Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO2 (PaCO2). This physiological response, termed cerebrovascular CO2 reactivity, i...

Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function.

The response of cerebral vasculature to exercise is different from other peripheral vasculature; it has a small vascular bed and is strongly regulated by cerebral autoregulation and the partial pre...

Cerebral blood flow during exercise: mechanisms of regulation

Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases.We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO2 (PaCO2) and O2 (PaO2) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range.We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n =16) examined iso-oxic changes in PaCO2, consisting of three hypocapnic stages (PaCO2 =∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (PaCO2 =∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n =10), during isocapnia, PaO2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar.With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in PaCO2 (R2, 0.63±0.26; P<0.05); VA diameter was unaltered in response to changed PaCO2 but yielded a diameter increase of +9% with severe hypoxia. (3) Intra- vs. extra-cerebral measures: MCA and PCA blood velocities yielded smaller reactivities and estimates of flow than VA and ICA flow. The findings respectively indicate: (1) disparate blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2012.228551

Regional brain blood flow in man during acute changes in arterial blood gases

It is known that cerebral blood flow declines with age in sedentary adults, although previous studies have involved small sample sizes, making the exact estimate of decline imprecise and the effects of possible moderator variables unknown. Animal studies indicate that aerobic exercise can elevate cerebral blood flow; however, this possibility has not been examined in humans. We examined how regular aerobic exercise affects the age-related decline in blood flow velocity in the middle cerebral artery (MCAv) in healthy humans. Maximal oxygen consumption, body mass index (BMI), blood pressure and MCAv were measured in healthy sedentary (n = 153) and endurance-trained (n = 154) men aged between 18 and 79 years. The relationships between age, training status, BMI and MCAv were examined using analysis of covariance methods. Mean +/- s.e.m. estimates of regression coefficients and 95% confidence intervals (95% CI) were calculated. The age-related decline in MCAv was -0.76 +/- 0.04 cm s(-1) year(-1) (95% CI = -0.69 to -0.83, r(2) = 0.66, P < 0.0005) and was independent of training status (P = 0.65). Nevertheless, MCAv was consistently elevated by 9.1 +/- 3.3 cm s(-1) (CI = 2.7-15.6, P = 0.006) in endurance-trained men throughout the age range. This approximately 17% difference between trained and sedentary men amounted to an approximate 10 year reduction in MCAv 'age' and was robust to between-group differences in BMI and blood pressure. Regular aerobic-endurance exercise is associated with higher MCAv in men aged 18-79 years. The persistence of this finding in older endurance-trained men may therefore help explain why there is a lower risk of cerebrovascular disease in this population.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2008.158279

Elevation in cerebral blood flow velocity with aerobic fitness throughout healthy human ageing.

Measurement of cerebrovascular reactivity to CO2 has been widely applied in clinical practice to evaluate cerebral vascular function – e.g. in patients with carotid artery stenosis (Widder et al. 1994), hypertension (Serrador et al. 2005), stroke (Wijnhoud et al. 2006) and heart failure (Xie et al. 2005), and a related impairment has been linked to cerebral ischaemic events (Cosentino & Volpe, 2005; Wijnhoud et al. 2006). The acute manipulation of Pa,CO2 through hyperventilation has been used as an intervention to rapidly reduce intracranial pressure or to adjust cerebral blood flow (CBF) to metabolic needs. Furthermore, changes in cerebrovascular CO2 reactivity affect stability of the ventilatory responsiveness to CO2 via alterations in the degree of washout in central chemoreceptor hydrogen [H+]; these changes have been documented in a range of physiological (Cummings et al. 2007) and pathophysiological (Xie et al. 2005; Ainslie et al. 2007) conditions.

In most instances CBF reactivity is expressed as the percentage change in CBF per mmHg change in Pa,CO2, or end-tidal CO2(PET,CO2) obviating the more invasive Pa,CO2 measurement. The tight correlation between the percentage of change in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler ultrasonography during PET,CO2 variations (Markwalder et al. 1984; Ide et al. 2003) has encouraged the use of transcranial Doppler (TCD) ultrasonography to measure CO2 cerebrovascular reactivity. However, several considerations are important when using Pa,CO2 (or PET,CO2) to investigate cerebral blood flow reactivity. First, PET,CO2 has been shown to underestimate Pa,CO2 at rest (Robbins et al. 1990) and to overestimate Pa,CO2 during exercise (Jones et al. 1979; Robbins et al. 1990). Similarly, a positive PET,CO2–Pa,CO2 gradient is seen in animals exposed to increased CO2 (Jennings & Chen, 1975; Oliven et al. 1985; Tojima et al. 1988). Such alterations in the Pa,CO2–PET,CO2 relationship may have implications for the true representation and physiological interpretation of cerebrovascular reactivity to CO2. In humans, it is not known how the Pa,CO2–PET,CO2 relationship is altered throughout the hypercapnic and hypocapnic range. To address these inaccuracies, Jones et al. (1979) developed a regression equation using PET,CO2 and tidal volume to provide an estimate of Pa,CO2 (ePa,CO2) during exercise to compensate for the overestimation of Pa,CO2 by PET,CO2. Thus, we reasoned that since hypercapnia evokes an increase in ventilation (and tidal volume), this empirical equation could also be used to estimate Pa,CO2 during step changes in PET,CO2. Therefore, cerebrovascular CO2 reactivity during hypercapnia and hypocapnia could be expressed in three different ways (Pa,CO2, ePa,CO2 and PET,CO2) and compared accordingly.

The second consideration when investigating CBF reactivity is whether cerebrovascular reactivity to CO2 might be even better expressed as a percentage of brain tissue PCO2. This idea evolves from a study by Shapiro and colleagues who showed that changes in CBF corelated more closely with jugular venous CO2 tension (Pjv,CO2) than Pa,CO2 (r= 0.83 versus r= 0.72, respectively), suggesting that Pa,CO2 is not the effective stimulus for cerebral vasodilatation (Shapiro et al. 1966). In contrast, Severinghaus & Lassen (1967) provided data to indicate that brain tissue PCO2 (based on Pjv,CO2) was not the ultimate determinant of CBF during a single step of hypocapnia, and that Pa,CO2– or arterial wall PCO2– may have an important role. Whether there is a differential control of CBF via brain tissue PCO2 or Pa,CO2 during hypercapnia and hypocapnia remains to be established. With respect to ventilation, however, it is clear that the central contribution to the ventilatory response to CO2 is determined not by Pa,CO2 but by changes in brain tissue PCO2 and [H+] (Ahmad & Loeschcke, 1982; Smith et al. 2006). Thus, the stimulus at the central chemoreceptor level might also be better represented by the PCO2 of the venous cerebral outflow (Fencl, 1986; Xie et al. 2006).

Given the outlined literature, it would appear that potential difference in cerebrovascular reactivity when expressed against Pa,CO2 or Pjv,CO2, and the potential relationship to CO2 ventilatory drive, has not been fully described in humans. Therefore the aims of this study were (1) to compare the accuracy of PET,CO2 and ePa,CO2 for predicting Pa,CO2 during step hyper- and hypocapnia changes, and (2) to compare CBF and ventilatory sensitivities to Pa,CO2, Pjv,CO2, ePa,CO2 and PET,CO2. Based on the aforementioned studies, we tested two original hypotheses: first, that PET,CO2 but not ePa,CO2 would overestimate Pa,CO2 during step changes in PCO2, and therefore result in apparent lower cerebrovascular CO2 reactivity; and second that because the changes in cerebral vascular tone occurring with changes in CO2 tension serve to limit changes in brain tissue PCO2 and thus Pjv,CO2, both PET,CO2 and Pa,CO2 reactivities would be lower when compared with Pjv,CO2. We also reasoned that, if MCAv–Pjv,CO2 reactivity determines brain PCO2, in those individuals with a low MCAv–Pjv,CO2 reactivity there would theoretically be less CO2 washout at the level of the central chemoreceptors and therefore a greater ventilatory stimulus.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2007.137075

Human cerebrovascular and ventilatory CO2 reactivity to end‐tidal, arterial and internal jugular vein PCO2

Dynamic cerebral autoregulation and baroreflex sensitivity during modest and severe step changes in arterial PCO2.

Cerebral blood flow (CBF) is highly regulated by changes in arterial Pco2 and arterial Po2. Evidence from animal studies indicates that various vasoactive factors, including release of norepinephri...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.90613.2008

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

We hypothesized that 1) acute severe hypoxia, but not hyperoxia, at sea level would impair dynamic cerebral autoregulation (CA); 2) impairment in CA at high altitude (HA) would be partly restored w...

https://www.physiology.org/doi/pdf/10.1152/japplphysiol.00778.2007

Differential effects of acute hypoxia and high altitude on cerebral blood flow velocity and dynamic cerebral autoregulation: alterations with hyperoxia

Human cerebral arterio-venous vasoactive exchange during alterations in arterial blood gases running title: cerebral vasoactive agents and arterial blood gases

Ken McGrattan

Papers

Human cerebrovascular and ventilatory CO2 reactivity to end‐tidal, arterial and internal jugular vein PCO2

Dynamic cerebral autoregulation and baroreflex sensitivity during modest and severe step changes in arterial PCO2.

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Differential effects of acute hypoxia and high altitude on cerebral blood flow velocity and dynamic cerebral autoregulation: alterations with hyperoxia

Human cerebral arterio-venous vasoactive exchange during alterations in arterial blood gases running title: cerebral vasoactive agents and arterial blood gases