CTEXP) and a scan at end-inspiration (plateau pressure, CTINSP) to assess the regional expansion induced by tidal ventilation. PET data were reconstructed by ordered-subset expectation maximization iterative algorithm and corrected for decay, scatter, random counts, and attenuation.

Image Analysis

Images were analyzed (Figure 1) by specifically developed software (Matlab R2007a). On CTFUSION we identified the lung field and segmented it in the following regions of interest (ROIs) based on density (27): normally aerated (−900 ≤ Hounsfield units [HU] < −500), poorly aerated (−500 ≤ HU < −100), nonaerated (−100 ≤ HU). From CTEXP and CTINSP we defined two further ROIs: regions derecruited throughout the respiratory cycle (comprising voxels nonaerated on both CTINSP and CTEXP) and regions undergoing cyclic recruitment–derecruitment (nonaerated on CTEXP but poorly or normally aerated CTINSP).

Figure 1.
Representative images obtained by computed tomography (CT; gray scale on left) obtained at end-expiration, end-inspiration, and by positron emission tomography (PET; the image shows the last frame acquired during dynamic imaging, between 47 and 57 min ...

For each of the aforementioned ROIs we computed:

  • uptake rate of 18FDG (Ki), by Patlak graphical analysis (28), as a measure of metabolic rate
  • mean density on CTFUSION of the voxels belonging to each ROI
  • weight of the ROI, multiplying its volume by its average density on CTFUSION
  • CT-derived end-expiratory lung volume (EELVCT), defined as the gas volume of the ROI on CTEXP
  • CT-derived Vt (VtCT), defined as the difference between gas volume on CTINSP and EELVCT

In computing the VtCT of “normally” (VtCT, normally-aerated) and “poorly” aerated tissue (VtCT, poorly-aerated) the corresponding ROI obtained on CTFUSION was applied on both CTEXP and CTINSP. Consequently, VtCT reflects the tidal change in gas volume of those voxels whose mean density falls within either the normally or poorly aerated compartment boundaries on CTFUSION. The computation of VtCT, normally-aerated is thus not affected by the potential increase in the number of voxels belonging to the normally aerated compartment going from CTEXP to CTINSP.

Kinormally-aerated and Kipoorly-aerated were analyzed both as original values and they were also normalized by Kinonaerated. The rationale for dividing Ki of aerated tissue by Ki of nonaerated tissue is to reference the metabolic activity of a region exposed to mechanical ventilation to that of a region that is not. The purpose of this normalization is to take into account the level of metabolic activity “intrinsic” to the pulmonary parenchyma of each subject (i.e., independent of the effect of airway pressure), reducing the effect of interpatient variability in pulmonary metabolic activity related to factors other than mechanical ventilation.


SPSS 16.0 was used. Paired and unpaired comparisons were performed by Wilcoxon and Mann-Whitney U tests, respectively. Association between variables was assessed by linear correlation. A P < 0.05 was considered as statistically significant. Data are reported as mean ± SD unless otherwise specified.


Thirteen patients were enrolled in the study; patients had a PaO2/FiO2 of 160 ± 47 mm Hg (two patients had a PaO2/FiO2 > 200 mm Hg), a total PEEP of 13.4 ± 2.7 cm H2O, and a plateau pressure of 24.9 ± 4.3 cm H2O. The time elapsed between intubation and imaging was 9.1 ± 7.3 days. All patients underwent the imaging protocol without developing clinically relevant complications. Table 1 reports main clinical variables and outcomes of the patients. Seven patients (54%) had pneumonia as ALI/ARDS etiology, but we did not find any difference between these and the other patients in clinical or image-derived variables.


Association between Intratidal Recruitment–Derecruitment and Metabolic Activity

The amount of tissue undergoing cyclic recruitment–derecruitment was small: only 17.9 ± 6.0% of the lung weight collapsed at end-expiration gained aeration during inspiration, corresponding to 2.9 ± 1.7% of total lung weight.

No systematic difference between Ki of regions undergoing cyclic recruitment–derecruitment (Kirecruiting–derecruiting) and Ki of regions derecruited throughout the respiratory cycle (Kiderecruited) was observed (Figure 2A). As expected, the regions undergoing cyclic recruitment–derecruitment had a lower density at mean airway pressure (and thus during PET imaging) than regions that remained derecruited throughout the respiratory cycle: −102 ± 77 versus −4 ± 15 HU on CTFUSION (P < 0.001). To take into account the possible effect of the different densities on Ki (5), we normalized both Kirecruiting–derecruiting and Kiderecruited by the density of the respective ROIs measured on CTFUSION but, again, no systematic difference could be disclosed (Figure 2B). Eight patients (61%) had values of Kirecruiting–derecruiting greater than Kiderecruited and five did not. These two subsets of patients did not show any significant difference in Vt/kg predicted body weight (PBW), plateau pressure, duration of mechanical ventilation before PET study, or amount of tissue undergoing cyclic recruitment–derecruitment (Figure 3).

Figure 2.
(A) Individual values of [18F] fluoro-2-deoxy-D-glucose (18FDG) influx rate constant (Ki) for lung regions derecruited both at end-expiration and end-inspiration (derecruited) and regions undergoing cyclic recruitment–derecruitment (recruiting–derecruiting). ...
Figure 3.
Comparison of variables potentially associated with ventilator-induced lung injury between patients displaying an [18F]fluoro-2-deoxy-D-glucose (18FDG) influx rate (Ki) of the lung regions undergoing cyclic derecruitment–recruitment higher (Ki ...

Association between Plateau Pressures, Gas Volume Changes, and Metabolic Activity

We first considered the imaged lung as a whole. To assess the relationship between metabolic activity of the lung and the pressure exerted by mechanical ventilation, we tested the correlation between the metabolic activity of the imaged lung (Kiwhole-lung) and plateau pressure, demonstrating a statistically significant positive correlation (r2 = 0.47, P < 0.05). When assessing the role of the volume distending the lung, we found no significant correlation between Kiwhole-lung and the delivered Vt, expressed as Vt/kg PBW (r2 = 0.24); however, when Vt to the imaged lung, measured by CT, was normalized by end-expiratory gas volume, we found a significant correlation between Kiwhole-lung and VtCT,whole-lung/EELVCT, whole-lung (r2 = 0.42, P = 0.02). We corroborated this finding with a significant, albeit expectedly weaker, correlation between Kiwhole-lung and Vt/EELVCT, whole-lung (r2 = 0.34, P = 0.04).

We then analyzed separately the normally aerated and poorly aerated tissue. When Kinormally-aerated and Kinormally-aerated/Kinonaerated were plotted as a function of plateau pressure, we found, in both cases, a tight relationship (respectively r2 = 0.52, P < 0.01 and r2 = 0.54, P < 0.01; Figure 4). The relationship between Kinormally-aerated and plateau pressure was not linear: Kinormally-aerated increased steeply for values of plateau pressure higher than 26 to 27 cm H2O and a second-order polynomial curvilinear function yielded a better curve fit, increasing the r2 from 0.53 to 0.6. The association between plateau pressure and Kinormally-aerated/Kinonaerated suggests that the association between Kinormally-aerated and plateau pressure was likely not due to an underlying greater pulmonary parenchymal metabolic activity in patients with higher plateau pressure. The poorly aerated tissue showed different results: the correlation between plateau pressure and Kipoorly-aerated was looser (r2 = 0.32, P = 0.04), and that with Kipoorly-aerated/Kinonaerated was not significant (r2 = 0.28).

Figure 4.
(A) The plot of [18F]fluoro-2-deoxy-D-glucose (18FDG) influx rate of the normally aerated tissue (Kinormally-aerated) versus the plateau airway pressure shows a statistically significant correlation between the variables, with a nonlinear shape characterized ...

We did not find any significant correlation between either Kinormally-aerated or Kinormally-aerated/Kinonaerated and Vt/kg PBW. However, both Kinormally-aerated and Kinormally-aerated/Kinonaerated showed a tight linear correlation with Vt to the aerated lung normalized by the regional end-expiratory lung volume (VtCT, normally-aerated/EELVCT, normally-aerated; Figure 5).

Figure 5.
[18F]fluoro-2-deoxy-D-glucose (18FDG) influx rate of the normally aerated tissue (A) before (Kinormally-aerated) and (B) after (Kinormally-aerated/Kinonaerated) normalization by 18FDG influx rate of nonaerated tissue not exposed to tidal ventilation was ...

No correlation could be found between the metabolic activity of the poorly aerated tissue (expressed either as Kipoorly-aerated or Kipoorly-aerated/Kinonaerated) and the Vt expressed either as Vt/kg PBW or as VtCT, poorly-aerated/EELVCT, poorly-aerated.


The main findings of this study can be summarized as follows: (1) in a mixed population of patients with ALI/ARDS, the regions undergoing intratidal recruitment–derecruitment did not have an increased metabolic activity in comparison to regions collapsed throughout the respiratory cycle; (2) the metabolic activity of normally aerated tissue was associated with plateau pressure, showing a pronounced increase above 26 to 27 cm H2O; and (3) the metabolic activity of normally aerated tissue was also associated with the regional Vt normalized by regional end-expiratory lung gas volume. The two associations persisted also after normalization of Ki of the normally aerated lung by that of the nonaerated (i.e., not exposed to ventilation) lung.

We did not find any difference in metabolic activity between regions undergoing intratidal recruitment–derecruitment and regions collapsed throughout the respiratory cycle. The repetitive alveolar collapse and expansion has been shown to promote lung injury in several animal studies (7), and it is commonly accepted as a potential source of injury in patients, although the relevance of this mechanism has been challenged (29). To our knowledge, the effective role of “atelectrauma” in promoting lung injury in patients with ALI/ARDS undergoing a protective ventilatory strategy has never been directly shown. CT has been extensively used to detect the presence of tissue undergoing intratidal recruitment–derecruitment (30, 31). Is PET adequate to assess the presence of inflammation linked to cyclic recruitment–derecruitment? Animal studies have shown that neutrophils are primary effectors of “atelectrauma,” (9, 32) and, in the setting of pulmonary inflammation, PET is a sensitive tool to detect the activation of these cells. Microautoradiography studies conducted both in animals (2, 5, 19, 33) and in humans (20, 21, 34) suggest that uptake of 18FDG occurs primarily by neutrophils. Furthermore, neutrophil depletion profoundly blunts the injury induced by mechanical ventilation (35) and the uptake of 18FDG, albeit without abolishing it (3, 36). Because the remaining signal could possibly arise from lung parenchymal cells, PET with 18FDG is considered to provide a “global” measure of inflammatory response of the lung (21). The capability of PET to detect atelectrauma has been directly investigated in at least two studies. Monkman and coworkers (37) demonstrated that the uptake of 18FDG was markedly reduced if PEEP was set above the lower inflection point of the pressure–volume curve (presumably reducing the amount of tissue undergoing cyclic recruitment–derecruitment). Musch and coworkers promoted unilateral cyclic alveolar collapse and overexpansion by ventilating six sheep between −10 and +50 cm H2O. After 90 minutes the Ki of the injured lung had increased more than twofold (3). In the same experiment it was also shown that cyclic recruitment–derecruitment promoted inflammation only in the presence of high inspiratory volumes and pressures: the relatively low plateau pressure and Vt used in our patients might have blunted the effect of atelectrauma. On the other hand, the lack of increased 18FDG uptake in the recruiting–derecruiting lung might not necessarily mean that these regions are not inflamed, because cyclic recruitment–derecruitment might cause a release of proinflammatory cytokines not associated with increased sequestration of neutrophils (38). Other authors demonstrated that macrophages and monocytes (not characterized by an intense 18FDG uptake [19]) might be relevant in the generation of VILI (39). A third possible explanation for the lack of increased metabolic activity in regions undergoing cyclic recruitment–derecruitment is the relatively limited amount of parenchyma undergoing this process, albeit in line with literature data (30). This was likely favored by the relatively high PEEP and low plateau pressure used and by the rather long duration of mechanical ventilation before the study, as lung recruitability rapidly decreases during the course of the disease (40). Because the levels of PEEP and plateau pressure applied in our study are quite similar to those reported in the “high PEEP” arm of two recent trials (41, 42), it is tempting to raise a question on whether atelectrauma is still at play in ALI/ARDS patients managed with a high PEEP strategy and low plateau pressure.

Plateau pressure was significantly correlated with metabolic activity of the whole lung and the correlation was even tighter for the normally aerated tissue, whereas for poorly aerated tissue it was looser. Interestingly, the correlation increased steeply above 26 to 27 cm H2O. In our study, we did not randomize patients to different levels of plateau pressure, but we simply recorded the plateau pressure resulting from the clinical ventilatory setting. Thus the question is if plateau pressure higher than 27 cm H2O caused the increase in Ki or if high Ki and high plateau pressure were simply associated in the most severely ill patients. Although we acknowledge that only a randomized design could definitively answer this question, we addressed it by dividing the Ki of normally aerated tissue by that of nonaerated tissue. In each patient the ratio Kinormally-aerated/Kinonaerated expresses the level of metabolic activity of regions exposed to the effects of mechanical ventilation relative to that of regions that are not. The rationale for this normalization is supported by data showing that alveolar inflammation caused by VILI does not occur in atelectatic regions (43). Although its meaning should be interpreted cautiously, this normalization could potentially reduce the confounding effect of interpatient differences in the level of background disease-related pulmonary metabolic activity on any additional inflammatory effect induced by mechanical ventilation. What happens when plateau pressure rises above 26 to 27 cm H2O? Although there is no evidence of a “safe” plateau pressure, and mortality rate appears linearly correlated with plateau pressure (44), it is generally recommended to limit plateau pressure below 30 cm H2O. Terragni and coworkers identified a threshold for plateau pressure around 27 cm H2O as discriminating the patients between “more” and “less” protected from mechanical ventilation (14). Later on, the same group showed a reduction of inflammatory markers when the plateau pressure was reduced from 28–30 cm H2O to 25–27 cm H2O (14). In keeping with these findings, our results suggest that for plateau pressure 26 to 27 cm H2O might be a safer limit than 30 cm H2O.

Vt indexed by PBW was not directly correlated with lung metabolic activity. This was probably because Vt was not randomly set but patients were clinically managed with Vt in a relatively narrow range, averaging 6.7 ± 1.1 ml/kg PBW. Moreover, the clinicians likely reduced Vts in more severely ill patients to avoid an excessive plateau pressure. Thus, our results should not be interpreted as indicating that an increase in Vt would not be associated with increased inflammatory activity. On the other hand, we found a tight relationship between pulmonary 18FDG uptake and Vt normalized by end-expiratory lung gas volume. As for plateau pressure, this relationship could be demonstrated for the entire lung and, even more strongly, for the normally aerated tissue, suggesting that the smaller the “baby lung” receiving the tidal inflation, the more this will promote inflammation. This finding has potential clinical relevance because it supports the evidence (45, 46) that, to set the appropriate Vt, end-expiratory lung volume should be taken into account. In this study we used CT to measure end-expiratory lung volumes, whose measurements are in tight agreement with those obtained by bedside methods (15, 47). In contrast to normally aerated tissue, the metabolic activity of the poorly aerated tissue was not associated with its distending volume. Our explanation for this different behavior is that in the poorly aerated tissue the “original” process of ARDS might be more responsible for the inflammatory process than the subsequent hit exerted by mechanical ventilation. On the contrary, the effects of tidal distension might be more relevant in the generation of inflammation in the normally aerated tissue. The regional heterogeneity that characterizes the relationship between metabolic activity and lung distension is in keeping with preclinical data showing that, during experimental lung injury, gene expression is significantly different between dependent and nondependent lung regions. Finally, other factors, such as infection and sedation (propofol has been shown to impact the respiratory burst of neutrophils in humans [48]), might have influenced our measurements of metabolic activity.

Although the relevance of hyperinflation has been recently shown by Grasso and colleagues (49), in contrast to their animal model the amount of tissue undergoing tidal hyperinflation in our population was very small (0.5 ± 0.6% of total lung weight). Moreover, the intensity of the 18FDG signal arising from the hyperinflated lung is expected to be extremely low, even if the metabolic activity of the hyperinflated pulmonary tissue was high, because of its low density. For these reasons, in this study we deliberately did not analyze the 18FDG signal arising from hyperinflated areas.

In conclusion, under the assumption that the intensity of metabolic activity detected by PET with 18FDG reflects inflammation, we demonstrated that in a mixed population of patients with ALI/ARDS managed with relatively high PEEP, inflammation of the normally aerated tissue, and of the whole lung, is associated both with plateau pressure, showing a pronounced increase above 26 to 27 cm H2O, and with the ratio between regional Vt and end-expiratory lung volume.

Supplementary Material

[Online Supplement]


The authors thank Sabrina Morzenti, B.S. (Medical Physics Unit, San Gerardo Hospital) for technical support.


Supported in part by a grant from the European Society of Intensive Care Medicine (ECCRN Young Investigator Award 2006), by departmental funding, and by National Institutes of Health grant R01HL094639 (G.M.).

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.201008-1318OC on January 21, 2011

Author Disclosure: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.


1. Bellani G, Messa C, Guerra L, Spagnolli E, Foti G, Patroniti N, Fumagalli R, Musch G, Fazio F, Pesenti A. Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: A [18F]-fluoro-2-deoxy-d-glucose PET/CT study. Crit Care Med 2009;37:2216–2222. [PubMed]
2. Jones HA, Clark RJ, Rhodes CG, Schofield JB, Krausz T, Haslett C. In vivo measurement of neutrophil activity in experimental lung inflammation. Am J Respir Crit Care Med 1994;149:1635–1639. [PubMed]
3. Musch G, Venegas JG, Bellani G, Winkler T, Schroeder T, Petersen B, Harris RS, Melo MF. Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury. Anesthesiology 2007;106:723–735. [PubMed]
4. Hartwig W, Carter EA, Jimenez RE, Jones R, Fischman AJ, Fernandez-Del Castillo C, Warshaw AL. Neutrophil metabolic activity but not neutrophil sequestration reflects the development of pancreatitis-associated lung injury. Crit Care Med 2002;30:2075–2082. [PubMed]
5. Chen DL, Schuster DP. Positron emission tomography with [18F]fluorodeoxyglucose to evaluate neutrophil kinetics during acute lung injury. Am J Physiol Lung Cell Mol Physiol 2004;286:L834–L840. [PubMed]
6. Bellani G, Guerra L, Pesenti A, Messa C. Imaging of lung inflammation during severe influenza A: H1N1. Intensive Care Med 2010;36:717. [PubMed]
7. Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med 1994;149:1327–1334. [PubMed]
8. Schiller HJ, McCann UG II, Carney DE, Gatto LA, Steinberg JM, Nieman GF. Altered alveolar mechanics in the acutely injured lung. Crit Care Med 2001;29:1049–1055. [PubMed]
9. Kawano T, Mori S, Cybulsky M, Burger R, Ballin A, Cutz E, Bryan AC. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol 1987;62:27–33. [PubMed]
10. Imanaka H, Shimaoka M, Matsuura N, Nishimura M, Ohta N, Kiyono H. Ventilator-induced lung injury is associated with neutrophil infiltration, macrophage activation, and TGF-beta 1 mRNA upregulation in rat lungs. Anesth Analg 2001;92:428–436. [PubMed]
11. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008;295:L379–L399. [PMC free article] [PubMed]
12. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, Bruno F, Slutsky AS. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54–61. [PubMed]
13. 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. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301–1308. [PubMed]
14. Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, Faggiano C, Quintel M, Gattinoni L, Ranieri VM. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology 2009;111:826–835. [PubMed]
15. Patroniti N, Bellani G, Manfio A, Maggioni E, Giuffrida A, Foti G, Pesenti A. Lung volume in mechanically ventilated patients: measurement by simplified helium dilution compared to quantitative CT scan. Intensive Care Med 2004;30:282–289. [PubMed]
16. Gattinoni L, D'Andrea L, Pelosi P, Vitale G, Pesenti A, Fumagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA 1993;269:2122–2127. [PubMed]
17. Terragni PP, Rosboch G, Tealdi A, Corno E, Menaldo E, Davini O, Gandini G, Herrmann P, Mascia L, Quintel M, et al. Tidal hyperinflation during low tidal volume ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 2007;175:160–166. [PubMed]
18. Jones HA. Inflammation imaging. Proc Am Thorac Soc 2005;2:545–548, 513–514. [PubMed]
19. Jones HA, Schofield JB, Krausz T, Boobis AR, Haslett C. Pulmonary fibrosis correlates with duration of tissue neutrophil activation. Am J Respir Crit Care Med 1998;158:620–628. [PubMed]
20. Chen DL, Rosenbluth DB, Mintun MA, Schuster DP. FDG-PET imaging of pulmonary inflammation in healthy volunteers after airway instillation of endotoxin. J Appl Physiol 2006;100:1602–1609. [PubMed]
21. Chen DL, Bedient TJ, Kozlowski J, Rosenbluth DB, Isakow W, Ferkol TW, Thomas B, Mintun MA, Schuster DP, Walter MJ. [18F]fluorodeoxyglucose positron emission tomography for lung antiinflammatory response evaluation. Am J Respir Crit Care Med 2009;180:533–539. [PMC free article] [PubMed]
22. Costa EL, Musch G, Winkler T, Schroeder T, Harris RS, Jones HA, Venegas JG, Vidal Melo MF. Mild endotoxemia during mechanical ventilation produces spatially heterogeneous pulmonary neutrophilic inflammation in sheep. Anesthesiology 2010;112:658–669. [PMC free article] [PubMed]
23. Caironi P, Ichinose F, Liu R, Jones RC, Bloch KD, Zapol WM. 5-Lipoxygenase deficiency prevents respiratory failure during ventilator-induced lung injury. Am J Respir Crit Care Med 2005;172:334–343. [PMC free article] [PubMed]
24. Chen CM, Penuelas O, Quinn K, Cheng KC, Li CF, Zhang H, Slutsky AS. Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats. Crit Care Med 2009;37:2235–2241. [PMC free article] [PubMed]
25. Hoetzel A, Schmidt R, Vallbracht S, Goebel U, Dolinay T, Kim HP, Ifedigbo E, Ryter SW, Choi AM. Carbon monoxide prevents ventilator-induced lung injury via caveolin-1. Crit Care Med 2009;37:1708–1715. [PMC free article] [PubMed]
26. Bellani G, Castagna L, Guerra L, Abd EL, Aziz El Sayed Deab S, Morzenti S, Messa C, Pesenti A. Intra-tidal recruitment-derecruitment during mechanical ventilation in patients with acute lung injury: A pet/ct study [abstract]. Intensive Care Med 2009;35:103.
27. Gattinoni L, Caironi P, Pelosi P, Goodman LR. What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 2001;164:1701–1711. [PubMed]
28. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 1983;3:1–7. [PubMed]
29. Hubmayr RD. Perspective on lung injury and recruitment: a skeptical look at the opening and collapse story. Am J Respir Crit Care Med 2002;165:1647–1653. [PubMed]
30. Caironi P, Cressoni M, Chiumello D, Ranieri M, Quintel M, Russo SG, Cornejo R, Bugedo G, Carlesso E, Russo R, et al. Lung opening and closing during ventilation of acute respiratory distress syndrome. Am J Respir Crit Care Med 2010;181:578–586. [PubMed]
31. Gattinoni L, Pelosi P, Crotti S, Valenza F. Effects of positive end-expiratory pressure on regional distribution of tidal volume and recruitment in adult respiratory distress syndrome. Am J Respir Crit Care Med 1995;151:1807–1814. [PubMed]
32. Sugiura M, McCulloch PR, Wren S, Dawson RH, Froese AB. Ventilator pattern influences neutrophil influx and activation in atelectasis-prone rabbit lung. J Appl Physiol 1994;77:1355–1365. [PubMed]
33. Jones HA, Cadwallader KA, White JF, Uddin M, Peters AM, Chilvers ER. Dissociation between respiratory burst activity and deoxyglucose uptake in human neutrophil granulocytes: implications for interpretation of (18)F-FDG PET images. J Nucl Med 2002;43:652–657. [PubMed]
34. Chen DL, Ferkol TW, Mintun MA, Pittman JE, Rosenbluth DB, Schuster DP. Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography. Am J Respir Crit Care Med 2006;173:1363–1369. [PMC free article] [PubMed]
35. Wolters PJ, Wray C, Sutherland RE, Kim SS, Koff J, Mao Y, Frank JA. Neutrophil-derived IL-6 limits alveolar barrier disruption in experimental ventilator-induced lung injury. J Immunol 2009;182:8056–8062. [PMC free article] [PubMed]
36. Zhou Z, Kozlowski J, Schuster DP. Physiologic, biochemical, and imaging characterization of acute lung injury in mice. Am J Respir Crit Care Med 2005;172:344–351. [PMC free article] [PubMed]
37. Monkman SL, Andersen CC, Nahmias C, Ghaffer H, Bourgeois JM, Roberts RS, Schmidt B, Kirpalani HM. Positive end-expiratory pressure above lower inflection point minimizes influx of activated neutrophils into lung. Crit Care Med 2004;32:2471–2475. [PubMed]
38. Steinberg JM, Schiller HJ, Halter JM, Gatto LA, Lee HM, Pavone LA, Nieman GF. Alveolar instability causes early ventilator-induced lung injury independent of neutrophils. Am J Respir Crit Care Med 2004;169:57–63. [PubMed]
39. Wilson MR, O'Dea KP, Zhang D, Shearman AD, van Rooijen N, Takata M. Role of lung-marginated monocytes in an in vivo mouse model of ventilator-induced lung injury. Am J Respir Crit Care Med 2009;179:914–922. [PMC free article] [PubMed]
40. Grasso S, Mascia L, Del Turco M, Malacarne P, Giunta F, Brochard L, Slutsky AS, Marco Ranieri V. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 2002;96:795–802. [PubMed]
41. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327–336. [PubMed]
42. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, et al. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2008;299:637–645. [PubMed]
43. 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;174:279–289. [PubMed]
44. Hager DN, Krishnan JA, Hayden DL, Brower RG. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005;172:1241–1245. [PMC free article] [PubMed]
45. Patroniti N, Bellani G, Cortinovis B, Foti G, Maggioni E, Manfio A, Pesenti A. Role of absolute lung volume to assess alveolar recruitment in acute respiratory distress syndrome patients. Crit Care Med 2010;38:1300–1307. [PubMed]
46. Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F, Polli F, Tallarini F, Cozzi P, Cressoni M, Colombo A, et al. Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med 2008;178:346–355. [PubMed]
47. Chiumello D, Cressoni M, Chierichetti M, Tallarini F, Botticelli M, Berto V, Mietto C, Gattinoni L. Nitrogen washout/washin, helium dilution and computed tomography in the assessment of end expiratory lung volume. Crit Care 2008;12:R150. [PMC free article] [PubMed]
48. Erol A, Reisli R, Reisli I, Kara R, Otelcioglu S. Effects of desflurane, sevoflurane and propofol on phagocytosis and respiratory burst activity of human polymorphonuclear leucocytes in bronchoalveolar lavage. Eur J Anaesthesiol 2009;26:150–154. [PubMed]
49. Grasso S, Stripoli T, Sacchi M, Trerotoli P, Staffieri F, Franchini D, De Monte V, Valentini V, Pugliese P, Crovace A, et al. Inhomogeneity of lung parenchyma during the open lung strategy: a computed tomography scan study. Am J Respir Crit Care Med 2009;180:415–423. [PubMed]

Articles from American Journal of Respiratory and Critical Care Medicine are provided here courtesy of American Thoracic Society
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...