Synopsis
We demonstrate hyperpolarized 129Xe MRI in healthy pediatric
control subjects and cystic fibrosis patients as young as age 7, for the first time. Subjects experienced a transient nadir in SpO2 that quickly returns
to baseline with normal breathing.
Despite having similarly high lung function (i.e., normal FEV1), CF
patients had nearly 4-fold increase in 129Xe ventilation defect
volume compared to their healthy peers, with statistical significance.
Importantly, ventilation defects were present even in CF patients with
FEV1 near or exceeding 100% predicted, suggesting that 129Xe
MRI is more sensitive to early CF lung disease than traditional clinical
spirometry.Purpose
While
the safety, tolerability, and efficacy of hyperpolarized (HP)
129Xe
has been reported in adults,
1, 2 similar metrics for pediatric subjects have not
been reported. The purpose of this study
was both to evaluate the safety and tolerability of hyperpolarized
129Xe
MRI in pediatric patients and to assess the sensitivity of
129Xe
ventilation MRI to early/mild lung disease in clinically-healthy cystic
fibrosis (CF) patients with high forced expiratory volume in 1 second (FEV
1). We
hypothesize that: 1) HP
129Xe gas is a safe inhaled contrast agent
for pediatric pulmonary imaging, 2)
129Xe MRI can visualize and
quantify ventilation abnormalities in early CF lung disease, and 3)
129Xe
ventilation defect volume is more sensitive to impaired lung function than
traditional FEV
1 in young CF patients.
Methods
Hyperpolarized
129Xe MRI was acquired in 11 cystic fibrosis patients (8-16 y.o.;
4M/7F; FEV
1 72-120% predicted) and 15 healthy control subjects (7-15
y.o.; 11M/4F; FEV
1 89-127% predicted) on a 3T Philips Achieva MRI
scanner using a homebuilt saddle coil
3 and hyperpolarized gas prepared from our
Center’s homebuilt polarizer
4 or a commercially-available polarizer (Polarean
Inc., Durham, NC). Two doses were
administered: calibration (~250 cc Xe diluted to ~500 cc with N
2) and
ventilation (either 1/12th [n=5 initial controls] or 1/6th
[n=21] of the subject’s predicted total lung capacity
5). During
the imaging session, SpO
2 and heart-rate were recorded at three
time-points (immediately post-inhalation, nadir SpO
2, and 2 minutes
post-inhalation) and compared to resting baseline values. Central nervous system (CNS) effects were
assessed at the time of scanning.
129Xe
ventilation defect percentage (VDP) was calculated using a threshold of <60%
mean whole lung
129Xe signal and compared to FEV
1,
6 which was acquired within 15 days of the MRI.
Results
Safety: Relative to baseline, all subjects experienced a SpO2
nadir after receiving Xe gas (calibration: -2.7 ± 2.7%, p = 2.7x10-5 and imaging: -5.5 ± 6.4%, p=4.8x10-4). There were no significant SpO2 differences
at 2-minute post-inhalation relative to baseline (calibration: p=0.13, imaging:
p=0.07). The magnitude of the SpO2
nadir was not significantly different between controls and CF patients for either
calibration (control: -2.6±2.4%, CF: -2.8±3.3%, p=0.84) or imaging doses
(control: -4.6±4.2%, CF: -6.5±8.5%, p=0.51), and there were no significant
changes in heart-rate throughout the study for any time-point or group
comparisons (p
≥ 0.20). All CNS effects were mild, consistent
with the anesthetic properties of xenon (e.g., tingling, dizziness, euphoria),
and resolved quickly (<30s) after breathing room air.
129Xe ventilation: Compared to controls, CF patients had a
significantly elevated VDP (CF: 18.2±10.1%, controls 5.1±2.6%, p =0.0024), ranging between
4.6% and 39%. All controls demonstrated homogeneous
ventilation and low VDP. The pattern of 129Xe
ventilation defects varied greatly across the CF patients (Figure 1); some CF subjects had homogeneous ventilation resembling that of the
controls and low VDP, while others had large defects and correspondingly high
VDP. There were no significant differences in FEV1 between CF and control groups (CF 98±16.0%,
controls 103±10.8%, p=0.35).
Discussion
129Xe MRI was well
tolerated by all subjects and generated no unexpected adverse effects. SpO
2 decreases were consistent with
expected behavior following anoxic breath-holds and resolved quickly as did all
CNS effects; these results are consistent with previous adult studies. Importantly, control versus CF group
separation was clear and significant with
129Xe VDP and not with FEV
1,
suggesting
129Xe VDP may be more sensitive to early CF lung disease
than traditional spirometry.
Conclusion
To our knowledge, this study is the
first assessment of the safety of
129Xe MRI in children and also
the first measurement of the sensitivity
of
129Xe MRI to detect ventilation deficiencies in early CF lung disease. We found that
129Xe
MRI can spatially resolve and quantify ventilation defects in young CF
patients-- even in clinically-healthy CF patients with high (≥85%) FEV
1s. Furthermore, as a non-ionizing imaging
modality,
129Xe MRI VDP can act as an outcome measure for the
individualized longitudinal assessment of CF lung disease progression and
therapeutic efficacy.
Acknowledgements
No acknowledgement found.References
1. Driehuys, B., S. Martinez-Jimenez, Z.I.
Cleveland, et al., Chronic Obstructive Pulmonary Disease: Safety and
Tolerability of Hyperpolarized Xe-129 MR Imaging in Healthy Volunteers and
Patients. Radiology, 2012. 262(1): p.
279-289.
2.
Shukla, Y., A. Wheatley, M. Kirby, et al., Hyperpolarized 129Xe magnetic
resonance imaging: tolerability in healthy volunteers and subjects with
pulmonary disease. Acad Radiol, 2012.
19(8): p. 941-51.
3.
Loew, W., R. Thomen, R. Pratt, et al., A Volume Saddle Coil for Hyperpolarized
129Xe Lung Imaging. Proc. Intl. Soc.
Mag. Reson. Med, 2015. 23: p. 1507.
4.
Walkup, L., N. Higano, T. Ellis-Caleo, et al., Scaling-up an "open-source" 129Xe hyperpolarizer for human
pulmonary imaging applications, in Experimental
Nuclear Magnetic Resonance Conference. 2014: Boston, MA.
5.
Stocks, J. and P.H. Quanjer, Reference values for residual volume, functional
residual capacity and total lung capacity. ATS Workshop on Lung Volume
Measurements. Official Statement of The European Respiratory Society. Eur Respir J, 1995. 8(3): p. 492-506.
6. Thomen, R.P., A. Sheshadri, J.D. Quirk, et al.,
Regional ventilation changes in severe asthma after bronchial thermoplasty with
(3)He MR imaging and CT. Radiology,
2015. 274(1): p. 250-9.