Brain BOLD MRI O2 and CO2 stress testing: implications for perioperative neurocognitive disorder following surgery

Background Mechanical ventilation to alter and improve respiratory gases is a fundamental feature of critical care and intraoperative anesthesia management. The range of inspired O2 and expired CO2 during patient management can significantly deviate from values in the healthy awake state. It has long been appreciated that hyperoxia can have deleterious effects on organs, especially the lung and retina. Recent work shows intraoperative end-tidal (ET) CO2 management influences the incidence of perioperative neurocognitive disorder (POND). The interaction of O2 and CO2 on cerebral blood flow (CBF) and oxygenation with alterations common in the critical care and operating room environments has not been well studied. Methods We examine the effects of controlled alterations in both ET O2 and CO2 on cerebral blood flow (CBF) in awake adults using blood oxygenation level-dependent (BOLD) and pseudo-continuous arterial spin labeling (pCASL) MRI. Twelve healthy adults had BOLD and CBF responses measured to alterations in ET CO2 and O2 in various combinations commonly observed during anesthesia. Results Dynamic alterations in regional BOLD and CBF were seen in all subjects with expected and inverse brain voxel responses to both stimuli. These effects were incremental and rapid (within seconds). The most dramatic effects were seen with combined hyperoxia and hypocapnia. Inverse responses increased with age suggesting greater risk. Conclusions Human CBF responds dramatically to alterations in ET gas tensions commonly seen during anesthesia and in critical care. Such alterations may contribute to delirium following surgery and under certain circumstances in the critical care environment. Trial registration ClincialTrials.gov NCT02126215 for some components of the study. First registered April 29, 2014.

Consecutive imaging in 101 individuals (in 80 serial BP measurements during hypercapnic stimulus; controls and patients with concussion) revealed similar findings with modest changes in BP to the CO 2 delta as in this study. There is the occasional subject who responses vigorously to the CO 2 stimulus. Such   subjects can have increased BOLD responsiveness. [1] Such subjects could potentially be at greater risk of POND as discussed in this paper as having a greater diathesis risk to the CO 2 stress typical with anesthetic management. Such a subject is evident in Figure 6 of that manuscript. The CO 2 delta in that study was greater -20 mm Hg. A more modest hemodynamic response in a second subject exposed to the same stimulus is shown in Figure 7 of that manuscript. Thus, in the current study the BP alterations with the hypercapnic stimulus of only 10 mm Hg appear modest and should represent a minor confounder on the data as interpreted.
BOLD imaging as a surrogate for CBF changes with altered end-tidal gases -The BOLD signal is a composite of a number of influences as principally measured at the venular level of the cerebral circulation. We have assumed that an increase or decrease in BOLD signal is a surrogate for alterations in CBF as a consequence of altered end-tidal gas tensions -especially so for CO 2 . The BOLD signal can also be influences by changes in regional blood volume, alterations in hemoglobin and diffusion effects to identify some of the confounders. The working premise in this study is that the BOLD signal changes are due to altered CBF as CMRO 2 is minimally altered for the end-tidal gas tensions studied here. When establishing this research model we investigated the hypothesis that for the relative CO 2 delta under study the changes in BOLD signal were a robust surrogate for CBF changes. We examined the similarity in colorized maps of cerebrovascular reactivity to a 5 mm Hg step change in CO 2 for the BOLD signal and CBF as measured using the pCASL approach highlighted in this paper. Each of 15 adult subjects had a BOLD study followed after re-equilibration to baseline with a CBF study by pCASL to the same 5 mm Hg CO 2 stress test. The mean value voxel maps for the two approaches are shown below: The mean group CVR responsiveness is very similar in distribution for the two imaging approaches, indicating that BOLD CO 2 responsiveness is a robust surrogate for CBF responsiveness. With BOLD imaging 83% of the voxels responded to the hypercapnic signal at the p=0.001 statistical level; with pCASL the response for activation was 43%. A greater response with BOLD imaging is expected as the

Figure 2 A and B
A: Raw BOLD CVR -response to a 5 mm Hg CO 2 stress test: n=15.
B: Raw pCASL CVR -response to a 5 mm Hg CO 2 stress test: n=15.
data series was analyzed over 180 scans for the 6-minute study period with 90 scans at each of the CO 2 end-tidal tensions and only 44 images were obtained for the pCASL sequence with only 22 images at the baseline and hypercapnic intervals. When the two approaches were compared directly at the 2 nd level analysis only 4.1% of the BOLD voxels exceeded those as determined with pCASL imaging at the p=0.001 level. There were no voxels where the BOLD signal was statistically less than the pCASL voxels. These results would indicate that the BOLD response to CO 2 is a robust surrogate for CBF changes for the range of CO 2 delta as undertaken in this study.