A single-breath-hold protocol for hyperpolarized 129 Xe ventilation and gas exchange imaging.

Hyperpolarized 129 Xe MRI (Xe-MRI) is increasingly used to image the structure and function of the lungs. Because 129 Xe imaging can provide multiple contrasts (ventilation, alveolar airspace size, and gas exchange), imaging often occurs over several breath-holds, which increases the time, expense, and patient burden of scans. We propose an imaging sequence that can be used to acquire Xe-MRI gas exchange and high-quality ventilation images within a single, approximately 10 s, breath-hold. This method uses a radial one-point Dixon approach to sample dissolved 129 Xe signal, which is interleaved with a 3D spiral ("FLORET") encoding pattern for gaseous 129 Xe. Thus, ventilation images are obtained at higher nominal spatial resolution (4.2 × 4.2 × 4.2 mm3 ) compared with gas-exchange images (6.25 × 6.25 × 6.25 mm3 ), both competitive with current standards within the Xe-MRI field. Moreover, the short 10 s Xe-MRI acquisition time allows for 1 H "anatomic" images used for thoracic cavity masking to be acquired within the same breath-hold for a total scan time of about 14 s. Images were acquired using this single-breath method in 11 volunteers (N = 4 healthy, N = 7 post-acute COVID). For 11 of these participants, a separate breath-hold was used to acquire a "dedicated" ventilation scan and five had an additional "dedicated" gas exchange scan. The images acquired using the single-breath protocol were compared with those from dedicated scans using Bland-Altman analysis, intraclass correlation (ICC), structural similarity, peak signal-to-noise ratio, Dice coefficients, and average distance. Imaging markers from the single-breath protocol showed high correlation with dedicated scans (ventilation defect percent, ICC = 0.77, p = 0.01; membrane/gas, ICC = 0.97, p = 0.001; red blood cell/gas, ICC = 0.99, p < 0.001). Images showed good qualitative and quantitative regional agreement. This single-breath protocol enables the collection of essential Xe-MRI information within one breath-hold, simplifying scanning sessions and reducing costs associated with Xe-MRI.

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.

Human upper-airway respiratory airflow: In vivo comparison of computational fluid dynamics simulations and hyperpolarized 129Xe phase contrast MRI velocimetry.

Computational fluid dynamics (CFD) simulations of respiratory airflow have the potential to change the clinical assessment of regional airway function in health and disease, in pulmonary medicine and otolaryngology. For example, in diseases where multiple sites of airway obstruction occur, such as obstructive sleep apnea (OSA), CFD simulations can identify which sites of obstruction contribute most to airway resistance and may therefore be candidate sites for airway surgery. The main barrier to clinical uptake of respiratory CFD to date has been the difficulty in validating CFD results against a clinical gold standard. Invasive instrumentation of the upper airway to measure respiratory airflow velocity or pressure can disrupt the airflow and alter the subject's natural breathing patterns. Therefore, in this study, we instead propose phase contrast (PC) velocimetry magnetic resonance imaging (MRI) of inhaled hyperpolarized 129Xe gas as a non-invasive reference to which airflow velocities calculated via CFD can be compared. To that end, we performed subject-specific CFD simulations in airway models derived from 1H MRI, and using respiratory flowrate measurements acquired synchronously with MRI. Airflow velocity vectors calculated by CFD simulations were then qualitatively and quantitatively compared to velocity maps derived from PC velocimetry MRI of inhaled hyperpolarized 129Xe gas. The results show both techniques produce similar spatial distributions of high velocity regions in the anterior-posterior and foot-head directions, indicating good qualitative agreement. Statistically significant correlations and low Bland-Altman bias between the local velocity values produced by the two techniques indicates quantitative agreement. This preliminary in vivo comparison of respiratory airway CFD and PC MRI of hyperpolarized 129Xe gas demonstrates the feasibility of PC MRI as a technique to validate respiratory CFD and forms the basis for further comprehensive validation studies. This study is therefore a first step in the pathway towards clinical adoption of respiratory CFD.

Alveolar Airspace Size in Healthy and Diseased Infant Lungs Measured via Hyperpolarized 3He Gas Diffusion Magnetic Resonance Imaging.

BACKGROUND: Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. OBJECTIVE: This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry. METHODS: Lung specimens from 8 infants were obtained: 7 healthy left upper lobes (0-16 months, post-autopsy) and 1 left lung with filamin-A mutation, closely representing BPD lung disease (11 months, post-transplantation). Specimens were imaged using HP 3He diffusion MRI to generate apparent diffusion coefficients (ADCs) as biomarkers of alveolar airspace size, with comparison to mean linear intercept (Lm) via quantitative histology. RESULTS: Mean ADC and Lm were significantly increased throughout the diseased specimen (ADC = 0.26 ± 0.06 cm2/s, Lm = 587 ± 212 µm) compared with healthy specimens (ADC = 0.14 ± 0.03 cm2/s, Lm = 133 ± 37 µm; p < 1 × 10-7); increased values reflect enlarged airspaces. Mean ADCs in healthy specimens were significantly correlated to Lm (r = 0.69, p = 0.041). CONCLUSIONS: HP gas diffusion MRI is sensitive to healthy and diseased regional alveolar airspace size in infant lungs, with good comparison to quantitative histology in ex vivo specimens. This work demonstrates the translational potential of gas MRI techniques for in vivo assessment of normal and abnormal alveolar development in neonates with pulmonary disease.

Single-Session Bronchial Thermoplasty Guided by 129Xe Magnetic Resonance Imaging. A Pilot Randomized Controlled Clinical Trial.

Rationale: Adverse events have limited the use of bronchial thermoplasty (BT) in severe asthma.Objectives: We sought to evaluate the effectiveness and safety of using 129Xe magnetic resonance imaging (129Xe MRI) to prioritize the most involved airways for guided BT.Methods: Thirty subjects with severe asthma were imaged with volumetric computed tomography and 129Xe MRI to quantitate segmental ventilation defects. Subjects were randomized to treatment of the six most involved airways in the first session (guided group) or a standard three-session BT (unguided). The primary outcome was the change in Asthma Quality of Life Questionnaire score from baseline to 12 weeks after the first BT for the guided group compared with after three treatments for the unguided group.Measurements and Main Results: There was no significant difference in quality of life after one guided compared with three unguided BTs (change in Asthma Quality of Life Questionnaire guided = 0.91 [95% confidence interval, 0.28-1.53]; unguided = 1.49 [95% confidence interval, 0.84-2.14]; P = 0.201). After one BT, the guided group had a greater reduction in the percentage of poorly and nonventilated lung from baseline when compared with unguided (-17.2%; P = 0.009). Thirty-three percent experienced asthma exacerbations after one guided BT compared with 73% after three unguided BTs (P = 0.028).Conclusions: Results of this pilot study suggest that similar short-term improvements can be achieved with one BT treatment guided by 129Xe MRI when compared with standard three-treatment-session BT with fewer periprocedure adverse events.

Cyst Ventilation Heterogeneity and Alveolar Airspace Dilation as Early Disease Markers in Lymphangioleiomyomatosis.

Rationale: Lymphangioleiomyomatosis (LAM) is a rare disease associated with cystic destruction of the pulmonary parenchyma and chronic respiratory failure, and there are trials underway to determine if early intervention can prevent disease progression. An imaging technique that is sensitive to early regional disease would therefore be valuable for patient care and clinical trials.Objectives: We postulated that hyperpolarized 129Xe MRI would be sensitive to ventilation abnormalities and alveolar airspace dilation in patients with mild LAM disease and normal pulmonary function and that 129Xe MRI would reveal important features of cyst ventilation.Methods:129Xe ventilation and diffusion-weighted MR images were acquired in 22 patients with LAM during two breath-holds of hyperpolarized 129Xe. 129Xe ventilation defect percentage (VDP; percentage of voxels <60% of the mean whole-lung 129Xe MRI signal) and apparent diffusion coefficient (ADC), a measure of alveolar airspace size, were quantified and compared with pulmonary function test parameters with Spearman statistics. Sixteen patients with LAM had a recent, clinical chest computed tomography (CT) scan available, and cyst ventilation was assessed by thresholding cysts on the CT images and registration to the 129Xe ventilation images.Results: Ventilation deficits were observed in all patients with LAM, including those with normal pulmonary function and few cysts, and the mean VDP was 19.2% (95% confidence interval [CI], 14.8-23.5%). 129Xe VDP was strongly correlated with forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (r = -0.51, P = 0.02) and diffusing capacity of the lung for carbon monoxide (DlCO) (r = -0.60, P = 0.009) but not with FEV1 (r = -0.33, P = 0.13), likely because of the sensitivity of 129Xe MRI to mild LAM disease in patients with normal FEV1. The mean ADC was 0.048 cm2/s (95% CI, 0.042-0.053 cm2/s). In many cases, ADC was elevated relative to previously reported values in adults, and ADC was correlated with FEV1, FEV1/FVC ratio, and DlCO (P ≤ 0.02 for all). Co-registered 129Xe MRI and CT imaging revealed considerable ventilation heterogeneity within individual patients with LAM and across patients with similarly sized cysts.Conclusions:129Xe MRI provides a means to assess the complex regional ventilation and alveolar airspace size changes of LAM with high sensitivity and may be a clinically useful future tool for screening, managing patients, and measuring treatment efficacy.

Hyperpolarized 129Xe for investigation of mild cystic fibrosis lung disease in pediatric patients.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease which carries high morbidity and mortality from lung-function decline. Monitoring disease progression and treatment response in young patients is desirable, but serial imaging via CT is often considered prohibitive, and detailed functional information cannot be obtained using conventional imaging techniques. Hyperpolarized 129Xe magnetic resonance imaging (MRI) can depict and quantify regional ventilation, but has not been investigated in pediatrics. We hypothesized that 129Xe MRI is feasible and would demonstrate ventilation defects in mild CF lung disease with greater sensitivity than FEV1. METHODS: 11 healthy controls (age 6-16years) and 11 patients with mild CF (age 8-16years, Forced Expiratory Volume (FEV1) percent predicted >70%) were recruited for this study. Nine CF patients had an FEV1>85%. Each subject was imaged via hyperpolarized 129Xe MRI, and the ventilation defect percentage (VDP) was measured. FEV1 and VDP were compared between the groups. RESULTS: FEV1 for controls was 100.3%±8.5% (mean±sd) and for CF patients was 97.9%±16.0% (p=0.67). VDP was 6.4%±2.8% for controls and 18.3%±8.6% for CF (p<0.001). When considering the 9 CF patients with normal FEV1 (>85%), the mean FEV1 was 103.1%±12.3% (p=0.57 compared to controls) and VDP was 15.4%±6.3% (p=0.002). CONCLUSIONS: Hyperpolarized 129Xe MRI demonstrated ventilation defects in CF patients with normal FEV1 and more effectively discriminated CF from controls than FEV1. Thus 129Xe may be a useful outcome measure to detect mild CF lung disease, to investigate regional lung function in pediatric lung diseases, and to follow disease progression.

Retrospective respiratory self-gating and removal of bulk motion in pulmonary UTE MRI of neonates and adults.

PURPOSE: To implement pulmonary three-dimensional (3D) radial ultrashort echo-time (UTE) MRI in non-sedated, free-breathing neonates and adults with retrospective motion tracking of respiratory and intermittent bulk motion, to obtain diagnostic-quality, respiratory-gated images. METHODS: Pulmonary 3D radial UTE MRI was performed at 1.5 tesla (T) during free breathing in neonates and adult volunteers for validation. Motion-tracking waveforms were obtained from the time course of each free induction decay's initial point (i.e., k-space center), allowing for respiratory-gated image reconstructions that excluded data acquired during bulk motion. Tidal volumes were calculated from end-expiration and end-inspiration images. Respiratory rates were calculated from the Fourier transform of the motion-tracking waveform during quiet breathing, with comparison to physiologic prediction in neonates and validation with spirometry in adults. RESULTS: High-quality respiratory-gated anatomic images were obtained at inspiration and expiration, with less respiratory blurring at the expense of signal-to-noise for narrower gating windows. Inspiration-expiration volume differences agreed with physiologic predictions (neonates; Bland-Altman bias = 6.2 mL) and spirometric values (adults; bias = 0.11 L). MRI-measured respiratory rates compared well with the observed rates (biases = -0.5 and 0.2 breaths/min for neonates and adults, respectively). CONCLUSIONS: Three-dimensional radial pulmonary UTE MRI allows for retrospective respiratory self-gating and removal of intermittent bulk motion in free-breathing, non-sedated neonates and adults. Magn Reson Med 77:1284-1295, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Pulmonary MRI of neonates in the intensive care unit using 3D ultrashort echo time and a small footprint MRI system.

PURPOSE: To determine the feasibility of pulmonary magnetic resonance imaging (MRI) of neonatal lung structures enabled by combining two novel technologies: first, a 3D radial ultrashort echo time (UTE) pulse sequence capable of high spatial resolution full-chest imaging in nonsedated quiet-breathing neonates; and second, a unique, small-footprint 1.5T MRI scanner design adapted for neonatal imaging and installed within the neonatal intensive care unit (NICU). MATERIALS AND METHODS: Ten patients underwent MRI within the NICU, in accordance with an approved Institutional Review Board protocol. Five had clinical diagnoses of bronchopulmonary dysplasia (BPD), and five had putatively normal lung function. Pulmonary imaging was performed at 1.5T using 3D radial UTE and standard 3D fast gradient recalled echo (FGRE). Diagnostic quality, presence of motion artifacts, and apparent severity of lung pathology were evaluated by two radiologists. Quantitative metrics were additionally used to evaluate lung parenchymal signal. RESULTS: UTE images showed significantly higher signal in lung parenchyma (P < 0.0001) and fewer apparent motion artifacts compared to FGRE (P = 0.046). Pulmonary pathology was more severe in patients diagnosed with BPD relative to controls (P = 0.001). Infants diagnosed with BPD also had significantly higher signal in lung parenchyma, measured using UTE, relative to controls (P = 0.002). CONCLUSION: These results demonstrate the technical feasibility of pulmonary MRI in free-breathing, nonsedated infants in the NICU at high, isotropic resolutions approaching that achievable with computed tomography (CT). There is potential for pulmonary MRI to play a role in improving how clinicians understand and manage care of neonatal and pediatric pulmonary diseases. J. Magn. Reson. Imaging 2016. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:463-471.

Direct comparison of 129 Xe diffusion measurements with quantitative histology in human lungs.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is an irreversible lung disease characterized by small-airway obstruction and alveolar-airspace destruction. Hyperpolarized 129 Xe diffusion MRI of lung is a promising biomarker for assessing airspace enlargement, but has yet to be validated by direct comparison to lung histology. Here we have compared diffusion measurements of hyperpolarized (HP) 129 Xe in explanted lungs to regionally matched morphological measures of airspace size. METHODS: Explanted lungs from five COPD patients and two idiopathic pulmonary fibrosis (IPF) patients were imaged using MRI with hyperpolarized 129 Xe using a two-b-value gradient-echo diffusion sequence, and 34 histological samples were taken from these lungs for quantitative histology. Mean-linear-intercept (Lm ) was compared with spatially matched measures of apparent diffusion coefficient (ADC) from 129 Xe MRI. RESULTS: The mean ADC from COPD lung samples was 0.071 ± 0.011 cm2 /s, and for IPF lungs was 0.033 ± 0.001 cm2 /s (P < 10-15 between groups). The mean Lm in COPD samples was 0.076 ± 0.027 cm and 0.041 ± 0.004 cm in IPF (P = 2.7 × 10-7 between groups). The Pearson-correlation between ADC and Lm measurements was r = 0.59. CONCLUSIONS: Diffusion MRI of HP 129 Xe quantifies regional airspace enlargement in COPD. 129 Xe ADC showed much less overlap between groups than quantitative histology, consistent with our past experience with 3 He diffusion MRI in COPD. Magn Reson Med 77:265-272, 2017. © 2016 Wiley Periodicals, Inc.

Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.

BACKGROUND: Hyperpolarized 129Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. OBJECTIVE: To assess the feasibility, safety and tolerability of hyperpolarized 129Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. MATERIALS AND METHODS: Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent 129Xe MRI, receiving up to three doses of 129Xe gas prepared by either a commercially available or a homebuilt 129Xe polarizer. Subject heart rate and SpO2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range ±7 days) post-MRI. RESULTS: All children tolerated multiple doses of 129Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO2 (mean -6.0 ± standard deviation 7.2%, P≤0.001); however within 2 min post inhalation SpO2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 ± 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129Xe MRI, but all were deemed unrelated to the study. CONCLUSION: The feasibility, safety and tolerability of 129Xe MRI has been assessed in a small group of children as young as 6 years. SpO2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were consistent with the known anesthetic properties of xenon and with previous safety assessments of 129Xe MRI in adults. Hyperpolarized 129Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease.

Quantitative Magnetic Resonance Imaging of Bronchopulmonary Dysplasia in the Neonatal Intensive Care Unit Environment.

RATIONALE: Bronchopulmonary dysplasia (BPD) is a prevalent yet poorly characterized pulmonary complication of premature birth; the current definition is based solely on oxygen dependence at 36 weeks postmenstrual age without objective measurements of structural abnormalities across disease severity. OBJECTIVES: We hypothesize that magnetic resonance imaging (MRI) can spatially resolve and quantify the structural abnormalities of the neonatal lung parenchyma associated with premature birth. METHODS: Using a unique, small-footprint, 1.5-T MRI scanner within our neonatal intensive care unit (NICU), diagnostic-quality MRIs using commercially available sequences (gradient echo and spin echo) were acquired during quiet breathing in six patients with BPD, six premature patients without diagnosed BPD, and six full-term NICU patients (gestational ages, 23-39 wk) at near term-equivalent age, without administration of sedation or intravenous contrast. Images were scored by a radiologist using a modified Ochiai score, and volumes of high- and low-signal intensity lung parenchyma were quantified by segmentation and threshold analysis. MEASUREMENTS AND MAIN RESULTS: Signal increases, putatively combinations of fibrosis, edema, and atelectasis, were present in all premature infants. Infants with diagnosed BPD had significantly greater volume of high-signal lung (mean ± SD, 26.1 ± 13.8%) compared with full-term infants (7.3 ± 8.2%; P = 0.020) and premature infants without BPD (8.2 ± 6.4%; P = 0.026). Signal decreases, presumably alveolar simplification, only appeared in the most severe BPD cases, although cystic appearance did increase with severity. CONCLUSIONS: Pulmonary MRI reveals quantifiable, significant differences between patients with BPD, premature patients without BPD, and full-term control subjects. These methods could be implemented to individually phenotype disease, which may impact clinical care and predict future outcomes.