Rationale and Objectives
Longitudinal (T 1 ) and effective transverse (T 2 ∗) magnetic resonance (MR) relaxation times provide noninvasive measures of tissue oxygenation. The objective for this study was to quantify independent effects of inhaled O 2 and CO 2 on normal tissue T 1 and T 2 ∗ in rabbit liver, kidney, and paraspinal muscle.
Materials and Methods
Three gas challenges (100% O 2 , 10% CO 2 [balance air], and carbogen [90% O 2 + 10% CO 2 ]) were delivered to the rabbits in random order to isolate the effects of inspired O 2 and CO 2 . During each challenge, quantitative T 1 and T 2 ∗ maps were collected on a 1.5 Tesla MR imaging. Mean changes in T 1 (ΔT 1 ) and T 2 ∗ (ΔT 2 ∗) were calculated from regions of interest in each organ.
Results
Greatest ΔT 1 and ΔT 2 ∗ changes were observed in liver for 10% CO 2 and in kidney for 100% O 2 . ΔT 1 and ΔT 2 ∗ generally followed predicted patterns when transitioning from air breathing: lower T 1 /higher T 2 ∗ with inspired O 2 , higher T 1 /lower T 2 ∗ with inspired CO 2 , and variable T 1 /T 2 ∗ changes in the presence of both (ie, carbogen). New observations also emerged: 1) between-gas-challenge transitions revealed the greatest significance in ΔT 2 ∗ for the liver and kidney resulting from the isolation of independent O 2 and CO 2 effects; 2) ΔT 2 ∗ provided the best sensitivity and detected both tissue oxygenation and blood volume modulation; and 3) ΔT 1 sensitivity was restricted mainly to tissue oxygenation in the absence of counteracting vasodilatation.
Conclusion
Robust use of MR relaxation times as noninvasive biomarkers requires an understanding of their relative sensitivity to organ-specific physiological responses.
Noninvasive magnetic resonance (MR) measures of longitudinal (T 1 ) and effective transverse (T 2 ∗) relaxation times have demonstrated potential as indirect markers of oxygenation in the brain and peripheral tissues . Typically, changes in MR relaxation times are measured during experimental manipulation of the fraction of inspired O 2 (FiO 2 ) and CO 2 (FiCO 2 ) using one or more gas transitions. The manipulation of inspired gases may be directed to improve tissue oxygenation (eg, augmenting tumor oxygen for cancer therapy) or may also be applied to alter blood flow and volume, so as to provide a means for evaluating vasoreactivity (eg, brain). These concomitant changes in tissue oxygen and perfusion are known to exert independent, possibly opposing influences on MR relaxation times. Therefore, understanding their independent effects is critical for proper interpretation of MR measurements. For most extracranial tissues or tumors, our understanding of these physiological responses and related MR measurements is relatively poor compared to that in the brain. Investigations in normal tissue have been particularly limited but are essential in their own right and for cancer applications, because physiological differences in the normal host organ response may provide insight into the inconsistent MR results reported in tumors to date.
Oxygen-related T 1 changes are postulated to stem primarily from molecular O 2 dissolved in blood plasma and intra- and extracellular fluids . Increasing the FiO 2 will progressively increase O 2 dissolved in blood plasma, because the total amount of O 2 bound to hemoglobin (ie, the arterial oxygen saturation [SaO 2 ]) is normally close to 100% and will be relatively unaffected. As molecular O 2 is weakly paramagnetic, its presence effectively shortens T 1 . The expected T 1 reduction, however, has been consistently observed only in some tissues, such as spleen and myocardium . Other tissues, such as liver, kidney, and muscle, have shown smaller T 1 reductions or none at all .
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Materials and methods
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Gas Challenges
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Table 1
Expected and Observed T 1 and T 2 ∗ Changes for Different Inspired Gas Transitions
Gas Transition PaO 2 BF Hb/(HbO 2 + Hb) Expected Changes in MR Relaxation Times Observed Changes in MR Relaxation Times ΔT 1 ΔT 2 ∗ ΔT 1 ΔT 2 ∗ Air → 100% O 2 ↑ ↓ ↓ ↓ from increased PaO 2 , possibly reinforced by decreased blood volume. ↑ from decreased Hb related to PaO 2 , possibly reinforced by decreased blood volume ↓ liver ∗
↓ kidney ∗
↓ muscle ↑ liver
↑ kidney ∗∗
↑ muscle Air → 10% CO 2 NC ↑ ↑ ↑ from increased blood volume ↓ from increased Hb related to Bohr effect, reinforced by increased blood volume ↑ liver ∗
↑ kidney
↑ muscle ↓ liver ∗∗
↓ kidney
↑ muscle Air → carbogen ↑ ↑ ? Unclear because of competing effects of PaO 2 and blood volume Unclear because of competing effects of increased PaO 2 and Bohr effect on HbO 2 and Hb levels ↓ liver
↑ kidney
↑ muscle ↓ liver ∗
↓ kidney
↓ muscle ∗ 10% CO 2 → 100% O 2 ↑ ↓ ↓ ↓ from increased PaO 2 , reinforced by decreased blood volume ↑ from decreased Hb related to PaO 2 and Bohr effect, reinforced by decreased blood volume ↓ liver ∗
↓ kidney ∗
↓ muscle ↑ liver ∗∗
↑ kidney ∗∗
↑ muscle 10% CO 2 → carbogen ↑ ↓ ↓ ↓ from increased PaO 2 , possibly reinforced by decreased blood volume ↑ from decreased Hb related to PaO 2 , possibly reinforced by decreased blood volume ↓ liver
↓ kidney
↑ muscle ↑ liver †
↑ kidney †
↑ muscle 100% O 2 → carbogen NC ↑ ↑ ↑ from increased blood volume, with no change in PaO 2 . ↓ from increased Hb related to Bohr effect, reinforced by increased blood volume ↑ liver
↑ kidney ∗
↑ muscle ↓ liver ∗
↓ kidney ∗
↓ muscle ∗
Significance in ΔT 1 ΔT 2 ∗: † P < .10, ∗ P < .05, ∗∗ P < .01.
Observations that did not follow predicted changes are highlighted in bold.
BF, blood flow; Hb, deoxyhemoglobin; HbO 2 , oxyhemoglobin; NC, no change; PaO 2 , arterial partial pressure of O 2 .
Gases: air (21% O 2 ), 10% CO 2 (balance air), carbogen (90% O 2 + 10% CO 2 ).
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Animal Preparation
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MRI
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Data Analysis
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Results
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Table 2
Arterial Blood Gas Measurements
Gas Challenge tHb (g/dL) pH PaCO 2 (mm Hg) PaO 2 (mm Hg) SaO 2 (%) Air 12.0 ± 1.0 7.440 ± 0.001 34.4 ± 2.9 71.7 ± 2.3 99.7 ± 2.1 10% CO 2 12.5 ± 0.6 7.214 ± 0.014 70.4 ± 3.1 86.5 ± 6.3 98.2 ± 1.2 100% O 2 11.8 ± 0.1 7.401 ± 0.011 40.2 ± 4.5 454 ± 12 105.0 ± 2.8 carbogen 11.7 ± 0.4 7.215 ± 0.030 69.3 ± 6.9 445 ± 31 104.6 ± 2.8
Gases: air (21% O 2 ), 10% CO 2 (balance air), carbogen (90% O 2 + 10% CO 2 ).
PaCO 2 , arterial partial pressure of CO 2 ; PaO 2 , arterial partial pressure of O 2 ; SaO 2 , arterial oxygen saturation; tHb, total hemoglobin.
Mean ± SD ( n = 2).
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Discussion
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