Beyond Spirometry: Linking Wasted Ventilation to Exertional Dyspnea in the Initial Stages of COPD.

Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV1.

Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (ß = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

A 3D stack-of-spirals approach for rapid hyperpolarized 129 Xe ventilation mapping in pediatric cystic fibrosis lung disease.

PURPOSE: To demonstrate the feasibility of a rapid 3D stack-of-spirals (3D-SoS) imaging acquisition for hyperpolarized 129 Xe ventilation mapping in healthy pediatric participants and pediatric cystic fibrosis (CF) participants, in comparison to conventional Cartesian multislice (2D) gradient-recalled echo (GRE) imaging. METHODS: The 2D-GRE and 3D-SoS acquisitions were performed in 13 pediatric participants (5 healthy, 8 CF) during separate breath-holds. Images from both sequences were compared on the basis of ventilation defect percent (VDP) and other measures of image similarity. The nadir of transient oxygen saturation (SpO2 ) decline due to xenon breath-holding was measured with pulse oximetry, and expressed as a percent change relative to baseline. RESULTS: 129 Xe ventilation images were acquired in a breath-hold of 1.2-1.8 s with the 3D-SoS sequence, compared to 6.2-8.8 s for 2D-GRE. Mean ± SD VDP measures for 2D-GRE and 3D-SoS sequences were 5.02 ± 1.06% and 5.28 ± 1.08% in healthy participants, and 18.05 ± 8.26% and 18.75 ± 6.74% in CF participants, respectively. Across all participants, the intraclass correlation coefficient of VDP measures for both sequences was 0.98 (95% confidence interval: 0.94-0.99). The percent change in SpO2 was reduced to -2.1 ± 2.7% from -5.2 ± 3.5% with the shorter 3D-SoS breath-hold. CONCLUSION: Hyperpolarized 129 Xe ventilation imaging with 3D-SoS yielded images approximately five times faster than conventional 2D-GRE, reducing SpO2 desaturation and improving tolerability of the xenon administration. Analysis of VDP and other measures of image similarity demonstrate excellent agreement between images obtained with both sequences. 3D-SoS holds significant potential for reducing the acquisition time of hyperpolarized 129 Xe MRI, and/or increasing spatial resolution while adhering to clinical breath-hold constraints.

Inter- and intravisit repeatability of free-breathing MRI in pediatric cystic fibrosis lung disease.

PURPOSE: The purpose of this study is to assess the intra- and interscan repeatability of free-breathing phase-resolved functional lung (PREFUL) MRI in stable pediatric cystic fibrosis (CF) lung disease in comparison to static breath-hold hyperpolarized 129-xenon MRI (Xe-MRI) and pulmonary function tests. METHODS: Free-breathing 1-hydrogen MRI and Xe-MRI were acquired from 15 stable pediatric CF patients and seven healthy age-matched participants on two visits, 1 month apart. Same-visit MRI scans were also performed on a subgroup of the CF patients. Following the PREFUL algorithm, regional ventilation (RVent) and regional flow volume loop cross-correlation maps were determined from the free-breathing data. Ventilation defect percentage (VDP) was determined from RVent maps (VDPRVent ), regional flow volume loop cross-correlation maps (VDPCC ), VDPRVent ∪ VDPCC , and multi-slice Xe-MRI. Repeatability was evaluated using Bland-Altman analysis, coefficient of repeatability (CR), and intraclass correlation. RESULTS: Minimal bias and no significant differences were reported for all PREFUL MRI and Xe-MRI VDP parameters between intra- and intervisits (all P > 0.05). Repeatability of VDPRVent , VDPCC , VDPRVent ∪ VDPCC , and multi-slice Xe-MRI were lower between the two-visit scans (CR = 14.81%, 15.36%, 16.19%, and 9.32%, respectively) in comparison to the same-day scans (CR = 3.38%, 2.90%, 1.90%, and 3.92%, respectively). pulmonary function tests showed high interscan repeatability relative to PREFUL MRI and Xe-MRI. CONCLUSION: PREFUL MRI, similar to Xe-MRI, showed high intravisit repeatability but moderate intervisit repeatability in CF, which may be due to inherent disease instability, even in stable patients. Thus, PREFUL MRI may be considered a suitable outcome measure for future treatment response studies.

Intra- and Inter-visit Repeatability of 129 Xenon Multiple-Breath Washout MRI in Children With Stable Cystic Fibrosis Lung Disease.

BACKGROUND: Multiple-breath washout (MBW) 129 Xe MRI (MBW Xe-MRI) is a promising technique for following pediatric cystic fibrosis (CF) lung disease progression. However, its repeatability in stable CF needs to be established to use it as an outcome measure for novel therapies. PURPOSE: To assess intravisit and intervisit repeatability of MBW Xe-MRI in healthy and CF children. STUDY TYPE: Prospective, longitudinal cohort study. SUBJECTS: A total of 18 pediatric subjects (7 healthy, 11 CF). FIELD STRENGTH/SEQUENCE: A 3 T/2D coronal hyperpolarized (HP) 129 Xe images using GRE sequence. ASSESSMENT: All subjects completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, nitrogen [N2 ] MBW for lung clearance index [LCI]) and ventilation defect percent (VDP) at baseline (visit 1) and 1-month after. Fractional ventilation (FV), coefficient of variation (CoVFV ) maps were calculated from MBW Xe-MRI data acquired between intervening air washout breaths performed after an initial xenon breath-hold. Skewness of FV and CoVFV map distributions was also assessed. STATISTICAL TESTS: Repeatability: intraclass correlation coefficients (ICC), within-subject coefficient of variation (CV%), repeatability coefficient (CR). Agreement: Bland-Altman. For correlations between MBW Xe-MRI, VDP and PFTs: Spearman's correlation. Significance threshold: P < 0.05. RESULTS: For FV, intravisit median [IQR] ICC was high in both healthy (0.94 [0.48, 0.99]) and CF (0.83 [0.04, 0.97]) subjects. CoVFV also had good intravisit ICC in healthy (0.92 [0.42, 0.99]) and CF (0.79 [0.02, 0.96]) subjects. Similarly, for FV, intervisit ICC was high in health (0.94 [0.68, 0.99]) and CF (0.89 [0.61, 0.97]). CoVFV also had good intervisit ICC in health (0.92 [0.42, 0.99]) and CF (0.78 [0.26, 0.94]). FV had better intervisit repeatability than VDP. CoVFV correlated significantly with LCI (R = 0.56). Skewness of FV distributions significantly distinguished between cohorts at baseline. DATA CONCLUSION: MBW Xe-MRI had high intravisit and intervisit repeatability in healthy and stable CF subjects. CoVFV correlated with LCI, suggesting the importance of ventilation heterogeneity to early CF. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 2.

L-citrulline attenuates lipopolysaccharide-induced inflammatory lung injury in neonatal rats.

BACKGROUND: Prenatal or postnatal lung inflammation and oxidative stress disrupt alveolo-vascular development leading to bronchopulmonary dysplasia (BPD) with and without pulmonary hypertension. L-citrulline (L-CIT), a nonessential amino acid, alleviates inflammatory and hyperoxic lung injury in preclinical models of BPD. L-CIT modulates signaling pathways mediating inflammation, oxidative stress, and mitochondrial biogenesis-processes operative in the development of BPD. We hypothesize that L-CIT will attenuate lipopolysaccharide (LPS)-induced inflammation and oxidative stress in our rat model of neonatal lung injury. METHODS: Newborn rats during the saccular stage of lung development were used to investigate the effect of L-CIT on LPS-induced lung histopathology and pathways involved in inflammatory, antioxidative processes, and mitochondrial biogenesis in lungs in vivo, and in primary culture of pulmonary artery smooth muscle cells, in vitro. RESULTS: L-CIT protected the newborn rat lung from LPS-induced: lung histopathology, ROS production, NFκB nuclear translocation, and upregulation of gene and protein expression of inflammatory cytokines (IL-1ß, IL-8, MCP-1α, and TNF-α). L-CIT maintained mitochondrial morphology, increased protein levels of PGC-1α, NRF1, and TFAM (transcription factors involved in mitochondrial biogenesis), and induced SIRT1, SIRT3, and superoxide dismutases protein expression. CONCLUSION: L-CIT may be efficacious in decreasing early lung inflammation and oxidative stress mitigating progression to BPD. IMPACT: The nonessential amino acid L-citrulline (L-CIT) mitigated lipopolysaccharide (LPS)-induced lung injury in the early stage of lung development in the newborn rat. This is the first study describing the effect of L-CIT on the signaling pathways operative in bronchopulmonary dysplasia (BPD) in a preclinical inflammatory model of newborn lung injury. If our findings translate to premature infants, L-CIT could decrease inflammation, oxidative stress and preserve mitochondrial health in the lung of premature infants at risk for BPD.

Sleep-disordered breathing symptoms and their association with structural and functional pulmonary changes in children born extremely preterm.

This study aimed to evaluate symptoms of sleep-disordered breathing (SDB) among children born extremely preterm, with and without a history of bronchopulmonary dysplasia (BPD), including associations between sleep and respiratory symptoms, physical activity, pulmonary function, and pulmonary magnetic resonance imaging (MRI). This multi-center cross-sectional study enrolled children aged 7-9 years born extremely preterm with and without BPD. Participants completed the Pediatric Sleep Questionnaire (PSQ), the modified Epworth sleepiness scale, a respiratory symptom questionnaire, pedometer measurements, pulmonary function testing, and pulmonary MRI. Spearman's correlations and univariate and multivariable linear regression modelling were performed. Twenty-eight of 45 children included had a history of moderate-to-severe BPD. The prevalence of sleep-related symptoms was low, with the exception of hyperactivity and inattention. There were no differences in mean (SD) scores on sleep questionnaires in children with and without BPD (PSQ: 0.21 (0.13) vs 0.16 (0.14), p = 0.3; modified Epworth: 2.4 (2.4) vs 1.8 (2.8), p = 0.4). Multiple regression analyses examining difference in sleep scores between groups, adjusting for gestational age and intraventricular hemorrhage, found no statistical difference (p > 0.05). Greater daytime sleepiness was moderately correlated with FEV1%-predicted (r = - 0.52); no other moderate-strong associations were identified.  Conclusions: There was no evidence of clinically important differences in sleep symptoms between children with and without BPD, suggesting that sleep symptoms may be related to prematurity-related factors other than a BPD diagnosis, including airflow limitation. Further research is necessary to explore the relationship between sleep symptoms, airway obstruction, and neurobehavioral symptoms among premature-born children.  Trial registration: NCT02921308. Date of registration: October 3, 2016. What is Known: • Presence of bronchopulmonary dysplasia (BPD) may further contribute to the development of SDB, though its impact is not well-studied. • Premature-born children have a greater risk of lung structural and functional differences, including sleep-disordered breathing (SDB). What is New: • There was no difference in sleep symptoms between children with and without BPD, suggesting that sleep symptoms are related to other prematurity-related factors, such as airflow limitation. • Greater daytime sleepiness was correlated with lower FEV1 in our population, which reflects greater airflow limitation.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

Hyperpolarized 129 Xe MRI of the rat brain with chemical shift saturation recovery and spiral-IDEAL readout.

PURPOSE: To demonstrate the feasibility of 129 Xe chemical shift saturation recovery (CSSR) combined with spiral-IDEAL imaging for simultaneous measurement of the time-course of red blood cell (RBC) and brain tissue signals in the rat brain. METHODS: Images of both the RBC and brain tissue 129 Xe signals from the brains of five rats were obtained using interleaved spiral-IDEAL imaging following chemical shift saturation pulses applied at multiple CSSR delay times, τ. A linear fit of the signals to τ was used to calculate the slope of the signal for both RBC and brain tissue compartments on a voxel-by-voxel basis. Gas transfer was evaluated by measuring the ratio of the whole brain tissue-to-RBC signal intensities as a function of τ. To investigate the relationship between the CSSR images and gas transfer in the brain, the experiments were repeated during hypercapnic ventilation. RESULTS: Hypercapnia, affected the ratio of the tissue-to-RBC signal intensity (p = 0.026), consistent with an increase in gas transfer. CONCLUSION: CSSR with spiral-IDEAL imaging is feasible for acquisition of 129 Xe RBC and brain tissue time-course images in the rat brain. Differences in the time-course of the signal intensity ratios are consistent with gas transfer changes expected under hypercapnic conditions.

Clinical Feasibility of Structural and Functional MRI in Free-Breathing Neonates and Infants.

BACKGROUND: Evaluation of structural lung abnormalities with magnetic resonance imaging (MRI) has previously been shown to be predictive of clinical neonatal outcomes in preterm birth. MRI during free-breathing with phase-resolved functional lung (PREFUL) may allow for complimentary functional information without exogenous contrast. PURPOSE: To investigate the feasibility of structural and functional pulmonary MRI in a cohort of neonates and infants with no cardiorespiratory disease. Macrovascular pulmonary blood flows were also evaluated. STUDY TYPE: Prospective. POPULATION: Ten term infants with no clinically defined cardiorespiratory disease were imaged. Infants recruited from the general population and neonatal intensive care unit (NICU) were studied. FIELD STRENGTH/SEQUENCE: T1 -weighted VIBE, T2 -weighted BLADE uncorrected for motion. Ultrashort echo time (UTE) and 3D-flow data were acquired during free-breathing with self-navigation and retrospective reconstruction. Single slice 2D-gradient echo (GRE) images were acquired during free-breathing for PREFUL analysis. Imaging was performed at 3 T. ASSESSMENT: T1 , T2 , and UTE images were scored according to the modified Ochiai scheme by three pediatric body radiologists. Ventilation/perfusion-weighted maps were extracted from free-breathing GRE images using PREFUL analysis. Ventilation and perfusion defect percent (VDP, QDP) were calculated from the segmented ventilation and perfusion-weighted maps. Time-averaged cardiac blood velocities from three-dimensional-flow were evaluated in major pulmonary arteries and veins. STATISTICAL TEST: Intraclass correlation coefficient (ICC). RESULTS: The ICC of replicate structural scores was 0.81 (95% CI: 0.45-0.95) across three observers. Elevated Ochiai scores, VDP, and QDP were observed in two NICU participants. Excluding these participants, mean ± standard deviation structural scores were 1.2 ± 0.8, while VDP and QDP were 1.0% ± 1.1% and 0.4% ± 0.5%, respectively. Main pulmonary arterial blood flows normalized to body surface area were 3.15 ± 0.78 L/min/m2 . DATA CONCLUSION: Structural and functional pulmonary imaging is feasible using standard clinical MRI hardware (commercial whole-body 3 T scanner, table spine array, and flexible thoracic array) in free-breathing infants. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Hyperpolarized 129Xe magnetic resonance spectroscopy in a rat model of bronchopulmonary dysplasia.

Premature infants often require mechanical ventilation and oxygen therapy, which can result in bronchopulmonary dysplasia (BPD), characterized by developmental arrest and impaired lung function. Conventional clinical methods for assessing the prenatal lung are not adequate for the detection and assessment of long-term health risks in infants with BPD, highlighting the need for a noninvasive tool for the characterization of lung microstructure and function. Theoretical diffusion models, like the model of xenon exchange (MOXE), interrogate alveolar gas exchange by predicting the uptake of inert hyperpolarized (HP) 129Xe gas measured with HP 129Xe magnetic resonance spectroscopy (MRS). To investigate HP 129Xe MRS as a tool for noninvasive characterization of pulmonary microstructural and functional changes in vivo, HP 129Xe gas exchange data were acquired in an oxygen exposure rat model of BPD that recapitulates the fewer and larger distal airways and pulmonary vascular stunting characteristics of BPD. Gas exchange parameters from MOXE, including airspace mean chord length (Lm), apparent hematocrit in the pulmonary capillaries (HCT), and pulmonary capillary transit time (tx), were compared with airspace mean axis length and area density (MAL and ρA) and percentage area of tissue and air (PTA and PAA) from histology. Lm was significantly larger in the exposed rats (P = 0.003) and correlated with MAL, ρA, PTA, and PAA (0.59<|ρ|<0.66 and P < 0.05). Observed increase in HCT (P = 0.012) and changes in tx are also discussed. These findings support the use of HP 129Xe MRS for detecting fewer, enlarged distal airways in this rat model of BPD, and potentially in humans.

Effect of inhaled oxygen concentration on 129 Xe chemical shift of red blood cells in rat lungs.

PURPOSE: To investigate the dependence of dissolved 129 Xe chemical shift on the fraction of inhaled oxygen, Fi O2 , in the lungs of healthy rats. METHODS: The chemical shifts of 129 Xe dissolved in red blood cells, δRBC , and blood plasma and/or tissue, δPlasma , were measured using MRS in 12 Sprague Dawley rats mechanically ventilated at Fi O2 values of 0.14, 0.19, and 0.22. Regional effects on the chemical shifts were controlled using a chemical shift saturation recovery sequence with a fixed delay time. MRS was also performed at an Fi CO2 value of 0.085 to investigate the potential effect of the vascular response on δRBC and δPlasma . RESULTS: δRBC increased with decreasing Fi O2 (P = .0002), and δPlasma showed no dependence on Fi O2 (P = .23). δRBC at Fi CO2 = 0 (210.7 ppm ± 0.1) and at Fi CO2 = 0.085 (210.6 ppm ± 0.2) were not significantly different (P = .67). δPlasma at Fi CO2 = 0 (196.9 ppm ± 0.3) and at Fi CO2 = 0.085 (197.0 ppm ± 0.1) were also not significantly different (P = .81). CONCLUSION: Rat lung δRBC showed an inverse relationship to Fi O2 , opposite to the relationship previously demonstrated for in vitro human blood. Rat lung δRBC did not depend on Fi CO2 .

Protocols for multi-site trials using hyperpolarized 129 Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129 Xe MRI clinical trials consortium.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Application of a stretched-exponential model for morphometric analysis of accelerated diffusion-weighted 129Xe MRI of the rat lung.

OBJECTIVE: Diffusion-weighted, hyperpolarized 129Xe MRI is useful for the characterization of microstructural changes in the lung. A stretched exponential model was proposed for morphometric extraction of the mean chord length (Lm) from diffusion-weighted data. The stretched exponential model enables accelerated mapping of Lm in a single-breathhold using compressed sensing. Our purpose was to compare Lm maps obtained from stretched-exponential model analysis of accelerated versus unaccelerated diffusion-weighted 129Xe MRI data obtained from healthy/injured rat lungs. MATERIAL AND METHODS: Lm maps were generated using a stretched-exponential model analysis of previously acquired fully sampled diffusion-weighted 129Xe rat data (b values = 0 … 110 s/cm2) and compared to Lm maps generated from retrospectively undersampled data simulating acceleration factors of 7/10. The data included four control rats and five rats receiving whole-lung irradiation to mimic radiation-induced lung injury. Mean Lm obtained from the accelerated/unaccelerated maps were compared to histological mean linear intercept. RESULTS: Accelerated Lm estimates were similar to unaccelerated Lm estimates in all rats, and similar to those previously reported (< 12% different). Lm was significantly reduced (p < 0.001) in the irradiated rat cohort (90 ± 20 µm/90 ± 20 µm) compared to the control rats (110 ± 20 µm/100 ± 15 µm) and agreed well with histological mean linear intercept. DISCUSSION: Accelerated mapping of Lm using a stretched-exponential model analysis is feasible, accurate and agrees with histological mean linear intercept. Acceleration reduces scan time, thus should be considered for the characterization of lung microstructural changes in humans where breath-hold duration is short.

Hyperpolarized 129 Xe imaging of embryonic stem cell-derived alveolar-like macrophages in rat lungs: proof-of-concept study using superparamagnetic iron oxide nanoparticles.

PURPOSE: To measure regional changes in hyperpolarized 129 Xe MRI signal and apparent transverse relaxation ( T2∗ ) because of instillation of SPION-labeled alveolar-like macrophages (ALMs) in the lungs of rats and compare to histology. METHODS: MRI was performed in 6 healthy mechanically ventilated rats before instillation, as well as 5 min and 1 h after instillation of 4 million SPION-labeled ALMs into either the left or right lung. T2∗ maps were calculated from 2D multi-echo data at each time point and changes in T2∗ were measured and compared to control rats receiving 4 million unlabeled ALMs. Histology of the ex vivo lungs was used to compare the regional MRI findings with the locations of the SPION-labeled ALMs. RESULTS: Regions of signal loss were observed immediately after instillation of unlabeled and SPION-labeled ALMs and persisted at least 1 h in the case of the SPION-labeled ALMs. This was reflected in the measurements of T2∗ . One hour after the instillation of SPION-labeled ALMs, the T2∗ decreased to 54.0 ± 7.0% of the baseline, compared to a full recovery to baseline after the instillation of unlabeled ALMs. Histology confirmed the co-localization of SPION-labeled ALMs with regions of signal loss and T2∗ decreases for each rat. CONCLUSION: Hyperpolarized 129 Xe MRI can detect the presence of SPION-labeled ALMs in the airways 1 h after instillation. This approach is promising for targeting and tracking of stem cells for the treatment of lung disease.

Assessing the feasibility of hyperpolarized 129 Xe multiple-breath washout MRI in pediatric cystic fibrosis.

PURPOSE: To assess the feasibility of hyperpolarized 129 Xe multiple-breath washout MRI in pediatric cystic fibrosis (CF) participants with preserved lung function. Fractional ventilation (r), defined as the fractional gas replacement per breath, was mapped using 2 signal models: (1) constant T1 and (2) variable T1 as a function of the hyperpolarized gas washout. METHODS: A total of 17 pediatric participants were recruited (mean age 11.7 ± 2.8 years), including 7 children with clinically stable CF and 10 aged-matched healthy controls. Pulmonary function tests were performed, including spirometry, to measure the forced expiratory volume in 1 second and nitrogen multiple-breath washout to measure the lung clearance index. Hyperpolarized 129 Xe MRI was performed during consecutive breaths of air following a single 129 Xe inhalation, and fractional ventilation maps were calculated. RESULTS: The forced expiratory volume in 1 second was similar in both groups (P = .32), but there was a statistically significant difference in lung clearance index between healthy and CF participants (P = .001). With variable T1 modeling, CF participants had a mean r of 0.44 ± 0.08 and healthy participants had a mean r of 0.37 ± 0.12 (P = .20). With constant T1 modeling, CF participants had a mean r' of 0.48 ± 0.08, and healthy participants had a mean r' of 0.43 ± 0.12 (P = .32). Therefore, assuming a constant T1 leads to a relative bias in r of 15.1% ± 6.4% and 20.8% ± 7.4% for CF and healthy participants, respectively (P = .12). CONCLUSION: This study demonstrates that hyperpolarized 129 Xe multiple-breath washout imaging is feasible in pediatric participants with CF, and inclusion of variable T1 modeling reduces bias in the fractional ventilation measurements.

Chemical shift of 129 Xe dissolved in red blood cells: Application to a rat model of bronchopulmonary dysplasia.

PURPOSE: To measure the chemical shift of hyperpolarized 129 Xe dissolved in the red blood cells(δRBC ) of a cohort of rats exposed to hyperoxia and intermittent hypoxia (IH) to mimic human bronchopulmonary dysplasia, and to investigate the effect of xenon-blood distribution time on δRBC . METHODS: δRBC was measured from spectra acquired using a chemical shift saturation recovery sequence from 15 Sprague-Dawley rats exposed to hyperoxia-IH and 10 age-matched control rats. Sensitization to the xenon-blood distribution time was achieved by varying the time between saturation pulses, τ. δRBC was compared with blood fraction measured by histology of the cohort and blood oxygenation measured directly using pulse oximetry following a hypoxic challenge in an identically exposed cohort. RESULTS: The mean δRBC in the hyperoxia-IH exposed rats was 0.55 ± 0.04 ppm lower than that of the healthy cohort (P = .0038), and this difference did not depend on τ (P = .996). The blood fraction of the exposed cohort was lower than that of the healthy cohort (P = .0397). Oximetry measurements showed that the baseline arterial oxygen saturation (Sa O2 ) of each cohort was not different (P = .72), but after a hypoxic challenge, the Sa O2 of the exposed cohort was lower than that of the healthy cohort (P = .003). CONCLUSION: δRBC is reduced in rats exposed to hyperoxia-IH compared with control rats. The change in δRBC is consistent with enhanced blood oxygen desaturation of the exposed cohort measured by pulse oximetry during a hypoxic challenge. This suggests that the observed change in δRBC reflects enhanced desaturation in the hyperoxia-IH exposed cohort compared with the healthy cohort.

Hyperpolarised 129Xe magnetic resonance imaging to monitor treatment response in children with cystic fibrosis.

Pulmonary magnetic resonance imaging using hyperpolarised 129Xe gas (XeMRI) can quantify ventilation inhomogeneity by measuring the percentage of unventilated lung volume (ventilation defect per cent (VDP)). While previous studies have demonstrated its sensitivity for detecting early cystic fibrosis (CF) lung disease, the utility of XeMRI to monitor response to therapy in CF is unknown. The aim of this study was to assess the ability of XeMRI to capture treatment response in paediatric CF patients undergoing inpatient antibiotic treatment for a pulmonary exacerbation.15 CF patients aged 8-18 years underwent XeMRI, spirometry, plethysmography and multiple-breath nitrogen washout at the beginning and end of inpatient treatment of a pulmonary exacerbation. VDP was calculated from XeMRI images obtained during a static breath hold using semi-automated k-means clustering and linear binning approaches.XeMRI was well tolerated. VDP, lung clearance index and the forced expiratory volume in 1 s all improved with treatment; however, response was not uniform in individual patients. Of all outcome measures, VDP showed the largest relative improvement (-42.1%, 95% CI -52.1--31.9%, p<0.0001).These data support further investigation of XeMRI as a tool to capture treatment response in CF lung disease.

Accelerated interleaved spiral-IDEAL imaging of hyperpolarized 129 Xe for parametric gas exchange mapping in humans.

PURPOSE: To demonstrate the feasibility of mapping gas exchange with single breath-hold hyperpolarized (HP) 129 Xe in humans, acquiring parametric maps of lung physiology. The potential benefit of acceleration using parallel imaging for this application is also explored. METHODS: Six healthy volunteers were scanned with a modified spiral-IDEAL sequence to acquire gas exchange-weighted images using a single dose of 129 Xe. These images were fit with the model of xenon exchange (MOXE) on a voxel-wise basis calculating parametric maps of lung physiology, specifically: air-capillary barrier thickness (δ), alveolar septal thickness (d), capillary transit time (tx ), pulmonary hematocrit (HCT), and alveolar surface area-to-volume ratio (SVR). An accelerated version of the sequence was also tested in subset of 4 volunteers and compared to the fully sampled (FS) results. RESULTS: Mean image-wide values calculated from MOXE parametric maps derived from FS dissolved 129 Xe spiral-IDEAL images were: δ = 0.89 ± 0.17 µm, d = 7.5 ± 0.5 µm, tx = 1.1 ± 0.2s, HCT = 28.8 ± 2.3%, and SVR = 140 ± 16 cm-1 , in good agreement with previously published values based on whole-lung spectroscopy of healthy human subjects. Parallel imaging sufficiently reduces artifacting in accelerated images, but increases disagreement with MOXE parameters derived from FS data with mean voxel-wise unsigned relative differences of: δ = 39 ± 9%, d = 22 ± 3%, tx = 117 ± 43%, HCT = 11 ± 2%, and SVR = 31 ± 12%. CONCLUSION: Dissolved HP 129 Xe spiral-IDEAL imaging for gas exchange mapping is feasible in humans using a single breath-hold. Accelerated gas exchange mapping is also shown to be feasible but requires further improvements to increase quantitative accuracy.

Effect of T1 relaxation on ventilation mapping using hyperpolarized 129 Xe multiple breath wash-out imaging.

PURPOSE: To investigate the effect of incorporating T1 as a function of wash-out breath number (T1 (n)) on estimation of fractional ventilation (r) using hyperpolarized 129 Xe multiple breath wash-out (MBWO) imaging in rats. METHODS: MBWO imaging was performed in 8 healthy mechanically ventilated rats at several inter-image delay times (τ) and tidal volumes (TV). r maps were calculated from the imaging data using a model of T1 (n) (assuming that the longitudinal relaxation rate of 129 Xe in the lung is directly proportional to pA O2 ) and compared to r maps obtained by assuming a fixed T1 measured before wash-out breaths (r'). RESULTS: Fractional ventilation was overestimated by up to 19.3% when T1 was fixed. An inverse relationship between bias (Δr) and ventilation was observed at all τ and TV. Additionally, Δr significantly increased when TV was decreased (F statistic F(2,7) = 48.97, P < 10-4 ). Histograms from r' maps were significantly more skewed toward lower values as compared to r histograms at all τ and TV (P < 0.05) except TV = Vdose - 1 mL. CONCLUSION: Analysis of hyperpolarized 129 Xe MBWO imaging using a model incorporating T1 (n) corrects for an overestimating bias in the mapping of fractional ventilation in mechanically ventilated rats introduced by assuming a fixed T1 .