It is well established that mild hypercapnia improves peripheral perfusion and increases tissue PO2. Our main question was whether peripheral vasodilation is a direct effect of the CO2 or a secondary result of increased cardiac output and related central autonomic homeostatic responses. We found that mild hypercapnia did not increase subcutaneous tissue oxygenation when systemic blood flow and mean arterial pressure remained constant during cardiopulmonary bypass. Increased tissue oxygenation during mild hypercapnia thus most likely results from a hyperdynamic circulatory response and shifting oxyhaemoglobin dissociation curve rather than direct peripheral vasodilation.
Even mild systemic hypercapnia provokes sympatho-excitation15
which increases cardiac output, enhances systemic vascular conductance,18, 19
and — because of active venoconstriction — increases venous return.19, 20
The increase in capacitance vessel tone is mediated via
peripheral and central chemoreceptors and does not necessarily parallel changes in overall vascular resistance18
— and, as our results demonstrate, does not increase subcutaneous perfusion. Venoconstriction nonetheless increases venous return and is, thus, invariably associated with a sustained increase in cardiac output,14, 18, 19, 31
an effect that dominates a small direct depressant effect of hypercapnic acidosis on the isolated myocardium.32, 33
Hypercapnia increases both sympathetic and cardiac vagus nerve activity in anaesthetized dogs. Such co-activation of vagus and sympathetic systems, which can be initiated reflexively or by action on higher centres, has been shown to be of distinct physiological benefit in controlling reactions that relate cardiac function to body need. Since the sympathetic and parasympathetic systems are co-activated during systemic hypercapnia, blood pressure and heart rate response depends on the functional balance between these two systems. We were unable to evaluate heart rate during bypass, but have previously shown that both mean arterial blood pressure and heart rate remained essentially unchanged during hypercapnia even though cardiac output increases 25%.11
Recent evidence indicates that both the sympathetic and parasympathetic nervous systems contribute to regulation of peripheral microcirculation.34
The presence of parasympathetic-related, high-frequency microvascular oscillations has been recently documented in adrenergically rich peripheral regions — even during nonpulsatile perfusion34
— and has important implications for local flow homeostasis. Interestingly, nonpulsatile flow in the systemic circulation, as during cardiopulmonary bypass, progressively increases sympathetic nerve activity,35
leading to arterial vasoconstriction and increased systemic vascular resistance.35
This increase in sympathetic nerve activity is due to suppression of baroreflex-mediated inhibition of the vasomotor centre and is associated with local parasympathetic activation34
in an effort to preserve tissue perfusion. Mild hypercapnia during constant systemic blood flow did not increase tissue oxygenation; however, we can not exclude the possibility of a differential action of CO2
in regional vascular resistance,36
which could have diverted systemic perfusion to areas other than subcutaneous tissues.37
Our results provided data only from the subcutaneous tissue. If any perfusion improvements occurred because of a change in vascular resistance, we missed them due to lack of monitoring. Potential redistribution cannot be excluded either.
In striking contrast to the unchanged subcutaneous oxygenation during constant systemic blood flow, mild hypercapnia markedly improved cerebral regional oxygen saturation. And the magnitude of the increase was similar to that we have previously observed in patients undergoing elective non-cardiac surgery.31
This finding is consistent with the fact that sympathetic control of the cerebral vessels is weaker than of other vascular beds,38
and the contractile state of the cerebrovascular smooth muscle appears to depend mainly on local metabolic factors including the partial pressure of CO2
. Thus, the vasodilator effect of CO2
is particularly marked in the cerebral circulation where a CO2
concentration of 7 to 10% nearly doubles cerebral blood flow (CBF) in humans,39
while mild hypercapnia (PaCO2
~ 50 mmHg) impairs autoregulation of CBF and is associated with an overall increase in cerebral oxygenation.11, 40
A similar cerebrovascular response during cardiopulmonary bypass leads to an increase in CBF41
that is associated with a reduction in cerebral oxygen consumption.42
On the other hand, peripheral vasomotor tone during hypercapnia is essentially the result of a balance between the direct effects of CO2
and the level of sympathetic activity.38
Of course, because neither cerebral nor other vital organ blood flows were monitored in the study, it was not possible to exclude any role of redistribution of blood flow between the organ systems.
The mechanism by which CO2
exerts its direct effects on the cerebral vasculature seems to involve nitric oxide (NO), ATP-sensitive potassium channels, and cyclooxygenase-dependent pathways. The CO2
-NO axis is considered a cardinal pathway for CBF regulation in humans. Thus, although ATP-sensitive and Ca2+
-activated potassium channels are also major systems that respond to hypercapnic acidosis, their response is incomplete in the absence of NO donors. In both animals43
hypercapnic vasodilatation is mediated by inhibition of nitric oxide synthase — the enzyme responsible for nitric oxide synthesis. It is probable that the vasodilation to hypercapnic acidosis is mediated either by increased synthesis of NO or increased sensitivity to NO.
A secondary goal of our study was to compare a new fluoroscopic optode based oxygen-monitoring system (Foxy) with the current standard, polarographic electrode system (Licox). The fluorescence optode system is known to be more accurate in lower tissue oxygen environments than the polarographic one, because it does not consume oxygen. However, increased bias and impaired linearity of the relationship between the oxygen-monitoring systems when PsqO2 was above 150 mmHg indicates reduced accuracy of the fluorescence optode at high tissue oxygenation. Other drawbacks of the fluorescence method include substantial light sensitivity, sensitivity to movement, and the lack of a small calibre temperature probe. These limitations make its use in the clinical setting impractical.
Another potential limitation of our study was that we allowed only a 30-minute equilibration period at each designated of arterial PCO2
concentration. (A period of 30 minutes was chosen because the bypass period sometimes lasted only an hour.) However, 20 to 30 minutes is sufficient to obtain stable tissue oxygen values with tonometric systems that accommodate tissue oxygen probes. A further potential limitation of our study was that 3 of our 10 patients were obese and obesity is known to influence tissue oxygenation.8
However, because of our crossover design, the effect on tissue oxygenation should have been the same at both concentrations of carbon dioxide. And lastly, we did not provide a positive control by increasing the bypass pump outflow during the study, which would have simulated increased cardiac output. Although we initially thought about putting this in our protocol, because we were working with patients as study subjects, we decided that it would be risky to include it. The clinical importance of the relationship between the bypass pump outflow and weaning the patient off the pump is just too fragile.
In summary, mild hypercapnia — which normally markedly increases subcutaneous tissue oxygenation — failed to do so during cardiopulmonary bypass when the bypass pump controlled systemic blood flow. In contrast, cerebral oxygen saturation increased as usual. The increase in subcutaneous oxygen partial pressure that normally accompanies mild hypercapnia thus results largely from increased cardiac output and compensatory autonomic circulatory responses. Potential contribution of shifting of oxyhaemoglobin dissociation curve and decreased oxygen consumption should also be considered.