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Cystic Fibrosis: Combined Hyperpolarized ³He-enhanced and Conventional Proton MR Imaging in the Lung-Preliminary Observations¹

¹ From the Departments of Radiology, Division of Pediatric Radiology (L.F.D., J.R.M., H.P.M., J.S., D.P.F., P.B., H.C.C., C.E.R.) and Pediatrics, Division of Pulmonary Medicine (J.M.M.), Duke University Medical Center, Durham, NC. From the 1998 RSNA scientific assembly. Received September 17, 1998; revision requested November 10; revision received November 19; accepted March 29, 1999. Address reprint requests to L.F.D., Department of Radiology, Children's Hospital Medical Center and the University of Cincinnati, 3333 Burnet Ave, Cincinnati, OH 45229-3039.

	Abstract

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Four patients with cystic fibrosis (CF) were examined with combined hyperpolarized helium 3–enhanced and conventional proton magnetic resonance (MR) imaging. After inhalation of the polarized ³He gas, single breath-hold, gradient-echo images (resonant frequency of ³He) were obtained to depict lung ventilation. Conventional T2-weighted fast spin-echo (hydrogen) images were also obtained to depict morphologic abnormalities. ³He images were successfully and reproducibly generated that showed both morphologic abnormalities and, often more extensive, ventilation abnormalities. ³He MR imaging may provide a method for evaluating progression of pulmonary disease in patients with CF.

Index terms: Fibrosis, cystic, 60.252 • Helium, 60.12147 • Lung, MR, 60.12143 • Magnetic resonance (MR), contrast enhancement, 60.12143 • Magnetic resonance (MR), nuclei other than H, 60.12147

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Image scoring systems have been used clinically and as a research tool to objectively evaluate the progression of lung disease in patients with cystic fibrosis (CF) (1–7). The goal is to facilitate objective evaluation of existing and newly developed therapeutic regimens, such as gene therapy and mucolytic agents (1–7). Current options for pulmonary evaluation in patients with CF include chest radiography, thin-section computed tomography (CT), pulmonary function testing, and single photon emission CT (SPECT) for pulmonary perfusion or ventilation imaging (1–7). Pulmonary function tests help analysis of global lung function. Unfortunately, CF may cause focal nonuniform lung injury, which is not accurately depicted by means of an assessment of global function. For this reason, imaging studies have been used primarily to develop scoring systems with which to monitor progression of disease (1–7).

Thin-section CT and chest radiography are performed to evaluate morphologic changes of CF to determine the severity of disease. Findings in multiple studies in patients with CF suggest thin-section CT is superior to chest radiography for the evaluation of lung disease, such as bronchiectasis, peribronchial thickening, mucus plugging, and emphysema (1–4). Thin-section CT is also more sensitive for early lung changes. However, there has been concern that the morphologic changes seen at thin-section CT and chest radiography may not reflect early functional pulmonary disease, which has been depicted at SPECT perfusion or ventilation imaging. Functional imaging may offer a more sensitive way with which to detect early changes of CF in patients with minimal disease (1,6,8). Morphologically normal lung can at times demonstrate marked functional abnormalities at ventilation and perfusion imaging (1,8). This is of particular importance in the evaluation of progression in young patients with minimal disease and no or minimal findings at thin-section CT. Since many protocols that evaluate new therapies involve young children with minimal or no lung disease, the detection of early lung changes in CF is critical. Functional and morphologic evaluation can be performed with a combination of both thin-section CT and SPECT, but the cost and radiation dose associated with both examinations is prohibitive, especially when these examinations are performed serially.

The optimal single imaging modality with which to grade progression of the pulmonary changes seen in patients with CF would provide both morphologic and functional information and, because of the sequential nature of following up of progression of disease, would not use radiation. Use of combined hyperpolarized helium 3–enhanced and conventional proton magnetic resonance (MR) imaging may meet these criteria. By imaging with a hyperpolarized ventilation contrast agent, such as ³He, high signal intensity (SI) can be generated within the pulmonary air spaces. In patients with CF, ³He MR imaging may provide both functional information related to airway occlusion and absent ventilation, as has been previously demonstrated with SPECT (1), and anatomic information by means of conventional proton-based, fast spin-echo (SE) imaging. The purpose of this study was to evaluate the preliminary findings with combined ³He and proton MR imaging in four patients with CF.

	Materials and Methods

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Four young adult patients with CF (two men and two women; age range, 18–24 years; mean age, 20 years) and moderate to severe lung disease underwent hyperpolarized ³He MR imaging. The study was approved by our institutional review board, and all studies were performed with written informed consent. Hyperpolarized ³He MR images were obtained on a 1.5-T imager (Signa, revision 5.6; GE Medical Systems, Milwaukee, Wis) equipped with a broadband receiver that can adjust the radio frequency for the gyromagnetic ratio of both ³He (3,456.31 Hz/G) and hydrogen (4,257.26 Hz/G). A specially designed quadrature transmit-receive torso surface coil (26 cm long), which does not interfere with hydrogen imaging with the body coil, was constructed for ³He imaging (Medical Advances, Milwaukee, Wis).

Initially, with the ³He torso coil in place, conventional proton-based MR images were obtained throughout the chest with use of the body coil. Fast SE intermediate- and T2-weighted images were obtained in the coronal plane (repetition time msec/echo time msec = 3,000/80, 6-mm section thickness, 2-mm gap, 128 x 256 matrix, 32-cm field of view, one signal acquired, respiratory gating). After acquisition of the proton images and without moving the patient or the ³He torso coil, hyperpolarized ³He images were obtained with use of the ³He torso coil.

³He gas was hyperpolarized by means of a process that involves a collision exchange between rubidium and helium gases mixed together, heated to 180°C, and subjected to high-intensity laser illumination for several hours (9). When the container is cooled to room temperature, the rubidium is absorbed on the surface of the production container with residual concentrations of less than one in 100,000,000,000 atoms per cubic centimeter. The helium gas was polarized by using a prototypic unit (Magnetic Imaging Technologies, Durham, NC). Unit calibration tests demonstrated 9%–11% polarization of the helium after the process. After the ³He was polarized and cooled, it was placed in a delivery apparatus—a plastic bag with an attached tube containing a simple plastic stopcock on-off valve. The bag had a maximum capacity of 1 L. The bag was filled to between 0.7 and 0.9 L. Subjects were instructed to inhale the gas and hold their breath.

Immediately after the patients inhaled the ³He gas, gradient-echo images were obtained in the coronal plane (9.5/3.0 with 8° flip angle, single breath hold, 6-mm section thickness, 2-mm gap, 128 x 256 matrix, 32-cm field of view, one signal acquired). ³He gas inhalation and MR imaging were repeated in each subject to evaluate reproducibility.

During the examination, the patient's respiratory rate, pulse rate, and blood oxygenation levels were monitored. The patient's ability to cooperate with the examination was noted as were any changes in these vital signs during the study.

For comparison, the conventional proton fast SE and ³He images were printed with identical anatomic levels side by side. This aided interpretation of absent ventilation on the ³He images by defining the expected extent of the lung. Grading systems were constructed to help interpret both the ³He images and the conventional proton images. Each lung was divided into six zones that were independently graded. Three lung regions were based on superior to inferior thirds: upper, middle, and lower. Each region was then divided into an anterior and posterior zone, which yielded a total of six zones per lung.

Each lung zone was given a functional score based on the degree of ventilation as seen on the ³He MR images. Scores were based on the percentage of lung ventilated (percentage ventilation = area enhanced/total area of zone). Scores ranged from 0 (normal) to 4 (less than 25% of lung zone ventilated) (Table 1). The potential scores per patient (12 lung zones) ranged from 0 to 48. The ³He MR studies of two healthy male volunteers, who had no history or symptoms of pulmonary disease, showed diffuse homogeneous SI throughout the lungs (Fig 1). These studies were used as a normal reference. Imaging in the healthy volunteers was also approved by our institutional review board.

View larger version (196K): [in this window] [in a new window]   Figure 1. Normal 3He MR image in a 53-year-old male volunteer. Coronal gradient-echo image (9.5/8 with 8° flip angle) through the posterior lung shows homogeneous high SI diffusely throughout the lungs. High SI from the hyperpolarized 3He is seen within the left main bronchus (arrow).

In each patient, scores were compared with findings at chest radiography and pulmonary function testing (Table 3). Chest radiographs were scored for the severity of disease on the basis of the scoring system described by Brasfield et al (4,5). The potential Brasfield scores ranged from 0 (normal) to 25 (severe disease) (4,5). Findings at MR imaging were also compared with those at pulmonary function testing in each subject. Parameters evaluated included the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV₁). The percentage of predicted values was calculated for each pulmonary function parameter by means of the Knudson equations (10).

	Results

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In all subjects, areas of absent lung ventilation were depicted on the hyperpolarized ³He MR images. These areas of absent ventilation ranged from wedge- shaped peripheral defects to entire lung zones (Figs 2, 3). The ³He lung zone scores ranged from normal ventilation (score, 0) to completely absent ventilation (score, 4). Total ³He ventilation scores ranged from 18 (38% of maximum score) to 31 (65% of maximum score) (Table 3). In all subjects, the lack of ventilation was most severe in the upper posterior lung zones, and ventilation was most normal in the lower lung zones. The mean ³He score for the upper posterior lung zone in the four subjects was 3.9. The mean score for the lower lung zones was 1.2. Concerning reproducibility, the individual lung zone scores were identical in all subjects for the two ³He data sets obtained at each examination.

View larger version (120K): [in this window] [in a new window]   Subject 2. Severe ventilation defects are disproportionately greater in distribution than are morphologic abnormalities in a 24-year-old woman with CF. (a) Coronal conventional fast SE MR image (3,000/80) at the level of the trachea shows areas of mildly increased linear and punctate nodular SI (arrowheads) within the upper and middle lung zones bilaterally, as well as bilateral hilar and subcarinal lymphadenopathy (arrows). (b) Coronal 3He gradient-echo MR image (9.5/8 with 8° flip angle) shows complete (right) and nearly complete (left) absence of SI within the upper lungs (arrows). There are also large areas of absent SI within the middle and lower lungs (arrowheads).

View larger version (121K): [in this window] [in a new window]   Subject 2. Severe ventilation defects are disproportionately greater in distribution than are morphologic abnormalities in a 24-year-old woman with CF. (a) Coronal conventional fast SE MR image (3,000/80) at the level of the trachea shows areas of mildly increased linear and punctate nodular SI (arrowheads) within the upper and middle lung zones bilaterally, as well as bilateral hilar and subcarinal lymphadenopathy (arrows). (b) Coronal 3He gradient-echo MR image (9.5/8 with 8° flip angle) shows complete (right) and nearly complete (left) absence of SI within the upper lungs (arrows). There are also large areas of absent SI within the middle and lower lungs (arrowheads).

View larger version (152K): [in this window] [in a new window]   Subject 1. Severe functional and morphologic abnormalities in a 20-year-old woman with CF. (a) Coronal conventional fast SE MR image (3,000/80) through the posterior lung shows bullous change (arrow) and increased linear and nodular SI (arrowheads) involving the upper and lower lobes bilaterally. (b) Coronal 3He gradient-echo MR image (9.5/8 with 8° flip angle) shows complete absence of SI in the upper lung bilaterally (arrows). There is also a large, wedge-shaped area of absent SI (arrowhead) within the lateral portion of the right middle lung.

View larger version (151K): [in this window] [in a new window]   Subject 1. Severe functional and morphologic abnormalities in a 20-year-old woman with CF. (a) Coronal conventional fast SE MR image (3,000/80) through the posterior lung shows bullous change (arrow) and increased linear and nodular SI (arrowheads) involving the upper and lower lobes bilaterally. (b) Coronal 3He gradient-echo MR image (9.5/8 with 8° flip angle) shows complete absence of SI in the upper lung bilaterally (arrows). There is also a large, wedge-shaped area of absent SI (arrowhead) within the lateral portion of the right middle lung.

In a comparison of the percentage of maximum score for the functional ³He image and morphologic conventional image scores for individual lung zones, ³He ventilation scores indicated more severe disease than did the morphologic scores in 29 (60%) of the 48 lung zones evaluated (Fig 2). The severity of disease indicated by the ³He image scores was equal to that indicated by the morphologic conventional image scores in 19 (40%) lung zones (Fig 3). In no zones was the morphologic score higher than the ³He ventilation score. In many of the lung zones, the degree of absent ventilation was severe despite minimal morphologic changes (Fig 2). In addition, the percentage of maximum total ³He scores was greater than that of the morphologic scores in all cases (Table 3).

In the four patients, there was general correlation between the total MR imaging scores, the Brasfield chest radiograph scores, and the pulmonary function test results (Table 3). The small number of subjects precluded statistical analysis. The FVC was 3.03 L (88% of predicted value) for subject 1, 1.74 L (51% of predicted value) for subject 2, 3.18 L (75% of predicted value) for subject 3, and 2.60 L (58% of predicted value) for subject 4. The FEV₁ was 1.96 L (62% of predicted value) for subject 1, 0.89 L (29% of predicted value) for subject 2, 1.55 L (39% of predicted value) for subject 3, and 1.28 L (30% of predicted value) for subject 4.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
MR imaging based on the evaluation of hydrogen protons has become the imaging modality of choice for evaluation of many organ systems and disease states. However, the role of MR imaging in the evaluation of pathologic lung conditions has been extremely limited as a result of the low concentration of hydrogen protons in normal lung tissue, which results in very low SI. One of the factors contributing to this lack of SI is that only a minority (one proton in 10,000,000 atoms) becomes polarized when an external magnetic field is applied (9). As a result of imaging with a hyperpolarized ventilation contrast agent, high SI can be generated within the pulmonary airspaces. Imaging with hyperpolarized ³He, available on a research basis in forms with as much as 30% polarized molecules (9,11), offers a potential increase in signal-to-noise ratios of 100,000 times the values for proton imaging. The ³He can be imaged by adapting a conventional MR imaging system by tuning the radio frequency from the resonant frequency of hydrogen to that of helium (9,11). Because SI is generated by the hyperpolarized substance and is not related to T1 recovery time, very short repetition times can be used, which result in very quick image generation. Images of a subject's entire lungs have been generated in as few as 10 seconds (9). High-spatial-resolution images have been safely obtained in healthy volunteers by having the subjects inhale hyperpolarized ³He while lying inside a conventional MR imaging unit (9,11). The value of ³He MR imaging in patients with pathologic lung conditions has not yet been defined (11).

In this study, high-quality images of the lung were generated in all subjects, even in the presence of moderate to severe pulmonary disease from CF. Because of the short time of acquisition for the ³He images, all of the subjects were able to cooperate with the length of breath holding required. We did not test the ability of young children to cooperate with this examination. The time of breath holding for ³He MR imaging is approximately 10 seconds. For CT examinations, we have had success with breath holding for longer times in children as young as 4 years and routinely in children older than 6 years. Therefore, we would not anticipate difficulty with cooperation for ³He MR imaging except with very young children. For very young children, it may be possible to achieve ³He MR imaging by using a "stop ventilation" technique (12). None of our patients demonstrated any signs of respiratory compromise related to the administration of the ³He gas. Therefore, no technical or safety issues seem to prohibit the evaluation of patients with CF by means of ³He MR imaging. In addition, in this small series, results of ³He MR imaging were reproducible, with identical imaging findings in two separate data acquisitions.

In all subjects, abnormalities of both ventilation and morphology were readily detected. In the majority of individual lung zones and for all total ³He scores, the ³He functional MR image scores demonstrated more severe findings than did the scores for changes on conventional morphologic MR images. In many lung zones, severe ventilation abnormalities were seen despite minimal morphologic abnormalities. Morphologic changes at chest radiography and thin-section CT have been used as the basis for following up patients with CF for progression of disease (1–5). However, a study (1) comparing functional information obtained at pulmonary perfusion SPECT with morphologic changes seen at thin-section CT suggested that functional changes may be present prior to the occurrence of morphologic changes. Our preliminary results and the results of the previous study (1) suggest that functional abnormalities may be more sensitive to pulmonary changes of CF than are morphologic changes. Because many treatment protocols involve young children with minimal or no apparent lung disease, the ability to detect early changes in CF is critical for a modality to be used in following up progression of disease.

The standard of reference for evaluation of morphologic changes in CF is thin-section CT (1–3). To our knowledge, conventional hydrogen proton MR imaging has not been previously described as a method with which to evaluate morphologic changes in patients with CF. This is most likely related to the previously limited use of MR imaging in pulmonary imaging. However, with both the increasing speed at which fast SE images can be generated and improved techniques of respiratory gating, our preliminary results show promising potential for MR imaging to be accurate in this capacity. However, the unknown accuracy of MR imaging for depicting morphologic pulmonary changes is a limitation of our study. Further studies are needed that compare findings with combined ³He and proton MR imaging to those with thin-section CT.

Because both functional and morphologic information concerning the pulmonary status of patients with CF can be generated on hyperpolarized ³He MR imaging studies in a safe, reproducible, and technically feasible manner and because radiation is not used, ³He MR imaging may be an ideal way of serially evaluating patients with CF for progression of disease. We believe our preliminary results warrant further investigation, including application of this technology in the cases of younger patients with CF and minimal lung disease.

	Acknowledgments

 
We thank J. Antonio Jackson, Craig Kornegay, BS, Brad Wheeler, BS, David Zollinger, BS, and Geri Zollinger, MS, from Magnetic Imaging Technologies for their assistance with the ³He gas polarizing system, and Ralph Hashoian from Medical Advances for his design of the ³He radio-frequency coil.

	Footnotes

 
Abbreviations: CF = cystic fibrosis FEV₁ = forced expiratory volume in 1 second FVC = forced vital capacity SE = spin echo SI = signal intensity

Author contributions: Guarantors of integrity of entire study, L.F.D., J.R.M.; study concepts, L.F.D., J.R.M., H.P.M., D.P.F., J.M.M.; study design, L.F.D., J.R.M., H.P.M.; literature research, all authors; clinical studies, all authors; data acquisition, all authors; data analysis, L.F.D., H.P.M., D.P.F.; manuscript preparation, L.F.D.; manuscript editing and review, all authors.

	References

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