Assessing the pulmonary vascular responsiveness to oxygen with proton MRI.

Ventilation-perfusion matching occurs passively and is also actively regulated through hypoxic pulmonary vasoconstriction (HPV). The extent of HPV activity in humans, particularly normal subjects, is uncertain. Current evaluation of HPV assesses changes in ventilation-perfusion relationships/pulmonary vascular resistance with hypoxia and is invasive, or unsuitable for patients because of safety concerns. We used a noninvasive imaging-based approach to quantify the pulmonary vascular response to oxygen as a metric of HPV by measuring perfusion changes between breathing 21% and 30%O2 using arterial spin labeling (ASL) MRI. We hypothesized that the differences between 21% and 30%O2 images reflecting HPV release would be 1) significantly greater than the differences without [Formula: see text] changes (e.g., 21-21% and 30-30%O2) and 2) negatively associated with ventilation-perfusion mismatch. Perfusion was quantified in the right lung in normoxia (baseline), after 15 min of 30% O2 breathing (hyperoxia) and 15 min normoxic recovery (recovery) in healthy subjects (7 M, 7 F; age = 41.4 ± 19.6 yr). Normalized, smoothed, and registered pairs of perfusion images were subtracted and the mean square difference (MSD) was calculated. Separately, regional alveolar ventilation and perfusion were quantified from specific ventilation, proton density, and ASL imaging; the spatial variance of ventilation-perfusion (σ2V̇a/Q̇) distributions was calculated. The O2-responsive MSD was reproducible (R2 = 0.94, P < 0.0001) and greater (0.16 ± 0.06, P < 0.0001) than that from subtracted images collected under the same [Formula: see text] (baseline = 0.09 ± 0.04, hyperoxia = 0.08 ± 0.04, recovery = 0.08 ± 0.03), which were not different from one another (P = 0.2). The O2-responsive MSD was correlated with σ2V̇a/Q̇ (R2 = 0.47, P = 0.007). These data suggest that active HPV optimizes ventilation-perfusion matching in normal subjects. This noninvasive approach could be applied to patients with different disease phenotypes to assess HPV and ventilation-perfusion mismatch.NEW & NOTEWORTHY We developed a new proton MRI method to noninvasively quantify the pulmonary vascular response to oxygen. Using a hyperoxic stimulus to release HPV, we quantified the resulting redistribution of perfusion. The differences between normoxic and hyperoxic images were greater than those between images without [Formula: see text] changes and negatively correlated with ventilation-perfusion mismatch. This suggests that active HPV optimizes ventilation-perfusion matching in normal subjects. This approach is suitable for assessing patients with different disease phenotypes.

The spatial-temporal dynamics of pulmonary blood flow are altered in pulmonary arterial hypertension.

Global fluctuation dispersion (FDglobal), a spatial-temporal metric derived from serial images of the pulmonary perfusion obtained with MRI-arterial spin labeling, describes temporal fluctuations in the spatial distribution of perfusion. In healthy subjects, FDglobal is increased by hyperoxia, hypoxia, and inhaled nitric oxide. We evaluated patients with pulmonary arterial hypertension (PAH, 4F, aged 47 ± 15, mean pulmonary artery pressure 48 ± 7 mmHg) and healthy controls (CON, 7F, aged 47 ± 12) to test the hypothesis that FDglobal is increased in PAH. Images were acquired at ∼4-5 s intervals during voluntary respiratory gating, inspected for quality, registered using a deformable registration algorithm, and normalized. Spatial relative dispersion (RD = SD/mean) and the percent of the lung image with no measurable perfusion signal (%NMP) were also assessed. FDglobal was significantly increased in PAH (PAH = 0.40 ± 0.17, CON = 0.17 ± 0.02, P = 0.006, a 135% increase) with no overlap in values between the two groups, consistent with altered vascular regulation. Both spatial RD and %NMP were also markedly greater in PAH vs. CON (PAH RD = 1.46 ± 0.24, CON = 0.90 ± 0.10, P = 0.0004; PAH NMP = 13.4 ± 6.1%; CON = 2.3 ± 1.4%, P = 0.001 respectively) consistent with vascular remodeling resulting in poorly perfused regions of lung and increased spatial heterogeneity. The difference in FDglobal between normal subjects and patients with PAH in this small cohort suggests that spatial-temporal imaging of perfusion may be useful in the evaluation of patients with PAH. Since this MR imaging technique uses no injected contrast agents and has no ionizing radiation it may be suitable for use in diverse patient populations.NEW & NOTEWORTHY Using proton MRI-arterial spin labeling to obtain serial images of pulmonary perfusion, we show that global fluctuation dispersion (FDglobal), a metric of temporal fluctuations in the spatial distribution of perfusion, was significantly increased in female patients with pulmonary arterial hypertension (PAH) compared with healthy controls. This potentially indicates pulmonary vascular dysregulation. Dynamic measures using proton MRI may provide new tools for evaluating individuals at risk of PAH or for monitoring therapy in patients with PAH.

Face Masks and the Cardiorespiratory Response to Physical Activity in Health and Disease.

To minimize transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus responsible for coronavirus disease (COVID-19), the U.S. Centers for Disease Control and Prevention and the World Health Organization recommend wearing face masks in public. Some have expressed concern that these may affect the cardiopulmonary system by increasing the work of breathing, altering pulmonary gas exchange and increasing dyspnea, especially during physical activity. These concerns have been derived largely from studies evaluating devices intentionally designed to severely affect respiratory mechanics and gas exchange. We review the literature on the effects of various face masks and respirators on the respiratory system during physical activity using data from several models: cloth face coverings and surgical masks, N95 respirators, industrial respirators, and applied highly resistive or high-dead space respiratory loads. Overall, the available data suggest that although dyspnea may be increased and alter perceived effort with activity, the effects on work of breathing, blood gases, and other physiological parameters imposed by face masks during physical activity are small, often too small to be detected, even during very heavy exercise. There is no current evidence to support sex-based or age-based differences in the physiological responses to exercise while wearing a face mask. Although the available data suggest that negative effects of using cloth or surgical face masks during physical activity in healthy individuals are negligible and unlikely to impact exercise tolerance significantly, for some individuals with severe cardiopulmonary disease, any added resistance and/or minor changes in blood gases may evoke considerably more dyspnea and, thus, affect exercise capacity.

Quantitative Mapping of Specific Ventilation in the Human Lung using Proton Magnetic Resonance Imaging and Oxygen as a Contrast Agent.

Specific ventilation imaging (SVI) is a functional magnetic resonance imaging technique capable of quantifying specific ventilation - the ratio of the fresh gas entering a lung region divided by the region's end-expiratory volume - in the human lung, using only inhaled oxygen as a contrast agent. Regional quantification of specific ventilation has the potential to help identify areas of pathologic lung function. Oxygen in solution in tissue shortens the tissue's longitudinal relaxation time (T1), and thus a change in tissue oxygenation can be detected as a change in T1-weighted signal with an inversion recovery acquired image. Following an abrupt change between two concentrations of inspired oxygen, the rate at which lung tissue within a voxel equilibrates to a new steady-state reflects the rate at which resident gas is being replaced by inhaled gas. This rate is determined by specific ventilation. To elicit this sudden change in oxygenation, subjects alternately breathe 20-breath blocks of air (21% oxygen) and 100% oxygen while in the MRI scanner. A stepwise change in inspired oxygen fraction is achieved through use of a custom three-dimensional (3D)-printed flow bypass system with a manual switch during a short end-expiratory breath hold. To detect the corresponding change in T1, a global inversion pulse followed by a single shot fast spin echo sequence was used to acquire two-dimensional T1-weighted images in a 1.5 T MRI scanner, using an eight-element torso coil. Both single slice and multi-slice imaging are possible, with slightly different imaging parameters. Quantification of specific ventilation is achieved by correlating the time-course of signal intensity for each lung voxel with a library of simulated responses to the air/oxygen stimulus. SVI estimations of specific ventilation heterogeneity have been validated against multiple breath washout and proved to accurately determine the heterogeneity of the specific ventilation distribution.

Regional pulmonary perfusion patterns in humans are not significantly altered by inspiratory hypercapnia.

Pulmonary vascular tone is known to be sensitive to both local alveolar Po2 and Pco2. Although the effects of hypoxia are well studied, the hypercapnic response is relatively less understood. We assessed changes in regional pulmonary blood flow in humans in response to hypercapnia using previously developed MRI techniques. Dynamic measures of blood flow were made in a single slice of the right lung of seven healthy volunteers following a block-stimulus paradigm (baseline, challenge, recovery), with CO2 added to inspired gas during the challenge block to effect a 7-Torr increase in end-tidal CO2. Effects of hypercapnia on blood flow were evaluated based on changes in spatiotemporal variability (fluctuation dispersion, FD) and in regional perfusion patterns in comparison to hypoxic effects previously studied. Hypercapnia increased FD 2.5% from baseline (relative to control), which was not statistically significant (P = 0.07). Regional perfusion patterns were not significantly changed as a result of increased FICO2 (P = 0.90). Reanalysis of previously collected data using a similar protocol but with the physiological challenge replaced by decreased FIO2 (FIO2 = 0.125) showed marked flow redistribution (P = 0.01) with the suggestion of a gravitational pattern, demonstrating hypoxia has the ability to affect regional change with a global stimulus. Taken together, these data indicate that hypercapnia of this magnitude does not lead to appreciable changes in the distribution of pulmonary perfusion, and that this may represent an interesting distinction between the hypoxic and hypercapnic regulatory response.NEW & NOTEWORTHY Although it is well known that the pulmonary circulation responds to local alveolar hypoxia, and that this mechanism may facilitate ventilation-perfusion matching, the relative role of CO2 is not well appreciated. This study demonstrates that an inspiratory hypercapnic stimulus is significantly less effective at inducing changes in pulmonary perfusion patterns than inspiratory hypoxia, suggesting that in these circumstances hypercapnia is not sufficient to induce substantial integrated feedback control of ventilation-perfusion mismatch across the lung.

Comparison of quantitative multiple-breath specific ventilation imaging using colocalized 2D oxygen-enhanced MRI and hyperpolarized 3He MRI.

Two magnetic resonance specific ventilation imaging (SVI) techniques, namely, oxygen-enhanced proton (OE-1H) and hyperpolarized 3He (HP-3He), were compared in eight healthy supine subjects [age 32 (6) yr]. An in-house radio frequency coil array for 1H configured with the 3He transmit-receive coil in situ enabled acquisition of SVI data from two nuclei from the same slice without repositioning the subjects. After 3 × 3 voxel downsampling to account for spatial registration errors between the two SV images, the voxel-by-voxel correlation coefficient of two SV maps ranged from 0.11 to 0.63 [0.46 mean (0.17 SD); P < 0.05]. Several indexes were analyzed and compared from the tidal volume-matched SV maps: the mean of SV log-normal distribution (SVmean), the standard deviation of the distribution as a measure of SV heterogeneity (SVwidth), and the gravitational gradient (SVslope). There were no significant differences in SVmean [OE-1H: 0.28 (0.08) and HP-3He: 0.32 (0.14)], SVwidths [OE-1H: 0.28 (0.08) and HP-3He: 0.27 (0.10)], and SVslopes [OE-1H: -0.016 (0.006) cm-1 and HP-3He: -0.013 (0.007) cm-1]. Despite the statistical similarities of the population averages, Bland-Altman analysis demonstrated large individual intertechnique variability. SDs of differences in these indexes were 42% (SVmean), 46% (SVwidths), and 62% (SVslopes) of their corresponding overall mean values. The present study showed that two independent, spatially coregistered, SVI techniques presented a moderate positive voxel-by-voxel correlation. Population averages of SVmean, SVwidth, and SVslope were in close agreement. However, the lack of agreement when the data sets were analyzed individually might indicate some fundamental mechanistic differences between the techniques. NEW & NOTEWORTHY To the best of our knowledge, this is the first cross-comparison of two different specific ventilation (SV) MRI techniques in the human lung (i.e., oxygen-enhanced proton and hyperpolarized 3He). The present study showed that two types of spatially coregistered SV images presented a modest positive correlation. The two techniques also yielded similar population averages of SV indexes such as log-normal mean, SV heterogeneity, and the gravitational slope, albeit with some intersubject variability.

Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia.

Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems.

Regional Ventilation Is the Main Determinant of Alveolar Deposition of Coarse Particles in the Supine Healthy Human Lung During Tidal Breathing.

BACKGROUND: To quantify the relationship between regional lung ventilation and coarse aerosol deposition in the supine healthy human lung, we used oxygen-enhanced magnetic resonance imaging and planar gamma scintigraphy in seven subjects. METHODS: Regional ventilation was measured in the supine posture in a 15 mm sagittal slice of the right lung. Deposition was measured by using planar gamma scintigraphy (coronal scans, 40 cm FOV) immediately postdeposition, 1 hour 30 minutes and 22 hours after deposition of 99mTc-labeled particles (4.9 µm MMAD, GSD 2.5), inhaled in the supine posture (flow 0.5 L/s, 15 breaths/min). The distribution of retained particles at different times was used to infer deposition in different airway regions, with 22 hours representing alveolar deposition. The fraction of total slice ventilation per quartile of lung height from the lung apex to the dome of the diaphragm at functional residual capacity was computed, and co-registered with deposition data-apices aligned-using a transmission scan as reference. The ratio of fractional alveolar deposition to fractional ventilation of each quartile (r) was used to evaluate ventilation and deposition matching (r > 1, regional aerosol deposition fraction larger than regional ventilation fraction). RESULTS: r was not significantly different from 1 for all regions (1.04 ± 0.25, 1.08 ± 0.22, 1.03 ± 0.17, 0.92 ± 0.13, apex to diaphragm, p > 0.40) at the alveolar level (r22h). For retention times r0h and r1h30, only the diaphragmatic region at r1h30 differed significantly from 1. CONCLUSIONS: These results support the hypothesis that alveolar deposition is directly proportional to ventilation for ∼5 µm particles that are inhaled in the supine posture and are consistent with previous simulation predictions that show that convective flow is the main determinant of aerosol transport to the lung periphery.

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 effect of lung deformation on the spatial distribution of pulmonary blood flow.

KEY POINTS: Pulmonary perfusion measurement using magnetic resonance imaging combined with deformable image registration enabled us to quantify the change in the spatial distribution of pulmonary perfusion at different lung volumes. The current study elucidated the effects of tidal volume lung inflation [functional residual capacity (FRC) + 500 ml and FRC + 1 litre] on the change in pulmonary perfusion distribution. Changes in hydrostatic pressure distribution as well as transmural pressure distribution due to the change in lung height with tidal volume inflation are probably bigger contributors to the redistribution of pulmonary perfusion than the changes in pulmonary vasculature resistance caused by lung tissue stretch. ABSTRACT: Tidal volume lung inflation results in structural changes in the pulmonary circulation, potentially affecting pulmonary perfusion. We hypothesized that perfusion is recruited to regions receiving the greatest deformation from a tidal breath, thus ensuring ventilation-perfusion matching. Density-normalized perfusion (DNP) magnetic resonance imaging data were obtained in healthy subjects (n = 7) in the right lung at functional residual capacity (FRC), FRC+500 ml, and FRC+1.0 l. Using deformable image registration, the displacement of a sagittal lung slice acquired at FRC to the larger volumes was calculated. Registered DNP images were normalized by the mean to estimate perfusion redistribution (nDNP). Data were evaluated across gravitational regions (dependent, middle, non-dependent) and by lobes (upper, RUL; middle, RML; lower, RLL). Lung inflation did not alter mean DNP within the slice (P = 0.10). The greatest expansion was seen in the dependent region (P < 0.0001: dependent vs non-dependent, P < 0.0001: dependent vs middle) and RLL (P = 0.0015: RLL vs RUL, P < 0.0001: RLL vs RML). Neither nDNP recruitment to RLL [+500 ml = -0.047(0.145), +1 litre = 0.018(0.096)] nor to dependent lung [+500 ml = -0.058(0.126), +1 litre = -0.023(0.106)] were found. Instead, redistribution was seen in decreased nDNP in the non-dependent [+500 ml = -0.075(0.152), +1 litre = -0.137(0.167)) and increased nDNP in the gravitational middle lung [+500 ml = 0.098(0.058), +1 litre = 0.093(0.081)] (P = 0.01). However, there was no significant lobar redistribution (P < 0.89). Contrary to our hypothesis, based on the comparison between gravitational and lobar perfusion data, perfusion was not redistributed to the regions of the most inflation. This suggests that either changes in hydrostatic pressure or transmural pressure distribution in the gravitational direction are implicated in the redistribution of perfusion away from the non-dependent lung.

Effect of Posture on Regional Deposition of Coarse Particles in the Healthy Human Lung.

BACKGROUND: Understanding the regional partition of deposition of inhaled particles within the lung is important for improving targeted delivery of inhaled aerosolized drugs. One factor affecting regional deposition is gravity. As the lung deforms under its own weight, changes in lung volume, in airway geometries, and in spatial patterns of ventilation distribution between postures have the potential to alter the regional distribution of deposited particles. METHODS: Using gamma-scintigraphy, we measured regional deposition and clearance of (99m)Tc labeled particles (5 µm) in 6 healthy subjects, with aerosol inhalation occurring both in the supine and seated postures at constant flow (0.5 L/sec) and breathing rate (15 breaths/min). After aerosol deposition, mucociliary clearance data were collected in the seated posture, immediately post-particle administration, 1 h 30 min, 4 h, and 22 h post-inhalation. Relative regional deposition was computed using retention (R) at the different time points, with (1-R(1h30min)), (R(1h30min)- R(4h)), and (R(4h)- R(22h)) corresponding to deposition in the large, intermediate, and small airways, respectively. Alveolar deposition was estimated as the relative retention at 22 h (R(22h)). RESULTS: Relative deposition of coarse particles in the alveolar region decreased from 60±8% seated to 34±16% supine (p=0.04). This change was accompanied by an increase in relative deposition in the intermediate (7±3% seated to 16±17% supine, P=0.09) and small airways (19±6% seated to 34±13% supine, p=0.06) when inhalation occurred in the supine posture. No change was observed in central to peripheral deposition (C/P ratio), the skew of the deposition distribution, or the apex-to-base ratio of deposition between seated and supine postures. CONCLUSIONS: Inhalation of coarse particles in the supine posture shifts relative deposition from the alveolar to the bronchial airways, when compared to the seated posture, likely driven by changes in functional residual capacity, and airway size, as well as changes in the regional distribution of ventilation between postures.

Rapid Prototyping of Inspired Gas Delivery System for Pulmonary MRI Research.

Specific ventilation imaging (SVI) is a noninvasive magnetic resonance imaging (MRI)-based method for determining the regional distribution of inspired air in the lungs, useful for the assessment of pulmonary function in medical research. This technique works by monitoring the rate of magnetic resonance signal change in response to a series of imposed step changes in inspired oxygen concentration. The current SVI technique requires a complex system of tubes, valves, and electronics that are used to supply and rapidly switch inspired gases while subjects are imaged, which makes the technique difficult to translate into the clinical setting. This report discusses the design and implementation of custom three-dimensional (3D) printed hardware that greatly simplifies SVI measurement of lung function. Several hardware prototypes were modeled using computer-aided design software and printed for evaluation. After finalization of the design, the new delivery system was evaluated based on O2 and N2 concentration step responses and validated against the current SVI protocol. The design performed rapid switching of supplied gas within 250 ms and consistently supplied the desired concentration of O2 during operation. It features a reduction in the number of commercial hardware components, from five to one, and a reduction in the number of gas lines between the operator's room and the scanner room, from four to one, as well as a substantially reduced preparation time from 25 to 5 min. 3D printing is well suited to the design of inexpensive custom MRI compatible hardware, making it particularly useful in imaging-based research.

Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia.

Hypoxic pulmonary vasoconstriction (HPV) is thought to actively regulate ventilation-perfusion (V̇a/Q̇) matching, reducing perfusion in regions of alveolar hypoxia. We assessed the extent of HPV in the healthy human lung using inhaled nitric oxide (iNO) under inspired oxygen fractions (FiO2 ) of 0.125, 0.21, and 0.30 (a hyperoxic stimulus designed to abolish HPV without the development of atelectasis). Dynamic measures of blood flow were made in a single sagittal slice of the right lung of five healthy male subjects using an arterial spin labeling (ASL) MRI sequence, following a block stimulus pattern (3 × 60 breaths) with 40 ppm iNO administered in the central block. The overall spatial heterogeneity, spatiotemporal variability, and regional pattern of pulmonary blood flow was quantified as a function of condition (FiO2 × iNO state). While spatial heterogeneity did not change significantly with iNO administration or FiO2 , there were statistically significant increases in Global Fluctuation Dispersion, (a marker of spatiotemporal flow variability) when iNO was administered during hypoxia (5.4 percentage point increase, P = 0.003). iNO had an effect on regional blood flow that was FiO2 dependent (P = 0.02), with regional changes in the pattern of blood flow occurring in hypoxia (P = 0.007) and normoxia (P = 0.008) tending to increase flow to dependent lung at the expense of nondependent lung. These findings indicate that inhaled nitric oxide significantly alters the distribution of blood flow in both hypoxic and normoxic healthy subjects, and suggests that some baseline HPV may indeed be present in the normoxic lung.

Validating the distribution of specific ventilation in healthy humans measured using proton MR imaging.

Specific ventilation imaging (SVI) uses proton MRI to quantitatively map the distribution of specific ventilation (SV) in the human lung, using inhaled oxygen as a contrast agent. To validate this recent technique, we compared the quantitative measures of heterogeneity of the SV distribution in a 15-mm sagittal slice of lung obtained in 10 healthy supine subjects, (age 37 ± 10 yr, forced expiratory volume in 1 s 97 ± 7% predicted) using SVI to those obtained in the whole lung from multiple-breath nitrogen washout (MBW). Using the analysis of Lewis et al. (Lewis SM, Evans JW, Jalowayski AA. J App Physiol 44: 416-423, 1978), the most likely distribution of SV from the MBW data was computed and compared with the distribution of SV obtained from SVI, after normalizing for the difference in tidal volume. The average SV was 0.30 ± 0.10 MBW, compared with 0.36 ± 0.10 SVI (P = 0.01). The width of the distribution, a measure of the heterogeneity, obtained using both methods was comparable: 0.51 ± 0.06 and 0.47 ± 0.08 in MBW and SVI, respectively (P = 0.15). The MBW estimated width of the SV distribution was 0.05 (10.7%) higher than that estimated using SVI, and smaller than the intertest variability of the MBW estimation [inter-MBW (SD) for the width of the SV distribution was 0.08 (15.8)%]. To assess reliability, SVI was performed twice on 13 subjects showing small differences between measurements of SV heterogeneity (typical error 0.05, 12%). In conclusion, quantitative estimations of SV heterogeneity from SVI are reliable and similar to those obtained using MBW, with SVI providing spatial information that is absent in MBW.

Cardiogenic mixing increases aerosol deposition in the human lung in the absence of gravity.

RATIONALE: Exposure to extraterrestrial dusts is an almost inevitable consequence of any proposed planetary exploration. Previous studies in humans showed reduced deposition in low-gravity compared with normal gravity (1G). However, the reduced sedimentation means that fewer particles deposit in the airways, increasing the number of particles transported to the lung periphery where they eventually deposit albeit at a smaller rate than in 1G. In this study, we determined the role that gravity and other mechanisms such as cardiogenic mixing play in peripheral lung deposition during breath holds. METHODS: Eight healthy subjects inhaled boluses of 0.5 µm-diameter particles to penetration volumes (Vp) of 300 and 1200ml that were followed by breath holds of up to 10 sec. Tests were performed in 1G and during short periods of microgravity (µG) aboard the NASA Microgravity Research Aircraft. Aerosol deposition and dispersion were calculated from these data. RESULTS: Results show that, for both Vp, deposition in 1G was significantly higher than in µG. In contrast, while dispersion was significantly higher in 1G compared to µG at Vp=1200ml, there was no significant gravitational effect on dispersion at Vp=300ml. Finally, for each G level and Vp, deposition and dispersion significantly increased with increasing breath-hold time. CONCLUSION: The most important finding of this study is that, even in the absence of gravity, aerosol deposition in the lung periphery increased with increasing residence time. Because the particles used in this study were too large to be significantly affected by Brownian diffusion, the increase in deposition is likely due to cardiogenic motion effects.

The heterogeneity of regional specific ventilation is unchanged following heavy exercise in athletes.

Heavy exercise increases ventilation-perfusion mismatch and decreases pulmonary gas exchange efficiency. Previous work using magnetic resonance imaging (MRI) arterial spin labeling in athletes has shown that, after 45 min of heavy exercise, the spatial heterogeneity of pulmonary blood flow was increased in recovery. We hypothesized that the heterogeneity of regional specific ventilation (SV, the local tidal volume over functional residual capacity ratio) would also be increased following sustained exercise, consistent with the previously documented changes in blood flow heterogeneity. Trained subjects (n = 6, maximal O2 consumption = 61 ± 7 ml·kg(-1)·min(-1)) cycled 45 min at their individually determined ventilatory threshold. Oxygen-enhanced MRI was used to quantify SV in a sagittal slice of the right lung in supine posture pre- (preexercise) and 15- and 60-min postexercise. Arterial spin labeling was used to measure pulmonary blood flow in the same slice bracketing the SV measures. Heterogeneity of SV and blood flow were quantified by relative dispersion (RD = SD/mean). The alveolar-arterial oxygen difference was increased during exercise, 23.3 ± 5.3 Torr, compared with rest, 6.3 ± 3.7 Torr, indicating a gas exchange impairment during exercise. No significant change in RD of SV was seen after exercise: preexercise 0.78 ± 0.15, 15 min postexercise 0.81 ± 0.13, 60 min postexercise 0.78 ± 0.08 (P = 0.5). The RD of blood flow increased significantly postexercise: preexercise 1.00 ± 0.12, 15 min postexercise 1.15 ± 0.10, 45 min postexercise 1.10 ± 0.10, 60 min postexercise 1.19 ± 0.11, 90 min postexercise 1.11 ± 0.12 (P < 0.005). The lack of a significant change in RD of SV postexercise, despite an increase in the RD of blood flow, suggests that airways may be less susceptible to the effects of exercise than blood vessels.

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.

Spatial-temporal dynamics of pulmonary blood flow in the healthy human lung in response to altered FI(O2).

The temporal dynamics of blood flow in the human lung have been largely unexplored due to the lack of appropriate technology. Using the magnetic resonance imaging method of arterial spin labeling (ASL) with subject-gated breathing, we produced a dynamic series of flow-weighted images in a single sagittal slice of the right lung with a spatial resolution of ~1 cm(3) and a temporal resolution of ~10 s. The mean flow pattern determined from a set of reference images was removed to produce a time series of blood flow fluctuations. The fluctuation dispersion (FD), defined as the spatial standard deviation of each flow fluctuation map, was used to quantify the changes in distribution of flow in six healthy subjects in response to 100 breaths of hypoxia (FI(O(2)) = 0.125) or hyperoxia (FI(O(2)) = 1.0). Two reference frames were used in calculation, one determined from the initial set of images (FD(global)), and one determined from the mean of each corresponding baseline or challenge period (FD(local)). FD(local) thus represented changes in temporal variability as a result of intervention, whereas FD(global) encompasses both FD(local) and any generalized redistribution of flow associated with switching between two steady-state patterns. Hypoxic challenge resulted in a significant increase (96%, P < 0.001) in FD(global) from the normoxic control period and in FD(local) (46%, P = 0.0048), but there was no corresponding increase in spatial relative dispersion (spatial standard deviation of the images divided by the mean; 8%, not significant). There was a smaller increase in FD(global) in response to hyperoxia (47%, P = 0.0015) for the single slice, suggestive of a more general response of the pulmonary circulation to a change from normoxia to hyperoxia. These results clearly demonstrate a temporal change in the sampled distribution of pulmonary blood flow in response to hypoxia, which is not observed when considering only the relative dispersion of the spatial distribution.

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.