Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: comparison with the multiple inert-gas elimination technique.

We have developed a novel functional proton magnetic resonance imaging (MRI) technique to measure regional ventilation-perfusion (V̇A/Q̇) ratio in the lung. We conducted a comparison study of this technique in healthy subjects (n = 7, age = 42 ± 16 yr, Forced expiratory volume in 1 s = 94% predicted), by comparing data measured using MRI to that obtained from the multiple inert gas elimination technique (MIGET). Regional ventilation measured in a sagittal lung slice using Specific Ventilation Imaging was combined with proton density measured using a fast gradient-echo sequence to calculate regional alveolar ventilation, registered with perfusion images acquired using arterial spin labeling, and divided on a voxel-by-voxel basis to obtain regional V̇A/Q̇ ratio. LogSDV̇ and LogSDQ̇, measures of heterogeneity derived from the standard deviation (log scale) of the ventilation and perfusion vs. V̇A/Q̇ ratio histograms respectively, were calculated. On a separate day, subjects underwent study with MIGET and LogSDV̇ and LogSDQ̇ were calculated from MIGET data using the 50-compartment model. MIGET LogSDV̇ and LogSDQ̇ were normal in all subjects. LogSDQ̇ was highly correlated between MRI and MIGET (R = 0.89, P = 0.007); the intercept was not significantly different from zero (-0.062, P = 0.65) and the slope did not significantly differ from identity (1.29, P = 0.34). MIGET and MRI measures of LogSDV̇ were well correlated (R = 0.83, P = 0.02); the intercept differed from zero (0.20, P = 0.04) and the slope deviated from the line of identity (0.52, P = 0.01). We conclude that in normal subjects, there is a reasonable agreement between MIGET measures of heterogeneity and those from proton MRI measured in a single slice of lung.NEW & NOTEWORTHY We report a comparison of a new proton MRI technique to measure regional V̇A/Q̇ ratio against the multiple inert gas elimination technique (MIGET). The study reports good relationships between measures of heterogeneity derived from MIGET and those derived from MRI. Although currently limited to a single slice acquisition, these data suggest that single sagittal slice measures of V̇A/Q̇ ratio provide an adequate means to assess heterogeneity in the normal lung.

The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung.

The gravitational gradient of intrapleural pressure is suggested to be less in prone posture than supine. Thus the gravitational distribution of ventilation is expected to be more uniform prone, potentially affecting regional ventilation-perfusion (Va/Q) ratio. Using a novel functional lung magnetic resonance imaging technique to measure regional Va/Q ratio, the gravitational gradients in proton density, ventilation, perfusion, and Va/Q ratio were measured in prone and supine posture. Data were acquired in seven healthy subjects in a single sagittal slice of the right lung at functional residual capacity. Regional specific ventilation images quantified using specific ventilation imaging and proton density images obtained using a fast gradient-echo sequence were registered and smoothed to calculate regional alveolar ventilation. Perfusion was measured using arterial spin labeling. Ventilation (ml·min(-1)·ml(-1)) images were combined on a voxel-by-voxel basis with smoothed perfusion (ml·min(-1)·ml(-1)) images to obtain regional Va/Q ratio. Data were averaged for voxels within 1-cm gravitational planes, starting from the most gravitationally dependent lung. The slope of the relationship between alveolar ventilation and vertical height was less prone than supine (-0.17 ± 0.10 ml·min(-1)·ml(-1)·cm(-1) supine, -0.040 ± 0.03 prone ml·min(-1)·ml(-1)·cm(-1), P = 0.02) as was the slope of the perfusion-height relationship (-0.14 ± 0.05 ml·min(-1)·ml(-1)·cm(-1) supine, -0.08 ± 0.09 prone ml·min(-1)·ml(-1)·cm(-1), P = 0.02). There was a significant gravitational gradient in Va/Q ratio in both postures (P < 0.05) that was less in prone (0.09 ± 0.08 cm(-1) supine, 0.04 ± 0.03 cm(-1) prone, P = 0.04). The gravitational gradients in ventilation, perfusion, and regional Va/Q ratio were greater supine than prone, suggesting an interplay between thoracic cavity configuration, airway and vascular tree anatomy, and the effects of gravity on Va/Q matching.

Magnetic resonance imaging quantification of pulmonary perfusion using calibrated arterial spin labeling.

UNLABELLED: This demonstrates a MR imaging method to measure the spatial distribution of pulmonary blood flow in healthy subjects during normoxia (inspired O(2), fraction (F(I)O(2)) = 0.21) hypoxia (F(I)O(2) = 0.125), and hyperoxia (F(I)O(2) = 1.00). In addition, the physiological responses of the subject are monitored in the MR scan environment. MR images were obtained on a 1.5 T GE MRI scanner during a breath hold from a sagittal slice in the right lung at functional residual capacity. An arterial spin labeling sequence (ASL-FAIRER) was used to measure the spatial distribution of pulmonary blood flow and a multi-echo fast gradient echo (mGRE) sequence was used to quantify the regional proton (i.e. H(2)O) density, allowing the quantification of density-normalized perfusion for each voxel (milliliters blood per minute per gram lung tissue). With a pneumatic switching valve and facemask equipped with a 2-way non-rebreathing valve, different oxygen concentrations were introduced to the subject in the MR scanner through the inspired gas tubing. A metabolic cart collected expiratory gas via expiratory tubing. Mixed expiratory O(2) and CO(2) concentrations, oxygen consumption, carbon dioxide production, respiratory exchange ratio, respiratory frequency and tidal volume were measured. Heart rate and oxygen saturation were monitored using pulse-oximetry. Data obtained from a normal subject showed that, as expected, heart rate was higher in hypoxia (60 bpm) than during normoxia (51) or hyperoxia (50) and the arterial oxygen saturation (SpO(2)) was reduced during hypoxia to 86%. Mean ventilation was 8.31 L/min BTPS during hypoxia, 7.04 L/min during normoxia, and 6.64 L/min during hyperoxia. Tidal volume was 0.76 L during hypoxia, 0.69 L during normoxia, and 0.67 L during hyperoxia. Representative quantified ASL data showed that the mean density normalized perfusion was 8.86 ml/min/g during hypoxia, 8.26 ml/min/g during normoxia and 8.46 ml/min/g during hyperoxia, respectively. In this subject, the relative dispersion, an index of global heterogeneity, was increased in hypoxia (1.07 during hypoxia, 0.85 during normoxia, and 0.87 during hyperoxia) while the fractal dimension (Ds), another index of heterogeneity reflecting vascular branching structure, was unchanged (1.24 during hypoxia, 1.26 during normoxia, and 1.26 during hyperoxia). Overview. This protocol will demonstrate the acquisition of data to measure the distribution of pulmonary perfusion noninvasively under conditions of normoxia, hypoxia, and hyperoxia using a magnetic resonance imaging technique known as arterial spin labeling (ASL). RATIONALE: Measurement of pulmonary blood flow and lung proton density using MR technique offers high spatial resolution images which can be quantified and the ability to perform repeated measurements under several different physiological conditions. In human studies, PET, SPECT, and CT are commonly used as the alternative techniques. However, these techniques involve exposure to ionizing radiation, and thus are not suitable for repeated measurements in human subjects.

Lung volume does not alter the distribution of pulmonary perfusion in dependent lung in supine humans.

There is a gravitational influence on pulmonary perfusion, including in the most dependent lung, where perfusion is reduced, termed Zone 4. Studies using xenon-133 show Zone 4 behaviour, present in the dependent 4 cm at total lung capacity (TLC), affects the dependent 11 cm at functional residual capacity (FRC) and almost all the lung at residual volume (RV). These differences were ascribed to increased resistance in extra-alveolar vessels at low lung volumes although other mechanisms have been proposed. To further evaluate the behaviour of perfusion in dependent lung using a technique that directly measures pulmonary perfusion and corrects for tissue distribution by measuring regional proton density, seven healthy subjects (age = 38 ± 6 years, FEV1 = 104 ± 7% predicted) underwent magnetic resonance imaging in supine posture. Data were acquired in the right lung during breath-holds at RV, FRC and TLC. Arterial spin labelling quantified regional pulmonary perfusion, which was normalized for regional proton density measured using a fast low-angle shot technique. The height of the onset of Zone 4 behaviour was not different between lung volumes (P = 0.23). There were no significant differences in perfusion (expressed as ml min⁻¹ g⁻¹) between lung volumes in the gravitationally intermediate (RV = 8.9 ± 3.1, FRC = 8.1 ± 2.9, TLC = 7.4 ± 3.6; P = 0.26) and dependent lung (RV = 6.6 ± 2.4, FRC = 6.1 ± 2.1, TLC = 6.4 ± 2.6; P = 0.51). However, at TLC perfusion was significantly lower in non-dependent lung than at FRC or RV (3.6 ± 3.3, 7.7 ± 1.5, 7.9 ± 2.0, respectively; P < 0.001). These data suggest that the mechanism of the reduction in perfusion in dependent lung is unlikely to be a result of lung volume related increases in resistance in extra-alveolar vessels. In supine posture, the gravitational influence on perfusion is remarkably similar over most of the lung, irrespective of lung volume.

Vertical distribution of specific ventilation in normal supine humans measured by oxygen-enhanced proton MRI.

Specific ventilation (SV) is the ratio of fresh gas entering a lung region divided by its end-expiratory volume. To quantify the vertical (gravitationally dependent) gradient of SV in eight healthy supine subjects, we implemented a novel proton magnetic resonance imaging (MRI) method. Oxygen is used as a contrast agent, which in solution changes the longitudinal relaxation time (T1) in lung tissue. Thus alterations in the MR signal resulting from the regional rise in O(2) concentration following a sudden change in inspired O(2) reflect SV-lung units with higher SV reach a new equilibrium faster than those with lower SV. We acquired T1-weighted inversion recovery images of a sagittal slice of the supine right lung with a 1.5-T MRI system. Images were voluntarily respiratory gated at functional residual capacity; 20 images were acquired with the subject breathing air and 20 breathing 100% O(2), and this cycle was repeated five times. Expired tidal volume was measured simultaneously. The SV maps presented an average spatial fractal dimension of 1.13 ± 0.03. There was a vertical gradient in SV of 0.029 ± 0.012 cm(-1), with SV being highest in the dependent lung. Dividing the lung vertically into thirds showed a statistically significant difference in SV, with SV of 0.42 ± 0.14 (mean ± SD), 0.29 ± 0.10, and 0.24 ± 0.08 in the dependent, intermediate, and nondependent regions, respectively (all differences, P < 0.05). This vertical gradient in SV is consistent with the known gravitationally induced deformation of the lung resulting in greater lung expansion in the dependent lung with inspiration. This SV imaging technique can be used to quantify regional SV in the lung with proton MRI.

Characterizing pulmonary blood flow distribution measured using arterial spin labeling.

The arterial spin labeling (ASL) method provides images in which, ideally, the signal intensity of each image voxel is proportional to the local perfusion. For studies of pulmonary perfusion, the relative dispersion (RD, standard deviation/mean) of the ASL signal across a lung section is used as a reliable measure of flow heterogeneity. However, the RD of the ASL signals within the lung may systematically differ from the true RD of perfusion because the ASL image also includes signals from larger vessels, which can reflect the blood volume rather than blood flow if the vessels are filled with tagged blood during the imaging time. Theoretical studies suggest that the pulmonary vasculature exhibits a lognormal distribution for blood flow and thus an appropriate measure of heterogeneity is the geometric standard deviation (GSD). To test whether the ASL signal exhibits a lognormal distribution for pulmonary blood flow, determine whether larger vessels play an important role in the distribution, and extract physiologically relevant measures of heterogeneity from the ASL signal, we quantified the ASL signal before and after an intervention (head-down tilt) in six subjects. The distribution of ASL signal was better characterized by a lognormal distribution than a normal distribution, reducing the mean squared error by 72% (p < 0.005). Head-down tilt significantly reduced the lognormal scale parameter (p = 0.01) but not the shape parameter or GSD. The RD increased post-tilt and remained significantly elevated (by 17%, p < 0.05). Test case results and mathematical simulations suggest that RD is more sensitive than the GSD to ASL signal from tagged blood in larger vessels, a probable explanation of the change in RD without a statistically significant change in GSD. This suggests that the GSD is a useful measure of pulmonary blood flow heterogeneity with the advantage of being less affected by the ASL signal from tagged blood in larger vessels.

Pulmonary perfusion in the prone and supine postures in the normal human lung.

Prone posture increases cardiac output and improves pulmonary gas exchange. We hypothesized that, in the supine posture, greater compression of dependent lung limits regional blood flow. To test this, MRI-based measures of regional lung density, MRI arterial spin labeling quantification of pulmonary perfusion, and density-normalized perfusion were made in six healthy subjects. Measurements were made in both the prone and supine posture at functional residual capacity. Data were acquired in three nonoverlapping 15-mm sagittal slices covering most of the right lung: central, middle, and lateral, which were further divided into vertical zones: anterior, intermediate, and posterior. The density of the entire lung was not different between prone and supine, but the increase in lung density in the anterior lung with prone posture was less than the decrease in the posterior lung (change: +0.07 g/cm(3) anterior, -0.11 posterior; P < 0.0001), indicating greater compression of dependent lung in supine posture, principally in the central lung slice (P < 0.0001). Overall, density-normalized perfusion was significantly greater in prone posture (7.9 +/- 3.6 ml.min(-1).g(-1) prone, 5.1 +/- 1.8 supine, a 55% increase; P < 0.05) and showed the largest increase in the posterior lung as it became nondependent (change: +71% posterior, +58% intermediate, +31% anterior; P = 0.08), most marked in the central lung slice (P < 0.05). These data indicate that central posterior portions of the lung are more compressed in the supine posture, likely by the heart and adjacent structures, than are central anterior portions in the prone and that this limits regional perfusion in the supine posture.

Vertical gradients in regional lung density and perfusion in the supine human lung: the Slinky effect.

In vivo radioactive tracer and microsphere studies have differing conclusions as to the magnitude of the gravitational effect on the distribution of pulmonary blood flow. We hypothesized that some of the apparent vertical perfusion gradient in vivo is due to compression of dependent lung increasing local lung density and therefore perfusion/volume. To test this, six normal subjects underwent functional magnetic resonance imaging with arterial spin labeling during breath holding at functional residual capacity, and perfusion quantified in nonoverlapping 15 mm sagittal slices covering most of the right lung. Lung proton density was measured in the same slices using a short echo 2D-Fast Low-Angle SHot (FLASH) sequence. Mean perfusion was 1.7 +/- 0.6 ml x min(-1) x cm(-3) and was related to vertical height above the dependent lung (slope = -3%/cm, P < 0.0001). Lung density averaged 0.34 +/- 0.08 g/cm3 and was also related to vertical height (slope = -4.9%/cm, P < 0.0001). By contrast, when perfusion was normalized for regional lung density, the slope of the height-perfusion relationship was not significantly different from zero (P = 0.2). This suggests that in vivo variations in regional lung density affect the interpretation of vertical gradients in pulmonary blood flow and is consistent with a simple conceptual model: the lung behaves like a Slinky (Slinky is a registered trademark of Poof-Slinky Incorporated), a deformable spring distorting under its own weight. The greater density of lung tissue in the dependent regions of the lung is analogous to a greater number of coils in the dependent portion of the vertically oriented spring. This implies that measurements of perfusion in vivo will be influenced by density distributions and will differ from excised lungs where density gradients are reduced by processing.

Dynamic lung mechanics in late-stage emphysema before and after lung volume reduction surgery.

This study evaluated the effects of lung volume reduction surgery (LVRS) on the heterogeneity of lung function in awake, late-stage emphysema patients with measurements taken before and after full recovery from LVRS. We assessed standard clinical measures of lung function and functional heterogeneity in six awake, late-stage emphysema patients before and 6 months after LVRS. Functional heterogeneity was quantified by measuring dynamic inspiratory resistance (R(L)(insp)) and elastance (E(L)(insp)) over a frequency range that included normal breathing ( approximately 0.33-8 Hz). Since LVRS involves targeted resection of emphysematous regions of the lung, we hypothesized that emphysema patients would be functionally more homogeneous post-LVRS. We also compared our measures of functional heterogeneity with indices of anatomic heterogeneity and severity using high-resolution computed tomography (HRCT). After LVRS, 6 min walk distance increased by 22% (940+/-91 versus 1158+/-299, p=0.031) and recoil pressure at TLC increased (9.0+/-2.0 versus 14+/-5, p=0.031), but changes in R(L)(insp) and E(L)(insp) varied greatly between subjects. A measure of anatomic severity quantified using HRCT positively correlated with airway resistance (r(s)=0.89, p=0.048). These results suggest that subjects with more severe disease as assessed by HRCT criteria had reduced overall effective airway caliber consequent to active airway constriction, reduced parenchymal tethering, and/or loss of parallel lung units. Furthermore, LVRS may not necessarily improve lung function via a substantial reduction in mechanical heterogeneity.

Steep head-down tilt has persisting effects on the distribution of pulmonary blood flow.

Head-down tilt has been shown to increase lung water content in animals and alter the distribution of ventilation in humans; however, its effects on the distribution of pulmonary blood flow in humans are unknown. We hypothesized that head-down tilt would increase the heterogeneity of pulmonary blood flow in humans, an effect analogous to the changes seen in the distribution of ventilation, by increasing capillary hydrostatic pressure and fluid efflux in the lung. To test this, we evaluated changes in the distribution of pulmonary blood flow in seven normal subjects before and after 1 h of 30 degrees head-down tilt using the magnetic resonance imaging technique of arterial spin labeling. Data were acquired in triplicate before tilt and at 10-min intervals for 1 h after tilt. Pulmonary blood flow heterogeneity was quantified by the relative dispersion (standard deviation/mean) of signal intensity for all voxels within the right lung. Relative dispersion was significantly increased by 29% after tilt and remained elevated during the 1 h of measurements after tilt (0.84 +/- 0.06 pretilt, 1.09 +/- 0.09 calculated for all time points posttilt, P < 0.05). We speculate that the mechanism most likely responsible for our findings is that increased pulmonary capillary pressures and fluid efflux in the lung resulting from head-down tilt alters regional blood flow distribution.

Bronchoscopic lung volume reduction using tissue engineering principles.

Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based on tissue engineering principles, was performed in six sheep with papain-induced experimental emphysema (EMPH). Physiologic measurements, at baseline, after generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes, diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest wall, pleural pressures generated during active respiratory muscle contraction, lung resistance and dynamic elastance. The animal model displayed hyperinflation (change in total lung capacity +8%; change in residual volume +66%), reduced DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced human EMPH. BLVR was well tolerated without complications, and it reduced lung volumes (change in total lung capacity -16%; change in residual volume -55%) in a pattern that resulted in significant improvements in vital capacity (10%). At autopsy, well-organized, peripheral scars associated with tissue contraction were observed at 33 of the 36 (91%) treated sites. There was no evidence of infection, abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved respiratory function safely and consistently. The BLVR technology employed in this study addresses the limitations identified in our prior attempt at BLVR therapy and appears safe and effective enough to justify a trial in humans.