Hemodynamic and metabolic changes during hypercapnia with normoxia and hyperoxia using pCASL and TRUST MRI in healthy adults

Abstract

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO₂). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO₂ or O₂ does not affect CMRO₂. We evaluated the null hypothesis that two common hypercapnic stimuli, 'CO₂ in air' and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO₂ were calculated for room-air, 'CO₂ in air' and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for 'CO₂ in air' and carbogen, respectively). CMRO₂ decreased for 'CO₂ in air' (-13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO₂ during carbogen did not significantly change. Our findings indicate that 'CO₂ in air' is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO₂ reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Keywords: Carbogen; cerebral metabolic rate of oxygen; cerebral venous oxygenation; hypercapnia; hyperoxia.

Figure 1.

Schematic overview of the experimental design. a) the subject in the MRI with the three different inspired gases and the physiological measurements of pEtCO₂ (purple) from the breathing mask, arterial oxygenation Y_a (red) from a pulse-oximeter, venous oxygenation Y_v (orange), and CBF (blue). Conceptual planning for cerebral venous oxygenation (Y_v) using T2-relaxation-underspin-tagging (TRUST) MRI is depicted by the orange region, where the dotted lines represent the measurement plane and the circle the location of the occipital part of the superior sagittal sinus. Whole-brain CBF values were acquired using a pseudo-continuous arterial spin labeling pCASL sequence (planning depicted in blue). b) The [O₂]_a, [O₂]_v, p_aO_2, and p_vO₂ values were calculated using a physiological blood oxygen content model (Dash et al.) and were applied for computing CMRO₂ and OEF using the formulas shown. c) Experimental design of the gas delivery paradigm. The dashed blue line represents the rest period (∼30 s) given to allow pEtCO₂ and Y_v to equilibrate. The order of ‘CO₂ in air’ and carbogen conditions and the TRUST and pCASL scan was randomized between subjects.

Figure 2.

Oxygen saturation and content in blood for the different breathing conditions. The measured pEtCO₂ values and assumed hematocrit values were used as input for the Dash et al. model to generate the subject-specific curves on saturation, hemoglobin bound and plasma dissolved O₂ content over a range of pO₂ between 0 and 550 mmHg. a) Group average hemoglobin bound O₂ saturation curve (light blue) as computed using Dash et al. physiological model and the plasma dissolved O₂ curve (magenta) as a function of the partial pressure of O₂ (pO₂). On the right y-axis, the measured ranges of hemoglobin blood oxygenation Y_a(%) and Y_v(%) for the different breathing conditions (room-air in blue, ‘CO₂ in air’ in orange, carbogen in red, and the corresponding O₂ content in μmol/ml blood on the left y-axis ([HbO₂]_a and [HbO₂]_v ranges). The associated partial pressure ranges of O₂ (p_vO₂ and p_aO₂) found via the O₂ saturation curve (light blue) are shown on the x-axis. Note the high p_aO₂ for the carbogen condition and the associated plasma dissolved O₂ content shown on the bottom left (red). b) A zoomed part of the O₂ saturation curve (light blue in a)) showing the traditional O₂ saturation curve by Severinghaus (dotted light-blue) compared to the revised model by Dash et al. with dependency on the subject’s pCO₂ and Hct. The hypercapnic conditions induce a right shift caused by the Bohr effect, shown by the arrow (‘CO₂ in air’ in orange, carbogen in red). The effect of this right shift, however, on the arteriovenous O₂ difference is negligible for all breathing conditions. See Figure 3 for the O₂ content and the arteriovenous difference values (boxplots) for all breathing conditions.

Figure 3.

Boxplots showing the group average O₂ content in μmol per ml blood for hemoglobin bound O₂ and plasma dissolved O₂ for the arterial and venous blood respectively, and the arteriovenous difference in O₂ content needed to compute the CMRO₂; [HbO₂]_a and [HbO₂]_v, [plasma O₂]_a, and [plasma O₂]_v, the total blood O₂ content [O₂]_a and [O₂]_v, and [O₂]_a-[O₂]_v for the different breathing conditions. Noticeable is the increased venous hemoglobin bound O₂ ([HbO₂]_v) for the hypercapnic conditions and the much-increased plasma dissolved O₂ (arterial, [plasma O₂]_a) content for the carbogen condition. Also, note the much smaller y-axis scale for the plasma dissolved O₂ content, showing that the venous plasma dissolved O₂ plays a negligible role in the arteriovenous difference to compute CMRO₂ for all breathing conditions. The boxplots show the minimum, maximum, median and interquartile range, open circles denote outliers.

Figure 4.

Group average CBF maps for the different conditions where a notable and similar increase in CBF is observed for ‘CO₂ in air’ and carbogen (see also Table 1). The individual maps were registered to MNI space before averaging and are overlaid on the 2 mm MNI brain template.

Figure 5.

Boxplots showing the group average global CBF, venous oxygenation (Y_v), computed oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) for the different conditions. Notable increases in CBF and Y_v are observed for both the ‘CO₂ in air’ and carbogen conditions, with a more considerable Y_v increase for the carbogen condition, as expected. A similar reduction in OEF is seen for both conditions. Only significant CMRO₂ changes are observed for the ‘CO₂ in air’ condition. The CBF increase for the ‘CO₂ in air’ and carbogen conditions was not significantly different. *p-value <0.05 significant change found (Student’s T-test) with respect to the preceding room-air condition, **p-value <0.005, ***p-value <0.001. The boxplots show the minimum, maximum, median and interquartile range, open circles denote outliers.