Effects of Single and Multiple Dose Tiotropium/Olodaterol in Chronic Obstructive Pulmonary Disease on Alveolar Gas Exchange Measured by Hyperpolarized
129
Xe MRI
Agilo L. Kern, Thomas Kayser, Robin A. Müller, Andreas Voskrebenzev, Filip Klimeš, Frank Wacker, Jens M. Hohlfeld, Jens Vogel‐Claussen ABSTRACT
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 129 Xe 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 (T 2 *) 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 T 2 * ( p = 0.13), M T 2 * ( p = 0.09) and S/V ( p = 0.47). Multiple‐dose treatment significantly increased RBC‐Gas, M‐Gas and M T 2 * compared with single‐dose treatment, but not RBC‐M ( p = 0.82), RBC T 2 * ( p = 0.48), septal thickness ( p = 0.61), and S/V ( p = 0.49).
Data Conclusion
Single‐dose TIO/OLO increased 129 Xe 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.