A novel method for tracking nitrogen kinetics in vivo under hyperbaric conditions using radioactive nitrogen-13 gas and positron emission tomography.

Decompression sickness (DCS) is caused by gaseous nitrogen dissolved in tissues forming bubbles during decompression. To date, no method exists to identify nitrogen within tissues, but with advances in positron-emission tomography (PET) technology, it may be possible to track gaseous radionuclides into tissues. We aimed to develop a method to track nitrogen movement in vivo and under hyperbaric pressure that could then be used to further our understanding of DCS using nitrogen-13 (13N2). A single anesthetized female Sprague-Dawley rat was exposed to 625 kPa, composed of air, isoflurane, and 13N2 for 10 min. The PET scanner recorded 13N2 during the hyperbaric exposure with energy windows of 250-750 keV. The PET showed an increase in 13N2 concentration in the lung, heart, and abdominal regions, which all reached a plateau after ∼4 min. This showed that it is possible to gain noninvasive in vivo measurements of nitrogen kinetics through the body while at hyperbaric pressures. Tissue samples showed radioactivity above background levels in the blood, brain, liver, femur, and thigh muscle when assessed using a γ counter. The method can be used to evaluate an array of challenges to our understanding of decompression physiology by quantifying nitrogen load through γ counts of 13N2, and signal intensity of the PET. Further development of the method will improve the specificity of the measured outcomes, and enable it to be used with larger mammals, including humans.NEW & NOTEWORTHY This article describes a method for the in vivo quantification and tracking of nitrogen through the mammalian body whilst exposed to hyperbaric pressure. The method has the potential to further our understanding of decompression sickness, and quantitatively evaluate the effectiveness of both the treatment and prevention of decompression sickness.

Machine learning with multimodal data for COVID-19.

In response to the unprecedented global healthcare crisis of the COVID-19 pandemic, the scientific community has joined forces to tackle the challenges and prepare for future pandemics. Multiple modalities of data have been investigated to understand the nature of COVID-19. In this paper, MIDRC investigators present an overview of the state-of-the-art development of multimodal machine learning for COVID-19 and model assessment considerations for future studies. We begin with a discussion of the lessons learned from radiogenomic studies for cancer diagnosis. We then summarize the multi-modality COVID-19 data investigated in the literature including symptoms and other clinical data, laboratory tests, imaging, pathology, physiology, and other omics data. Publicly available multimodal COVID-19 data provided by MIDRC and other sources are summarized. After an overview of machine learning developments using multimodal data for COVID-19, we present our perspectives on the future development of multimodal machine learning models for COVID-19.

Longitudinal assessment of demographic representativeness in the Medical Imaging and Data Resource Center open data commons.

Purpose: The Medical Imaging and Data Resource Center (MIDRC) open data commons was launched to accelerate the development of artificial intelligence (AI) algorithms to help address the COVID-19 pandemic. The purpose of this study was to quantify longitudinal representativeness of the demographic characteristics of the primary MIDRC dataset compared to the United States general population (US Census) and COVID-19 positive case counts from the Centers for Disease Control and Prevention (CDC). Approach: The Jensen-Shannon distance (JSD), a measure of similarity of two distributions, was used to longitudinally measure the representativeness of the distribution of (1) all unique patients in the MIDRC data to the 2020 US Census and (2) all unique COVID-19 positive patients in the MIDRC data to the case counts reported by the CDC. The distributions were evaluated in the demographic categories of age at index, sex, race, ethnicity, and the combination of race and ethnicity. Results: Representativeness of the MIDRC data by ethnicity and the combination of race and ethnicity was impacted by the percentage of CDC case counts for which this was not reported. The distributions by sex and race have retained their level of representativeness over time. Conclusion: The representativeness of the open medical imaging datasets in the curated public data commons at MIDRC has evolved over time as the number of contributing institutions and overall number of subjects have grown. The use of metrics, such as the JSD support measurement of representativeness, is one step needed for fair and generalizable AI algorithm development.

Toward fairness in artificial intelligence for medical image analysis: identification and mitigation of potential biases in the roadmap from data collection to model deployment.

Purpose: To recognize and address various sources of bias essential for algorithmic fairness and trustworthiness and to contribute to a just and equitable deployment of AI in medical imaging, there is an increasing interest in developing medical imaging-based machine learning methods, also known as medical imaging artificial intelligence (AI), for the detection, diagnosis, prognosis, and risk assessment of disease with the goal of clinical implementation. These tools are intended to help improve traditional human decision-making in medical imaging. However, biases introduced in the steps toward clinical deployment may impede their intended function, potentially exacerbating inequities. Specifically, medical imaging AI can propagate or amplify biases introduced in the many steps from model inception to deployment, resulting in a systematic difference in the treatment of different groups. Approach: Our multi-institutional team included medical physicists, medical imaging artificial intelligence/machine learning (AI/ML) researchers, experts in AI/ML bias, statisticians, physicians, and scientists from regulatory bodies. We identified sources of bias in AI/ML, mitigation strategies for these biases, and developed recommendations for best practices in medical imaging AI/ML development. Results: Five main steps along the roadmap of medical imaging AI/ML were identified: (1) data collection, (2) data preparation and annotation, (3) model development, (4) model evaluation, and (5) model deployment. Within these steps, or bias categories, we identified 29 sources of potential bias, many of which can impact multiple steps, as well as mitigation strategies. Conclusions: Our findings provide a valuable resource to researchers, clinicians, and the public at large.

Special Section Guest Editorial: Global Health, Bias, and Diversity in AI in Medical Imaging.

The editorial comments on the JMI Special Section on Global Health, Bias, and Diversity in AI in Medical Imaging.

Measuring short-term changes in specific ventilation using dynamic specific ventilation imaging.

Specific ventilation imaging (SVI) measures the spatial distribution of specific ventilation (SV) in the lung with MRI by using inhaled oxygen as a contrast agent. Because of the inherently low signal-to-noise ratio in the technique, multiple switches between inspiring air and O2 are utilized, and the high spatial resolution SV distribution is determined as an average over the entire imaging period (∼20 min). We hypothesized that a trade-off between spatial and temporal resolution could allow imaging at a higher temporal resolution, at the cost of a coarser, yet acceptable, spatial resolution. The appropriate window length and spatial resolution compromise were determined by generating synthetic data with signal- and contrast-to-noise characteristics reflective of that in previously published experimental data, with a known and unchanging distribution of SV, and showed that acceptable results could be obtained in an imaging period of ∼7 min (80 breaths), with a spatial resolution of ∼1 cm3. Previously published data were then reanalyzed. The average heterogeneity of the temporally resolved maps of SV was not different from the previous overall analysis, however, the temporally resolved maps were less effective at detecting the amount of bronchoconstriction resulting from methacholine administration. The results further indicated that the initial response to inhaled methacholine and subsequent inhalation of albuterol were largely complete within ∼22 min and ∼9 min, respectively, although there was a tendency for an ongoing developing effect in both cases. These results suggest that it is feasible to use a shortened SVI protocol, with a modest sacrifice in spatial resolution, to measure temporally dynamic processes.NEW & NOTEWORTHY Dynamic imaging providing maps of specific ventilation with a temporal resolution of ∼7 min with a spatial resolution of ∼1 cm3 using MRI was shown to be practical. The technique provides an ionizing radiation free means of temporally following the spatial pattern of specific ventilation. Reanalysis of previously published data showed that the effects of inhaled methacholine and albuterol were largely complete at ∼22 min and ∼9 min, respectively after administration.

Prone positioning redistributes gravitational stress in the lung in normal conditions and in simulations of oedema.

NEW FINDINGS: What is the central question of this study? How does the interaction between posture and gravity affect the stresses on the lung, particularly in highly inflated gravitationally non-dependent regions, which are potentially vulnerable to increased mechanical stress and injury? What is the main finding and its importance? Changes in stress attributable to gravity are not well characterized between postures. Using a new metric of gravitational stress, we show that regions of the lung near maximal inflation have the greatest gravitational stresses while supine, but not while prone. In simulations of increased lung weight consistent with severe pulmonary oedema, the prone lung has lower gravitational stress in vulnerable, non-dependent regions, potentially protecting them from overinflation and injury. ABSTRACT: Prone posture changes the gravitational vector, and potentially the stress induced by tissue deformation, because a larger lung volume is gravitationally dependent when supine, but non-dependent when prone. To evaluate this, 10 normal subjects (six male and four female; age, means ± SD = 27 ± 6 years; height, 171 ± 9 cm; weight, 69 ± 13 kg; forced expiratory volume in the first second/forced expiratory volume as a percentage of predicted, 93 ± 6%) were imaged at functional residual capacity, supine and prone, using magnetic resonance imaging, to quantify regional lung density. We defined regional gravitational stress as the cumulative weight, per unit area, of the column of lung tissue below each point. Gravitational stress was compared between regions of differing inflation to evaluate differences between highly stretched, and thus potentially vulnerable, regions and less stretched lung. Using reference density values for normal lungs at total lung capacity (0.10 ± 0.03 g/ml), regions were classified as highly inflated (density < 0.13 g/ml, i.e., close to total lung capacity), intermediate (0.13 ≤ density < 0.16 g/ml) or normally inflated (density ≥ 0.16 g/ml). Gravitational stress differed between inflation categories while supine (-1.6 ± 0.3 cmH2 O highly inflated; -1.4 ± 0.3 cmH2 O intermediate; -1.1 ± 0.1 cmH2 O normally inflated; P = 0.05) but not while prone (-1.4 ± 0.2 cmH2 O highly inflated; -1.3 ± 0.2 cmH2 O intermediate; -1.3 ± 0.1 cmH2 O normally inflated; P = 0.39), and increased more with height from dependent lung while supine (-0.24 ± 0.02 cmH2 O/cm supine; -0.18 ± 0.04 cmH2 O/cm prone; P = 0.05). In simulated severe pulmonary oedema, the gradient in gravitational stress increased in both postures (all P < 0.0001), was greater in the supine posture than when prone (-0.57 ± 0.21 cmH2 O/cm supine; -0.34 ± 0.16 cmH2 O/cm prone; P = 0.0004) and was similar to the gradient calculated from supine computed tomography images in a patient with acute respiratory distress syndrome (-0.51 cmH2 O/cm). The non-dependent lung has greater gravitational stress while supine and might be protected while prone, particularly in the presence of oedema.

Abnormal pulmonary perfusion heterogeneity in patients with Fontan circulation and pulmonary arterial hypertension.

KEY POINTS: The distribution of pulmonary perfusion is affected by gravity, vascular branching structure and active regulatory mechanisms, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. We evaluated pulmonary perfusion in patients who had undergone Fontan procedure, patients with pulmonary arterial hypertension (PAH) and two groups of controls using a proton magnetic resonance imaging technique, arterial spin labelling to measure perfusion. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Gravitational gradients were similar between all groups, but heterogeneity was significantly increased in both patient groups compared to controls and persisted after removing contributions from large blood vessels and gravitational gradients. Patients with Fontan physiology and patients with PAH have increased pulmonary perfusion heterogeneity that is not explainable by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects vascular remodelling in PAH and possibly in Fontan physiology. ABSTRACT: Many factors affect the distribution of pulmonary perfusion, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. An example is following the Fontan procedure, where pulmonary perfusion is passive, and heterogeneity may be increased because of the underlying pathophysiology leading to Fontan palliation, remodelling, or increased gravitational gradients from low flow. Another is pulmonary arterial hypertension (PAH), where gravitational gradients may be reduced secondary to high pressures, but remodelling may increase perfusion heterogeneity. We evaluated regional pulmonary perfusion in Fontan patients (n = 5), healthy young controls (Fontan control, n = 5), patients with PAH (n = 6) and healthy older controls (PAH control) using proton magnetic resonance imaging. Regional perfusion was measured using arterial spin labelling. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Mean perfusion was similar (Fontan = 2.50 ± 1.02 ml min-1  ml-1 ; Fontan control = 3.09 ± 0.58, PAH = 3.63 ± 1.95; PAH control = 3.98 ± 0.91, P = 0.26), and the slopes of gravitational gradients were not different (Fontan = -0.23 ± 0.09 ml min-1  ml-1  cm-1 ; Fontan control = -0.29 ± 0.23, PAH = -0.27 ± 0.09, PAH control = -0.25 ± 0.18, P = 0.91) between groups. Perfusion relative dispersion was greater in both Fontan and PAH than controls (Fontan = 1.46 ± 0.18; Fontan control = 0.99 ± 0.21, P = 0.005; PAH = 1.22 ± 0.27, PAH control = 0.91 ± 0.12, P = 0.02) but similar between patient groups (P = 0.13). These findings persisted after removing contributions from large blood vessels and gravitational gradients (all P < 0.05). We conclude that patients with Fontan physiology and PAH have increased pulmonary perfusion heterogeneity that is not explained by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects the effects of remodelling in PAH and possibly in Fontan physiology.

Vaping disrupts ventilation-perfusion matching in asymptomatic users.

Inhalation of e-cigarette's aerosols (vaping) has the potential to disrupt pulmonary gas exchange, but the effects in asymptomatic users are unknown. We assessed ventilation-perfusion (V̇A/Q̇) mismatch in asymptomatic e-cigarette users, using magnetic resonance imaging (MRI). We hypothesized that vaping induces V̇A/Q̇ mismatch through alterations in both ventilation and perfusion distributions. Nine young, asymptomatic "Vapers" with >1-yr vaping history, and no history of cardiopulmonary disease, were imaged supine using proton MRI, to assess the right lung at baseline and immediately after vaping. Seven young "Controls" were imaged at baseline only. Relative dispersion (SD/means) was used to quantify the heterogeneity of the individual ventilation and perfusion distributions. V̇A/Q̇ mismatch was quantified using the second moments of the ventilation and perfusion versus V̇A/Q̇ ratio distributions, log scale, LogSDV̇, and LogSDQ̇, respectively, analogous to the multiple inert gas elimination technique. Spirometry was normal in both groups. Ventilation heterogeneity was similar between groups at baseline (Vapers, 0.43 ± 0.13; Controls, 0.51 ± 0.11; P = 0.13) but increased after vaping (to 0.57 ± 0.17; P = 0.03). Perfusion heterogeneity was greater (P = 0.04) in Vapers at baseline (0.53 ± 0.06) compared with Controls (0.44 ± 0.10) but decreased after vaping (to 0.42 ± 0.07; P = 0.005). Vapers had greater (P = 0.01) V̇A/Q̇ mismatch at baseline compared with Controls (LogSDQ̇ = 0.61 ± 0.12 vs. 0.43 ± 0.12), which was increased after vaping (LogSDQ̇ = 0.73 ± 0.16; P = 0.03). V̇A/Q̇ mismatch is greater in Vapers and worsens after vaping. This suggests subclinical alterations in lung function not detected by spirometry.NEW & NOTEWORTHY This research provides evidence of vaping-induced disruptions in ventilation-perfusion matching in young, healthy, asymptomatic adults with normal spirometry who habitually vape. The changes in ventilation and perfusion distributions, both at baseline and acutely after vaping, and the potential implications on hypoxic vasoconstriction are particularly relevant in understanding the pathogenesis of vaping-induced dysfunction. Our imaging-based approach provides evidence of potential subclinical alterations in lung function below thresholds of detection using spirometry.

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.

Ventilation-perfusion heterogeneity measured by the multiple inert gas elimination technique is minimally affected by intermittent breathing of 100% O2.

Proton magnetic resonance (MR) imaging to quantify regional ventilation-perfusion ( V˙A/Q˙ ) ratios combines specific ventilation imaging (SVI) and separate proton density and perfusion measures into a composite map. Specific ventilation imaging exploits the paramagnetic properties of O2 , which alters the local MR signal intensity, in an FI O2 -dependent manner. Specific ventilation imaging data are acquired during five wash-in/wash-out cycles of breathing 21% O2 alternating with 100% O2 over ~20 min. This technique assumes that alternating FI O2 does not affect V˙A/Q˙ heterogeneity, but this is unproven. We tested the hypothesis that alternating FI O2 exposure increases V˙A/Q˙ mismatch in nine patients with abnormal pulmonary gas exchange and increased V˙A/Q˙ mismatch using the multiple inert gas elimination technique (MIGET).The following data were acquired (a) breathing air (baseline), (b) breathing alternating air/100% O2 during an emulated-SVI protocol (eSVI), and (c) 20 min after ambient air breathing (recovery). MIGET heterogeneity indices of shunt, deadspace, ventilation versus V˙A/Q˙ ratio, LogSD V˙ , and perfusion versus V˙A/Q˙ ratio, LogSD Q˙ were calculated. LogSD V˙ was not different between eSVI and baseline (1.04 ± 0.39 baseline, 1.05 ± 0.38 eSVI, p = .84); but was reduced compared to baseline during recovery (0.97 ± 0.39, p = .04). There was no significant difference in LogSD Q˙ across conditions (0.81 ± 0.30 baseline, 0.79 ± 0.15 eSVI, 0.79 ± 0.20 recovery; p = .54); Deadspace was not significantly different (p = .54) but shunt showed a borderline increase during eSVI (1.0% ± 1.0 baseline, 2.6% ± 2.9 eSVI; p = .052) likely from altered hypoxic pulmonary vasoconstriction and/or absorption atelectasis. Intermittent breathing of 100% O2 does not substantially alter V˙A/Q˙ matching and if SVI measurements are made after perfusion measurements, any potential effects will be minimized.

Heavy upright exercise increases ventilation-perfusion mismatch in the basal lung: indirect evidence for interstitial pulmonary edema.

Ventilation-perfusion (V̇a/Q̇) mismatch during exercise may result from interstitial pulmonary edema if increased pulmonary vascular pressure causes fluid efflux into the interstitium. If present, the increased fluid may compress small airways or blood vessels, disrupting V̇a/Q̇ matching, but this is unproven. We hypothesized that V̇a/Q̇ mismatch would be greatest in basal lung following heavy upright exercise, consistent with hydrostatic forces favoring edema accumulation in the gravitationally dependent lung. We applied new tools to reanalyze previously published magnetic resonance imaging data to determine regional V̇a/Q̇ mismatch following 45 min of heavy upright exercise in six athletes (V̇o2max = 61 ± 7 mL·kg-1·min-1). In the supine posture, regional alveolar ventilation and local perfusion were quantified from specific ventilation imaging, proton density, and arterial spin labeling data in a single sagittal slice of the right lung before exercise (PRE), 15 min after exercise (POST), and in recovery 60 min after exercise (REC). Indices of V̇a/Q̇ mismatch [second moments (log scale) of ventilation (LogSDV) and perfusion (LogSDQ) vs. V̇a/Q̇ distributions] were calculated for apical, middle, and basal lung thirds, which represent gravitationally nondependent, middle, and dependent regions, respectively, during upright exercise. LogSDV increased after exercise only in the basal lung (PRE 0.46 ± 0.06, POST 0.57 ± 0.14, REC 0.55 ±0.14, P = 0.01). Similarly, LogSDQ increased only in the basal lung (PRE 0.40 ± 0.06, POST 0.51 ± 0.10, REC 0.44 ± 0.09, P = 0.04). Increased V̇a/Q̇ mismatch in the basal lung after exercise is potentially consistent with interstitial pulmonary edema accumulating in gravitationally dependent lung during exercise.NEW & NOTEWORTHY We reanalyzed previously published MRI data with new tools and found increased ventilation-perfusion mismatch only in the basal lung of athletes following 45 min of cycling exercise. This is consistent with the development of interstitial edema in the gravitationally dependent lung during heavy exercise.

The spatial pattern of methacholine bronchoconstriction recurs when supine independently of posture during provocation but does not recur between postures.

The location of lung regions with compromised ventilation (often called ventilation defects) during a bronchoconstriction event may be influenced by posture. We aimed to determine the effect of prone versus supine posture on the spatial pattern of methacholine-induced bronchoconstriction in six healthy adults (ages 21-41, 3 women) using specific ventilation imaging. Three postural conditions were chosen to assign the effect of posture to the drug administration and/or imaging phase of the experiment: supine methacholine administration followed by supine imaging, prone methacholine administration followed by supine imaging, and prone methacholine administration followed by prone imaging. The two conditions in which imaging was performed supine had similar spatial patterns of bronchoconstriction despite a change in posture during methacholine administration; the odds ratio for recurrent constriction was mean (SD) = 7.4 (3.9). Conversely, dissimilar spatial patterns of bronchoconstriction emerged when posture during imaging was changed; the odds ratio for recurrent constriction between the prone methacholine/supine imaging condition and the prone methacholine/prone imaging condition was 1.2 (0.9). Logistic regression showed that height above the dependent lung border was a significant negative predictor of constriction in the two supine imaging conditions (P < 0.001 for each) but not in the prone imaging condition (P = 0.20). These results show that the spatial pattern of methacholine bronchoconstriction is recurrent in the supine posture, regardless of whether methacholine is given prone or supine but that prone posture during imaging eliminates that recurrent pattern and reduces its dependence on gravitational height.NEW & NOTEWORTHY The spatial pattern of methacholine bronchoconstriction in the supine posture is recurrent and skewed toward the dependent lung, regardless of whether inhaled methacholine is administered while supine or while prone. However, both the recurrent pattern and the gravitational skew are eliminated if imaging is performed prone. These results suggest that gravitational influence on regional lung inflation and airway topography at the time of measurement play a role in determining regional bronchoconstriction in the healthy lung.

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.

Susceptibility to high-altitude pulmonary edema is associated with a more uniform distribution of regional specific ventilation.

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects (n = 6) compared with HAPE-resistant controls (n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes Scond and Sacin, respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and Sacin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). Scond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). Sacin and Scond did not change significantly in hypoxia (P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena.NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.

Advances in functional and structural imaging of the human lung using proton MRI.

The field of proton lung MRI is advancing on a variety of fronts. In the realm of functional imaging, it is now possible to use arterial spin labeling (ASL) and oxygen-enhanced imaging techniques to quantify regional perfusion and ventilation, respectively, in standard units of measurement. By combining these techniques into a single scan, it is also possible to quantify the local ventilation-perfusion ratio, which is the most important determinant of gas-exchange efficiency in the lung. To demonstrate potential for accurate and meaningful measurements of lung function, this technique was used to study gravitational gradients of ventilation, perfusion, and ventilation-perfusion ratio in healthy subjects, yielding quantitative results consistent with expected regional variations. Such techniques can also be applied in the time domain, providing new tools for studying temporal dynamics of lung function. Temporal ASL measurements showed increased spatial-temporal heterogeneity of pulmonary blood flow in healthy subjects exposed to hypoxia, suggesting sensitivity to active control mechanisms such as hypoxic pulmonary vasoconstriction, and illustrating that to fully examine the factors that govern lung function it is necessary to consider temporal as well as spatial variability. Further development to increase spatial coverage and improve robustness would enhance the clinical applicability of these new functional imaging tools. In the realm of structural imaging, pulse sequence techniques such as ultrashort echo-time radial k-space acquisition, ultrafast steady-state free precession, and imaging-based diaphragm triggering can be combined to overcome the significant challenges associated with proton MRI in the lung, enabling high-quality three-dimensional imaging of the whole lung in a clinically reasonable scan time. Images of healthy and cystic fibrosis subjects using these techniques demonstrate substantial promise for non-contrast pulmonary angiography and detailed depiction of airway disease. Although there is opportunity for further optimization, such approaches to structural lung imaging are ready for clinical testing.

Measuring lung water: ex vivo validation of multi-image gradient echo MRI.

PURPOSE: To validate a fast gradient echo sequence for rapid (9 s) quantitative imaging of lung water. MATERIALS AND METHODS: Eleven excised pig lungs were imaged with a fast GRE sequence in triplicate, in the sagittal plane at 2 levels of inflation pressure (5 and 15 cm H(2) O), an intervention that alters T(2) *, but not total lung water. Images were acquired alternating between two closely-spaced echoes and data were fit (voxel-by-voxel) to a single exponential to determine T(2) * and water content, and compared with gravimetric measurements of total water. RESULTS: T(2) * averaged 1.08 ± 0.02 ms at 5 cm H(2) O and 1.02 ± 0.02 ms at 15 cm H(2) O (P < 0.05). The measure was reliable (R(2) = 0.99), with an average mean error of 1.8%. There was a significant linear relationship between the two measures of water content: The regression equations for the relationship were y = 0.92x + 19 (R(2) = 0.94), and y = 1.04x + 4 (R(2) = 0.96), for 5 and 15 cm H(2) O inflation pressure respectively. Y-intercepts were not statistically different from zero (P = 0.86). CONCLUSION: The multi-echo GRE sequence is a reliable and valid technique to assess water content in the lung. This technique enables rapid assessment of lung water, which is advantageous for in vivo studies.