Brett A. Simon

Characterization of the interstitial lung diseases via density-based and texture-based analysis of computed tomography images of lung structure and function1 ☆

RATIONALE AND OBJECTIVES Efforts to establish a quantitative approach to the computed tomography (CT)-based character ization of the lung parenchyma in interstitial lung disease (including emphysema) has been sought. The accuracy of these tools must be site independent. Multi-detector row CT has remained the gold standard for imaging the lung, and it provides the ability to image both lung structure as well as lung function. MATERIAL AND METHODS Imaging is via multi-detector row CT and protocols include careful control of lung volume during scanning. Characterization includes not only anatomic-based measures but also functional measures including regional parameters derived from measures of pulmonary blood flow and ventilation. Image processing includes the automated detection of the lungs, lobes, and airways. The airways provide the road map to the lung parenchyma. Software automatically detects the airways, the airway centerlines, and the branch points, and then automatically labels the airway tree segments with a standardized set of labels, allowing for intersubject as well intrasubject comparisons across time. By warping all lungs to a common atlas, the atlas provides the range of normality for the various parameters provided by CT imaging. RESULTS Imaged density and textural changes mark underlying structural changes at the most peripheral regions of the lung. Additionally, texture-based alterations in the parameters of blood flow may provide early evidence of pathologic processes. Imaging of stable xenon gas provides a regional measure of ventilation which, when coupled with measures of flow, provide for a textural analysis regional of ventilation-perfusion matching. CONCLUSION With the improved resolution and speed of CT imaging, the patchy nature of regional parenchymal pathology can be imaged as texture of structure and function. With careful control of imaging protocols and the use of objective image analysis methods it is possible to provide site-independent tools for the assessment of interstitial lung disease. There remains a need to validate these methods, which requires interdisciplinary and cross-institutional efforts to gather appropriate data bases of images along with a consensus on appropriate ground truths associated with the images. Furthermore, there is the growing need for scanner manufacturers to focus on not just visually pleasing images, but on quantitatifiably accurate images.

Non-invasive imaging of regional lung function using x-ray computed tomography.

The use of imaging technologies has progressed beyond the depiction of anatomic abnormalities to providing non-invasive regional structure and functional information in intact subjects. These data are particularly valuable in studies of the lung, since lung disease is heterogeneous and significant loss of function may occur before it is detectable by traditional whole lung measurements such as oxygenation, compliance, or spirometry. While many imaging modalities are available, X-ray computed tomography (CT) is emerging as the preferred method for imaging the lung because of its widespread availability, resolution, high signal/noise ratio for lung tissue, and speed. Utilizing the quantitative density and dimensional information available from conventional CT images, it is possible to measure whole and regional lung volumes, distribution of lung aeration and recruitment behavior under various clinical conditions and interventions, and important regional mechanical properties. In addition, using the radiodense gas xenon (Xe) as a contrast agent, regional ventilation or gas transport may also be obtained. This communication will review recent advances in CT based techniques for the measurement of regional lung function.

Tidal volume delivery during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome.

Objective:a) Characterize how ventilator and patient variables affect tidal volume during high-frequency oscillatory ventilation; and b) measure tidal volumes in adults with acute respiratory distress syndrome during high-frequency oscillatory ventilation. Design:Observational study. Setting:Research laboratory and medical intensive care unit. Patients:Test lung and patients with acute respiratory distress syndrome. Interventions:Using a previously validated hot wire anemometer placed in series with a Sensormedics 3100B high-frequency ventilator, an endotracheal tube, and a test lung, tidal volume was measured at different combinations of frequency (4, 6, 8, 10, and 12 Hz), pressure amplitude (50, 60, 70, 80, and 90 cm H2O), mean airway pressure (20, 30, and 40 cm H2O), test lung compliance (10, 30, and 50 mL/cm H2O), endotracheal tube internal diameter (6, 7, and 8 mm), bias flow (20, 30, and 40 L/min), and inspiratory/expiratory ratio (1:2 and 1:1). In patients, tidal volume was measured at baseline ventilator settings and at baseline frequency ±2 Hz and baseline pressure amplitude ±10 cm H2O. Measurements and Main Results:Measured tidal volumes were 23–225 mL during high-frequency oscillatory ventilation of the test lung. A 2-Hz increase in frequency and a 10-cm H2O increase in pressure amplitude caused a 21.3% ± 4.1% decrease and 21.4% ± 3.4% increase in tidal volume, respectively. Decreasing endotracheal tube internal diameter from 8 mm to 7 mm and from 7 mm to 6 mm caused a 15.3% ± 1.7% and 18.9% ± 2.1% reduction in tidal volume, respectively. Increasing bias flow from 20 L/min to 30 L/min increased tidal volume by 11.2% ± 3.9%. Further increases in bias flow, changes in compliance, and changes in mean airway pressure had little effect. Tidal volumes measured in acute respiratory distress syndrome patients were 44–210 mL. A 2-Hz increase in frequency was associated with a 23.1% ± 6.3% decrease in tidal volume. In contrast to the test lung data, a 10-cm H2O increase in pressure amplitude resulted in only a 5.6% ± 4.5% increase in tidal volume. Conclusions:Tidal volumes are not uniformly small during high-frequency oscillatory ventilation. The primary determinant of tidal volume in adults with acute respiratory distress syndrome during high-frequency oscillatory ventilation with the Sensormedics 3100B is frequency. Test lung findings suggest that endotracheal tube internal diameter is also an important determinant of tidal volume.

CT-measured regional specific volume change reflects regional ventilation in supine sheep

Computer tomography (CT) imaging techniques permit the noninvasive measurement of regional lung function. Regional specific volume change (sVol), determined from the change in lung density over a tidal breath, should correlate with regional ventilation and regional lung expansion measured with other techniques. sVol was validated against xenon (Xe)-CT-specific ventilation (sV) in four anesthetized, intubated, mechanically ventilated sheep. Xe-CT used expiratory gated axial scanning during the washin and washout of 55% Xe. sVol was measured from the tidal changes in tissue density (H, houndsfield units) of lung regions using the relationship sVol = [1,000(Hi - He)]/[He(1,000 + Hi)], where He and Hi are expiratory and inspiratory regional density. Distinct anatomical markings were used to define corresponding lung regions of interest between inspiratory, expiratory, and Xe-CT images, with an average region of interest size of 1.6 +/- 0.7 ml. In addition, sVol was compared with regional volume changes measured directly from the positions of implanted metal markers in an additional animal. A linear relationship between sVol and sV was demonstrated over a wide range of regional sV found in the normal supine lung, with an overall correlation coefficient (R(2)) of 0.66. There was a tight correlation (R(2) = 0.97) between marker-measured volume changes and sVol. Regional sVol, which involves significantly reduced exposure to radiation and Xe gas compared with the Xe-CT method, represents a safe and efficient surrogate for measuring regional ventilation in experimental studies and patients.

Molecular Cloning and Characterization of Canine Pre-B-Cell Colony-Enhancing Factor

During our previous attempt to search for the candidate genes to acute lung injury (ALI), we unexpectedly identified PBEF as the most highly upregulated gene in a canine model of ALI by crosshybridizing canine lung cRNA to the Affymetrix human gene chip HG-U133A. The result suggested that PBEF may be a potential biomarker in ALI. To extend and translate that finding, we have performed the molecular cloning and characterization of canine PBEF cDNA in this study. Deduced amino acid sequence alignment revealed that the PBEF gene is evolutionarily highly conserved, with the canine PBEF protein sequence 96% identical to human PBEF and 94% identical to both murine and rat PBEF counterparts. Canine PBEF protein was successfully expressed both by in vitro transcription coupled with translation in a cell-free system and by transfection of canine PBEF cDNA into the human lung type II alveolar adenocarcinoma cell line A549. The expressed canine PBEF protein was visualized by either an anti-V5 tag peptide polyclonal antibody or an anti-canine PBEF peptide polyclonal antibody. RT-PCR assay indicates that canine PBEF is expressed in canine lung, brain, heart, liver, spleen, kidney, pancreas, and muscle, with liver showing the highest expression, followed by muscle. Isolation of the canine PBEF cDNA and expression of its recombinant protein may provide molecular tools to study the molecular mechanism of ALI in the canine model and to elucidate the potential role of PBEF as an ALI biomarker.

Differences in regional wash-in and wash-out time constants for xenon-CT ventilation studies.

UNLABELLED Xenon-enhanced computed tomography (Xe-CT) has been used to measure regional ventilation by determining the wash-in (WI) and wash-out (WO) rates of stable Xe. We tested the common assumption that WI and WO rates are equal by measuring WO-WI in different anatomic lung regions of six anesthetized, supine sheep scanned using multi-detector-row computed tomography (MDCT). We further investigated the effect of tidal volume, image gating (end-expiratory EE versus end-inspiratory EI), local perfusion, and inspired Xe concentration on this phenomenon. RESULTS WO time constant was greater than WI in all lung regions, with the greatest differences observed in dependent base regions. WO-WI time constant difference was greater during EE imaging, smaller tidal volumes, and with higher Xe concentrations. Regional perfusion did not correlate with WI-WO. We conclude that Xe-WI rate can be significantly different from the WO rate, and the data suggest that this effect may be due to a combination of anatomic and fluid mechanical factors such as Rayleigh-Taylor instabilities set up at interfaces between two gases of different densities.

Quantifying mechanical heterogeneity in canine acute lung injury : Impact of mean airway pressure

Background:The heterogeneous pattern of acute lung injury (ALI) predisposes patients to ventilator-associated lung injury. Currently, there is no simple technique that can reliably quantify lung heterogeneity during the dynamic conditions of mechanical ventilation. Such a technique may be of use in optimizing mechanical ventilatory parameters such as rate, tidal volume, or positive end-expiratory pressure. Methods:To determine the impact of heterogeneity on respiratory mechanics, the authors measured respiratory impedance (Zrs), expressed as respiratory resistance (Rrs) and elastance (Ers), in 11 anesthetized dogs from 0.078 to 8.9 Hz using broadband pressure and flow excitations under baseline conditions and after ALI produced by infusion of 0.08 ml/kg oleic acid into the right atrium. Data were obtained at mean airway pressures (&OV0440;ao) of 5, 10, 15, and 20 cm H2O. The Zrs spectra were fit by various models of the respiratory system incorporating different distributions of parallel viscoelastic tissue properties. Results:Under baseline conditions, both Rrs and Ers exhibited dependence on oscillation frequency, reflecting viscoelastic behavior. The Ers demonstrated significant dependence on &OV0440;ao. After ALI, both the level and frequency dependence of Rrs and Ers increased, as well as the apparent heterogeneity of tissue properties. Both Rrs and Ers as well as heterogeneity decreased with increasing &OV0440;ao, approaching baseline levels at the highest levels of &OV0440;ao. Conclusions:These data demonstrate that Zrs can provide specific information regarding the mechanical heterogeneity of injured lungs at different levels of &OV0440;ao. Moderate increases in &OV0440;ao seem to be beneficial in ALI by reducing heterogeneity and recruiting lung units. These noninvasive measurements of lung heterogeneity may ultimately allow for the development of better ventilation protocols that optimize regional lung mechanics in patients with ALI.

Relationship between dynamic respiratory mechanics and disease heterogeneity in sheep lavage injury

Objective:Acute respiratory distress syndrome and acute lung injury are characterized by heterogeneous flooding/collapse of lung tissue. An emerging concept for managing these diseases is to set mechanical ventilation so as to minimize the impact of disease heterogeneity on lung mechanical stress and ventilation distribution. The goal of this study was to determine whether changes in lung mechanical heterogeneity with increasing positive end-expiratory pressure in an animal model of acute lung injury could be detected from the frequency responses of resistance and elastance. Design:Prospective, experimental study. Setting:Research laboratory at a veterinary hospital. Subjects:Female sheep weighing 48 ± 2 kg. Interventions:In five saline-lavaged sheep, we acquired whole-lung computed tomography scans, oxygenation, static elastance, and dynamic respiratory resistance and elastance at end-expiratory pressure levels of 7.5–20 cm H2O. Measurements and Main Results:As end-expiratory pressure increased, computed tomography-determined alveolar recruitment significantly increased but was accompanied by significant alveolar overdistension at 20 cm H2O. An optimal range of end-expiratory pressures (15–17.5 cm H2O) was identified where alveolar recruitment was significantly increased without significant overdistension. This range corresponded to the end-expiratory pressure levels that maximized oxygenation, minimized peak-to-peak ventilation pressures, and minimized indexes reflective of the mechanical heterogeneity (e.g., frequency dependence of respiratory resistance and low-frequency elastance). Static elastance did not demonstrate any significant pressure dependence or reveal an optimal end-expiratory pressure level. Conclusions:We conclude that dynamic mechanics are more sensitive than static mechanics in the assessment of the functional trade-off of recruitment relative to overdistension in a sheep model of lung injury. We anticipate that monitoring of dynamic respiratory resistance and elastance ventilator settings can be used to optimize ventilator management in acute lung injury.

Sphingosine 1-phosphate rescues canine LPS-induced acute lung injury and alters systemic inflammatory cytokine production in vivo.

S1P has been demonstrated to protect against the formation of lipopolysaccharide (LPS)-induced lung edema when administered concomitantly with LPS. In the current study, we sought to determine the effectiveness of S1P to attenuate lung injury in a translationally relevant canine model of ALI when administered as rescue therapy. Secondarily, we examined whether the attenuation of LPS-induced physiologic lung injury after administration of S1P was, at least in part, caused by an alteration in local and/or systemic inflammatory cytokine expression. We examined 18, 1-year-old male beagles prospectively in which we instilled bacterial LPS (2-4 mg/kg) intratracheally followed in 1 h with intravenous S1P (85 microg/kg) or vehicle and 8 h of high-tidal-volume mechanical ventilation. S1P attenuated the formation of Q(s)/Q(t) (32%), and both the presence of protein (72%) and neutrophils (95%) in BAL fluid compared with vehicle controls. Although lung tissue inflammatory cytokine production was found to vary regionally throughout the LPS-injured lung, S1P did not alter the expression pattern. Similarly, BAL cytokine production was not altered significantly by intravenous S1P in this model. Interestingly, S1P potentiated the LPS-induced systemic production of 3 inflammatory cytokines, TNF-alpha (6-fold), KC (1.2-fold), and IL-6 (3-fold), without resulting in end-organ dysfunction. In conclusion, intravenous S1P reduces inflammatory lung injury when administered as rescue therapy in our canine model of LPS-induced ALI. This improvement is observed in the absence of changes in local pulmonary inflammatory cytokine production and an augmentation of systemic inflammation.

Analysis of Regional Mechanics in Canine Lung Injury Using Forced Oscillations and 3D Image Registration

Acute lung injury is characterized by heterogeneity of regional mechanical properties, which is thought to be correlated with disease severity. The feasibility of using respiratory input impedance (Zrs) and computed tomographic (CT) image registration for assessing parenchymal mechanical heterogeneity was evaluated. In six dogs, measurements of Zrs before and after oleic acid injury at various distending pressures were obtained, followed by whole lung CT scans. Each Zrs spectrum was fit with a model incorporating variable distributions of regional compliances. CT image pairs at different inflation pressures were matched using an image registration algorithm, from which distributions of regional compliances from the resulting anatomic deformation fields were computed. Under baseline conditions, average model compliance decreased with increasing inflation pressure, reflecting parenchymal stiffening. After lung injury, these average compliances decreased at each pressure, indicating derecruitment, alveolar flooding, or alterations in intrinsic tissue elastance. However, average compliance did not change as inflation pressure increased, consistent with simultaneous recruitment and strain stiffening. Image registration revealed peaked distributions of regional compliances, and that small portions of the lung might undergo relative compression during inflation. The authors conclude that assessments of lung function using Zrs combined with the structural alterations inferred from image registration provide unique but complementary information on the mechanical derangements associated with lung injury.