Specific Ventilation Distribution Research Articles

Ventilatory heterogeneity in the normal human lung is unchanged by controlled breathing.

Measurement of ventilation heterogeneity with the multiple-breath nitrogen washout (MBW) is usually performed using controlled breathing with a fixed tidal volume and breathing frequency. However, it is unclear whether controlled breathing alters the underlying ventilatory heterogeneity. We hypothesized that the width of the specific ventilation distribution (a measure of heterogeneity) would be greater in tests performed during free breathing compared with those performed using controlled breathing. Eight normal subjects (age range = 23-50 yr, 5 female/3 male) twice underwent MRI-based specific ventilation imaging consisting of five repeated cycles with the inspired gas switching between 21% and 100% O2 every ~2 min (total imaging time = ~20 min). In each session, tests were performed with free breathing (FB, no constraints) and controlled breathing (CB) at a respiratory rate of 12 breaths/min and no tidal volume control. The specific ventilation (SV) distribution in a mid-sagittal slice of the right lung was calculated, and the heterogeneity was calculated as the full width at half max of a Gaussian distribution fitted on a log scale (SV width). Free breathing resulted in a range of breathing frequencies from 8.7 to 15.9 breaths/min (mean = 11.5 ± 2.2, P = 0.62, compared with CB). Heterogeneity (SV width) was unchanged by controlled breathing (FB: 0.38 ± 0.12; CB: 0.34 ± 0.09, P = 0.18, repeated-measures ANOVA). The imposition of a controlled breathing frequency did not significantly affect the heterogeneity of ventilation in the normal lung, suggesting that MBW and specific ventilation imaging as typically performed provide an unperturbed measure of ventilatory heterogeneity.NEW & NOTEWORTHY By using MRI-based specific ventilation imaging (SVI), we showed that the heterogeneity of specific ventilation was not different comparing free breathing and breathing with the imposition of a fixed breathing frequency of 12 breaths/min. Thus, multiple-breath washout and SVI as typically performed provide an unperturbed measure of ventilatory heterogeneity.

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 1.5T 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.

In silico modeling of oxygen-enhanced MRI of specific ventilation.

Specific ventilation imaging (SVI) proposes that using oxygen‐enhanced 1H MRI to capture signal change as subjects alternatively breathe room air and 100% O2 provides an estimate of specific ventilation distribution in the lung. How well this technique measures SV and the effect of currently adopted approaches of the technique on resulting SV measurement is open for further exploration. We investigated (1) How well does imaging a single sagittal lung slice represent whole lung SV? (2) What is the influence of pulmonary venous blood on the measured MRI signal and resultant SVI measure? and (3) How does inclusion of misaligned images affect SVI measurement? In this study, we utilized two patient‐based in silico models of ventilation, perfusion, and gas exchange to address these questions for normal healthy lungs. Simulation results from the two healthy young subjects show that imaging a single slice is generally representative of whole lung SV distribution, with a calculated SV gradient within 90% of that calculated for whole lung distributions. Contribution of O2 from the venous circulation results in overestimation of SV at a regional level where major pulmonary veins cross the imaging plane, resulting in a 10% increase in SV gradient for the imaging slice. A worst‐case scenario simulation of image misalignment increased the SV gradient by 11.4% for the imaged slice.

Pulmonary Delivery of Therapeutic and Diagnostic Gases.

The 21st Congress for the International Society for Aerosols in Medicine included, for the first time, a session on Pulmonary Delivery of Therapeutic and Diagnostic Gases. The rationale for such a session within ISAM is that the pulmonary delivery of gaseous drugs in many cases targets the same therapeutic areas as aerosol drug delivery, and is in many scientific and technical aspects similar to aerosol drug delivery. This article serves as a report on the recent ISAM congress session providing a synopsis of each of the presentations. The topics covered are the conception, testing, and development of the use of nitric oxide to treat pulmonary hypertension; the use of realistic adult nasal replicas to evaluate the performance of pulsed oxygen delivery devices; an overview of several diagnostic gas modalities; and the use of inhaled oxygen as a proton magnetic resonance imaging (MRI) contrast agent for imaging temporal changes in the distribution of specific ventilation during recovery from bronchoconstriction. Themes common to these diverse applications of inhaled gases in medicine are discussed, along with future perspectives on development of therapeutic and diagnostic gases.

Inert gas washout: background and application in various lung diseases.

Multiple breath inert gas washout (MBW) is a lung function technique to measure ventilation inhomogeneity. The technique was developed more than 60 years ago, but not much used for many decades. Technical improvements, easy protocols and higher sensitivity compared with standard lung function tests in some disease groups have led to a recent renaissance of MBW. The lung clearance index (LCI) is a common measure derived from MBW tests, and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry. The LCI measures the overall degree of pulmonary ventilation inhomogeneity. There are other MBW-derived parameters, which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity. How this specific ventilation distribution is exactly related to different disease processes has not entirely been examined yet. MBW measurements are performed during tidal breathing, making this technique attractive for children, even young children and infants. These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW, especially in paediatric lung diseases such as cystic fibrosis (CF). In these patients, LCI detects early airway damage and enables monitoring of disease progression and treatment response. Guidelines for the standardisation of the MBW technique were recently published. These guidelines will, hopefully, increase comparability of LCI data obtained in different centres or intervention trials in children and adults. In this non-systematic review article, we provide an overview of recent developments in MBW, with a special focus on children. We first explain the physiological and technical background to this technique with a short explanation of several methodological aspects that are important for understanding the principle behind the technique and enable high quality measurements. We then provide examples of MBW application in different lung diseases of children and adults, with regards to both clinical application and research activities. Lastly, we report on ongoing clinical trials using MBW as outcome and give an outlook on possible future developments.

Ventilation heterogeneity measured by multiple breath inert gas testing is not affected by inspired oxygen concentration in healthy humans.

Multiple breath washout (MBW) and oxygen-enhanced MRI techniques use acute exposure to 100% oxygen to measure ventilation heterogeneity. Implicit is the assumption that breathing 100% oxygen does not induce changes in ventilation heterogeneity; however, this is untested. We hypothesized that ventilation heterogeneity decreases with increasing inspired oxygen concentration in healthy subjects. We performed MBW in 8 healthy subjects (4 women, 4 men; age = 43 ± 15 yr) with normal pulmonary function (FEV1 = 98 ± 6% predicted) using 10% argon as a tracer gas and oxygen concentrations of 12.5%, 21%, or 90%. MBW was performed in accordance with ERS-ATS guidelines. Subjects initially inspired air followed by a wash-in of test gas. Tests were performed in balanced order in triplicate. Gas concentrations were measured at the mouth, and argon signals rescaled to mimic a N2 washout, and analyzed to determine the distribution of specific ventilation (SV). Heterogeneity was characterized by the width of a log-Gaussian fit of the SV distribution and from Sacin and Scond indexes derived from the phase III slope. There were no significant differences in the ventilation heterogeneity due to altered inspired oxygen: histogram width (hypoxia 0.57 ± 0.11, normoxia 0.60 ± 0.08, hyperoxia 0.59 ± 0.09, P = 0.51), Scond (hypoxia 0.014 ± 0.011, normoxia 0.012 ± 0.015, hyperoxia 0.010 ± 0.011, P = 0.34), or Sacin (hypoxia 0.11 ± 0.04, normoxia 0.10 ± 0.03, hyperoxia 0.12 ± 0.03, P = 0.23). Functional residual capacity was increased in hypoxia (P = 0.04) and dead space increased in hyperoxia (P = 0.0001) compared with the other conditions. The acute use of 100% oxygen in MBW or MRI is unlikely to affect ventilation heterogeneity.NEW & NOTEWORTHY Hyperoxia is used to measure the distribution of ventilation in imaging and MBW but may alter the underlying ventilation distribution. We used MBW to evaluate the effect of inspired oxygen concentration on the ventilation distribution using 10% argon as a tracer. Short-duration exposure to hypoxia (12.5% oxygen) and hyperoxia (90% oxygen) during MBW had no significant effect on ventilation heterogeneity, suggesting that hyperoxia can be used to assess the ventilation distribution.

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.

It's about numbers, not pictures

the article in the current issue by Horn and colleagues ([4][1]) from Sheffield presents a significant change in the manner in which MRI in the lung using hyperpolarized gas (3He in this case, but also potentially 129Xe) is used. Since its inception, hyperpolarized gas imaging has shown an ability

Ventilation heterogeneity: small length scales, big challenges

the distribution of regional ventilation is heterogeneous in normal lung and increases dramatically under pathological conditions. This has been demonstrated both in humans and in animal models using a number of different imaging techniques. General anesthesia and mechanical ventilation can

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.

Multiple-breath washout and washin experiments in steers

Multiple-breath N2 washouts (WO) and washins (WI) were performed during regular tidal breathing in 11 unsedated healthy steers approaching pulmonary functional maturity (mean body weight = 271 kg). They inspired 20% O2 in 80% Ar during the WO and air during the WI. For each steer, we computed two indexes of ventilation inhomogeneity from the N2 WO curves: 1) the curvilinearity of the logarithm of end-tidal N2 concentrations as a function of cumulative expired volume reflected in the ratio of two slopes fitted between 100 and 50% and between 50 and 10%, respectively, of end-tidal N2 concentration of the first breath of the WO; and 2) the N2 phase III slope divided by the mean expired concentration (Sn) of each breath also plotted as a function of cumulative expired volume. Equivalent computation of both parameters was done on WI and WO curves, and similar results were obtained. The mean slope ratio was 0.812 +/- 0.119 (SD) for all the steers, which is consistent with topographic gravity-dependent specific ventilation distribution inhomogeneity. Sn was independent of the breath number both for WO and WI (mean Sn = 0.130 +/- 0.057 liters-1), suggesting that emptying between unequally ventilated units, is synchronous. This behavior resembles that observed in rats postmortem (S. Verbanck, E.R. Weibel, and M. Paiva. J. Appl Physiol. 71: 847-854, 1991) but contrasts with experiments in humans, in whom convection-dependent ventilation inhomogeneities generate a marked increase in Sn throughout the entire WO (A. B. H. Crawford, M. Makowska, M. Paiva, and L. A. Engel. J. Appl. Physiol. 59: 838-846, 1985). This is surprising because one would expect gravity-dependent sequential emptying in animals of this size.

Specific ventilation distribution in microgravity.

We studied the contribution of inter- and intraregional inhomogeneities of specific ventilation (delta V/Vo) from the rebreathing inert gas trace in microgravity and on Earth. The rebreathing tests were carried out by four astronauts before, during, and after the 10-day Spacelab D-2 mission. Starting from functional residual capacity, the rebreathing maneuver consisted of eight reinspirations from a bag filled with 1.8-2.2 liters of test gas mixtures containing approximately 5% argon. The rate of argon equilibration in the rebreathing bag, termed RBeq, was quantified by determining the logarithm of the actual minus the equilibrated argon concentrations normalized to the inspired minus the equilibrated argon concentrations. A compartmental model of the lung (S. Verbanck and M. Paiva. J. Appl. Physiol. 76: 445-454, 1994) was used to validate the method for determining RBeq and to simulate the influence of intra- and interregional delta V/Vo inhomogeneities on the RBeq curve. The comparison between the experimental Earth-based and microgravity RBeq curves and model simulations shows that gravity-independent delta V/Vo inhomogeneity is at least as large as gravity-dependent delta V/Vo inhomogeneity.

Information content of the multibreath nitrogen washout: effects of experimental error

Methods that recover a continuous distribution of specific ventilation (ventilation-to-volume ratio, VA/V) from the multibreath N2 washout curve theoretically can resolve up to four modes of ventilation and reveal the major characteristics of the underlying distribution if experimental error is absent. This paper quantitatively assesses the effects of experimental error on resolution. The washout curves from five typical distributions were studied using linear programming and Monte Carlo methods. A measurement error of 0.1% was assumed in the mixed-expired N2 signal. Only 7 of the first 17 breaths contribute independent information about the underlying distribution, and only rough resolution of the underlying distribution is possible in the presence of error. Only two modes of ventilation plus an estimate of dead space can be confidently resolved. It is not possible to separate VA/V greater than 10 from dead space. A 10-fold reduction in experimental error will not greatly improve resolution. Experimental error, by reducing the linear independence of the defining kernels, significantly limits the information content and resolution of the multibreath N2 washout.

Gas transport in the human lung.

Gas transport in the human lung.