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.

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.

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.

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.

In vivo imaging of the progression of acute lung injury using hyperpolarized [1-13 C] pyruvate.

PURPOSE: To investigate pulmonary metabolic alterations during progression of acute lung injury. METHODS: Using hyperpolarized [1-13 C] pyruvate imaging, we measured pulmonary lactate and pyruvate in 15 ventilated rats 1, 2, and 4 h after initiation of mechanical ventilation. Lung compliance was used as a marker for injury progression. 5 untreated rats were used as controls; 5 rats (injured-1) received 1 ml/kg and another 5 rats (injured-2) received 2 ml/kg hydrochloric acid (pH 1.25) in the trachea at 70 min. RESULTS: The mean lactate-to-pyruvate ratio of the injured-1 cohort was 0.15 ± 0.02 and 0.15 ± 0.03 at baseline and 1 h after the injury, and significantly increased from the baseline value 3 h after the injury to 0.23 ± 0.02 (P = 0.002). The mean lactate-to-pyruvate ratio of the injured-2 cohort decreased from 0.14 ± 0.03 at baseline to 0.08 ± 0.02 1 h after the injury and further decreased to 0.07 ± 0.02 (P = 0.08) 3 h after injury. No significant change was observed in the control group. Compliance in both injured groups decreased significantly after the injury (P < 0.01). CONCLUSIONS: Our findings suggest that in severe cases of lung injury, edema and hyperperfusion in the injured lung tissue may complicate interpretation of the pulmonary lactate-to-pyruvate ratio as a marker of inflammation. However, combining the lactate-to-pyruvate ratio with pulmonary compliance provides more insight into the progression of the injury and its severity. Magn Reson Med 78:2106-2115, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Visualizing the Propagation of Acute Lung Injury.

BACKGROUND: Mechanical ventilation worsens acute respiratory distress syndrome, but this secondary "ventilator-associated" injury is variable and difficult to predict. The authors aimed to visualize the propagation of such ventilator-induced injury, in the presence (and absence) of a primary underlying lung injury, and to determine the predictors of propagation. METHODS: Anesthetized rats (n = 20) received acid aspiration (hydrochloric acid) followed by ventilation with moderate tidal volume (V(T)). In animals surviving ventilation for at least 2 h, propagation of injury was quantified by using serial computed tomography. Baseline lung status was assessed by oxygenation, lung weight, and lung strain (V(T)/expiratory lung volume). Separate groups of rats without hydrochloric acid aspiration were ventilated with large (n = 10) or moderate (n = 6) V(T). RESULTS: In 15 rats surviving longer than 2 h, computed tomography opacities spread outward from the initial site of injury. Propagation was associated with higher baseline strain (propagation vs. no propagation [mean ± SD]: 1.52 ± 0.13 vs. 1.16 ± 0.20, P < 0.01) but similar oxygenation and lung weight. Propagation did not occur where baseline strain was less than 1.29. In healthy animals, large V(T) caused injury that was propagated inward from the lung periphery; in the absence of preexisting injury, propagation did not occur where strain was less than 2.0. CONCLUSIONS: Compared with healthy lungs, underlying injury causes propagation to occur at a lower strain threshold and it originates at the site of injury; this suggests that tissue around the primary lesion is more sensitive. Understanding how injury is propagated may ultimately facilitate a more individualized monitoring or management.

The effect of exogenous substrate concentrations on true and apparent metabolism of hyperpolarized pyruvate in the isolated perfused lung.

Although relatively metabolically inactive, the lung has an important role in maintaining systemic glycolytic intermediate and cytosolic redox balance. Failure to perform this function appropriately may lead to lung disease progression, including systemic aspects of these disorders. In this study, we experimentally probe the response of the isolated, perfused organ to varying glycolytic intermediate (pyruvate and lactate) concentrations, and the effect on the apparent metabolism of hyperpolarized 1-(13)C pyruvate. Twenty-four separate conditions were studied, from sub-physiological to super-physiological concentrations of each metabolite. A three-compartment model is developed, which accurately matches the full range of experiments and includes a full account of evolution of agent concentration and polarization. The model is then refined using a series of approximations which are shown to be applicable to cases of physiological relevance, and which facilitate an intuitive understanding of the saturation and scaling behavior. Perturbations of the model assumptions are used to determine the sensitivity to input parameter estimates, and finally the model is used to examine the relationship between measurements accessible by NMR and the underlying physiological parameters of interest. Based on the observed scaling of lactate labeling with lactate and pyruvate concentrations, we conclude that the level of hyperpolarized lactate signal in the lung is primarily determined by the rate at which NAD(+) is reduced to NADH. Further, although weak dependences on other factors are predicted, the modeled NAD(+) reduction rate is largely governed by the intracellular lactate pool size. Conditions affecting the lactate pool can therefore be expected to display the highest contrast in hyperpolarized (13)C-pyruvate imaging. The work is intended to serve as a basis both to interpret the signal dynamics of hyperpolarized measurements in the normal lung and to understand the cause of alterations seen in a variety of disease and exposure models.

Metabolic spectroscopy of inflammation in a bleomycin-induced lung injury model using hyperpolarized 1-(13) C pyruvate.

Metabolic activity in the lung is known to change in response to external insults, inflammation, and cancer. We report measurements of metabolism in the isolated, perfused rat lung of healthy controls and in diseased lungs undergoing acute inflammation using hyperpolarized 1-(13) C-labeled pyruvate. The overall apparent activity of lactate dehydrogenase is shown to increase significantly (on average by a factor of 3.3) at the 7 day acute stage and to revert substantially to baseline at 21 days, while other markers indicating monocarboxylate uptake and transamination rate are unchanged. Elevated lung lactate signal levels correlate well with phosphodiester levels as determined with (31) P spectroscopy and with the presence of neutrophils as determined by histology, consistent with a relationship between intracellular lactate pool labeling and the density and type of inflammatory cells present. We discuss several alternate hypotheses, and conclude that the most probable source of the observed signal increase is direct uptake and metabolism of pyruvate by inflammatory cells and primarily neutrophils. This signal is seen in high contrast to the low baseline activity of the lung.

Imaging the interaction of atelectasis and overdistension in surfactant-depleted lungs.

OBJECTIVE: Atelectasis and surfactant depletion may contribute to greater distension-and thereby injury-of aerated lung regions; recruitment of atelectatic lung may protect these regions by attenuating such overdistension. However, the effects of atelectasis (and recruitment) on aerated airspaces remain elusive. We tested the hypothesis that during mechanical ventilation, surfactant depletion increases the dimensions of aerated airspaces and that lung recruitment reverses these changes. DESIGN: Prospective imaging study in an animal model. SETTING: Research imaging facility. SUBJECTS: Twenty-seven healthy Sprague Dawley rats. INTERVENTIONS: Surfactant depletion was obtained by saline lavage in anesthetized, ventilated rats. Alveolar recruitment was accomplished using positive end-expiratory pressure and exogenous surfactant administration. MEASUREMENTS AND MAIN RESULTS: Airspace dimensions were estimated by measuring the apparent diffusion coefficient of He, using diffusion-weighted hyperpolarized gas magnetic resonance imaging. Atelectasis was demonstrated using computerized tomography and by measuring oxygenation. Saline lavage increased atelectasis (increase in nonaerated tissue from 1.2% to 13.8% of imaged area, p < 0.001), and produced a concomitant increase in mean apparent diffusion coefficient (~33%, p < 0.001) vs. baseline; the heterogeneity of the computerized tomography signal and the variance of apparent diffusion coefficient were also increased. Application of positive end-expiratory pressure and surfactant reduced the mean apparent diffusion coefficient (~23%, p < 0.001), and its variance, in parallel to alveolar recruitment (i.e., less computerized tomography densities and heterogeneity, increased oxygenation). CONCLUSIONS: Overdistension of aerated lung occurs during atelectasis is detectable using clinically relevant magnetic resonance imaging technology, and could be a key factor in the generation of lung injury during mechanical ventilation. Lung recruitment by higher positive end-expiratory pressure and surfactant administration reduces airspace distension.

Accelerated fractional ventilation imaging with hyperpolarized Gas MRI.

PURPOSE: To investigate the utility of accelerated imaging to enhance multibreath fractional ventilation (r) measurement accuracy using hyperpolarized gas MRI. Undersampling shortens the breath-hold time, thereby reducing the O2 -induced signal decay and allows subjects to maintain a more physiologically relevant breathing pattern. Additionally, it may improve r estimation accuracy by reducing radiofrequency destruction of hyperpolarized gas. METHODS: Image acceleration was achieved using an eight-channel phased array coil. Undersampled image acquisition was simulated in a series of ventilation images and data was reconstructed for various matrix sizes (48-128) using generalized auto-calibrating partially parallel acquisition. Parallel accelerated r imaging was also performed on five mechanically ventilated pigs. RESULTS: Optimal acceleration factor was fairly invariable (2.0-2.2×) over the range of simulated resolutions. Estimation accuracy progressively improved with higher resolutions (39-51% error reduction). In vivo r values were not significantly different between the two methods: 0.27 ± 0.09, 0.35 ± 0.06, 0.40 ± 0.04 (standard) versus 0.23 ± 0.05, 0.34 ± 0.03, 0.37 ± 0.02 (accelerated); for anterior, medial, and posterior slices, respectively, whereas the corresponding vertical r gradients were significant (P < 0.001): 0.021 ± 0.007 (standard) versus 0.019 ± 0.005 (accelerated) (cm(-1) ). CONCLUSION: Quadruple phased array coil simulations resulted in an optimal acceleration factor of ∼2× independent of imaging resolution. Results advocate undersampled image acceleration to improve accuracy of fractional ventilation measurement with hyperpolarized gas MRI.

Ratiometric analysis in hyperpolarized NMR (I): test of the two-site exchange model and the quantification of reaction rate constants.

Conventional methods for the analysis of in vivo hyperpolarized (13) C NMR data from the lactate dehydrogenase (LDH) reaction usually make assumptions on the stability of rate constants and/or the validity of the two-site exchange model. In this study, we developed a framework to test the validity of the assumption of stable reaction rate constants and the two-site exchange model in vivo via ratiometric fitting of the time courses of the signal ratio L(t)/P(t). Our analysis provided evidence that the LDH enzymatic kinetics observed by hyperpolarized NMR are in near-equilibrium and satisfy the two-site exchange model for only a specific time window. In addition, we quantified both the forward and reverse exchange rate constants of the LDH reaction for the transgenic and mouse xenograft models of breast cancer using the ratio fitting method developed, which includes only two modeling parameters and is less sensitive to the influence of instrument settings/protocols, such as flip angles, degree of polarization and tracer dosage. We further compared the ratio fitting method with a conventional two-site exchange modeling method, i.e. the differential equation fitting method, using both the experimental and simulated hyperpolarized NMR data. The ratio fitting method appeared to fit better than the differential equation fitting method for the reverse rate constant on the mouse tumor data, with less relative errors on average, whereas the differential equation fitting method also resulted in a negative reverse rate constant for one tumor. The simulation results indicated that the accuracy of both methods depends on the width of the transport function, noise level and rate constant ratio; one method may be more accurate than the other based on the experimental/biological conditions aforementioned. We were able to categorize our tumor models into specific conditions of the computer simulation and to estimate the errors of rate quantification. We also discussed possible approaches to the development of more accurate rate quantification methods for hyperpolarized NMR.

Positive end-expiratory pressure increments during anesthesia in normal lung result in hysteresis and greater numbers of smaller aerated airspaces.

BACKGROUND: Although it is recognized that pulmonary hysteresis can influence the effects of positive end-expiratory pressure (PEEP), the extent to which expansion of previously opened (vs. newly opening) peripheral airspaces contribute to increased lung volume is unknown. METHODS: Following a recruitment maneuver, rats were ventilated with constant tidal volumes and imaged during ascending and descending ramps of PEEP. RESULTS: The authors estimated peripheral airspace dimensions by measuring the apparent diffusion coefficient of He in 10 rats. In a separate group (n = 5) undergoing a similar protocol, the authors used computerized tomography to quantify lung volume. Hysteresis was confirmed by larger end-inspiratory lung volume (mean ± SD; all PEEP levels included): 8.4 ± 2.8 versus 6.8 ± 2.0 ml (P < 0.001) and dynamic compliance: 0.52 ± 0.12 versus 0.42 ± 0.09 ml/cm H2O (P < 0.001) during descending versus ascending PEEP ramps. Apparent diffusion coefficient increased with PEEP, but it was smaller during the descending versus ascending ramps for corresponding levels of PEEP: 0.168 ± 0.019 versus 0.183 ± 0.019 cm/s (P < 0.001). Apparent diffusion coefficient was smaller in the posterior versus anterior lung regions, but the effect of PEEP and hysteresis on apparent diffusion coefficient was greater in the posterior regions. CONCLUSIONS: The authors' study results suggest that in healthy lungs, larger lung volumes due to hysteresis are associated with smaller individual airspaces. This may be explained by opening of previously nonaerated peripheral airspaces rather than expansion of those already aerated. Setting PEEP on a descending ramp may minimize distension of individual airspaces.

Multislice fractional ventilation imaging in large animals with hyperpolarized gas MRI.

The noninvasive assessment of regional lung ventilation is of critical importance in the quantification of the severity of disease and evaluation of response to therapy in many pulmonary diseases. This work presents, for the first time, the implementation of a hyperpolarized (HP) gas MRI technique to measure whole-lung regional fractional ventilation (r) in Yorkshire pigs (n = 5) through the use of a gas mixing and delivery device in the supine position. The proposed technique utilizes a series of back-to-back HP gas breaths with images acquired during short end-inspiratory breath-holds. In order to decouple the radiofrequency pulse decay effect from the ventilatory signal build-up in the airways, the regional distribution of the flip angle (α) was estimated in the imaged slices by acquiring a series of back-to-back images with no interscan time delay during a breath-hold at the tail end of the ventilation sequence. Analysis was performed to assess the sensitivity of the multislice ventilation model to noise, oxygen and the number of flip angle images. The optimal α value was determined on the basis of the minimization of the error in r estimation: α(opt) = 5-6º for the set of acquisition parameters in pigs. The mean r values for the group of pigs were 0.27 ± 0.09, 0.35 ± 0.06 and 0.40 ± 0.04 for the ventral, middle and dorsal slices, respectively (excluding conductive airways r 0.9). A positive gravitational (ventral-dorsal) ventilation gradient effect was present in all animals. The trachea and major conductive airways showed a uniform near-unity r value, with progressively smaller values corresponding to smaller diameter airways, and ultimately leading to lung parenchyma. The results demonstrate the feasibility of the measurement of the fractional ventilation in large species, and provide a platform to address the technical challenges associated with long breathing time scales through the optimization of acquisition parameters in species with a pulmonary physiology very similar to that of humans.

Measurement of Regional 2D Gas Transport Efficiency in Rabbit Lung Using Hyperpolarized 129Xe MRI.

While hyperpolarized xenon-129 (HXe) MRI offers a wide array of tools for assessing functional aspects of the lung, existing techniques provide only limited quantitative information about the impact of an observed pathology on overall lung function. By selectively destroying the alveolar HXe gas phase magnetization in a volume of interest and monitoring the subsequent decrease in the signal from xenon dissolved in the blood inside the left ventricle of the heart, it is possible to directly measure the contribution of that saturated lung volume to the gas transport capacity of the entire lung. In mechanically ventilated rabbits, we found that both xenon gas transport and transport efficiency exhibited a gravitation-induced anterior-to-posterior gradient that disappeared or reversed direction, respectively, when the animal was turned from supine to prone position. Further, posterior ventilation defects secondary to acute lung injury could be re-inflated by applying positive end expiratory pressure, although at the expense of decreased gas transport efficiency in the anterior volumes. These findings suggest that our technique might prove highly valuable for evaluating lung transplants and lung resections, and could improve our understanding of optimal mechanical ventilator settings in acute lung injury.

Lung Metabolism and Inflammation during Mechanical Ventilation; An Imaging Approach.

Acute respiratory distress syndrome (ARDS) is a major cause of mortality in critically ill patients. Patients are currently managed by protective ventilation and alveolar recruitment using positive-end expiratory pressure (PEEP). However, the PEEP's effect on both pulmonary metabolism and regional inflammation is poorly understood. Here, we demonstrate the effect of PEEP on pulmonary anaerobic metabolism in mechanically ventilated injured rats, using hyperpolarized carbon-13 imaging. Pulmonary lactate-to-pyruvate ratio was measured in 21 rats; 14 rats received intratracheal instillation of hydrochloric-acid, while 7 rats received sham saline. 1 hour after acid/saline instillation, PEEP was lowered to 0 cmH2O in 7 injured rats (ZEEP group) and in all sham rats; PEEP was continued in the remaining 7 injured rats (PEEP group). Pulmonary compliance, oxygen saturation, histological injury scores, ICAM-1 expression and myeloperoxidase expression were measured. Lactate-to-pyruvate ratio progressively increased in the dependent lung during mechanical ventilation at ZEEP (p < 0.001), but remained unchanged in PEEP and sham rats. Lactate-to-pyruvate ratio was correlated with hyaline membrane deposition (r = 0.612), edema severity (r = 0.663), ICAM-1 (r = 0.782) and myeloperoxidase expressions (r = 0.817). Anaerobic pulmonary metabolism increases during lung injury progression and is contained by PEEP. Pulmonary lactate-to-pyruvate ratio may indicate in-vivo neutrophil activity due to atelectasis.

Assessment of Pulmonary Gas Transport in Rabbits Using Hyperpolarized Xenon-129 Magnetic Resonance Imaging.

Many forms of lung disease manifest themselves as pathological changes in the transport of gas to the circulatory system, yet the difficulty of imaging this process remains a central obstacle to the comprehensive diagnosis of lung disorders. Using hyperpolarized xenon-129 as a surrogate marker for oxygen, we derived the temporal dynamics of gas transport from the ratio of two lung images obtained with different timing parameters. Additionally, by monitoring changes in the total hyperpolarized xenon signal intensity in the left side of the heart induced by depletion of xenon signal in the alveolar airspaces of interest, we quantified the contributions of selected lung volumes to the total pulmonary gas transport. In a rabbit model, we found that it takes at least 200 ms for xenon gas to enter the lung tissue and travel the distance from the airspaces to the heart. Additionally, our method shows that both lungs contribute fairly equally to the gas transport in healthy rabbits, but that this ratio changes in a rabbit model of acid aspiration. These results suggest that hyperpolarized xenon-129 MRI may improve our ability to measure pulmonary gas transport and detect associated pathological changes.

Mild loss of lung aeration augments stretch in healthy lung regions.

Inspiratory stretch by mechanical ventilation worsens lung injury. However, it is not clear whether and how the ventilator damages lungs in the absence of preexisting injury. We hypothesized that subtle loss of lung aeration during general anesthesia regionally augments ventilation and distension of ventilated air spaces. In eight supine anesthetized and intubated rats, hyperpolarized gas MRI was performed after a recruitment maneuver following 1 h of volume-controlled ventilation with zero positive end-expiratory pressure (ZEEP), FiO2 0.5, and tidal volume 10 ml/kg, and after a second recruitment maneuver. Regional fractional ventilation (FV), apparent diffusion coefficient (ADC) of (3)He (a measurement of ventilated peripheral air space dimensions), and gas volume were measured in lung quadrants of ventral and dorsal regions of the lungs. In six additional rats, computed tomography (CT) images were obtained at each time point. Ventilation with ZEEP decreased total lung gas volume and increased both FV and ADC in all studied regions. Increases in FV were more evident in the dorsal slices. In each lung quadrant, higher ADC was predicted by lower gas volume and by increased mean values (and heterogeneity) of FV distribution. CT scans documented 10% loss of whole-lung aeration and increased density in the dorsal lung, but no macroscopic atelectasis. Loss of pulmonary gas at ZEEP increased fractional ventilation and inspiratory dimensions of ventilated peripheral air spaces. Such regional changes could help explain a propensity for mechanical ventilation to contribute to lung injury in previously uninjured lungs.