Tilo Winkler

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.

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.

Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics

Bronchoconstriction in asthma results in patchy ventilation forming ventilation defects (VDefs). Patchy ventilation is clinically important because it affects obstructive symptoms and impairs both gas exchange and the distribution of inhaled medications. The current study combined functional imaging, oscillatory mechanics and theoretical modelling to test whether the degrees of constriction of airways feeding those units outside VDefs were related to the extent of VDefs in bronchoconstricted asthmatic subjects. Positron emission tomography was used to quantify the regional distribution of ventilation and oscillatory mechanics were measured in asthmatic subjects before and after bronchoconstriction. For each subject, ventilation data was mapped into an anatomically based lung model that was used to evaluate whether airway constriction patterns, consistent with the imaging data, were capable of matching the measured changes in airflow obstruction. The degree and heterogeneity of constriction of the airways feeding alveolar units outside VDefs was similar among the subjects studied despite large inter-subject variability in airflow obstruction and the extent of the ventilation defects. Analysis of the data amongst the subjects showed an inverse relationship between the reduction in mean airway conductance, measured in the breathing frequency range during bronchoconstriction, and the fraction of lung involved in ventilation defects. The current data supports the concept that patchy ventilation is an expression of the integrated system and not just the sum of independent responses of individual airways.

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.

Lung Physiology and Aerosol Deposition Imaged with Positron Emission Tomography

Physiological conditions and pathophysiological changes in the lungs may affect many applications in aerosol medicine and pulmonary drug delivery. In the diseased lung, spatial heterogeneity in function and structure may cause substantial changes in aerosol transport and local deposition among different lung regions. Non-uniform aerosol deposition affects airway or tissue pharmacological dosing, which could reduce the therapeutic effectiveness of inhalation therapy. This review article presents examples of pulmonary imaging using PET and PET-CT in lung physiology with an emphasis on their implications for aerosol medicine. Measurements of regional ventilation, perfusion, and ventilation/perfusion ratio, by imaging local kinetics of intravenously injected Nitrogen-13 in saline solution, and of pulmonary inflammation, by assessing the regional uptake of the radiotracer (18)F-FDG, are presented. These examples demonstrate that it is possible to access both preexisting conditions, such as heterogeneity of ventilation, perfusion, and/or inflammatory stimuli, which may affect inhalation therapy, and the functional effects of inhaled medications or inflammatory agents on lung regional function. The imaging techniques described could be efficient tools to evaluate quantitatively and noninvasively these processes in vivo. Furthermore, it can be expected that imaging of respiratory structure and function will yield sensitive biomarkers of disease, which will help and speed drug discovery, and the evaluation of novel inhalation therapies.

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.

Measurement of Regional Specific Lung Volume Change Using Respiratory-Gated PET of Inhaled 13N-Nitrogen

Regional specific lung volume change (sVol), defined as the regional tidal volume divided by the regional end-expiratory gas volume, is a key variable in lung mechanics and in the pathogenesis of ventilator-induced lung injury. Despite the usefulness of PET to study regional lung function, there is no established method to assess sVol with PET. We present a method to measure sVol from respiratory-gated PET images of inhaled 13N-nitrogen (13NN), validate the method against regional specific ventilation (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{s{\dot{V}}}\) \end{document}), and study the effect of region-of-interest (ROI) volume and orientation on the sVol–\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{s{\dot{V}}}\) \end{document} relationship. Methods: Four supine sheep were mechanically ventilated (tidal volume VT = 8 mL/kg, respiratory rate adjusted to normocapnia) at low (n = 2, positive end-expiratory pressure = 0) and high (n = 2, positive end-expiratory pressure adjusted to achieve a plateau pressure of 30 cm H2O) lung volumes. Respiratory-gated PET scans were obtained after inhaled 13NN equilibration both at baseline and after a period of mechanical ventilation. We calculated sVol from 13NN-derived regional fractional gas content at end-inspiration (FEI) and end-expiration (FEE) using the formula sVol = (FEI − FEE)/(FEE[1 − FEI]). \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{s{\dot{V}}}\) \end{document} was computed as the inverse of the subsequent 13NN washout curve time constant. ROIs were defined by dividing the lung field with equally spaced coronal, sagittal, and transverse planes, perpendicular to the ventrodorsal, laterolateral, and cephalocaudal axes, respectively. Results: sVol–\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(s\mathrm{{\dot{V}}}\) \end{document} linear regressions for ROIs based on the ventrodorsal axis yielded the highest R2 (range, 0.71–0.92 for mean ROI volumes from 7 to 162 mL), the cephalocaudal axis the next highest (R2 = 0.77–0.88 for mean ROI volumes from 38 to 162 mL), and the laterolateral axis the lowest (R2 = 0.65–0.83 for mean ROI volumes from 8 to 162 mL). ROIs based on the ventrodorsal axis yielded lower standard errors of estimates of sVol from \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{s{\dot{V}}}\) \end{document} than those based on the laterolateral axis or the cephalocaudal axis. Conclusion: sVol can be computed with PET using the proposed method and is highly correlated with \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{s{\dot{V}}}\) \end{document}. Errors in sVol are smaller for larger ROIs and for orientations based on the ventrodorsal axis.