Inadequate Cerebral Oxygen Delivery and Central Fatigue during Strenuous Exercise

Lars Nybo; Peter Rasmussen


Exerc Sport Sci Rev. 2007;35(3):110-118. 

In This Article

Cerebral Metabolism and Mitochondrial PO

Because the brain relies on aerobic metabolism, it is clear that the oxygen tension within the mitochondria is critical for the cerebral function. However, it is not clear what the critical PO2 level is. Thus, impairment of the mitochondrial oxidation has been observed in the range of approximately 0.5-20 mm Hg (depending on the methodology used for evaluation of Pmito), and the physiological level in a resting human is estimated to range from close to zero and up to 40 mm Hg[5,27]. Obviously, it is not possible to measure Pmito directly in vivo, and the wide range of the reported values for Pmito may relate to the methodological differences and difficulties; however, it may also relate to large differences within the brain. Although, the regional CBF is matched largely to the metabolic activity, flow and energy turnover are distributed heterogeneously in the brain, and there may be relatively large differences across brain regions. Pmito depends on the balance between oxygen supply and use and the oxygen conductance from the capillary to the mitochondria (L). Thus, the mitochondrial oxygen tension is determined by the capillary PO2, the oxygen use (cerebral metabolic rate (CMR); CMRO2), and L as expressed by equation 1:[8,29]

As the brain lacks capillary recruitment, O2 diffusibility (L) remains stable at any measured blood flow level and is determined at the lowest capillary oxygen tension, where Pmito is assumed to approach zero. PCap can be estimated from measurement of arterial and cerebral venous blood,


is the PO2 when hemoglobin is half saturated, and ha is Hill coefficient for arterial blood.

The average oxygen consumption may be calculated on the basis of the cerebral a-v difference for oxygen and CBF. However, it may not be simple to estimate flow during strenuous whole-body exercise, and interpretation and comparison of results from different studies require care, including consideration of whether a regional or a global CBF has been estimated. Mixed cerebral venous blood may be obtained from the internal jugular vein, but this blood may not be representative of all brain regions, and it provides only a measure of the average oxygen tension and saturation of the blood leaving the brain. Venous blood from active brain areas may have different oxygen content. Nevertheless, this method may provide the best functional estimate of changes in Pmito in exercising subjects. The calculation does not allow for an absolute determination of the cerebral Pmito, but it provides a useful indication of changes in the average cerebral Pmito relative to a basal level and thus the global oxygen state of the brain. As illustrated in Figure 1, it seems that a reduction in the average Pmito by more than 6-7 mm Hg - either induced by arterial hypoxia or reduced CBF - is associated with impaired cerebral aerobic metabolism (as increased lactate spillover indicates that aerobic pyruvate metabolism cannot match the required glycolytic rate). In addition, there is a reduced ability to activate the motor neurons at this Pmito level, implying that a drop by more than 6-7 mm Hg in Pmito or a reduction in cerebral oxygen delivery by more than 15% needs to be prevented for optimal motor function of the brain. Brain cells can survive for a relatively long time on anaerobic energy turnover; glycolytic metabolism by the astrocytes may protect against cell damage, and for a limited period, it may postpone fatigue. However, anaerobic metabolism of a glucose molecule only produces energy for resynthesis of 2 ATP, whereas aerobic metabolism of glucose is much more efficient and may provide up to 36 ATP. Thus, even if the brain cells could get rid of the produced lactate and maintain the lactate dehydrogenase-catalyzed conversion of pyruvate to lactate and concomitant interconversion of the reduced form of nicotinamide adenine dinucleotide to the oxidized form, NAD+ (as required to allow for further breakdown of glucose to pyruvate via the Embden-Meyerhof pathway), the brain would have to increase its glucose uptake substantially. In accordance, the cerebral glucose uptake increases during hypoxia and maximal exercise.[2,29] However, during hypoxia, the increase is modest,[2] and the enhanced cerebral uptake and anaerobic metabolism of glucose are not sufficient to maintain optimal function of the brain as judged from the impaired motor activation after 10-min exposure to hypoxia.[29]

These observations have been made in resting subjects, and the tolerable reduction in Pmito may be even lower when the brain is activated by strenuous exercise, which raises the metabolism in the involved motor areas of the brain. Thus, the Pmito depends on the integration of supply and demand, and increased regional CMRO2 will lower the cerebral Pmito (equation 1) unless flow in the active brain area increases to compensate for the increased use. To maintain Pmito, or at least avoid critically large reductions of Pmito in the active brain areas, the capillary oxygen tension and saturation must be kept at a relatively high level, and this requires that the increase in flow is proportionally larger than the increase in metabolism. There is practically no capillary recruitment in the brain; the oxygen extraction rises linearly with distance as the blood traverses the capillary network from arterial to venous ends, and the capillary geometry is such that all segments of the capillary bed supply equal amounts of brain tissue.[15] Therefore, compared with muscle tissue, the maximal extraction fraction is much lower for the brain.

As described by equation 2, the oxygen saturation and tension of the capillaries may be estimated on the basis of arterial and cerebral venous blood sampling. With this methodology, the lowest capillary saturation level consistent with unimpaired metabolic function of the brain is estimated to approximately 70%, corresponding to a capillary PO2 between 35 and 40 mm Hg (depending on temperature, pH, and CO2 level). In resting subjects with a normal PaO2, the highest extraction fraction (a-v difference for oxygen divided by arterial oxygen content) seems to be 55%-60%. Presyncope symptoms emerge during head-up tilt when the jugular venous saturation becomes reduced by approximately 15%[19], corresponding to a oxygen extraction fraction of approximately 55%. However, the global cerebral oxygen extraction rarely exceeds 50% during exercise ( Table ). Because physical or mental activation of the brain involves increased energy turnover in the active regions, whereas other regions may have unchanged or a decreased metabolic rate, the mixed venous blood may not reflect oxygen extraction in the activated brain regions. Furthermore, the highest obtainable global extraction fraction during hypoxia may become even lower because the PO2 gradient between the capillary and mitochondria will be too low to allow for sufficient oxygen flux/diffusion from blood to the mitochondria. Accordingly, the CMR for oxygen declines during exercise with severe hypoxia, and oxygen delivery to the brain becomes inadequate, although the oxygen extraction fraction is below 50% ( Table ).

Cerebral metabolism and oxygenation can be estimated noninvasively by determining capillary-oxygenation-level-dependent (COLD) monitoring with near-infrared spectroscopy (NIRS). Near-infrared spectroscopy works by emitting light at a defined wavelength into the tissue; after absorbance by hemoglobin that depends on its conformal state, some of the emitted light reaches to an optode, and oxygenation can be calculated according to a modified Lambert-Beer law. Near-infrared spectroscopy can be applied over any region of the skull; however, for subject's comfort, the forehead is usually preferred. The penetration depth of NIRS remains unknown in vivo but is likely restricted to a few centimeters. Although NIRS is a relative measure, it faithfully tracks the capillary oxygenation level as estimated from arterial and jugular venous blood saturation.[29] The COLD signal, nonetheless, still depends on the chosen algorithm, and the signal may vary some 5% from "true" blood oxygenation, depending on the apparatus.[29] Therefore, NIRS provides a rough estimate of capillary oxygen saturation, and the COLD signal is usually converted to hemoglobin oxygen saturation to provide a useful measure of the relation between oxygen availability and demand.

Comparison of the CMR for oxygen during different exercise conditions could indicate whether oxygen delivery has been adequate to support the aerobic metabolism. Although global and regional CMRO2 may be determined with various methods during strenuous exercise, the estimate is associated with a host of problems. The rigorous movements associated with strenuous exercise preclude the use of advanced imaging techniques such as functional magnetic resonance imaging and positron emission tomography.

Therefore, evaluations of cerebral metabolism during whole-body exercise have concentrated on measurements of CBF and the arteriovenous differences across the brain. However, the cerebral circulation receives blood from both the carotid and spinal arteries, making evaluation of the inflow troublesome. Furthermore, the venous drainage goes to both the spinal venous plexus and the internal jugular veins. The internal jugular vein is relatively easily catheterized and, therefore, used for sampling of cerebral venous blood but may not represent venous blood from all regions of the brain. To further complicate the evaluation, contribution to the drainage of each vein depends on body position; it is asymmetrical and may vary between subjects.[29] Despite these problems, the standard has been considered the Kety-Schmidt method, which derives CBF based on Fick principle - that is, wash out of a freely diffusible tracer determined from arterial and internal jugular venous blood samples.[25] Although the evaluation of the CBF with the Kety-Schmidt technique provides a measure of jugular venous flow, the method can provide useful values of global CBF at rest and during submaximal exercise.[18] However, a major difficulty with this method for determination of CBF and calculation of the CMRO2 during maximal exercise is the time resolution of the method. The Kety-Schmidt method requires approximately 30 min of tracer infusion, followed by at least 10 min of blood sampling, which is not compatible with maximal whole-body exercise.

Alternatively, CBF can be evaluated continuously by ultrasound Doppler sonography in the carotid artery or the basal cranial arteries. The exercise response in the basal arteries is similar to that in the carotid arteries,[9] thereby indicating some relation between changes in regional and global CBF. However, determination of flow or flow velocities in the basal cerebral arteries estimates regional rather than global CBF, and data from studies using different methods for evaluation of CBF must be interpreted with caution.[18] A crucial assumption in the interpretation of Doppler-derived flow velocity data is an unchanged caliber of the insonated vessel; however, it seems that vascular tone (vessel diameter) is regulated distally to the basal cerebral vessels, and in general, CBF velocities obtained by transcranial ultrasound Doppler seems to reflect regional CBF.[13]

When evaluated with the Kety-Schmidt technique, whole-brain blood flow and CMRO2 seem to be unchanged during exercise compared with those during rest, although the 10%-25% increase in flow derived by ultrasound Doppler assessment of the arterial inflow to the brain or in the basal cerebral vessels indicates that flow to large parts of the brain increases in response to motor activation.[10,11,13] However, even if global or regional CBF and CMRO2 may be determined, an unchanged or even elevated CMRO2 does not necessarily imply that oxygen delivery has been adequate. It may be argued that oxygen delivery is not sufficient to allow for a further increase in the CMRO2, which may be required during periods with intense neuronal firing (e.g., mentally demanding exercise).


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