Effects of Single and Multiple Dose Tiotropium/Olodaterol in Chronic Obstructive Pulmonary Disease on Alveolar Gas Exchange Measured by Hyperpolarized 129Xe MRI.

BACKGROUND: Long-acting muscarinic antagonists/long-acting beta adrenoreceptor agonists lead to lung deflation and improved microvascular perfusion in hyperinflated chronic obstructive pulmonary disease (COPD), but with an unclear time course. PURPOSE: To investigate the effect of inhalation of tiotropium/olodaterol (TIO/OLO) on MRI measures of gas uptake and microvascular blood volume after single and multiple doses. STUDY TYPE: Prospective, randomized, investigator-blinded, placebo-controlled single-dose crossover study with open-label multiple-dose extension. POPULATION: 31 participants with COPD and lung hyperinflation (residual volume > 135% predicted, ≥ 10 pack-years smoking). FIELDSTRENGTH/SEQUENCE: 1.5 T/Interleaved 3D radial gas and dissolved-phase MRI using multi-echo FLASH, high-resolution spectroscopy, chemical shift saturation recovery spectroscopy. ASSESSMENT: Ratios of 129Xe in membrane tissues (M) to gas (M-Gas), red blood cells (RBC) to gas (RBC-Gas), RBC to M (RBC-M) were calculated from dissolved-phase imaging. Dissolved-phase apparent transverse relaxation times (T2*) from high-resolution spectra were also calculated, and septal wall thickness and surface-volume ratio (S/V) were assessed by fitting a model of xenon exchange functions. Parameters were compared for single-dose (5 μg/5 μg TIO/OLO) versus placebo using saline, and single-dose versus multiple-dose (daily 5 μg/5 μg TIO/OLO for 14 days) treatments. STATISTICAL TESTS: Linear mixed models with contrasts of estimated marginal means, significance level 0.05. RESULTS: Compared with placebo, single-dose treatment significantly increased RBC-Gas and septal thickness but not RBC-M (p = 0.06), M-Gas (p = 0.16), RBC T2* (p = 0.13), M T2* (p = 0.09) and S/V (p = 0.47). Multiple-dose treatment significantly increased RBC-Gas, M-Gas and M T2* compared with single-dose treatment, but not RBC-M (p = 0.82), RBC T2* (p = 0.48), septal thickness (p = 0.61), and S/V (p = 0.49). DATA CONCLUSION: Single-dose TIO/OLO increased 129Xe in RBC-Gas. Multiple-dose treatment increased M-Gas and further increased RBC-Gas compared to single-dose treatment. TECHNICAL EFFICACY: Stage 4. EVIDENCE LEVEL: 2.