Perfusion imaging heterogeneity during NO inhalation distinguishes pulmonary arterial hypertension (PAH) from healthy subjects and has potential as an imaging biomarker.

BACKGROUND: Without aggressive treatment, pulmonary arterial hypertension (PAH) has a 5-year mortality of approximately 40%. A patient's response to vasodilators at diagnosis impacts the therapeutic options and prognosis. We hypothesized that analyzing perfusion images acquired before and during vasodilation could identify characteristic differences between PAH and control subjects. METHODS: We studied 5 controls and 4 subjects with PAH using HRCT and 13NN PET imaging of pulmonary perfusion and ventilation. The total spatial heterogeneity of perfusion (CV2Qtotal) and its components in the vertical (CV2Qvgrad) and cranio-caudal (CV2Qzgrad) directions, and the residual heterogeneity (CV2Qr), were assessed at baseline and while breathing oxygen and nitric oxide (O2 + iNO). The length scale spectrum of CV2Qr was determined from 10 to 110 mm, and the response of regional perfusion to O2 + iNO was calculated as the mean of absolute differences. Vertical gradients in perfusion (Qvgrad) were derived from perfusion images, and ventilation-perfusion distributions from images of 13NN washout kinetics. RESULTS: O2 + iNO significantly enhanced perfusion distribution differences between PAH and controls, allowing differentiation of PAH subjects from controls. During O2 + iNO, CV2Qvgrad was significantly higher in controls than in PAH (0.08 (0.055-0.10) vs. 6.7 × 10-3 (2 × 10-4-0.02), p < 0.001) with a considerable gap between groups. Qvgrad and CV2Qtotal showed smaller differences: - 7.3 vs. - 2.5, p = 0.002, and 0.12 vs. 0.06, p = 0.01. CV2Qvgrad had the largest effect size among the primary parameters during O2 + iNO. CV2Qr, and its length scale spectrum were similar in PAH and controls. Ventilation-perfusion distributions showed a trend towards a difference between PAH and controls at baseline, but it was not statistically significant. CONCLUSIONS: Perfusion imaging during O2 + iNO showed a significant difference in the heterogeneity associated with the vertical gradient in perfusion, distinguishing in this small cohort study PAH subjects from controls.

Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma.

RATIONALE: Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV). OBJECTIVES: To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma. METHODS: Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O2) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sVlow) and the remaining lung (sVhigh) were quantified and compared. MEASUREMENTS AND MAIN RESULTS: In the sVlow region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O2 conditions (baseline vs. bronchoconstriction, mean ± SD, 1.02 ± 0.20 vs. 0.35 ± 0.19 and 1.03 ± 0.20 vs. 0.32 ± 0.16, respectively; P < 0.05). In the sVlow region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O2 conditions (1.02 ± 0.19 vs. 0.72 ± 0.08 [P < 0.001] and 1.08 ± 0.19 vs. 0.91 ± 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 ± 0.04 vs. 1.00 ± 0.02; P < 0.05). The sVlow subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sVlow subregions that were hyperoxic under 80% O2 conditions. CONCLUSIONS: HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature.

Lung Metabolic Activation as an Early Biomarker of Acute Respiratory Distress Syndrome and Local Gene Expression Heterogeneity.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an inflammatory condition comprising diffuse lung edema and alveolar damage. ARDS frequently results from regional injury mechanisms. However, it is unknown whether detectable inflammation precedes lung edema and opacification and whether topographically differential gene expression consistent with heterogeneous injury occurs in early ARDS. The authors aimed to determine the temporal relationship between pulmonary metabolic activation and density in a large animal model of early ARDS and to assess gene expression in differentially activated regions. METHODS: The authors produced ARDS in sheep with intravenous lipopolysaccharide (10 ng ⋅ kg ⋅ h) and mechanical ventilation for 20 h. Using positron emission tomography, the authors assessed regional cellular metabolic activation with 2-deoxy-2-[(18)F]fluoro-D-glucose, perfusion and ventilation with NN-saline, and aeration using transmission scans. Species-specific microarray technology was used to assess regional gene expression. RESULTS: Metabolic activation preceded detectable increases in lung density (as required for clinical diagnosis) and correlated with subsequent histologic injury, suggesting its predictive value for severity of disease progression. Local time courses of metabolic activation varied, with highly perfused and less aerated dependent lung regions activated earlier than nondependent regions. These regions of distinct metabolic trajectories demonstrated differential gene expression for known and potential novel candidates for ARDS pathogenesis. CONCLUSIONS: Heterogeneous lung metabolic activation precedes increases in lung density in the development of ARDS due to endotoxemia and mechanical ventilation. Local differential gene expression occurs in these early stages and reveals molecular pathways relevant to ARDS biology and of potential use as treatment targets.

MATHEMATICAL MODELING OF VENTILATION DEFECTS IN ASTHMA.

Airway narrowing by smooth muscle constriction is a hallmark of asthma attacks that may cause severe difficulties of breathing. However, the causes of asthma and the underlying mechanisms are not fully understood. Bronchoconstriction within a bronchial tree involves complex interactions among the airways that lead to the emergence of regions of poor ventilation (ventilation defects, VDefs) in the lungs. The emphasis of this review is on mathematical modeling of the mechanisms involved in bronchoconstriction and the emergence of the complex airway behavior that leads to VDefs. Additionally, the review discusses characteristic model behaviors and experimental data to demonstrate advances and limitations of different models.

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 NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F]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 [F]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 [F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [F]fluoro-2-deoxy-D-glucose phosphorylation.

Lung [(18)F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch in the early stage of experimental acute smoke inhalation.

BACKGROUND: Acute lung injury occurs in a third of patients with smoke inhalation injury. Its clinical manifestations usually do not appear until 48-72 h after inhalation. Identifying inflammatory changes that occur in pulmonary parenchyma earlier than that could provide insight into the pathogenesis of smoke-induced acute lung injury. Furthermore, noninvasive measurement of such changes might lead to earlier diagnosis and treatment. Because glucose is the main source of energy for pulmonary inflammatory cells, the authors hypothesized that its pulmonary metabolism is increased shortly after smoke inhalation, when classic manifestations of acute lung injury are not yet expected. METHODS: In five sheep, the authors induced unilateral injury with 48 breaths of cotton smoke while the contralateral lung served as control. The authors used positron emission tomography with: (1) [F]fluorodeoxyglucose to measure metabolic activity of pulmonary inflammatory cells; and (2) [N]nitrogen in saline to measure shunt and ventilation-perfusion distributions separately in the smoke-exposed and control lungs. RESULTS: The pulmonary [F]fluorodeoxyglucose uptake rate was increased at 4 h after smoke inhalation (mean ± SD: 0.0031 ± 0.0013 vs. 0.0026 ± 0.0010 min; P < 0.05) mainly as a result of increased glucose phosphorylation. At this stage, there was no worsening in lung aeration or shunt. However, there was a shift of perfusion toward units with lower ventilation-to-perfusion ratio (mean ratio ± SD: 0.82 ± 0.10 vs. 1.12 ± 0.02; P < 0.05) and increased heterogeneity of the ventilation-perfusion distribution (mean ± SD: 0.21 ± 0.07 vs. 0.13 ± 0.01; P < 0 .05). CONCLUSION: Using noninvasive imaging, the authors demonstrated that increased pulmonary [F]fluorodeoxyglucose uptake and ventilation-perfusion mismatch occur early after smoke inhalation.

Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep.

BACKGROUND: Lung derecruitment is common during general anesthesia. Mechanical ventilation with physiological tidal volumes could magnify derecruitment, and produce lung dysfunction and inflammation. The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes in regional lung perfusion and inflammation. METHODS: Six anesthetized supine sheep were ventilated with VT=8 ml/kg and positive end-expiratory pressure=0. Transmission scans were performed at 2-h intervals to assess regional aeration. Emission scans were acquired at baseline and after 16 h for the following tracers: (1) F-fluorodeoxyglucose to evaluate lung inflammation and (2) NN to calculate regional perfusion and shunt fraction. RESULTS: Gas fraction decreased from baseline to 16 h in dorsal (0.31±0.13 to 0.14±0.12, P<0.01), but not in ventral regions (0.61±0.03 to 0.63±0.07, P=nonsignificant), with time constants of 1.5-44.6 h. Although the vertical distribution of relative perfusion did not change from baseline to 16 h, shunt increased in dorsal regions (0.34±0.23 to 0.63±0.35, P<0.01). The average pulmonary net F-fluorodeoxyglucose uptake rate in six regions of interest along the ventral-dorsal direction increased from 3.4±1.4 at baseline to 4.1±1.5 10(-3)/min after 16 h (P<0.01), and the corresponding average regions of interest F-fluorodeoxyglucose phosphorylation rate increased from 2.0±0.2 to 2.5±0.2 10(-2)/min (P<0.01). CONCLUSIONS: When normal lungs are mechanically ventilated without positive end-expiratory pressure, loss of aeration occurs continuously for several hours and is preferentially localized to dorsal regions. Progressive lung derecruitment was associated with increased regional shunt, implying an insufficient hypoxic pulmonary vasoconstriction. The increased pulmonary net uptake and phosphorylation rates of F-fluorodeoxyglucose suggest an incipient inflammation in these initially normal lungs.

Effects of ventilation strategy on distribution of lung inflammatory cell activity.

INTRODUCTION: Leukocyte infiltration is central to the development of acute lung injury, but it is not known how mechanical ventilation strategy alters the distribution or activation of inflammatory cells. We explored how protective (vs. injurious) ventilation alters the magnitude and distribution of lung leukocyte activation following systemic endotoxin administration. METHODS: Anesthetized sheep received intravenous endotoxin (10 ng/kg/min) followed by 2 h of either injurious or protective mechanical ventilation (n = 6 per group). We used positron emission tomography to obtain images of regional perfusion and shunting with infused ¹³N[nitrogen]-saline and images of neutrophilic inflammation with ¹8F-fluorodeoxyglucose (¹8F-FDG). The Sokoloff model was used to quantify ¹8F-FDG uptake (Ki), as well as its components: the phosphorylation rate (k3, a surrogate of hexokinase activity) and the distribution volume of ¹8F-FDG (Fe) as a fraction of lung volume (Ki = Fe × k3). Regional gas fractions (fgas) were assessed by examining transmission scans. RESULTS: Before endotoxin administration, protective (vs. injurious) ventilation was associated with a higher ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO2/FiO2) (351 ± 117 vs. 255 ± 74 mmHg; P < 0.01) and higher whole-lung fgas (0.71 ± 0.12 vs. 0.48 ± 0.08; P = 0.004), as well as, in dependent regions, lower shunt fractions. Following 2 h of endotoxemia, PaO2/FiO2 ratios decreased in both groups, but more so with injurious ventilation, which also increased the shunt fraction in dependent lung. Protective ventilation resulted in less nonaerated lung (20-fold; P < 0.01) and more normally aerated lung (14-fold; P < 0.01). Ki was lower during protective (vs. injurious) ventilation, especially in dependent lung regions (0.0075 ± 0.0043/min vs. 0.0157 ± 0.0072/min; P < 0.01). ¹8F-FDG phosphorylation rate (k3) was twofold higher with injurious ventilation and accounted for most of the between-group difference in Ki. Dependent regions of the protective ventilation group exhibited lower k3 values per neutrophil than those in the injurious ventilation group (P = 0.01). In contrast, Fe was not affected by ventilation strategy (P = 0.52). Lung neutrophil counts were not different between groups, even when regional inflation was accounted for. CONCLUSIONS: During systemic endotoxemia, protective ventilation may reduce the magnitude and heterogeneity of pulmonary inflammatory cell metabolic activity in early lung injury and may improve gas exchange through its effects predominantly in dependent lung regions. Such effects are likely related to a reduction in the metabolic activity, but not in the number, of lung-infiltrating neutrophils.

Measuring Anatomical Distributions of Ventilation and Aerosol Deposition with PET-CT.

In disease, lung function and structure are heterogeneous, and aerosol transport and local deposition vary significantly among parts of the lung. Understanding such heterogeneity is relevant to aerosol medicine and for quantifying mucociliary clearance from different parts of the lung. In this chapter, we describe positron emission tomography (PET) imaging methods to quantitatively assess the deposition of aerosol and ventilation distribution within the lung. The anatomical information from computed tomography (CT) combined with the PET-deposition data allows estimates of airway surface concentration and peripheral tissue dosing in bronchoconstricted asthmatic subjects. A theoretical framework is formulated to quantify the effects of heterogeneous ventilation, uneven aerosol ventilation distribution in bifurcations, and varying escape from individual airways along a path of the airway tree. The framework is applied to imaging data from bronchoconstricted asthmatics to assess the contributions of these factors to the unevenness in lobar deposition. Results from this analysis show that the heterogeneity of ventilation contributes on average to more than one-third of the variability in interlobar deposition. Actual contribution of ventilation in individual lungs was variable and dependent on the breathing rate used by the subject during aerosol inhalation; the highest contribution was in patients breathing slowly. In subjects breathing faster, contribution of ventilation was reduced, with more expanded lobes showing lower deposition per unit ventilation than less expanded ones in these subjects. The lobar change in expansion measured from two static CT scans, which is commonly used as a surrogate for ventilation, did not correlate with aerosol deposition or with PET-measured ventilation. This suggests that dynamic information is needed to provide proper estimates of ventilation for asthmatic subjects. We hope that the enhanced understanding of the causes of heterogeneity in airway and tissue dosing using the tools presented here will help to optimize therapeutic effectiveness of inhalation therapy while minimizing toxicity.

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.

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 F-fluorodeoxyglucose (F-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 x kg x min), whereas six did not (controls), in sequentially performed studies. The authors imaged with positron emission tomography the intrapulmonary kinetics of infused N-nitrogen and F-FDG to compute regional perfusion and F-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 F-FDG uptake was observed in all lung regions of the endotoxin group. In this group, F-FDG uptake in the middle and dorsal regions was significantly larger than that in the ventral regions. Multivariate analysis showed that the F-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. F-FDG uptake may be a sensitive marker of pulmonary neutrophilic inflammation in the studied conditions.

The prone position results in smaller ventilation defects during bronchoconstriction in asthma.

The effect of body posture on regional ventilation during bronchoconstriction is unknown. In five subjects with asthma, we measured spirometry, low-frequency (0.15-Hz) lung elastance, and resistance and regional ventilation by intravenous (13)NN-saline positron emission tomography before and after nebulized methacholine. The subjects were imaged prone on 1 day and supine on another, but on both days the methacholine was delivered while prone. From the residual (13)NN after washout, ventilation defective areas were defined, and their location, volume, ventilation, and fractional gas content relative to the rest of the lung were calculated. Independent of posture, all subjects developed ventilation defective areas. Although ventilation within these areas was similarly reduced in both postures, their volume was smaller in prone than supine (25 vs. 41%, P < 0.05). The geometric center of the ventilation defective areas was gravitationally dependent relative to that of the lung in both postures. Mean lung fractional gas content was greater in the prone position before methacholine and did not increase as much as in the supine position after methacholine. In the prone position at baseline, areas that became ventilation defects had lower gas content than the rest of the lung. In both positions at baseline, there was a gradient of gas content in the vertical direction. In asthma, the size and location of ventilation defects is affected by body position and likely affected by small differences in lung expansion during bronchoconstriction.

Relation between shunt, aeration, and perfusion in experimental acute lung injury.

RATIONALE: In a pulmonary process characterized by spatially heterogeneous loss of aeration, the impairment of gas exchange is expected to depend on the regional distribution of perfusion relative to that of aeration. OBJECTIVES: To investigate how regional aeration, shunt, and perfusion are interrelated at different levels of end-expiratory pressure and how their interplay relates to global shunt fraction in acute lung injury. METHODS: Regional shunt and perfusion were assessed by imaging with positron emission tomography the pulmonary kinetics of [(13)N]nitrogen infused in saline solution in five sheep after lung lavage. The lung field was divided in six horizontal regions. MEASUREMENTS AND MAIN RESULTS: Each animal showed an inverse relation between regional shunt (Fs) and gas (Fg) fractions: Fs = -m . Fg + Fs(0). This relation was similar among animals (m = 1.25 +/- 0.14, Fs(0) = 0.75 +/- 0.15) and invariant with end-expiratory pressure, despite lack of correlation between global shunt and gas fractions and large interanimal variability in global shunt fraction. When this relation was used to estimate global shunt fraction as a perfusion-weighted average of the estimates of regional shunt fraction derived from regional gas fraction, 72% of the interanimal variability in global shunt fraction could be explained. CONCLUSIONS: Despite large interanimal variability in global shunt fraction, there was a consistent inverse relation between regional shunt and gas fractions, independent of end-expiratory pressure. Most of the interanimal variability in global shunt fraction could be explained by the combined effect of this relation and the distribution of perfusion on regional shunt, rather than by differences in global aeration.

Effect of the chest wall on pressure-volume curve analysis of acute respiratory distress syndrome lungs.

OBJECTIVE: Previously published methods to assess the chest wall effect on total respiratory system pressure-volume (P-V) curves in acute respiratory distress syndrome have been performed on the lung and chest wall in isolation. We sought to quantify the effect of the chest wall by considering the chest wall and lung in series. DESIGN: Prospective study. SETTING: Academic health center medical and surgical intensive care units. PATIENTS: Twenty-two patients with acute respiratory distress syndrome/acute lung injury. INTERVENTIONS: Using a sigmoidal equation, we fit the pressure-volume data of the lung alone, and defined for each curve the pressure at the point of maximum compliance increase (Pmci), decrease (Pmcd), and the point of inflection (Pinf). We calculated the pressure to which the total respiratory system must be inflated to achieve a volume that would place the lung at each point of interest. We compared these "corrected" pressures (Pmci,c, Pmcd,c, and Pinf,c) to the measured values of the total respiratory system. MEASUREMENTS AND MAIN RESULTS: The average difference between Pmci and Pmci,c was 0.12 cm H2O on inflation (2sd = 5.6 cm H2O) and -1.4 cm H2O on deflation (2sd = 5.0 cm H2O); between Pmcd and Pmcd,c was 1.73 cm H2O on inflation (2sd = 4.5 cm H2O) and -0.15 cm H2O on deflation (2sd = 4.9 cm H2O); and between Pinf and Pinf,c was 0.14 cm H2O on inflation (2sd = 6.7 cm H2O) and -0.35 cm H2O on deflation (2sd = 5.0 cm H2O). CONCLUSIONS: This method of "correcting" the total respiratory system P-V curve for the chest wall allows for calculation of an airway pressure that would place the lung at a desired volume on its P-V curve. For most patients, the chest wall had little influence on the total respiratory system P-V curve. However, there were patients in whom the chest wall did potentially have clinical significance.

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.

Elevation in lung volume and preventing catastrophic airway closure in asthmatics during bronchoconstriction.

BACKGROUND: Asthma exacerbations cause lung hyperinflation, elevation in load to inspiratory muscles, and decreased breathing capacity that, in severe cases, may lead to inspiratory muscle fatigue and respiratory failure. Hyperinflation has been attributed to a passive mechanical origin; a respiratory system time-constant too long for full exhalation. However, because the increase in volume is also concurrent with activation of inspiratory muscles during exhalation it is unclear whether hyperinflation in broncho-constriction is a passive phenomenon or is actively controlled to avoid airway closure. METHODS: Using CT scanning, we measured the distensibility of individual segmental airways relative to that of their surrounding parenchyma in seven subjects with asthma and nine healthy controls. With this data we tested whether the elevation of lung volume measured after methacholine (MCh) provocation was associated with airway narrowing, or to the volume required to preventing airway closure. We also tested whether the reduction in FVC post-MCh could be attributed to gas trapped behind closed segmental airways. FINDINGS: The changes in lung volume by MCh in subjects with and without asthma were inversely associated with their reduction in average airway lumen. This finding would be inconsistent with hyperinflation by passive elevation of airway resistance. In contrast, the change in volume of each subject was associated with the lung volume estimated to cause the closure of the least stable segmental airway of his/her lungs. In addition, the measured drop in FVC post MCh was associated with the estimated volume of gas trapped behind closed segmental airways at RV. CONCLUSIONS: Our data supports the concept that hyperinflation caused by MCh-induced bronchoconstriction is the result of an actively controlled process where parenchymal distending forces on airways are increased to counteract their closure. To our knowledge, this is the first imaging-based study that associates inter-subject differences in whole lung behavior with the interdependence between individual airways and their surrounding parenchyma.

Anatomically Based Analysis of Radioaerosol Distribution in Pulmonary Scintigraphy: A Feasibility Study in Asthmatics.

INTRODUCTION: Manual analysis of two-dimensional (2D) scintigraphy to evaluate aerosol deposition is usually subjective and has reduced sensitivity to quantify regional differences between central and distal airways. AIMS: (1) To present a method to analyze 2D scans based on three-dimensional (3D)-linked anatomically consistent regions of interest (ROIs); (2) to evaluate peripheral-to-central counts ratio (P/C2D) and penetration indices (PIs) for a set of 16 subjects with moderate-to-severe asthma; and (3) to compare the reproducibility of this method against one with manually traced ROIs. METHODS: Two-dimensional scans were analyzed using custom software that scaled onto 2D-projections' 3D anatomical features, obtained from population-averaged computed tomography (CT) chest scans. ROIs for a rectangular box (bROI) and an anatomically shaped ROI (aROI) were defined by computer and by manually tracing the standard rectangular box (manual ROI [mROI]). These ROIs were defined five nonconsecutive times for each scan and average value and variability of the P/C2D were estimated. Based on CT estimates of lung and airways, volumes lying under the bROI and aROI, a 2D penetration index (PI2D) and a 3D penetration index (PI3D), were defined as volume-normalized ratios of aerosol deposition in central and peripheral ROIs and in central and distal airways, respectively. RESULTS: P/C2D values and their variability, were influenced by the shape and method to define the ROIs: The P/C2D was systematically greater and more variable for mROI versus bROI (p < 0.005). The P/C2D for aROI was higher and its variability lower than those for the bROI (p < 0.001). The PI2D was in average the same for aROI and bROI, and is substantially (∼30 × ) greater than PI3D (p < 0.001). Both PI2D and PI3D, obtained with our analysis, compared well with literature values obtained with two scans (deposition and volume). CONCLUSION: Our results demonstrate that 2D scintigraphy can be analyzed using anatomically based ROIs from 3D CT data, allowing objective and enhanced reproducibility values describing the distribution pattern of radioaerosol deposition in the tracheobronchial tree.

PET imaging of regional 18F-FDG uptake and lung function after cigarette smoke inhalation.

UNLABELLED: Cigarette smoke is thought to promote local lung inflammation that leads to lung dysfunction. Lung neutrophilic inflammation is known to result in increased pulmonary uptake of (18)F-FDG. Using a sheep model of localized exposure to cigarette smoke, in this study we tested whether PET-imaged changes in regional intrapulmonary distribution of (18)F-FDG uptake are related to changes in regional lung function as assessed with the infused (13)NN-saline method. METHODS: Five anesthetized, mechanically ventilated sheep were exposed to unilateral inhalation of smoke from 10 tobacco cigarettes while the contralateral lung was ventilated with smoke-free gas. Two hours after the exposure, regional gas content was measured from a transmission scan; regional ventilation, perfusion, and shunt were measured from the kinetics of (13)NN-saline; and regional (18)F-FDG influx constant (K(i)) was calculated with the Patlak algorithm applied at a voxel-by-voxel level. RESULTS: K(i) was higher and more heterogeneous in the smoke-exposed lungs than in the control lungs (P < 0.05). Spatial heterogeneity of K(i) and impairment in regional lung function were quite variable among animals despite similar levels of smoke exposure. However, increases in mean K(i) correlated linearly with its spatial heterogeneity (Spearman correlation, r(s) = 0.94), and the highest levels of regional K(i) in smoke-exposed lungs and control lungs correlated with regional shunt fraction (r(s) = 0.78). Also, the heterogeneity of the ventilation-perfusion (V/Q) distribution of the smoke-exposed lungs was 10 times greater than that of the control lungs but correlated strongly with that of the control lungs (r = 0.998). CONCLUSION: Substantial interanimal variability and spatial heterogeneity in lung function and (18)F-FDG uptake seem to characterize the response to smoke exposure. The highest levels of local (18)F-FDG uptake were associated with differences in V/Q matching and shunt fraction among animals. The data also suggest that preexisting heterogeneity in V/Q could have been responsible for the large interanimal variability by affecting the heterogeneity and strength of the acute response to smoke inhalation.

Image-derived input function for assessment of 18F-FDG uptake by the inflamed lung.

UNLABELLED: Pulmonary uptake of (18)F-FDG assessed with PET has been used to quantify the metabolic activity of inflammatory cells in the lung. This assessment involves modeling of tracer kinetics and knowledge of a time-activity curve in pulmonary artery plasma as an input function, usually acquired by manual blood sampling. This paper presents and validates a method to accurately derive an input function from a blood-pool region of interest (ROI) defined in dynamic PET images. METHODS: The method is based on a 2-parameter model describing the activity of blood and that from spillover into the time-activity curve for the ROI. The model parameters are determined using an iterative algorithm, with 2 blood samples used to calibrate the raw PET-derived activity data. We validated both the 2-parameter model and the method to derive a quantitative input function from ROIs defined for the cavities of the right and left heart and for the descending aorta by comparing them against the time-activity curve obtained by manual blood sampling from the pulmonary artery in lungs with acute inflammation. RESULTS: The model accurately described the time-activity curve from sampled blood. The 2-sample calibration method provided an efficient algorithm to derive input functions that were virtually identical to those sampled manually, including the fast kinetics of the early phase. The (18)F-FDG uptake rates in acutely injured lungs obtained using this method correlated well with those obtained exclusively using manual blood sampling (R(2) > 0.993). Within some bounds, the model was found quite insensitive to the timing of calibration blood samples or the exact definition of the blood-pool ROIs. CONCLUSION: Using 2 mixed venous blood samples, the method accurately assesses the entire time course of the pulmonary (18)F-FDG input function and does not require the precise geometry of a specific blood-pool ROI or a population-based input function. This method may substantially facilitate studies involving modeling of pulmonary (18)F-FDG in patients with viral or bacterial infections, pulmonary fibrosis, and chronic obstructive pulmonary disease.