Rationale and Objectives
The objective of this study was to evaluate the tolerability of hyperpolarized 129 Xe gas inhaled from functional residual capacity and magnetic resonance imaging in healthy subjects and those with pulmonary disease.
Materials and Methods
Twelve healthy volunteers (mean age, 59 ± 17 years), seven subjects with asthma (mean age, 47 ± 7 years), 10 subjects with chronic obstructive pulmonary disease (mean age, 74 ± 4 years), three subjects with cystic fibrosis (mean age, 27 ± 10 years), and a single subject with radiation-induced lung injury (age, 66 years) were enrolled and evaluated over 43 visits with 136 anoxic inhalations of 500 mL 129 Xe gas mixed with 500 mL 4 He gas. Oxygen saturation and heart rate were monitored during the breath-hold and imaging; subjects were queried for adverse events (AEs) before and immediately following gas inhalation and for 24 hours after the last dose.
Results
No subjects withdrew from the study or reported serious, hypoxic, or severe AEs. Over the course of 136 dose administrations, two mild AEs (1%) were reported in two different subjects (two of 33 [6%]). One of these AEs (light-headedness) was temporally related and judged as possibly related to 129 Xe administration and resolved without treatment within 2 minutes. Statistically significant but clinically insignificant changes in oxygen saturation and heart rate were observed after inhalation ( P < .001), and both resolved 1 minute later, with no difference between subject groups.
Conclusions
Inhalation of hyperpolarized 129 Xe gas and subsequent magnetic resonance imaging were well tolerated in healthy subjects and ambulatory subjects with obstructive and restrictive pulmonary disease.
Noble gas magnetic resonance imaging (MRI) provides a way to measure static and dynamic gas distribution abnormalities as well as microstructural changes associated with normal lung and pulmonary disease. In recent years, hyperpolarized 3 He functional MRI has been evaluated in a wider variety of pulmonary conditions compared to hyperpolarized 129 Xe MRI because of higher polarizations , a well-established safety profile , and high reproducibility in chronic obstructive pulmonary disease (COPD) , asthma , cystic fibrosis (CF) , and radiation-induced lung injury (RILI) . However, recently, the cost of 3 He gas has increased and the supply has become limited , so translation to clinical use has been slow. This has motivated a recent resurgence in 129 Xe MRI research , because 129 Xe gas is more readily available, and methods have been developed to improve the volume of polarized gas required for research and clinical studies .
Xenon-129 is more lipid and tissue soluble than 3 He , and anaesthetic effects have been quantified using the minimum alveolar concentration, which is approximately 70%, representing the fractional pulmonary xenon gas concentration that results in autonomic nerve sensation blockage in 50% of subjects . There is a long and well-documented history of xenon gas use in pulmonary computed tomography , cerebral blood flow imaging , and lung scintigraphy , but to date, there have been few safety studies that prospectively evaluated the tolerability of hyperpolarized 129 Xe MRI across a wide range of subjects with pulmonary disease . Recently, Driehuys et al reported the tolerability of hyperpolarized 129 Xe gas in healthy volunteers and subjects with COPD using a 1-L 129 Xe (6%–10% polarized) dose inhaled from functional residual capacity (FRC). They reported that 91% of subjects (40 of 44) experienced mild but transient symptoms associated with 129 Xe inhalation, and two subjects experienced extreme dizziness and depressed consciousness. We hypothesized that this adverse event (AE) profile could be improved by reducing the 129 Xe gas dose . We also hypothesized that potential image quality decreases related to the reduced dose could be offset by reducing gas depolarization potential by limiting contact with air and reducing the dead space of the inhalation apparatus. In an extension of the important findings reported by Driehuys et al, we aimed to evaluate the tolerability of a 500-mL inhaled dose of 129 Xe gas mixed with 500-mL 4 He gas in a 1-L total volume from FRC, half the inhaled dose of 129 Xe gas reported by Driehuys et al, in healthy subjects and ambulatory patients with diminished pulmonary function and asthma, COPD, CF, or RILI. Extending previous findings to subjects with a wider range of pulmonary function may help provide a foundation for the potential clinical use of 129 Xe MRI.
Materials and methods
Study Subjects and Design
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Subject Monitoring
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Pulmonary Function Testing
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Gas Hyperpolarization and Dose Preparation
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Z=A/(A+B=D+FRC[L]), Z
=
A
/
(
A
+
B
=
D
+
FRC
[
L
]
)
,
where A is the volume of 129 Xe inhaled, B is the volume of 4 He inhaled, and D is the volume of the dead space of the breathing apparatus.
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Imaging Breath-hold Maneuver
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Statistical Methods
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Results
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Table 1
Subject Demographics
Parameter All ( n = 33) Healthy Volunteers ( n = 12) Asthma ( n = 7) COPD ( n = 10) CF ( n = 3) RILI ( n = 1) Age (y) 58 ± 18 (20–79) 59 ± 17 (26–79) 47 ± 7 (36–58) 74 ± 4 (66–79) 27 ± 10 (20–38) 66 Men 20 6 4 8 2 1 BMI (kg/m 2 ) 25 ± 4 (18–33) 24 ± 3 (20–29) 27 ± 4 (20–33) 25 ± 5 (18–32) 24 ± 4 (21–29) 31 FEV 1%pred 80 ± 27 (27–129) 105 ± 12 (92–129) 76 ± 6 (70–86) 58 ± 24 (27–107) 57 ± 11 (49–70) 70 FEV 1 /FVC 63 ± 16 (26–91) 76 ± 6 (68–91) 67 ± 7 (54–76) 45 ± 14 (26–68) 59 ± 14 (47–75) 80 RV %pred 135 (43 (84–255) 105 ± 16 (84–133) 131 ± 10 (118–146) 159 ± 46 (86–229) 201 ± 47 (171–255) 101 RV/TLC 0.42 ± 0.12 (0.23–0.77) 0.35 ± 0.09 (0.23–0.53) 0.37 ± 0 (0.3–0.4) 0.52 ± 0.14 (0.27–0.77) 0.43 ± 0.03 (0.4–0.46) 0.45 IC %pred 99 ± 27 (27–170) 116 ± 22 (88–170) 105 ± 13 (93–129) 85 ± 31 (27–128) 91 ± 19 (75–112) 61 FRC %pred 116 ± 31 (80–201) 99 ± 14 (80–120) 105 ± 17 (84–130) 141 ± 35 (102–201) 130 ± 38 (100–173) 93
BMI, body mass index; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FEV 1 , forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; IC, inspiratory capacity; % pred , percentage predicted; RILI, radiation-induced lung injury; RV, residual volume; TLC, total lung capacity.
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Table 2
Subject Clinical Visits and Total 129 Xe Doses
Parameter All ( n = 33) Healthy Volunteers ( n = 12) Asthma ( n = 7) COPD ( n = 10) CF ( n = 3) RILI ( n = 1) Number of visits 1 26 10 7 5 3 1 ≥2 7 2 0 5 0 0 Number of 129 Xe Doses 2–4 27 10 7 6 3 1 5–9 4 0 0 4 0 0 ≥10 2 2 0 0 0 0
CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; RILI, radiation-induced lung injury.
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Table 3
Actual and Theoretical Mean Fractional Concentrations of 129 Xe for Subject Groups
Subject Group Volumes (L) Mean Fractional Concentrations 129 Xe FRC RV Actual ∗ Theoretical † Healthy volunteers ( n = 12) 0.48 ± 0.06 3.15 ± 0.54 1.99 ± 0.40 0.12 ± 0.02 0.16 ± 0.03 Asthma ( n = 7) 0.50 ± 0.00 3.37 ± 0.60 2.39 ± 0.19 0.12 ± 0.02 0.15 ± 0.01 COPD ( n = 10) 0.50 ± 0.00 4.91 ± 1.06 3.91 ± 0.99 0.09 ± 0.02 0.11 ± 0.02 CF ( n = 3) 0.50 ± 0.00 4.04 ± 1.01 2.92 ± 0.38 0.10 ± 0.02 0.13 ± 0.01 RILI ( n = 1) 0.50 ± 0.00 2.95 ± 0.00 2.16 ± 0.00 0.13 ± 0.0 0.16 ± 0.0 All ( n = 33) 0.50 ± 0.01 3.68 ± 0.64 2.67 ± 0.39 0.11 ± 0.02 0.14 ± 0.03
CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FRC, functional residual capacity; RILI, radiation-induced lung injury; RV, residual volume.
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FLOAT NOT FOUND
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Table 4
All Adverse Events
Type All ( n = 33) Healthy Volunteers ( n = 12) Asthma ( n = 7) COPD ( n = 10) CF ( n = 3) RILI ( n = 1) Total 2 0 1 1 0 0 Serious 0 0 0 0 0 0 Hypoxic 0 0 0 0 0 0 Withdrawn 0 0 0 0 0 0 Intensity Mild 0 0 1 ∗ 1 † 0 0 Moderate 0 0 0 0 0 0 Severe 0 0 0 0 0 0 Relationship 129 Xe related 1 0 1 0 0 0 Unrelated 1 0 0 1 0 0
CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; RILI, radiation-induced lung injury.
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Table 5
SpO 2 and HR Changes Following Inhalation of 129 Xe
Parameter Healthy Volunteers ( n = 12) Asthma ( n = 7) COPD ( n = 10) CF ( n = 3) RILI ( n = 1) SpO 2 (%) Mean decrease after 129 Xe inhalation from BL −3 ± 1.4 −3 ± 2.3 −4 ± 1.4 −6 ± 2.1 −11 ± 0.7 Mean recovery from BL as a difference 0 ± 0.7 0 ± 1.2 0 ± 0.7 −1 ± 0.5 −1 ± 0.0 HR (beats/min) Mean decrease after 129 Xe inhalation from BL 1 ± 4.1 2 ± 3.8 0 ± 3.4 −2 ± 7.1 1 ± 5.6 Mean recovery from BL as a difference 1 ± 4.5 1 ± 4.6 −1 ± 3.1 −2 ± 5.4 1 ± 3.5
BL, baseline; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; HR, heart rate; RILI, radiation-induced lung injury; SpO 2 , oxygen saturation.
P = .858 determined with analysis of variance ( P < .05 indicates significance).
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Discussion
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Conclusions
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Acknowledgments
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Appendix
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Table A1
Actual and Theoretical Fractional Xenon Concentrations for Every 129 Xe Subject Dose
Subject Visit Volumes (L) Fractional 129 Xe Concentration 129 Xe FRC RV Actual ∗ Theoretical † Healthy volunteers ( n = 12) 1 1 0.5 2.93 1.53 0.13 0.20 1 1 0.5 2.93 1.53 0.13 0.20 1 1 0.5 2.93 1.53 0.13 0.20 1 1 0.5 2.93 1.53 0.13 0.20 1 2 0.5 2.93 1.53 0.13 0.20 1 2 0.5 2.93 1.53 0.13 0.20 1 2 0.5 2.93 1.53 0.13 0.20 1 2 0.5 2.93 1.53 0.13 0.20 1 3 0.25 2.93 1.53 0.06 0.10 1 3 0.5 2.93 1.53 0.13 0.20 1 3 0.35 2.93 1.53 0.09 0.14 1 3 0.5 2.93 1.53 0.13 0.20 1 3 0.5 2.93 1.53 0.13 0.20 2 1 0.5 3.74 1.99 0.11 0.17 2 1 0.5 3.74 1.99 0.11 0.17 2 1 0.5 3.74 1.99 0.11 0.17 2 2 0.25 3.74 1.99 0.05 0.08 2 2 0.5 3.74 1.99 0.11 0.17 2 2 0.3 3.74 1.99 0.06 0.10 2 3 0.5 3.74 1.99 0.11 0.17 2 3 0.5 3.74 1.99 0.11 0.17 2 3 0.5 3.74 1.99 0.11 0.17 2 3 0.5 3.74 1.99 0.11 0.17 2 4 0.5 3.74 1.99 0.11 0.17 2 4 0.5 3.74 1.99 0.11 0.17 2 4 0.5 3.74 1.99 0.11 0.17 3 1 0.5 2.82 2.65 0.13 0.14 3 1 0.5 2.82 2.65 0.13 0.14 3 1 0.5 2.82 2.65 0.13 0.14 3 1 0.5 2.82 2.65 0.13 0.14 4 1 0.5 2.55 2.20 0.14 0.16 4 1 0.5 2.55 2.20 0.14 0.16 4 1 0.5 2.55 2.20 0.14 0.16 4 1 0.5 2.55 2.20 0.14 0.16 5 1 0.5 3.37 2.18 0.11 0.16 5 1 0.5 3.37 2.18 0.11 0.16 5 1 0.5 3.37 2.18 0.11 0.16 6 1 0.5 2.55 2.06 0.14 0.16 6 1 0.5 2.55 2.06 0.14 0.16 6 1 0.5 2.55 2.06 0.14 0.16 6 1 0.5 2.55 2.06 0.14 0.16 7 1 0.5 3.23 1.77 0.12 0.18 7 1 0.5 3.23 1.77 0.12 0.18 8 1 0.5 2.48 1.95 0.14 0.17 8 1 0.5 2.48 1.95 0.14 0.17 9 1 0.5 3.38 2.62 0.11 0.14 9 1 0.5 3.38 2.62 0.11 0.14 10 1 0.5 4.55 2.21 0.09 0.16 10 1 0.5 4.55 2.21 0.09 0.16 11 1 0.5 2.31 1.30 0.15 0.22 11 1 0.5 2.31 1.30 0.15 0.22 12 1 0.5 3.23 2.93 0.12 0.13 12 1 0.5 3.23 2.93 0.12 0.13 Mean ± SD 0.48 ± 0.06 3.15 ± 0.54 1.99 ± 0.40 0.12 ± 0.02 0.16 ± 0.03 Asthma ( n = 7) 13 1 0.5 2.78 2.17 0.13 0.16 13 1 0.5 2.78 2.17 0.13 0.16 13 1 0.5 2.78 2.17 0.13 0.16 13 1 0.5 2.78 2.17 0.13 0.16 14 1 0.5 ND ND ND ND 14 1 0.5 ND ND ND ND 14 1 0.5 ND ND ND ND 14 1 0.5 ND ND ND ND 15 1 0.5 3.27 2.38 0.12 0.15 15 1 0.5 3.27 2.38 0.12 0.15 15 1 0.5 3.27 2.38 0.12 0.15 15 1 0.5 3.27 2.38 0.12 0.15 16 1 0.5 2.67 2.18 0.14 0.16 16 1 0.5 2.67 2.18 0.14 0.16 16 1 0.5 2.67 2.18 0.14 0.16 16 1 0.5 2.67 2.18 0.14 0.16 17 1 0.5 3.93 2.52 0.10 0.14 17 1 0.5 3.93 2.52 0.10 0.14 17 1 0.5 3.93 2.52 0.10 0.14 17 1 0.5 3.93 2.52 0.10 0.14 18 1 0.5 4.30 2.42 0.09 0.15 18 1 0.5 4.30 2.42 0.09 0.15 18 1 0.5 4.30 2.42 0.09 0.15 18 1 0.5 4.30 2.42 0.09 0.15 19 1 0.5 3.25 2.69 0.12 0.14 19 1 0.5 3.25 2.69 0.12 0.14 19 1 0.5 3.25 2.69 0.12 0.14 19 1 0.5 3.25 2.69 0.12 0.14 Mean ± SD 0.50 ± 0.00 3.37 ± 0.60 2.39 ± 0.19 0.12 ± 0.02 0.15 ± 0.01 COPD ( n = 10) 20 1 0.5 3.95 3.64 0.10 0.11 20 1 0.5 3.95 3.64 0.10 0.11 20 2 0.5 3.95 3.64 0.10 0.11 20 2 0.5 3.95 3.64 0.10 0.11 21 1 0.5 4.63 4.00 0.09 0.10 21 1 0.5 4.63 4.00 0.09 0.10 21 1 0.5 4.63 4.00 0.09 0.10 21 2 0.5 4.63 4.00 0.09 0.10 21 2 0.5 4.63 4.00 0.09 0.10 22 1 0.5 5.37 3.78 0.08 0.10 22 1 0.5 5.37 3.78 0.08 0.10 22 1 0.5 5.37 3.78 0.08 0.10 22 1 0.5 5.37 3.78 0.08 0.10 22 2 0.5 5.37 3.78 0.08 0.10 22 2 0.5 5.37 3.78 0.08 0.10 23 1 0.5 3.95 3.65 0.10 0.11 23 1 0.5 3.95 3.65 0.10 0.11 23 1 0.5 3.95 3.65 0.10 0.11 23 1 0.5 3.95 3.65 0.10 0.11 23 2 0.5 3.95 3.65 0.10 0.11 23 2 0.5 3.95 3.65 0.10 0.11 24 1 0.5 5.79 5.03 0.07 0.08 24 1 0.5 5.79 5.03 0.07 0.08 24 1 0.5 5.79 5.03 0.07 0.08 24 1 0.5 5.79 5.03 0.07 0.08 24 2 0.5 5.79 5.03 0.07 0.08 24 2 0.5 5.79 5.03 0.07 0.08 25 1 0.5 6.56 5.16 0.07 0.08 25 1 0.5 6.56 5.16 0.07 0.08 25 1 0.5 6.56 5.16 0.07 0.08 25 1 0.5 6.56 5.16 0.07 0.08 26 1 0.5 3.16 2.60 0.12 0.14 26 1 0.5 3.16 2.60 0.12 0.14 26 1 0.5 3.16 2.60 0.12 0.14 26 1 0.5 3.16 2.60 0.12 0.14 27 1 0.5 6.56 5.39 0.07 0.08 27 1 0.5 6.56 5.39 0.07 0.08 27 1 0.5 6.56 5.39 0.07 0.08 27 1 0.5 6.56 5.39 0.07 0.08 28 1 0.5 4.76 3.39 0.09 0.11 28 1 0.5 4.76 3.39 0.09 0.11 28 1 0.5 4.76 3.39 0.09 0.11 28 1 0.5 4.76 3.39 0.09 0.11 29 1 0.5 4.26 2.05 0.09 0.16 29 1 0.5 4.26 2.05 0.09 0.16 29 1 0.5 4.26 2.05 0.09 0.16 29 1 0.5 4.26 2.05 0.09 0.16 Mean ± SD 0.50 ± 0.00 4.91 ± 1.06 3.91 ± 0.99 0.09 ± 0.02 0.11 ± 0.02 CF ( n = 3) 30 1 0.5 3.90 3.01 0.10 0.12 30 1 0.5 3.90 3.01 0.10 0.12 31 1 0.5 2.98 2.45 0.13 0.14 31 1 0.5 2.98 2.45 0.13 0.14 32 1 0.5 5.23 3.29 0.08 0.12 32 1 0.5 5.23 3.29 0.08 0.12 Mean ± SD 0.50 ± 0.00 4.04 ± 1.01 2.92 ± 0.38 0.10 ± 0.02 0.13 ± 0.01 RILI ( n = 1) 33 1 0.5 2.95 2.16 0.13 0.16 33 1 0.5 2.95 2.16 0.13 0.16 Mean ± SD 0.50 ± 0.00 2.95 ± 0.00 2.16 ± 0.00 0.13 ± 0.0 0.16 ± 0.0 Mean total 0.50 ± 0.01 3.68 ± 0.64 2.67 ± 0.39 0.11 ± 0.02 0.14 ± 0.03
CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; FRC, functional residual capacity; RILI, radiation-induced lung injury; RV, residual volume; SD, standard deviation.
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