Evaluating bronchodilator effects in chronic obstructive pulmonary disease using diffusion-weighted hyperpolarized helium-3 magnetic resonance imaging

The objective of this study was to evaluate the regional effects of bronchodilator administration in chronic obstructive pulmonary disease (COPD) using hyperpolarized helium-3 ((3)He) MRI apparent diffusion coefficient (ADC). Ten COPD ex-smokers provided written, informed consent and underwent diffusion-weighted, hyperpolarized (3)He MRI, spirometry, and plethysmography before and 25 ± 2 min after bronchodilator administration. Pre- and postsalbutamol whole-lung (WL) ADC maps were generated and registered together to identify the lung regions containing the (3)He signal at both time points, and mean ADC within those regions of interest (ROI) was determined for a measurement of previously ventilated ROI ADC (ADC(P)). Lung ROI with (3)He signal at both time points was used as a binary mask on postsalbutamol WL ADC maps to obtain an ADC measurement for newly ventilated ROI (ADC(N)). Postsalbutamol, no significant differences were detected in WL ADC (P = 0.516). There were no significant differences between ADC(N) and ADC(P) postsalbutamol (P = 1.00), suggesting that the ADC(N) lung regions were not more emphysematous than the lung ROI participating in ventilation before bronchodilator administration. Postsalbutamol, a statistically significant decrease in ADC(P) (P = 0.01) was detected, and there were significant differences between ADC(P) in the most anterior and most posterior image slices (P = 0.02), suggesting a reduction in regional gas trapping following bronchodilator administration. Regional evaluation of tissue microstructure using hyperpolarized (3)He MRI ADC provides insights into lung alterations that accompany improvements in regional (3)He gas distribution after bronchodilator administration.     

Imaging alveolar-duct geometry during expiration via ³He lung morphometry

Acinar geometry has been the subject of several morphological and imaging studies in the past; however, surprisingly little is known about how the acinar microstructure changes when the lung inflates or deflates. Lung morphometry with hyperpolarized (3)He diffusion MRI allows non-destructive evaluation of lung microstructure and acinar geometry, which has important applications in understanding basic lung physiology and disease. In this study, we have measured the alveolar and acinar duct sizes at physiologically relevant volumes by (3)He lung morphometry in six normal, excised, and unfixed canine lungs. Our results imply that, during a 37% decrease in lung volume, the acinar duct radius decreases by 19%, whereas the alveolar depth increases by 9% (P < 0.0001 and P < 0.05, respectively via paired t-tests with a Bonferroni correction). A comparison to serial sections under the microscope validates the imaging results and opens the door to in vivo human studies of lung acinar geometry and physiology during respiration using (3)He lung morphometry.     

Evaluation of emphysema severity and progression in a rabbit model: comparison of hyperpolarized 3He and 129Xe diffusion MRI with lung morphometry.

The apparent diffusion coefficients (ADCs) of hyperpolarized (3)He and (129)Xe gases were measured in the lungs of rabbits with elastase-induced emphysema and correlated against the mean chord length from lung histology. In vivo measurements were performed at baseline and 2, 4, 6, and 8 wk after instillation of elastase (mild and moderate emphysema groups) or saline (control group). ADCs were determined from acquisitions that used two b values. To investigate the effect of b value on the results, b-value pairs of 0 and 1.6 s/cm(2) and 0 and 4.0 s/cm(2) were used for (3)He, and b-value pairs of 0 and 5.0 s/cm(2) and 0 and 10.0 s/cm(2) were used for (129)Xe. At 8 wk after instillation, the rabbits were euthanized, and the lungs were analyzed histologically and morphometrically. ADCs for the rabbits in the control group did not change significantly from baseline to week 8, whereas ADCs for the rabbits in the emphysema groups increased significantly (P < 0.05) for all gas and b-value combinations except (129)Xe with the b-value pair of 0 and 5.0 s/cm(2). The largest percent change in mean ADC from baseline to week 8 (15.3%) occurred with (3)He and the b-value pair of 0 and 1.6 s/cm(2) for rabbits in the moderate emphysema group. ADCs (all b values) were strongly correlated (r = 0.62-0.80, P < 0.001) with mean chord lengths from histology. These results further support the ability of diffusion-weighted MRI with hyperpolarized gases to detect regional and global structural changes of emphysema within the lung.     

Magnetic resonance assessment of parenchymal elasticity in normal and edematous, ventilator-injured lung

Magnetic resonance elastography (MRE) is a MR imaging method capable of spatially resolving the intrinsic mechanical properties of normal lung parenchyma. We tested the hypothesis that the mechanical properties of edematous lung exhibit local properties similar to those of a fluid-filled lung at transpulmonary pressures (P(tp)) up to 25 cm H(2)O. Pulmonary edema was induced in anesthetized female adult Sprague-Dawley rats by mechanical ventilation to a pressure of 40 cm H(2)O for ～30 min. Prior to imaging the wet weight of each ex vivo lung set was measured. MRE, high-resolution T(1)-weighted spin echo and T(2)* gradient echo data were acquired at each P(tp) for both normal and injured ex vivo lungs. At P(tp)s of 6 cm H(2)O and greater, the shear stiffness of normal lungs was greater than injured lungs (P ≤ 0.0003). For P(tp)s up to 12 cm H(2)O, shear stiffness was equal to 1.00, 1.07, 1.16, and 1.26 kPa for the injured and 1.31, 1.89, 2.41, and 2.93 kPa for normal lungs at 3, 6, 9, and 12 cm H(2)O, respectively. For injured lungs MRE magnitude signal and shear stiffness within regions of differing degrees of alveolar flooding were calculated as a function of P(tp). Differences in shear stiffness were statistically significant between groups (P < 0.001) with regions of lower magnitude signal being stiffer than those of higher signal. These data demonstrate that when the alveolar space filling material is fluid, MRE-derived parenchymal shear stiffness of the lung decreases, and the lung becomes inherently softer compared with normal lung.     

Synthesis and characterization of a new bioactivated paramagnetic gadolinium(III) complex [Gd(DOTA-FPG)(H2O)] for tracing gene expression

A smart contrast agent for magnetic resonance imaging (MRI) can be used to exploit an enzymatic activity specific to the tissue or disease state signified by converting an MRI-inactivated agent to an activated MRI agent. In this study, a beta-galactopyranose-containing gadolinium(III) complex [Gd(DOTA-FPG)(H 2O)] was designed, synthesized, and characterized as being potentially suitable for a bioactivated MRI contrast agent. The (17)O NMR experiments were conducted to estimate the water exchange rate k e x 298 and rotational correlation time tau R 298 . The k ex 298 value of [Gd(DOTA-FPG)(H 2O)] is similar to that of [Gd(DO3A-bz-NO 2)(H 2O)]. The rotational correlation time value of [Gd(DOTA-FPG)(H 2O)] is dramatically longer than that of [Gd(DOTA)(H 2O)] (-) Relaxometric studies show that the percentage change in the T 1 value of [Gd(DOTA-FPG)(H 2O)] decreases dramatically in the presence of beta-galactosidase and human serum albumin. The T(1) change percentage of [Gd(DOTA-FPG)(H 2O)] (60%) is significantly higher than those of Egad and gadolinium(III)-1-(4-(2-(1-(4,7,10-triscarboxymethyl-(1,4,7,10-tetraazacyclododecyl)))-ethylcarbamoyloxymethyl)-2-nitrophenyl)-beta- d-glucopyronuronate. The signal intensity of the MR image for [Gd(DOTA-FPG)(H 2O)] in the presence of human serum albumin and beta-galactosidase (2670 +/- 210) is significantly higher than that of [Gd(DOTA-FPG)(H 2O)] in the sodium phosphate buffer solution (1490 +/- 160). In addition, the MR images show a higher-intensity enhancement in CT26/beta-gal tumor with beta-galactosidase gene expression but not for the CT26 tumor without beta-galactosidase gene expression. We conclude that [Gd(DOTA-FPG)(H 2O)] is a suitable candidate for a bioactivated MRI contrast agent in tracing gene expression.     

Ventilation distribution in rats: Part 2 -- A comparison of electrical impedance tomography and hyperpolarised helium magnetic resonance imaging

ABSTRACT: BACKGROUND: Hyperpolarised helium MRI (He3 MRI) is a new technique that enables imaging of the air distribution within the lungs. This allows accurate determination of the ventilation distribution in vivo. The technique has the disadvantages of requiring an expensive helium isotope, complex apparatus and moving the patient to a compatible MRI scanner. Electrical impedance tomography (EIT) a non-invasive bedside technique that allows constant monitoring of lung impedance, which is dependent on changes in air space capacity in the lung. We have used He3MRI measurements of ventilation distribution as the gold standard for assessment of EIT. METHODS: Seven rats were ventilated in supine, prone, left and right lateral position with 70% helium/30% oxygen for EIT measurements and pure helium for He3 MRI. The same ventilator and settings were used for both measurements. Image dimensions, geometric centre and global in homogeneity index were calculated. RESULTS: EIT images were smaller and of lower resolution and contained less anatomical detail than those from He3 MRI. However, both methods could measure positional induced changes in lung ventilation, as assessed by the geometric centre. The global in homogeneity index were comparable between the techniques. CONCLUSION: EIT is a suitable technique for monitoring ventilation distribution and inhomgeneity as assessed by comparison with He3 MRI.     

Influence of vascular distending pressure on regional flows in isolated perfused dog lungs

To confirm the regional differences in vascular pressure vs. flow properties of lung regions that have been documented in zone 2 conditions [pulmonary venous pressure (Ppv) less than alveolar pressure], regional distending pressure vs. flow curves in zone 3 were generated by use of isolated blood-perfused dog lungs (3 right and 5 left lungs). Each lung was kept inflated at constant inflation pressure (approximately 50% of full inflation volume) while radioactively labeled microspheres were injected at different settings of Ppv. To achieve maximal vascular distension, Ppv was increased to approximately 30 cmH2O above alveolar pressure for the first injection. Subsequent injections were made at successively lower Ppv's. The difference between pulmonary arterial pressure and Ppv was kept constant for all injections. As was found in zone 2 conditions, there were differences in the regional distending pressure vs. flow curves among lung regions. To document the regional variability in the curves, the distribution of flow at a regional Ppv of 30 cmH2O above alveolar pressure was analyzed. There was a statistically significant linear gradient in this flow distribution from dorsal to ventral regions of the lungs but no consistent gradient in the caudad to cephalad direction. These results indicate that, even in near-maximally distended vessels, the dorsal regions of isolated perfused dog lungs have lower intrinsic vascular resistance compared with ventral regions.     

Mapping and quantifying hyperpolarized 3He magnetic resonance imaging apparent diffusion coefficient gradients.

We measured hyperpolarized 3He magnetic resonance imaging (MRI) apparent diffusion coefficients (ADC) and quantified ADC gradients in each three-by-three voxel region of interest (ROI). Such local ADC gradients can be represented in vector maps showing the magnitude (|G3x3|) and direction of ADC gradients, providing a qualitative visualization tool and quantitative measurement of airway and air space heterogeneity. Twenty-four subjects (15 male, mean age=67+/-7 yr) with global initiative for chronic obstructive lung disease (GOLD) stage II (n=9, mean age 68+/-6 yr), GOLD stage III chronic obstructive pulmonary disease (COPD; n=7, mean age 67+/-8 yr), and age-matched healthy volunteers (n=8, mean age 67+/-6 yr) were enrolled based on their age and spirometry results. Hyperpolarized 3He MRI was performed on a whole body 3.0 Tesla system. Mean 3He ADC and ADC standard deviation were calculated for the center coronal slice, and the mean magnitude and direction of the ADC gradient vectors were calculated for each three-by-three voxel matrix (|G3x3|). While the 3He ADC standard deviation was not significantly different, mean |G3x3| was significantly different between subjects with stage II (0.14+/-0.03 cm/s) and stage III COPD (0.19+/-0.03 cm/s; P<0.005) and between healthy subjects (0.12+/-0.03 cm/s) and those with stage II COPD (P<0.02). The second order statistic |G3x3| may provide a sensitive measure of ADC heterogeneity for ROI representing 9.4x9.4x30 mm or 2.6 cm3 of lung tissue.     

In vivo lung morphometry with hyperpolarized 3He diffusion MRI in canines with induced emphysema: disease progression and comparison with computed tomography.

Despite a long history of development, diagnostic tools for in vivo regional assessment of lungs in patients with pulmonary emphysema are not yet readily available. Recently, a new imaging technique, in vivo lung morphometry, was introduced by our group. This technique is based on MRI measurements of diffusion of hyperpolarized (3)He gas in lung air spaces and provides quantitative in vivo tomographic information on lung microstructure at the level of the acinar airways. Compared with standard diffusivity measurements that strongly depend on pulse sequence parameters (mainly diffusion time), our approach evaluates a "hard number," the average acinar airway radius. For healthy dogs, we find here a mean acinar airway radius of approximately 0.3 mm compared with 0.36 mm in healthy humans. The purpose of the present study is the application of this technique for quantification of emphysema progression in dogs with experimentally induced disease. The diffusivity measurements and resulting acinar airway geometrical characteristics were correlated with the local lung density and local lung-specific air volume calculated from quantitative computed tomography data obtained on the same dogs. The results establish an important association between the two modalities. The observed sensitivity of our method to emphysema progression suggests that this technique has potential for the diagnosis of emphysema and tracking of disease progression or improvement via a pharmaceutical intervention.     

Mechanical strain promotes osteoblast ECM formation and improves its osteoinductive potential

Background

Hyperpolarised helium MRI (He3 MRI) is a new technique that enables imaging of the air distribution within the lungs. This allows accurate determination of the ventilation distribution in vivo. The technique has the disadvantages of requiring an expensive helium isotope, complex apparatus and moving the patient to a compatible MRI scanner. Electrical impedance tomography (EIT) a non-invasive bedside technique that allows constant monitoring of lung impedance, which is dependent on changes in air space capacity in the lung. We have used He3MRI measurements of ventilation distribution as the gold standard for assessment of EIT.

Methods

Seven rats were ventilated in supine, prone, left and right lateral position with 70% helium/30% oxygen for EIT measurements and pure helium for He3 MRI. The same ventilator and settings were used for both measurements. Image dimensions, geometric centre and global in homogeneity index were calculated.

Results

EIT images were smaller and of lower resolution and contained less anatomical detail than those from He3 MRI. However, both methods could measure positional induced changes in lung ventilation, as assessed by the geometric centre. The global in homogeneity index were comparable between the techniques.

Conclusion

EIT is a suitable technique for monitoring ventilation distribution and inhomgeneity as assessed by comparison with He3 MRI.     

Long-range diffusion of hyperpolarized 3He in explanted normal and emphysematous human lungs via magnetization tagging.

Long-range diffusivity of hyperpolarized 3He gas was measured from the decay rate of sinusoidally modulated longitudinal nuclear magnetization in three normal donor and nine severely emphysematous explanted human lungs. This (long-range) diffusivity, which we call Dsec, is measured over seconds and centimeters and is approximately 10 times smaller in healthy lungs (0.022 cm2/s) than the more traditionally measured Dmsec, which is measured over milliseconds and submillimeters. The increased restriction of Dsec reflects the complex, tortuous paths required to navigate long distances through the maze of branching peripheral airways. In emphysematous lungs, Dsec is substantially increased, with some regions showing nearly the unrestricted value of the self-diffusion coefficient (0.88 cm2/s for dilute 3He in air, a 40-fold increase). This suggests the presence of large collateral pathways opened by alveolar destruction that bypass the airways proper. This destruction was confirmed by comparison with histology in seven lungs and by removal of trapped gas via holes in the pleural surface in five lungs.     

3He MRI-based assessment of posture-dependent regional ventilation gradients in rats.

A recently developed method for quantitative assessment of regional lung ventilation was employed for the study of posture-dependent ventilation differences in rats. The measurement employed hyperpolarized (3)He MRI to detect the build-up of the signal intensity after increasing numbers of (3)He breaths, which allowed for computation of a regional ventilation parameter. A group of six anesthetized rats was studied in both supine and prone postures. Three-dimensional maps of the ventilation parameter were obtained with high spatial resolution (voxel volume approximately 2 mm(3)). Vertical (dorsal-ventral) gradients of the ventilation index, defined as the regional ventilation normalized by the average ventilation within the whole lung, were investigated. Variations in the regional distribution of the ventilation parameter, as well as of the ventilation index, could be detected, depending on the posture of the rats. In supine posture, ventilation was elevated in the dependent parts of the lungs, with a linear gradient of the ventilation index of -0.11 +/- 0.03 cm(-1). In prone posture, the distribution of ventilation was more uniform, with a significantly (P < 0.001) smaller gradient of the ventilation index of -0.01 +/- 0.02 cm(-1). It is concluded that the (3)He MRI-based method can detect and quantify regional ventilation gradients in animals as small as the rat and that these gradients depend on prone or supine posture of the animal.     

Regional correlation of emphysematous changes in lung function and structure: a comparison between pulmonary function testing and hyperpolarized MRI metrics

Regional and global relationships of lung function and structure were studied using hyperpolarized 3He MRI in a rat elastase-induced model of emphysema (n = 4) and healthy controls (n = 5). Fractional ventilation (r) and apparent diffusion coefficient (ADC) of 3He were measured at a submillimeter planar resolution in ventral, middle, and dorsal slices 6 mo after model induction. Pulmonary function testing (PFT) was performed before MRI to yield forced expiratory volume in 50 ms (FEV??), airway resistance (R(I)), and dynamic compliance (C(dyn)). Cutoff threshold values of ventilation and diffusion, r* and ADC*, were computed corresponding to 80% population of pixels falling above or below each threshold value, respectively. For correlation analysis, r* was compared with FEV??/functional residual capacity (FRC), R(I) and C(dyn), whereas ADC* was compared with FEV??/FRC, total lung capacity (TLC), and C(dyn). Regional correlation of r and ADC was evaluated by dividing each of the three lung slices into four quadrants. C(dyn) was significantly larger in elastase rats (0.92 ± 0.16 vs. 0.61 ± 0.12 ml/cmH?O). The difference of R(I) and FEV?? was insignificant between the two groups. The r* of healthy rats was significantly larger than the elastase group (0.42 ± 0.03 vs. 0.28 ± 0.06), whereas ADC* was significantly smaller in healthy animals (0.27 ± 0.04 vs. 0.36 ± 0.01 cm2/s). No systematic difference in these quantities was observed between the three lung slices. A significant 33% increase in ADC* and a significant 31% decline in r* for elastase rats was observed compared with a significant 51% increase in C(dyn) and a nonsignificant 26% decline in FEV??/FRC. Correlation of imaging and PFT metrics revealed that r and ADC divide the rats into two separate clusters in the sample space.     

Mechanical properties of small airways in excised pony lungs.

We evaluated the pressure-flow relationships in collaterally ventilating segments of excised pony lungs by infusing N2, He, Ne, or SF6 at known flows (V) through a catheter wedged in a peripheral airway. Measurements were made at segment- (Ps) to-airway opening (Pao) pressure differentials of 3-15 cmH2O when the lungs were held at transpulmonary pressures of 5, 10, and 15 cmH2O. The data were analyzed both by calculating collateral resistance (Ps-Pao/V) and by constructing Moody-type plots of normalized pressure drop [(Ps-Pao)/(1/2 rho U2, where rho is density and U is velocity)] against Reynolds number to assess the pattern of flow through the segment and the change in dimension of the flow channels as Ps and Pao were changed. The interpretations from these analyses were compared with radiographic measurements of the diameters of small airways within the collaterally ventilating lung segment at similar pressures. Collateral resistance increased as Ps-Pao increased at high Reynolds numbers, i.e., high flows or dense gas (SF6). Analysis of the Moody-type plots revealed that flow was density dependent at Reynolds number greater than 100, which frequently occurred when N2 was the inflow gas. The radiographic data revealed that small airway diameter increased as Ps-Pao increased at all lung volumes. In addition, at 5 cmH2O Pao, small-airway diameter was smaller for a given Ps in the nonhomogeneous case (Ps greater than Pao) than small-airway diameter for the same Ps in the homogeneous case (Ps = Pao). We interpret these data to suggest that the surrounding lung prevented the segment from expanding in the nonhomogeneous case.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperpolarized 129Xe MR Imaging of Alveolar Gas Uptake in Humans

Background

One of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange.

Methods and Principal Findings

Here we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) ¹²⁹Xe to probe the regional uptake of alveolar gases by directly imaging HP ¹²⁹Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP ¹²⁹Xe magnetization is rapidly replenished by diffusive exchange with alveolar ¹²⁹Xe. The dissolved HP ¹²⁹Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs.

Conclusions

The features observed in dissolved-phase ¹²⁹Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP ¹²⁹Xe imaging reports on pulmonary function at a fundamental level.     

Effect of increases in lung volume on clearance of aerosolized solute from human lungs

To study the effect of increases in lung volume on solute uptake, we measured clearance of 99mTc-diethylenetriaminepentaacetic acid (Tc-DTPA) at different lung volumes in 19 healthy humans. Seven subjects inhaled aerosol (1 micron activity median aerodynamic diam) at ambient pressure; clearance and functional residual capacity (FRC) were measured at ambient pressure (control) and at increased lung volume produced by positive pressure [12 cmH2O continuous positive airway pressure (CPAP)] or negative pressure (voluntary breathing). Six different subjects inhaled aerosol at ambient pressure; clearance and FRC were measured at ambient pressure and CPAP of 6, 12, and 18 cmH2O pressure. Six additional subjects inhaled aerosol at ambient pressure or at CPAP of 12 cmH2O; clearance and FRC were determined at CPAP of 12 cmH2O. According to the results, Tc-DTPA clearance from human lungs is accelerated exponentially by increases in lung volume, this effect occurs whether lung volume is increased by positive or negative pressure breathing, and the effect is the same whether lung volume is increased during or after aerosol administration. The effect of lung volume must be recognized when interpreting the results of this method.     

Effect of increased surface tension and assisted ventilation on 99mTc-DTPA clearance

Experiments were performed to determine the effects of conventional mechanical ventilation (CMV) and high-frequency oscillation (HFO) on the clearance of technetium-99m-labeled diethylenetriamine pentaacetate (99mTc-DTPA) from lungs with altered surface tension properties. A submicronic aerosol of 99mTc-DTPA was insufflated into the lungs of anesthetized, tracheotomized rabbits before and 1 h after the administration of the aerosolized detergent dioctyl sodium sulfosuccinate (OT). Rabbits were ventilated by one of four methods: 1) spontaneous breathing; 2) CMV at 12 cmH2O mean airway pressure (MAP); 3) HFO at 12 cmH2O MAP; 4) HFO at 16 cmH2O MAP. Administration of OT resulted in decreased arterial PO2 (PaO2), increased lung wet-to-dry weight ratios, and abnormal lung pressure-volume relationships, compatible with increased surface tension. 99mTc-DTPA clearance was accelerated after OT in all groups. The post-OT rate of clearance (k) was significantly faster (P less than 0.05) in the CMV at 12 cmH2O MAP [k = 7.57 +/- 0.71%/min (SE)] and HFO at 16 cmH2O MAP (k = 6.92 +/- 0.61%/min) groups than in the spontaneously breathing (k = 4.32 +/- 0.55%/min) and HFO at 12 cmH2O MAP (4.68 +/- 0.63%/min) groups. The clearance curves were biexponential in the former two groups. We conclude that pulmonary clearance of 99mTc-DTPA is accelerated in high surface tension pulmonary edema, and this effect is enhanced by both conventional ventilation and HFO at high mean airway pressure.     

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.     

Cardiogenic oscillations in He and SF6 expirograms during airway and venous loading

Cardiogenic oscillations in the expired partial pressure profiles of two inert gases (He and SF6) were monitored in seven anesthetized paralyzed mechanically ventilated dogs. He and SF6 were administered either intravenously by a membrane oxygenator and partial arteriovenous bypass [venous loading (VL)] or by washin into lung gas [airway loading (AL)]. The single-breath expirograms obtained during constant-flow expiration after inspiration of test gas-free air displayed distinct and regular cardiogenic oscillations. The relative oscillation amplitude (ROA), calculated as oscillation amplitude divided by mixed expired-inspired partial pressure difference, was in the range of 1-8%. The ROA for both He and SF6 was approximately 4.2 times higher in VL than in AL, which indicated that among lung units that emptied sequentially in the cardiac cycle, the effects of alveolar ventilation-perfusion (VA/Q) inequality were more pronounced than those of alveolar ventilation-alveolar volume (VA/VA) inequality. In AL, He and SF6 oscillations were 180 degrees out of phase compared with CO2 and O2 oscillations and with He and SF6 oscillations in VL, which suggests that regions with low VA/VA had high VA/Q and very low Q/VA. The ROA was practically unaffected by breath holding in both AL and VL, which indicates that there was little diffusive or convective (cardiogenic) mixing between the lung units that were responsible for cardiogenic oscillations. The ROA was consistently higher for He than for SF6, and the He-to-SF6 ratio was independent of route of test gas loading, averaging 1.6 in both AL and VL. This result may be explained by laminar Taylor dispersion, whereby oscillations generated in peripheral lung regions are dissipated in inverse proportion to diffusion coefficient during transit through the proximal (larger) airways.     

Elastic moduli of lungs during postnatal development in the piglet

Several manifestations of lung disease during infancy suggest that mechanical interdependence can be relatively high in newborn lungs. To test this possibility, we measured elastic moduli and pleural membrane tension in lungs excised from piglets ranging in age from less than 12 h to 85 days. Near maximum inflation, newborn lungs (less than 12 h, n = 6) had no detectable pleural membrane tension, although 3- to 5-day-old lungs (n = 6) had tension greater than 5,000 dyn/cm. In contrast, parenchymal recoil was greater in the newborn lungs [19.3 +/- 3.0 (SD) vs. 14.3 +/- 2.4 cmH2O at 90% of maximum inflation volume, P less than 0.01]. Shear moduli were higher (13.5 +/- 4.6 vs. 9.2 +/- 1.5 cmH2O at 15 cmH2O transpulmonary pressure, P less than 0.05) and Poisson ratios were lower in the newborn lungs as compared with the 3- to 5-day-old lungs. Postnatal lung growth between 3 and 85 days was characterized by 1) a constant shear modulus (0.6 times transpulmonary pressure); 2) decrease in the bulk modulus (from 6.8 to 5.1 times transpulmonary pressure, P less than 0.005); and 3) evidence of gas trapping at progressively higher transpulmonary pressures. Therefore, growth of parenchyma in the piglet lung is associated with reduced stiffness to volume change but with no effect on overall stiffness to shape change. Nevertheless, a relatively great stiffness to shape change occurs transiently in newborn piglet lungs.