Guido Musch

Self-organized patchiness in asthma as a prelude to catastrophic shifts

Asthma is a common disease affecting an increasing number of children throughout the world. In asthma, pulmonary airways narrow in response to contraction of surrounding smooth muscle. The precise nature of functional changes during an acute asthma attack is unclear. The tree structure of the pulmonary airways has been linked to complex behaviour in sudden airway narrowing and avalanche-like reopening. Here we present experimental evidence that bronchoconstriction leads to patchiness in lung ventilation, as well as a computational model that provides interpretation of the experimental data. Using positron emission tomography, we observe that bronchoconstricted asthmatics develop regions of poorly ventilated lung. Using the computational model we show that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity breaks the symmetry and leads to large clusters of poorly ventilated lung units. These clusters are generated by interaction of short- and long-range feedback mechanisms, which lead to catastrophic shifts similar to those linked to self-organized patchiness in nature. This work might have implications for the treatment of asthma, and might provide a model for studying diseases of other distributed organs.

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 [(18)F]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 [(18)F]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 H(2)O, 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.

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

Objective: Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [18F]-fluoro-2-deoxy-d-glucose (18FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with 18FDG. Design: Prospective clinical investigation. Patients: Ten patients with ALI/ARDS; four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. Interventions: In each individual we performed an 18FDG PET/computed tomography of the thorax. Measurements and Main Results: 18FDG cellular influx rate constant (Ki) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, Ki was higher than in controls, also after accounting for the increased lung density. Ki values differed greatly among patients, but in all patients Ki of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest Ki values corresponded to regions with the lowest aeration, in others these regions had lower Ki than normally and mildly hypoaerated regions. Conclusion: In patients with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patients.

Mechanism by Which a Sustained Inflation Can Worsen Oxygenation in Acute Lung Injury

BackgroundSustained lung inflations (recruitment maneuvers [RMs]) are occasionally used during mechanical ventilation of patients with acute lung injury to restore aeration to atelectatic alveoli. However, RMs do not improve, and may even worsen, gas exchange in a fraction of these patients. In this study, the authors sought to determine the mechanism by which an RM can impair gas exchange in acute lung injury. MethodsThe authors selected a model of acute lung injury that was unlikely to exhibit sustained recruitment in response to a lung inflation. In five sheep, lung injury was induced by lavage with 0.2% polysorbate 80 in saline. Positron emission tomography and [13N]nitrogen were used to assess regional lung function in dependent, middle, and nondependent lung regions. Physiologic data and positron emission scans were collected before and 5 min after a sustained inflation (continuous positive airway pressure of 50 cm H2O for 30 s). ResultsAll animals showed greater loss of aeration and higher perfusion and shunting blood flow in the dependent region. After the RM, Pao2 decreased in all animals by 35 ± 22 mmHg (P < 0.05). This decrease in Pao2 was associated with redistribution of pulmonary blood flow from the middle, more aerated region to the dependent, less aerated region (P < 0.05) and with an increase in the fraction of pulmonary blood flow that was shunted in the dependent region (P < 0.05). Neither respiratory compliance nor aeration of the dependent region improved after the RM. ConclusionsWhen a sustained inflation does not restore aeration to atelectatic regions, it can worsen oxygenation by increasing the fraction of pulmonary blood flow that is shunted in nonaerated regions.

Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury

Background:Alveolar overdistension and repetitive derecruitment–recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident. Methods:The authors assessed cellular metabolic activity with [18F]fluorodeoxyglucose and regional gas exchange with [13N]nitrogen. In 12 sheep, the left (“test”) lung was overdistended with end-inspiratory pressure of 50 cm H2O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of −10 cm H2O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H2O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right (“control”) lung was protected from VILI. Results:Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [18F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [18F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone. Conclusion:The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.

Changes in Regional Ventilation after Autologous Blood Clot Pulmonary Embolism

BACKGROUND Previous studies have suggested that pulmonary embolism (PE) and pulmonary artery occlusion result in a shift in alveolar ventilation away from unperfused regions. This study aimed to directly assess changes in regional specific ventilation (sV(A)) due to autologous blood clot PE using positron emission tomography. METHODS Pulmonary embolism was created in six anesthetized, paralyzed, and mechanically ventilated sheep by injecting cylindrical clots of autologous blood (7 mm in diameter and height). Clots were progressively infused into a central vein until a stable mean pulmonary artery pressure between 30 and 40 mmHg was achieved. A multislice positron emission tomography camera was used to image 15 contiguous, 6.5-mm-thick transverse cross-sections of the chest beginning just above the diaphragm. sV(A) from perfused regions (sV(A),(p)) was assessed as the ventilatory turnover rate of the tracer NN after central venous injection of NN-labeled saline. RESULTS Pulmonary embolism obstructed flow to 64% of imaged areas. Before PE, (sV(A),(p))was equivalent in areas that would remain perfused and those that would become embolized after PE (0.021 +/- 0.007 0.021 +/- 0.006 s(-1); P = nonsignificant). After PE, sV(A),(p) of areas remaining perfused increased to 0.033 +/- 0.011 s (-1) (P < 0.005). This effect on regional sV(A),(p) could have been caused by active redistribution of sV(A),(p) or by a reduction in tracer concentration of perfused areas due to the dead space common to perfused and embolized regions. Model simulations indicated that the common dead-space effect could only explain a small part of the sV(A),(p) increase. CONCLUSIONS An increase in sV(A),(p) of perfused regions occurs following PE with 7-mm autologous blood clots. This increase is most likely caused by a shift in ventilation away from embolized areas mediated by hypocapnic pneumoconstriction.

Spatial Heterogeneity of Lung Perfusion Assessed with 13N PET as a Vascular Biomarker in Chronic Obstructive Pulmonary Disease

Although it is known that structural and functional changes in the pulmonary vasculature and parenchyma occur in the progress of chronic obstructive pulmonary disease (COPD), information is limited on early regional perfusion (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r) alterations. Methods: We studied 6 patients with mild or moderate COPD and 9 healthy subjects (6 young and 3 age-matched). The PET 13NN-labeled saline injection method was used to compute images of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r and regional ventilation (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r). Transmission scans were used to assess regional density. We used the squared coefficient of variation to quantify \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity and length-scale analysis to quantify the contribution to total perfusion heterogeneity of regions ranging from less than 12 to more than 108 mm. Results: Perfusion distribution in COPD subjects showed larger \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity, higher contribution from large length scales and lower contribution from small length scales, and larger heterogeneity of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r normalized by tissue density than did healthy subjects. Dorsoventral gradients of \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r were present in healthy subjects, with larger ventilation in dependent regions, whereas no gradient was present in COPD. Heterogeneity of ventilation–perfusion ratios was larger in COPD. Conclusion: \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r is significantly redistributed in COPD. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{Q}}}\) \end{document}r heterogeneity in COPD patients is greater than in healthy subjects, mainly because of the contribution of large lung regions and not because of changes in tissue density or \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{{\dot{V}}}\) \end{document}r. The assessment of spatial heterogeneity of lung perfusion with 13NN-saline PET may serve as a vascular biomarker in COPD.

Mild endotoxemia during mechanical ventilation produces spatially heterogeneous pulmonary neutrophilic inflammation in sheep.

Background:There is limited information on the regional inflammatory effects of mechanical ventilation and endotoxemia on the production of acute lung injury. Measurement of 18F-fluorodeoxyglucose (18F-FDG) uptake with positron emission tomography allows for the regional, in vivo and noninvasive, assessment of neutrophilic inflammation. The authors tested whether mild endotoxemia combined with large tidal volume mechanical ventilation bounded by pressures within clinically acceptable limits could yield measurable and anatomically localized neutrophilic inflammation. Methods:Sheep were mechanically ventilated with plateau pressures = 30-32 cm H2O and positive end-expiratory pressure = 0 for 2 h. Six sheep received intravenous endotoxin (10 ng · kg−1 · min−1), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused 13N-nitrogen and 18F-FDG to compute regional perfusion and 18F-FDG uptake. Transmission scans were used to assess aeration. Results:Mean gas fraction and perfusion distribution were similar between groups. In contrast, a significant increase in 18F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, 18F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the 18F-FDG uptake was associated with regional aeration (P < 0.01) and perfusion (P < 0.01). Conclusions:Mild short-term endotoxemia in the presence of heterogeneous lung aeration and mechanical ventilation with pressures within clinically acceptable limits produces marked spatially heterogeneous increases in pulmonary neutrophilic inflammation. The dependence of inflammation on aeration and perfusion suggests a multifactorial basis for that finding. 18F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions.

Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*.

Objectives:Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia. Design:Interventional animal study. Setting:Experimental laboratory and PET facility. Subjects:Eighteen 2- to 4-month-old sheep. Interventions:Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30–32 cm H2O) with high-strain (VT = 18.2 ± 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (VT = 18.4 ± 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (VT = 8.1 ± 0.2 mL/kg, positive end-expiratory pressure = 17 ± 3 cm H2O). At baseline, we acquired respiratory-gated PET scans of inhaled 13NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [18F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest. Measurements and Main Results:Baseline regional tidal strain had a significant effect on [18F]fluoro-2-deoxy-D-glucose net uptake rate Ki in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k3 in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k3-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 ± 0.17) than high-strain (1.21 ± 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 ± 0.44; p < 0.001) and lower k3 (p < 0.001) and Ki (p < 0.05) than high-strain lipopolysaccharide. Conclusions:Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [18F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [18F]fluoro-2-deoxy-D-glucose phosphorylation.

Modeling Pulmonary Kinetics of 2-Deoxy-2-[18F]fluoro-d-glucose During Acute Lung Injury

RATIONALE AND OBJECTIVES Dynamic positron emission tomographic imaging of the radiotracer 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) is increasingly used to assess metabolic activity of lung inflammatory cells. To analyze the kinetics of (18)F-FDG in brain and tumor tissues, the Sokoloff model has been typically used. In the lungs, however, a high blood-to-parenchymal volume ratio and (18)F-FDG distribution in edematous injured tissue could require a modified model to properly describe (18)F-FDG kinetics. MATERIALS AND METHODS We developed and validated a new model of lung (18)F-FDG kinetics that includes an extravascular/noncellular compartment in addition to blood and (18)F-FDG precursor pools for phosphorylation. Parameters obtained from this model were compared with those obtained using the Sokoloff model. We analyzed dynamic PET data from 15 sheep with smoke or ventilator-induced lung injury. RESULTS In the majority of injured lungs, the new model provided better fit to the data than the Sokoloff model. Rate of pulmonary (18)F-FDG net uptake and distribution volume in the precursor pool for phosphorylation correlated between the two models (R(2)=0.98, 0.78), but were overestimated with the Sokoloff model by 17% (P< .05) and 16% (P< .0005) compared to the new one. The range of the extravascular/noncellular (18)F-FDG distribution volumes was up to 13% and 49% of lung tissue volume in smoke- and ventilator-induced lung injury, respectively. CONCLUSION The lung-specific model predicted (18)F-FDG kinetics during acute lung injury more accurately than the Sokoloff model and may provide new insights in the pathophysiology of lung injury.