The jugular venous‐to‐arterial PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during rebreathing and end‐tidal forcing: Relationship with cerebral perfusion

Abstract

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous and arterial difference (Pjv‐aCO2)] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv‐aCO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end‐tidal forcing (ETF) protocols (termed: ETF‐1 and ETF‐2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF‐1 (n = 11) and ETF‐2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv‐aCO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF‐1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF‐2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv‐aCO2 difference did not change during the rebreathing protocol (−0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF‐1 (−3.9 ± 1.1 mmHg; P < 0.001) and ETF‐2 (−3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv‐aCO2 difference during ETF (−0.095 ± 0.089 mmHg cm−1 s−1; P = 0.001) but not during rebreathing (−0.028 ± 0.045 mmHg · cm−1 · s−1; P = 0.067). These findings suggest that, although the Pjv‐aCO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2. imageKey points Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue . Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow. We assessed these assumptions by measuring arterial and jugular venous bulb and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end‐tidal forcing. The difference between arterial and jugular venous bulb remained present during both rebreathing and end‐tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the difference during end‐tidal forcing but not rebreathing. These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings.

Does central chemoreceptor blood flow increase with CO2 tension?

“…Methodological considerations regarding variability between individuals and the influence of hyperoxia on cerebral vasoconstriction were discussed (Carr et al, 2023). For example, Mattos et al (2019) found that a 10 min exposure of isocapnic hyperoxia (100% F IO 2 ) decreased CBF by ∼63 mL/min compared to normoxia (21% F IO 2 ).…”

“…Recently, in the Journal of Physiology, Carr et al (2023) carefully quantified the arterial-to-jugular venous P CO 2 difference (P jv−a CO 2 ) and its association with middle cerebral artery blood velocity (MCAv, a proxy measurement for CBF) during hyperoxic hypercapnic modified rebreathing and during two protocols of a hypercapnic end-tidal forcing (ETF) technique. With the ETF method, participants were exposed to different progressive isocapnic levels until a physiological steady state occurs (i.e.…”

Revisiting the assumption of a rebreathing‐induced arterial–brain CO2 equilibrium half a century later

“…In this issue of The Journal of Physiology, Carr et al (2023) have shown via careful experimentation in healthy humans that equilibrium of arterial with jugular venous bulb CO 2 (assumed to represent the P CO 2 in medullary chemosensitive sites) is not achieved at any time during hyperoxic rebreathing. Rather, the arterial-jugular venous P CO 2 difference was quickly reduced to about half its air-breathing control value at the onset of rebreathing but then, on average, remained at this substantial gradient despite a rising CBF as P aCO 2 rose with continued rebreathing.…”

“…Accordingly, the present findings showed that although the arterial-to-jugular venous bulb P CO 2 difference was substantial and did show considerable within-and between-subject variability as P aCO 2 rose during rebreathing, importantly, on average the jugular venous P CO 2 rose in parallel with P aCO 2 . Thus, Carr et al (2023) felt justified in proposing that the modified rebreathing method was '…ideal for assessing central CO 2 chemosensitivity independent of the confounding influence of an increase in CBF'! We agree that the present findings support this recommendation.…”

“…In summary, Carr et al (2023) have provided an important contribution in their careful experimental testing of a heretofore widely accepted assumption based on a theoretical model. Hopefully, others among us might be stimulated by their lead to question and subject to experimentation some of the many remaining assumptions underlying chemosensitivity testing in the intact human before another half-century has lapsed.…”