Simultaneous quantification of hyperpolarized xenon-129 ventilation and gas exchange with multi-breath xenon-polarization transfer contrast (XTC) MRI.

PURPOSE: To demonstrate the feasibility of a multi-breath xenon-polarization transfer contrast (XTC) MR imaging approach for simultaneously evaluating regional ventilation and gas exchange parameters. METHODS: Imaging was performed in five healthy volunteers and six chronic obstructive pulmonary disease (COPD) patients. The multi-breath XTC protocol consisted of three repeated schemes of six wash-in breaths of a xenon mixture and four normoxic wash-out breaths, with and without selective saturation of either the tissue membrane or red blood cell (RBC) resonances. Acquisitions were performed at end-exhalation while subjects maintained tidal breathing throughout the session. The no-saturation, membrane-saturation, and RBC-saturation images were fit to a per-breath gas replacement model for extracting voxelwise tidal volume (TV), functional residual capacity (FRC), and fractional ventilation (FV), as well as tissue- and RBC-gas exchange (fMem and fRBC , respectively). The sensitivity of the derived model was also evaluated via simulations. RESULTS: With the exception of FRC, whole-lung averages for all metrics were decreased in the COPD subjects compared to the healthy cohort, significantly so for FV, fRBC , and fMem . Heterogeneity was higher overall in the COPD subjects, particularly for fRBC , fMem , and fRBC:Mem . The anterior-to-posterior gradient associated with the gravity-dependence of lung function in supine imaging was also evident for FV, fRBC , and fMem values in the healthy subjects, but noticeably absent in the COPD cohort. CONCLUSION: Multi-breath XTC imaging generated high-resolution, co-registered maps of ventilation and gas exchange parameters acquired during tidal breathing and with low per-breath xenon doses. Clear differences between healthy and COPD subjects were apparent and consistent with spirometry.

Imatinib alleviates lung injury and prolongs survival in ventilated rats.

Imatinib, a tyrosine kinase inhibitor, attenuates pulmonary edema and inflammation in lung injury. However, the physiological effects of this drug and their impact on outcomes are poorly characterized. Using serial computed tomography (CT), we tested the hypothesis that imatinib reduces injury severity and improves survival in ventilated rats. Hydrochloric acid (HCl) was instilled in the trachea (pH 1.5, 2.5 mL/kg) of anesthetized, intubated supine rats. Animals were randomized (n = 17 each group) to receive intraperitoneal imatinib or vehicle immediately prior to HCl. All rats then received mechanical ventilation. CT was performed hourly for 4 h. Images were quantitatively analyzed to assess the progression of radiological abnormalities. Injury severity was confirmed via hourly blood gases, serum biomarkers, bronchoalveolar lavage (BAL), and histopathology. Serial blood drug levels were measured in a subset of rats. Imatinib reduced mortality while delaying functional and radiological injury progression: out of 17 rats per condition, 2 control vs. 8 imatinib-treated rats survived until the end of the experiment (P = 0.02). Imatinib attenuated edema after lung injury (P < 0.05), and survival time in both groups was negatively correlated with increased lung mass (R2 = 0.70) as well as other physiological and CT parameters. Capillary leak (BAL protein concentration) was significantly lower in the treated group (P = 0.04). Peak drug concentration was reached after 70 min, and the drug half-life was 150 min. Imatinib decreased both mortality and lung injury severity in mechanically ventilated rats. Pharmacological inhibition of edema could be used during mechanical ventilation to improve the severity and outcome of lung injury.

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.

Investigating the impact of RF saturation-pulse parameters on compartment-selective gas-phase depolarization with xenon polarization transfer contrast MRI.

PURPOSE: To demonstrate the utility of continuous-wave (CW) saturation pulses in xenon-polarization transfer contrast (XTC) MRI and MRS, to investigate the selectivity of CW pulses applied to dissolved-phase resonances, and to develop a correction method for measurement biases from saturation of the nontargeted dissolved-phase compartment. METHODS: Studies were performed in six healthy Sprague-Dawley rats over a series of end-exhale breath holds. Discrete saturation schemes included a series of 30 Gaussian pulses (8 ms FWHM), spaced 25 ms apart; CW saturation schemes included single block pulses, with variable flip angle and duration. In XTC imaging, saturation pulses were applied on both dissolved-phase resonance frequencies and off-resonance, to correct for other sources of signal loss and compromised selectivity. In spectroscopy experiments, saturation pulses were applied at a set of 19 frequencies spread out between 185 and 200 ppm to map out modified z-spectra. RESULTS: Both modified z-spectra and imaging results showed that CW RF pulses offer sufficient depolarization and improved selectivity for generating contrast between presaturation and postsaturation acquisitions. A comparison of results obtained using a variety of saturation parameters confirms that saturation pulses applied at higher powers exhibit increased cross-contamination between dissolved-phase resonances. CONCLUSION: Using CW RF saturation pulses in XTC contrast preparation, with the proposed correction method, offers a potentially more selective alternative to traditional discrete saturation. The suppression of the red blood cell contribution to the gas-phase depolarization opens the door to a novel way of quantifying exchange time between alveolar volume and hemoglobin.

Preclinical MRI Using Hyperpolarized 129Xe.

Although critical for development of novel therapies, understanding altered lung function in disease models is challenging because the transport and diffusion of gases over short distances, on which proper function relies, is not readily visualized. In this review we summarize progress introducing hyperpolarized 129Xe imaging as a method to follow these processes in vivo. The work is organized in sections highlighting methods to observe the gas replacement effects of breathing (Gas Dynamics during the Breathing Cycle) and gas diffusion throughout the parenchymal airspaces (3). We then describe the spectral signatures indicative of gas dissolution and uptake (4), and how these features can be used to follow the gas as it enters the tissue and capillary bed, is taken up by hemoglobin in the red blood cells (5), re-enters the gas phase prior to exhalation (6), or is carried via the vasculature to other organs and body structures (7). We conclude with a discussion of practical imaging and spectroscopy techniques that deliver quantifiable metrics despite the small size, rapid motion and decay of signal and coherence characteristic of the magnetically inhomogeneous lung in preclinical models (8).

Ventilation heterogeneity imaged by multibreath wash-ins of hyperpolarized 3 He and 129 Xe in healthy rabbits.

KEY POINTS: Multibreath imaging to estimate regional gas mixing efficiency is superior to intensity-based single-breath ventilation markers, as it is capable of revealing minute but essential measures of ventilation heterogeneity which may be sensitive to subclinical alterations in the early stages of both obstructive and restrictive respiratory disorders. Large-scale convective stratification of ventilation in central-to-peripheral directions is the dominant feature of observed ventilation heterogeneity when imaging a heavy/less diffusive xenon gas mixture; smaller-scale patchiness, probably originating from asymmetric lung function at bronchial airway branching due to the interaction of convective and diffusive flows, is the dominant feature when imaging a lighter/more diffusive helium gas mixture. Since detecting low regional ventilation is crucial for characterizing diseased lungs, our results suggest that dilution with natural abundance helium and imaging at higher lung volumes seem advisable when imaging with hyperpolarized 129 Xe; this will allow the imaging gas to reach slow-filling and/or non-dependent lung regions, which might otherwise be impossible to distinguish from total ventilation shunt regions. The ability to differentiate these regions from those of total shunt is worse with typical single-breath imaging techniques. ABSTRACT: The mixing of freshly inhaled gas with gas already present in the lung can be directly assessed with heretofore unachievable precision via magnetic resonance imaging of signal build-up resulting from multiple wash-ins of a hyperpolarized (HP) gas. Here, we used normoxic HP 3 He and 129 Xe mixtures to study regional ventilation at different spatial scales in five healthy mechanically ventilated supine rabbits at two different inspired volumes. To decouple the respective effects of density and diffusion rates on ventilation heterogeneity, two additional studies were performed: one in which 3 He was diluted with an equal fraction of natural abundance xenon, and one in which 129 Xe was diluted with an equal fraction of 4 He. We observed systematic differences in the spatial scale of specific ventilation heterogeneity between HP 3 He and 129 Xe. We found that large-scale, central-to-peripheral convective ventilation inhomogeneity is the dominant cause of observed heterogeneity when breathing a normoxic xenon gas mixture. In contrast, small-scale ventilation heterogeneity in the form of patchiness, probably originating from asymmetric lung function at bronchial airway branching due to interactions between convective and diffusive flows, is the dominant feature when breathing a normoxic helium gas mixture, for which the critical zone occurs more proximally and at an imageable spatial scale. We also showed that the existence of particular underventilated non-dependent lung regions when breathing a heavy gas mixture is the result of the density of that mixture - rather than, for example, its diffusion rate or viscosity. Finally, we showed that gravity-dependent ventilation heterogeneity becomes substantially more uniform at higher inspired volumes for xenon gas mixtures compared to helium mixtures.

Diminishing Efficacy of Prone Positioning With Late Application in Evolving Lung Injury.

OBJECTIVES: It is not known how lung injury progression during mechanical ventilation modifies pulmonary responses to prone positioning. We compared the effects of prone positioning on regional lung aeration in late versus early stages of lung injury. DESIGN: Prospective, longitudinal imaging study. SETTING: Research imaging facility at The University of Pennsylvania (Philadelphia, PA) and Medical and Surgical ICUs at Massachusetts General Hospital (Boston, MA). SUBJECTS: Anesthetized swine and patients with acute respiratory distress syndrome (acute respiratory distress syndrome). INTERVENTIONS: Lung injury was induced by bronchial hydrochloric acid (3.5 mL/kg) in 10 ventilated Yorkshire pigs and worsened by supine nonprotective ventilation for 24 hours. Whole-lung CT was performed 2 hours after hydrochloric acid (Day 1) in both prone and supine positions and repeated at 24 hours (Day 2). Prone and supine images were registered (superimposed) in pairs to measure the effects of positioning on the aeration of each tissue unit. Two patients with early acute respiratory distress syndrome were compared with two patients with late acute respiratory distress syndrome, using electrical impedance tomography to measure the effects of body position on regional lung mechanics. MEASUREMENTS AND MAIN RESULTS: Gas exchange and respiratory mechanics worsened over 24 hours, indicating lung injury progression. On Day 1, prone positioning reinflated 18.9% ± 5.2% of lung mass in the posterior lung regions. On Day 2, position-associated dorsal reinflation was reduced to 7.3% ± 1.5% (p < 0.05 vs Day 1). Prone positioning decreased aeration in the anterior lungs on both days. Although prone positioning improved posterior lung compliance in the early acute respiratory distress syndrome patients, it had no effect in late acute respiratory distress syndrome subjects. CONCLUSIONS: The effects of prone positioning on lung aeration may depend on the stage of lung injury and duration of prior ventilation; this may limit the clinical efficacy of this treatment if applied late.

Measuring pulmonary gas exchange using compartment-selective xenon-polarization transfer contrast (XTC) MRI.

PURPOSE: To demonstrate the feasibility of generating red blood cell (RBC) and tissue/plasma (TP)-specific gas-phase (GP) depolarization maps using xenon-polarization transfer contrast (XTC) MR imaging. METHODS: Imaging was performed in three healthy subjects, an asymptomatic smoker, and a chronic obstructive pulmonary disease (COPD) patient. Single-breath XTC data were acquired through a series of three GP images using a 2D multi-slice GRE during a 12 s breath-hold. A series of 8 ms Gaussian inversion pulses spaced 30 ms apart were applied in-between the images to quantify the exchange between the GP and dissolved-phase (DP) compartments. Inversion pulses were either centered on-resonance to generate contrast, or off-resonance to correct for other sources of signal loss. For an alternative scheme, inversions of both RBC and TP resonances were inserted in lieu of off-resonance pulses. Finally, this technique was extended to a multi-breath protocol consistent with tidal breathing, involving 30 consecutive acquisitions. RESULTS: Inversion pulses shifted off-resonance by 20 ppm to mimic the distance between the RBC and TP resonances demonstrated selectivity, and initial GP depolarization maps illustrated stark magnitude and distribution differences between healthy and diseased subjects that were consistent with traditional approaches. CONCLUSION: The proposed DP-compartment selective XTC MRI technique provides information on gas exchange between all three detectable states of xenon in the lungs and is sufficiently sensitive to indicate differences in lung function between the study subjects. Investigated extensions of this approach to imaging schemes that either minimize breath-hold duration or the overall number of breath-holds open avenues for future research to improve measurement accuracy and patient comfort.

Hyperpolarized Metabolic Imaging Detects Latent Hepatocellular Carcinoma Domains Surviving Locoregional Therapy.

BACKGROUND AND AIMS: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence. APPROACH AND RESULTS: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1-13 C-pyruvate and its downstream metabolites, 1-13 C-lactate and 1-13 C-alanine, predicted histological viability. CONCLUSIONS: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application.

Investigating biases in the measurement of apparent alveolar septal wall thickness with hyperpolarized 129Xe MRI.

PURPOSE: To investigate biases in the measurement of apparent alveolar septal wall thickness (SWT) with hyperpolarized xenon-129 (HXe) as a function of acquisition parameters. METHODS: The HXe MRI scans with simultaneous gas-phase and dissolved-phase excitation were performed using 1-dimensional projection scans in mechanically ventilated rabbits. The dissolved-phase magnetization was periodically saturated, and the dissolved-phase xenon uptake dynamics were measured at end inspiration and end expiration with temporal resolutions up to 10 ms using a Look-Locker-type acquisition. The apparent alveolar septal wall thickness was extracted by fitting the signal to a theoretical model, and the findings were compared with those from the more commonly use chemical shift saturation recovery MRI spectroscopy technique with several different delay time arrangements. RESULTS: It was found that repeated application of RF saturation pulses in chemical shift saturation recovery acquisitions caused exchange-dependent gas-phase saturation that heavily biased the derived SWT value. When this bias was reduced by our proposed method, the SWT dependence on lung inflation disappeared due to an inherent insensitivity of HXe dissolved-phase MRI to thin alveolar structures with very short T2∗ . Furthermore, perfusion-based macroscopic gas transport processes were demonstrated to cause increasing apparent SWTs with TE (2.5 µm/ms at end expiration) and a lung periphery-to-center SWT gradient. CONCLUSION: The apparent SWT measured with HXe MRI was found to be heavily dependent on the acquisition parameters. A method is proposed that can minimize this measurement bias, add limited spatial resolution, and reduce measurement time to a degree that free-breathing studies are feasible.

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome.

Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactate-to-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

Positional Therapy and Regional Pulmonary Ventilation.

BACKGROUND: Prone ventilation redistributes lung inflation along the gravitational axis; however, localized, nongravitational effects of body position are less well characterized. The authors hypothesize that positional inflation improvements follow both gravitational and nongravitational distributions. This study is a nonoverlapping reanalysis of previously published large animal data. METHODS: Five intubated, mechanically ventilated pigs were imaged before and after lung injury by tracheal injection of hydrochloric acid (2 ml/kg). Computed tomography scans were performed at 5 and 10 cm H2O positive end-expiratory pressure (PEEP) in both prone and supine positions. All paired prone-supine images were digitally aligned to each other. Each unit of lung tissue was assigned to three clusters (K-means) according to positional changes of its density and dimensions. The regional cluster distribution was analyzed. Units of tissue displaying lung recruitment were mapped. RESULTS: We characterized three tissue clusters on computed tomography: deflation (increased tissue density and contraction), limited response (stable density and volume), and reinflation (decreased density and expansion). The respective clusters occupied (mean ± SD including all studied conditions) 29.3 ± 12.9%, 47.6 ± 11.4%, and 23.1 ± 8.3% of total lung mass, with similar distributions before and after lung injury. Reinflation was slightly greater at higher PEEP after injury. Larger proportions of the reinflation cluster were contained in the dorsal versus ventral (86.4 ± 8.5% vs. 13.6 ± 8.5%, P < 0.001) and in the caudal versus cranial (63.4 ± 11.2% vs. 36.6 ± 11.2%, P < 0.001) regions of the lung. After injury, prone positioning recruited 64.5 ± 36.7 g of tissue (11.4 ± 6.7% of total lung mass) at lower PEEP, and 49.9 ± 12.9 g (8.9 ± 2.8% of total mass) at higher PEEP; more than 59.0% of this recruitment was caudal. CONCLUSIONS: During mechanical ventilation, lung reinflation and recruitment by the prone positioning were primarily localized in the dorso-caudal lung. The local effects of positioning in this lung region may determine its clinical efficacy.

Assessment of flip angle-TR equivalence for standardized dissolved-phase imaging of the lung with hyperpolarized 129Xe MRI.

PURPOSE: To investigate the feasibility of describing the impact of any flip angle-TR combination on the resulting distribution of the hyperpolarized xenon-129 (HXe) dissolved-phase magnetization in the chest using a single virtual parameter, TR90°,equiv . METHODS: HXe MRI scans with simultaneous gas- (GP) and dissolved-phase (DP) excitation were performed using 2D projection scans in mechanically ventilated rabbits. Measurements with DP flip angles ranging from 6-90° and TRs ranging from 8.3-500 ms were conducted. DP maps based on acquisitions of similar radio frequency pulse-induced relaxation rates were compared. RESULTS: The observed distribution of the DP magnetization was strongly affected by acquisition flip angle and TR. However, for flip angles up to 60°, measurements with the same radio frequency pulse-induced relaxation rates, resulted in very similar DP images despite the presence of significant macroscopic gas transport processes. For flip angles approaching 90°, the downstream signal component decreased noticeably relative to acquisitions with lower flip angles. Nevertheless, the total DP signal continued to follow an empirically verified conversion equation over the entire investigated parameter range, which yields the equivalent TR of a hypothetical 90° measurement for any experimental flip angle-TR combination. CONCLUSION: We have introduced a method for converting the flip angle and TR of a given HXe DP measurement to a standardized metric based on the virtual quantity, TR90°,equiv , using their equivalent RF relaxation rates. This conversion permits the comparison of measurements obtained with different pulse sequence types or by different research groups using various acquisition parameters.

Detection of lung transplant rejection in a rat model using hyperpolarized [1-13 C] pyruvate-based metabolic imaging.

The current standard for noninvasive imaging of acute rejection consists of X-ray/CT, which derive their contrast from changes in ventilation, inflammation and edema, as well as remodeling during rejection. We propose the use of hyperpolarized [1-13 C] pyruvate MRI-which provides real-time metabolic assessment of tissue-as an early biomarker for tissue rejection. In this preliminary study, we used µCT-derived parameters and HP 13 C MR-derived biomarkers to predict rejection in an orthotopic left lung transplant model in both allogeneic and syngeneic rats. On day 3, the normalized lung density-a parameter that accounts for both lung volume (mL) and density (HU)-was -0.335 (CI: -0.598, -0.073) and - 0.473 (CI: -0.726, -0.220) for the allograft and isograft, respectively (not significant, 0.40). The lactate-to-pyruvate ratios-derived from the HP 13 C MRI-for the allograft and isograft were 0.200 (CI: 0.161, 0.240) and 0.114 (CI: 0.074, 0.153), respectively (significant, 0.020). Both techniques showed tissue rejection on day 7. A separate sub-study revealed CD8+ cells as the primary source of the lactate-to-pyruvate signal. Our study suggests that hyperpolarized (HP) [1-13 C] pyruvate MRI is a promising early biomarker for tissue rejection that provides metabolic assessment in real time based on changes in cellularity and metabolism of lung tissue and the infiltrating inflammatory cells, and may be able to predict tissue rejection earlier than X-ray/CT.

Unstable Inflation Causing Injury. Insight from Prone Position and Paired Computed Tomography Scans.

RATIONALE: It remains unclear how prone positioning improves survival in acute respiratory distress syndrome. Using serial computed tomography (CT), we previously reported that "unstable" inflation (i.e., partial aeration with large tidal density swings, indicating increased local strain) is associated with injury progression. OBJECTIVES: We prospectively tested whether prone position contains the early propagation of experimental lung injury by stabilizing inflation. METHODS: Injury was induced by tracheal hydrochloric acid in rats; after randomization to supine or prone position, injurious ventilation was commenced using high tidal volume and low positive end-expiratory pressure. Paired end-inspiratory (EI) and end-expiratory (EE) CT scans were acquired at baseline and hourly up to 3 hours. Each sequential pair (EI, EE) of CT images was superimposed in parametric response maps to analyze inflation. Unstable inflation was then measured in each voxel in both dependent and nondependent lung. In addition, five pigs were imaged (EI and EE) prone versus supine, before and (1 hour) after hydrochloric acid aspiration. MEASUREMENTS AND MAIN RESULTS: In rats, prone position limited lung injury propagation and increased survival (11/12 vs. 7/12 supine; P = 0.01). EI-EE densities, respiratory mechanics, and blood gases deteriorated more in supine versus prone rats. At baseline, more voxels with unstable inflation occurred in dependent versus nondependent regions when supine (41 ± 6% vs. 18 ± 7%; P < 0.01) but not when prone. In supine pigs, unstable inflation predominated in dorsal regions and was attenuated by prone positioning. CONCLUSIONS: Prone position limits the radiologic progression of early lung injury. Minimizing unstable inflation in this setting may alleviate the burden of acute respiratory distress syndrome.

Rapid assessment of pulmonary gas transport with hyperpolarized 129Xe MRI using a 3D radial double golden-means acquisition with variable flip angles.

PURPOSE: To demonstrate the feasibility of using a 3D radial double golden-means acquisition with variable flip angles to monitor pulmonary gas transport in a single breath hold with hyperpolarized xenon-129 MRI. METHODS: Hyperpolarized xenon-129 MRI scans with interleaved gas-phase and dissolved-phase excitations were performed using a 3D radial double golden-means acquisition in mechanically ventilated rabbits. The flip angle was either held fixed at 15 ° or 5 °, or it was varied linearly in ascending or descending order between 5 ° and 15 ° over a sampling interval of 1000 spokes. Dissolved-phase and gas-phase images were reconstructed at high resolution (32 × 32 × 32 matrix size) using all 1000 spokes, or at low resolution (22 × 22 × 22 matrix size) using 400 spokes at a time in a sliding-window fashion. Based on these sliding-window images, relative change maps were obtained using the highest mean flip angle as the reference, and aggregated pixel-based changes were tracked. RESULTS: Although the signal intensities in the dissolve-phase maps were mostly constant in the fixed flip-angle acquisitions, they varied significantly as a function of average flip angle in the variable flip-angle acquisitions. The latter trend reflects the underlying changes in observed dissolve-phase magnetization distribution due to pulmonary gas uptake and transport. CONCLUSION: 3D radial double golden-means acquisitions with variable flip angles provide a robust means for rapidly assessing lung function during a single breath hold, thereby constituting a particularly valuable tool for imaging uncooperative or pediatric patient populations.

Hyperpolarized gas diffusion MRI of biphasic lung inflation in short- and long-term emphysema models.

During lung inflation, airspace dimensions are affected nonlinearly by both alveolar expansion and recruitment, potentially confounding the identification of emphysematous lung by hyperpolarized helium-3 diffusion magnetic resonance imaging (HP MRI). This study aimed to characterize lung inflation over a broad range of inflation volume and pressure values in two different models of emphysema, as well as in normal lungs. Elastase-treated rats (n = 7) and healthy controls (n = 7) were imaged with HP MRI. Gradual inflation was achieved by incremental changes to both inflation volume and airway pressure. The apparent diffusion coefficient (ADC) was measured at each level of inflation and fitted to the corresponding airway pressures as the second-order response equation, with minimizing residue (χ2 < 0.001). A biphasic ADC response was detected, with an initial ADC increase followed by a decrease at airway pressures >18 cmH2O. Discrimination between treated and control rats was optimal when airway pressure was intermediate (between 10 and 11 cmH2O). Similar findings were confirmed in mice following long-term exposure to cigarette smoke, where optimal discrimination between treated and healthy mice occurred at a similar airway pressure as in the rats. We subsequently explored the evolution of ADC measured at the intermediate inflation level in mice after prolonged smoke exposure and found a significant increase (P < 0.01) in ADC over time. Our results demonstrate that measuring ADC at intermediate inflation enhances the distinction between healthy and diseased lungs, thereby establishing a model that may improve the diagnostic accuracy of future HP gas diffusion studies.

Tidal changes on CT and progression of ARDS.

BACKGROUND: Uncertain prediction of outcome in acute respiratory distress syndrome (ARDS) impedes individual patient management and clinical trial design. OBJECTIVES: To develop a radiological metric of injurious inflation derived from matched inspiratory and expiratory CT scans, calibrate it in a model of experimental lung injury, and test it in patients with ARDS. METHODS: 73 anaesthetised rats (acid aspiration model) were ventilated (protective or non-protective) for up to 4 hours to generate a spectrum of lung injury. CT was performed (inspiratory and expiratory) at baseline each hour, paired inspiratory and expiratory images were superimposed and voxels tracked in sequential scans. In nine patients with ARDS, paired inspiratory and expiratory CT scans from the first intensive care unit week were analysed. RESULTS: In experimental studies, regions of lung with unstable inflation (ie, partial or reversible airspace filling reflecting local strain) were the areas in which subsequent progression of injury was greatest in terms of progressive infiltrates (R=0.77) and impaired compliance (R=0.67, p<0.01). In patients with ARDS, a threshold fraction of tissue with unstable inflation was apparent: >28% in all patients who died and ≤28% in all who survived, whereas segregation of survivors versus non-survivors was not possible based on oxygenation or lung mechanics. CONCLUSIONS: A single set of superimposed inspiratory-expiratory CT scans may predict progression of lung injury and outcome in ARDS; if these preliminary results are validated, this could facilitate clinical trial recruitment and individualised care.

In vivo pH mapping of injured lungs using hyperpolarized [1-13 C]pyruvate.

PURPOSE: To optimize the production of hyperpolarized 13 C-bicarbonate from the decarboxylation of hyperpolarized [1-13 C]pyruvate and use it to image pH in the lungs and heart of rats with acute lung injury. METHODS: Two forms of catalysis are compared calorimetrically to maximize the rate of decarboxylation and rapidly produce hyperpolarized bicarbonate from pyruvate while minimizing signal loss. Rats are injured using an acute lung injury model combining ventilator-induced lung injury and acid aspiration. Carbon images are obtained from both healthy (n = 4) and injured (n = 4) rats using a slice-selective chemical shift imaging sequence with low flip angle. pH is calculated from the relative HCO3- and CO2 signals using the Henderson-Hasselbalch equation. RESULTS: It is demonstrated that base catalysis is more effective than metal-ion catalysis for this decarboxylation reaction. Bicarbonate polarizations up to 17.2% are achieved using the base-catalyzed reaction. A mean pH difference between lung and heart of 0.14 pH units is measured in the acute lung injury model. A significant pH difference between injured and uninjured lungs is also observed. CONCLUSION: It is demonstrated that hyperpolarized 13 C-bicarbonate can be efficiently produced from the base-catalyzed decarboxylation of pyruvate. This method is used to obtain the first regional pH image of the lungs and heart of an animal. Magn Reson Med 78:1121-1130, 2017. © 2016 International Society for Magnetic Resonance in Medicine.