Hyperpolarized 3He functional magnetic resonance imaging of bronchoscopic airway bypass in chronic obstructive pulmonary disease

1Imaging Research Laboratories, Robarts Research Institute; 2Department of Medical Biophysics; 3Division of Respirology, Department of Medicine, 4Department of Medical Imaging, University of Western Ontario, London, Ontario Correspondence and reprints: Dr Grace Parraga, Imaging Research Laboratories, Robarts Research Institute, PO Box 5015, 100 Perth Drive, London, Ontario N6A 5K8. Telephone 519-913-5265, fax 519-913-5260, e-mail gep@imaging.robarts.ca CASE PRESENTATION A 73-year-old male exsmoker with Global initiative for chronic Obstructive Lung Disease (GOLD) stage III chronic obstructive pulmonary disease (COPD) underwent airway bypass (AB) in February 2009 as part of the Exhale Airway Stents for Emphysema (EASE) trial. Thirty-two months before AB (June 2006), he reported a 70 pack-year smoking history, having ceased smoking approximately 13 years earlier, and was enrolled in a longitudinal hyperpolarized 3He magnetic resonance imaging (MRI) study. At the initial study visit 32 months pre-AB, his measured forced expiratory volume in 1 s (FEV1) was 1.2 L (32% predicted); all other measured parameters are presented in Table 1. Hyperpolarized 3He MRI was performed at 3.0 Tesla using a fastgradient recalled echo-pulse sequence for static ventilation imaging as previously described (1-3). Images were acquired with the subject in breath-hold, after inspiration of 1.0 L of 5 mL/kg 3He mixed with nitrogen gas from functional residual capacity. Proton MRI of the thorax was also acquired as previously described (4) within 3 min of 3He MRI, with the same breath-hold volume to obtain a structural image of the thorax that enabled clear delineation of the thoracic cavity. This MRI approach has been previously used in acute COPD therapy (5) and longitudinal studies (6). MRI reproducibility in COPD was also previously evaluated at the Imaging Research Laboratories, Robarts Research Institute (London, Ontario) (1) and elsewhere (7,8), and was high, supporting its use in serial studies. In Figure 1, 3He MRI performed at 32 months pre-AB (top left panel), shows heterogeneous distribution of gas with large ventilation defects and regionally heterogeneous 3He MR signal intensity characteristic of COPD. On returning for follow-up imaging 24 months later (eight months pre-AB [Figure 1, top right panel]), 3He MRI showed a decrease in ventilation of the right upper and lower, and left upper lung regions as well as a decreased signal-to-noise ratio. Quantitative analysis (9) revealed a ventilation volume (VV) decrease of 3.8 L over the two-year period, and a corresponding decrease in per cent ventilated volume (PVV) from 73% to 26%. The functional imaging changes observed were coincident with a large decrease in forced vital capacity (FVC), and small decreases in FEV1 and inspiratory capacity (Table 1). There were no exacerbations or hospitalizations reported during this 24-month period. At this time, the subject was enrolled in a randomized double-blind study evaluating the safety and efficacy of AB in subjects with homogeneous emphysema and severe hyperinflation. Clinical trial primary end points consisted of the change in the modified Medical Research Council scale (∆mMRC) ≥1 and ∆FVC ≥12% predicted. As part of the EASE protocol, he underwent six weeks of pulmonary rehabilitation before AB. In February 2009, four stents were placed: two in the right lower and two in the left upper lung. EASE trial follow-up occurred one, three, six and 12 months poststenting, with 3He MRI at the sixand 12-month post-AB time points. At six months post-AB, his FVC increased by 8% predicted; he was, therefore, categorized as an AB nonresponder. In contrast, at six months post-AB, visually obvious changes in the 3He MRI gas distribution that generally correspond to stent placement were observed throughout the right lung case report

Obstructive Lung Disease (GOLD) stage III chronic obstructive pulmonary disease (COPD) underwent airway bypass (AB) in February 2009 as part of the Exhale Airway Stents for Emphysema (EASE) trial. Thirty-two months before AB (June 2006), he reported a 70 pack-year smoking history, having ceased smoking approximately 13 years earlier, and was enrolled in a longitudinal hyperpolarized 3 He magnetic resonance imaging (MRI) study. At the initial study visit 32 months pre-AB, his measured forced expiratory volume in 1 s (FEV 1 ) was 1.2 L (32% predicted); all other measured parameters are presented in Table 1. Hyperpolarized 3 He MRI was performed at 3.0 Tesla using a fastgradient recalled echo-pulse sequence for static ventilation imaging as previously described (1)(2)(3). Images were acquired with the subject in breath-hold, after inspiration of 1.0 L of 5 mL/kg 3 He mixed with nitrogen gas from functional residual capacity. Proton MRI of the thorax was also acquired as previously described (4) within 3 min of 3 He MRI, with the same breath-hold volume to obtain a structural image of the thorax that enabled clear delineation of the thoracic cavity. This MRI approach has been previously used in acute COPD therapy (5) and longitudinal studies (6). MRI reproducibility in COPD was also previously evaluated at the Imaging Research Laboratories, Robarts Research Institute (London, Ontario) (1) and elsewhere (7,8), and was high, supporting its use in serial studies. In Figure 1, 3 He MRI performed at 32 months pre-AB (top left panel), shows heterogeneous distribution of gas with large ventilation defects and regionally heterogeneous 3 He MR signal intensity characteristic of COPD. On returning for follow-up imaging 24 months later (eight months pre-AB [ Figure 1, top right panel]), 3 He MRI showed a decrease in ventilation of the right upper and lower, and left upper lung regions as well as a decreased signal-to-noise ratio. Quantitative analysis (9) revealed a ventilation volume (VV) decrease of 3.8 L over the two-year period, and a corresponding decrease in per cent ventilated volume (PVV) from 73% to 26%. The functional imaging changes observed were coincident with a large decrease in forced vital capacity (FVC), and small decreases in FEV 1 and inspiratory capacity ( Table 1). There were no exacerbations or hospitalizations reported during this 24-month period.
At this time, the subject was enrolled in a randomized double-blind study evaluating the safety and efficacy of AB in subjects with homogeneous emphysema and severe hyperinflation. Clinical trial primary end points consisted of the change in the modified Medical Research Council scale (∆mMRC) ≥1 and ∆FVC ≥12% predicted. As part of the EASE protocol, he underwent six weeks of pulmonary rehabilitation before AB. In February 2009, four stents were placed: two in the right lower and two in the left upper lung. EASE trial follow-up occurred one, three, six and 12 months poststenting, with 3 He MRI at the six-and 12-month post-AB time points. At six months post-AB, his FVC increased by 8% predicted; he was, therefore, categorized as an AB nonresponder. In contrast, at six months post-AB, visually obvious changes in the 3 He MRI gas distribution that generally correspond to stent placement were observed throughout the right lung case report ©2012 Pulsus Group Inc. All rights reserved A 73-year-old exsmoker with Global initiative for chronic Obstructive Lung Disease stage III chronic obstructive pulmonary disease underwent airway bypass (AB) as part of the Exhale Airway Stents for Emphysema (EASE) trial, and was the only EASE subject to undergo hyperpolarized 3 He magnetic resonance imaging for evaluation of lung function pre-and post-AB. 3 He magnetic resonance imaging was acquired twice previously (32 and eight months pre-AB) and twice post-AB (six and 12 months post-AB). Six months post-AB, his increase in forced vital capacity was <12% predicted, and he was classified as an AB nonresponder. However, post-AB, he also demonstrated improvements in quality of life scores, 6 min walk distance and improvements in 3 He gas distribution in the regions of stent placement. Given the complex relationship between well-established pulmonary function and quality of life measurements, the present case provides evidence of the value-added information functional imaging may provide in chronic obstructive pulmonary disease interventional studies.  (Table 1).

DISCUSSION
AB is an investigational procedure that involves the creation of extraanatomical passages reinforced by a drug-eluting stent in the airway wall, with stents delivered using Doppler-guidance to avoid pulmonary vasculature in airway regions where the stents are inserted. The aim of AB is to artificially connect the segmental airways to adjacent lung tissue, thereby allowing trapped gas to be exhaled. Bronchoscopic lung volume reduction methods, such as AB, provide a minimally invasive alternative to lung volume reduction surgery with the goal of improving COPD quality of life, pulmonary function and survival (10)(11)(12). Unfortunately, for many of these approaches, significant improvements in intermediate end points such as FEV 1 and residual volume/ total lung capacity have not been realized postintervention (13)(14)(15) and, occasionally, these results are discordant with symptomatic or other functional improvements.  We highlighted hyperpolarized 3 He MRI in a single case of COPD in an exsmoker who underwent AB. Results of pulmonary function tests and 3 He MRI suggest a decline in lung function over the pre-AB, two-year time period. Post-AB however, significant improvements in gas distribution were visually and quantitatively apparent after six months and 12 months, including increases in VV and PVV. Regional changes in ventilation were visualized throughout the lung, even in regions not associated with stent placement, perhaps due to redistribution of ventilation following the release of trapped gas. It is worth noting that the most visually prominent changes occurred in the right lower and left upper lobes -the same regions where stents were originally placed. The resultant changes in VV and PVV were much greater than the smallest detectable difference previously estimated for 3 He MRI (5) based on a reproducibility study in COPD. Although 3 He MRI was not available immediately preceding AB, which would have enabled identification of ventilation improvements that were due to stent placement alone, the imaging results obtained provided functional information that was in agreement with 6MWD, SGRQ and mMRC, as well as DLCO, but not with spirometry and plethysmography measurements. Perhaps unexpectedly, both DLCO and PVV continued to increase post-AB, evidenced by large changes between six-and 12-month post-AB time points. These relatively late changes post-AB suggest continued improvements in gas distribution post-AB that coincided with improved gas transfer. The intriguing coincidence of improved 3 He gas distribution, DLCO and quality of life measures that endured 12 months post-AB in the only EASE trial subject for whom 3 He MRI was performed certainly generates new hypotheses to testespecially with respect to the use of imaging to guide stent placement and track regional changes in lung function.
The high cost and limited availability of 3 He MRI prohibits its prospective routine use in clinical research and its translation to clinical practice (16). However, its high short-term reproducibility (1) and sensitivity (5,6), coupled with the intriguing findings in longitudinal (6) and other acute COPD therapy studies (5), suggest that hyperpolarized noble gas imaging may be an ideal tool for visualization and quantitative evaluation of functional differences in COPD posttherapeutic intervention. The results of the present case study highlight the advantage of including functional MRI techniques such as hyperpolarized 129 Xe MRI (17,18) or conventional 1 H MRI (19) in COPD interventional studies, and suggest the application of these types of imaging in interventional studies may offer new insights into regional physiological changes in COPD following treatment.

ACKNOWLEDGEMENTS:
The authors gratefully acknowledge the late Peter T Macklem MD FRCPC OC, for his guidance and feedback on this study and case report. They also thank S Halko and S McKay for clinical coordination, and T Szekeres for MRI and A Wheatley for gas dispensing and administration.

FINANCIAL/NONFINANCIAL DISCLOSURES: No potential
conflicts of interest exist with any companies/organizations whose products or services are discussed in this article. Three of the authors (McCormack, Farquhar and Licskai) participated as investigators in the EASE trial and were reimbursed by Broncus for study-specific subject costs related to the AB procedures; MRI, however, was performed under a separate investigatorsponsored protocol for longitudinal 3 He MRI (Parraga and McCormack) and there was no Broncus involvement or funding for the MRI performed for this case.