Measuring diffusion limitation with a perfusion-limited gas--hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis

Abstract

Although xenon is classically taught to be a "perfusion-limited" gas, (129)Xe in its hyperpolarized (HP) form, when detected by magnetic resonance (MR), can probe diffusion limitation. Inhaled HP (129)Xe diffuses across the pulmonary blood-gas barrier, and, depending on its tissue environment, shifts its resonant frequency relative to the gas-phase reference (0 ppm) by 198 ppm in tissue/plasma barrier and 217 ppm in red blood cells (RBCs). In this work, we hypothesized that in patients with idiopathic pulmonary fibrosis (IPF), the ratio of (129)Xe spectroscopic signal in the RBCs vs. barrier would diminish as diffusion-limitation delayed replenishment of (129)Xe magnetization in RBCs. To test this hypothesis, (129)Xe spectra were acquired in 6 IPF subjects as well as 11 healthy volunteers to establish a normal range. The RBC:barrier ratio was 0.55 ± 0.13 in healthy volunteers but was 3.3-fold lower in IPF subjects (0.16 ± 0.03, P = 0.0002). This was caused by a 52% reduction in the RBC signal (P = 0.02) and a 58% increase in the barrier signal (P = 0.01). Furthermore, the RBC:barrier ratio strongly correlated with lung diffusing capacity for carbon monoxide (DLCO) (r = 0.89, P < 0.0001). It exhibited a moderate interscan variability (8.25%), and in healthy volunteers it decreased with greater lung inflation (r = -0.78, P = 0.005). This spectroscopic technique provides a noninvasive, global probe of diffusion limitation and gas-transfer impairment and forms the basis for developing 3D MR imaging of gas exchange.

Keywords: diffusion limitation; gas-transfer spectroscopy; hyperpolarized 129Xe; idiopathic pulmonary fibrosis.

Copyright © 2014 the American Physiological Society.

Figures

Fig. 1.

Acquisition scheme for the dissolved and gas-phase 129Xe spectra. First, 200 (N) dissolved-phase 129Xe spectra were acquired by pulsing and acquiring on the red blood cell (RBC) resonance, +3,832 Hz above the gas-phase resonance. Then, with identical acquisition parameters, transmit and receive frequencies were lowered to match the gas-phase 129Xe resonance, and a single reference spectrum was acquired. TR, repetition time; TE, echo time.

Fig. 2.

Curve fitting the dissolved-phase 129Xe spectra. The real and imaginary spectra were fit separately. The imaginary fit was rephased by 90° and averaged with the real spectrum to generate the final fit parameters, including amplitude, frequency, and spectral width for each peak.

Fig. 3.

A: a truncated dissolved-phase spectrum from a representative healthy volunteer and a subject with idiopathic pulmonary fibrosis (IPF). Compared with the healthy volunteer, this IPF subject exhibits a 2.9-fold reduction in the RBC:barrier ratio. B: for all subjects the RBC:barrier ratio was 0.55 ± 0.13 in the healthy volunteers but was 3.3-fold lower in the IPF patients (0.16 ± 0.03; *P = 0.0002).

Fig. 4.

Comparison of the RBC:gas ratio and the barrier:gas ratio in healthy volunteers and IPF subjects. The RBC:gas ratio (left) was reduced ∼2-fold in IPF vs. healthy subjects (*P = 0.02), and the barrier:gas ratio (right) was increased ∼1.6-fold in IPF subjects (*P = 0.01). These two effects together reduced the overall RBC:barrier ratio in the IPF subjects.

Fig. 5.

Bland-Altman plots showing the reproducibility of the RBC:barrier ratio. A: within a given session, RBC:barrier had a variability of 6.6%, which was not significant. B: over different scanning sessions, RBC:barrier was significantly reduced in the follow-up session (P = 0.01), with a mean variability of 8.25%.

Fig. 6.

Correlations of gas-transfer metrics. A: RBC:barrier was strongly correlated with lung diffusing capacity of carbon monoxide (DLCO) (r = 0.89, P < 0.001). B: in healthy subjects, the RBC:gas metric was significantly reduced by greater lung inflation (r = −0.78, P = 0.005).

Fig. 7.

Changes in the RBC:gas, RBC:barrier, and barrier:gas ratios observed during a breath-hold. Spectra were processed using a “sliding-window” processing technique to provide a pseudotemporal depiction. During the breath-hold, RBC:gas and RBC:barrier ratio are initially reduced by depletion of 129Xe magnetization in the larger vasculature (downstream signal). During the Valsalva maneuver RBC:gas diminishes while barrier:gas remains stable, resulting in diminishing RBC:barrier ratio. This is attributable to a reduction in capillary blood volume during the maneuver. Conversely, the Müller maneuver increases capillary blood volume, and hence the associated ratios. Exhalation increases overall gas transfer, but also maximally increases capillary blood volume, which is reflected in an increasing RBC:barrier.