Chronic obstructive pulmonary disease: safety and tolerability of hyperpolarized 129Xe MR imaging in healthy volunteers and patients

Abstract

Purpose: To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 ((129)Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging.

Materials and methods: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years ± 18.8 [standard deviation]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized (129)Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects' serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after (129)Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a χ(2) test and to subject age by using logistic regression. Changes in vital signs were tested for significance across subject group and time by using a repeated-measures multivariate analysis of variance test.

Results: The 44 subjects tolerated all xenon inhalations, no subjects withdrew, and no serious adverse events occurred. No significant changes in vital signs (P > .27) were observed, and no subjects exhibited changes in laboratory test or ECG results at follow-up that were deemed clinically important or required intervention. Most subjects (91%) did experience transient xenon-related symptoms, most commonly dizziness (59%), paresthesia (34%), euphoria (30%), and hypoesthesia (30%). All symptoms resolved without clinical intervention in 1.6 minutes ± 0.9.

Conclusion: Inhalation of hyperpolarized (129)Xe is well tolerated in healthy subjects and in those with mild or moderate COPD. Subjects do experience mild, transient, xenon-related symptoms, consistent with its known anesthetic properties.

Figures

Figure 1:

Schedule of study events. Healthy volunteers during the technical run-in phase received four 1-L doses of hyperpolarized (HP) 129Xe, while age-matched control subjects and subjects with COPD during the efficacy phase received three doses. Age-matched control subjects and subjects with COPD underwent pulmonary function testing, whereas healthy volunteers did not. The specific monitoring schedule for each dose is broken out at the bottom of the figure. DLCO-SB = single-breath diffusing capacity of lung for carbon monoxide, ECG = electrocardiography, Resp = respiratory rate recording, Spo2 = oxygen saturation as measured by pulse oximetry.

Figure 2:

Selected sections from representative 129Xe ventilation and 1H MR anatomic images in individual subjects. A, Steady-state free-precession 1H MR images in a healthy volunteer. B, Corresponding 129Xe ventilation MR images in the same healthy volunteer. C, Steady-state free-precession 1H MR images in a subject with COPD. D, Corresponding 129Xe ventilation MR images in the same subject with COPD show substantial ventilation defects and regions lacking ventilation.

Figure 3a:

Graphs show mean change in vital signs after xenon dose administration relative to baseline as a function of time. Data were acquired after inhaling the xenon dose and were averaged over all doses for a given time point (four doses for healthy volunteers, three doses for age-matched control subjects and subjects with COPD) but are separated by subject group. Dashed vertical lines = time after which subjects were permitted to move about freely. Graphs show (a) systolic blood pressure (BP), (b) diastolic blood pressure, (c) blood oxygen saturation (Spo2), (d) heart rate, and (e) respiratory rate. No clinically important changes in any of these vital signs were noted for any of the groups.

Figure 3b:

Graphs show mean change in vital signs after xenon dose administration relative to baseline as a function of time. Data were acquired after inhaling the xenon dose and were averaged over all doses for a given time point (four doses for healthy volunteers, three doses for age-matched control subjects and subjects with COPD) but are separated by subject group. Dashed vertical lines = time after which subjects were permitted to move about freely. Graphs show (a) systolic blood pressure (BP), (b) diastolic blood pressure, (c) blood oxygen saturation (Spo2), (d) heart rate, and (e) respiratory rate. No clinically important changes in any of these vital signs were noted for any of the groups.

Figure 3c:

Graphs show mean change in vital signs after xenon dose administration relative to baseline as a function of time. Data were acquired after inhaling the xenon dose and were averaged over all doses for a given time point (four doses for healthy volunteers, three doses for age-matched control subjects and subjects with COPD) but are separated by subject group. Dashed vertical lines = time after which subjects were permitted to move about freely. Graphs show (a) systolic blood pressure (BP), (b) diastolic blood pressure, (c) blood oxygen saturation (Spo2), (d) heart rate, and (e) respiratory rate. No clinically important changes in any of these vital signs were noted for any of the groups.

Figure 3d:

Graphs show mean change in vital signs after xenon dose administration relative to baseline as a function of time. Data were acquired after inhaling the xenon dose and were averaged over all doses for a given time point (four doses for healthy volunteers, three doses for age-matched control subjects and subjects with COPD) but are separated by subject group. Dashed vertical lines = time after which subjects were permitted to move about freely. Graphs show (a) systolic blood pressure (BP), (b) diastolic blood pressure, (c) blood oxygen saturation (Spo2), (d) heart rate, and (e) respiratory rate. No clinically important changes in any of these vital signs were noted for any of the groups.

Figure 3e:

Graphs show mean change in vital signs after xenon dose administration relative to baseline as a function of time. Data were acquired after inhaling the xenon dose and were averaged over all doses for a given time point (four doses for healthy volunteers, three doses for age-matched control subjects and subjects with COPD) but are separated by subject group. Dashed vertical lines = time after which subjects were permitted to move about freely. Graphs show (a) systolic blood pressure (BP), (b) diastolic blood pressure, (c) blood oxygen saturation (Spo2), (d) heart rate, and (e) respiratory rate. No clinically important changes in any of these vital signs were noted for any of the groups.