Ryan L. Hoiland

Transcranial Doppler ultrasound: Valid, invalid, or both?

despite considerable anatomical knowledge acquired by anatomists three centuries ago, little was known about the brains circulatory control until the latter half of the 19th century, when Angelo Mosso made the first estimations of human cerebral blood flow (CBF) by observing volume changes in open

Static autoregulation in humans: a review and reanalysis

INTRODUCTION Cerebral autoregulation (CA) is a theoretical construct characterized by the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF). We performed a comprehensive literature search to provide an up-to-date review on the static relationship between MAP and CBF. METHODS The results are based on 40 studies (49 individual experimental protocols) in healthy subjects between 18 and 65 years. Exclusion criteria were: a ΔMAP <5%, hypoxia/hyperoxia or hypo/hypercapnia, and unstable levels (<2 min stages). The partial pressure of arterial CO2 (PaCO2) was measured in a subset of the included studies (n=28); therefore, CBF was also adjusted to account for small changes in PaCO2. RESULTS The linear regression coefficient between MAP and CBF (or velocity) of 0.82±0.77%ΔCBF/%ΔMAP during decreases in MAP (n=23 experiments) was significantly different than the relationship of 0.21±0.47%ΔCBF/%ΔMAP during increases (n=26 experiments; p<0.001). After correction for increases/decreases in PaCO2, the slopes were not significantly different: 0.64±1.16%ΔCBF/%ΔMAP (n=16) and 0.39±0.30%ΔCBF/%ΔMAP (n=12) for increased vs. decreased MAP changes, respectively (p=0.60). CONCLUSION The autoregulatory ability of the cerebral circulation appears to be more active in buffering increases in MAP as compared to reductions in MAP. However, the statistical finding of hysteresis is lost following an attempt to correct for PaCO2.

Hypoxemia, oxygen content, and the regulation of cerebral blood flow

This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2 content (CaO2 ) rather than arterial O2 tension (PaO2 ) as the chief regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2 sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2 . We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2 and thus maintain cerebral O2 delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2 has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2 during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2 ) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2 via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.

Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery

This study assessed the dynamic response of global cerebral blood flow (CBF) and cerebral fuel utilization during and following incremental supine exercise to exhaustion. Global CBF increased more during exercise and recovery at high altitude (HA) compared with sea level (SL) such that cerebral oxygen delivery ( CDO2 ) was maintained. The increase in cerebral metabolic rate of oxygen during maximal exercise at HA was half the increase observed at SL. Arterial lactate production during exercise at the same absolute intensities was greater at HA compared with SL, but reduced at the same relative intensities. Cerebral carbohydrate uptake (lactate and glucose) is greater than oxygen uptake at HA compared with SL, indicating a shift towards an increased non‐oxidative metabolic utilization. These results suggest that CBF increases to maintain CDO2 during exercise at HA while changes in arterial lactate concentration and exercise intensity augment the oxidative and non‐oxidative pathways to cerebral metabolism at HA.

CrossTalk proposal: The middle cerebral artery diameter does change during alterations in arterial blood gases and blood pressure

Since the introduction of transcranial Doppler (TCD) ultrasound (Aaslid et al. 1982), the ostensible constancy of middle cerebral artery (MCA) diameter during changes in arterial blood gases and/or arterial blood pressure (ABP) has remained controversial (Kontos, 1989; Giller, 2003; Ainslie & Hoiland, 2014). Due to its ease of use, high temporal resolution, and non-invasive nature, TCD has significantly shaped the current understanding of human cerebrovascular physiology. However, TCD has always been tainted by the major assumption of an unchanged MCA diameter; that is, changes in MCA velocity (MCAv) are thought to accurately reflect changes in cerebral blood flow (CBF). While MCA diameter constancy, or lack thereof, is the focus of this Crosstalk series, we must note that CBF is typically the true variable of interest from a research perspective. Therefore, the significance of changes in MCA diameter are not determined by the magnitude of dilatation and constriction per se, but by the magnitude of effect on CBF. In keeping with Poiseuille’s Law,

Indomethacin‐induced impairment of regional cerebrovascular reactivity: implications for respiratory control

Anterior and posterior cerebral circulations have differential reactivity to changes in arterial blood gases, but the implications for the chemoreflex control of breathing are unclear. Indomethacin‐induced blunting of cerebrovascular flow responsiveness did not affect central or peripheral respiratory chemoreflex magnitude using steady‐state end‐tidal forcing techniques. Posterior reactivity was related to hypoxic ventilatory decline, suggesting that CO2 washout from central chemoreceptors modulates hypoxic ventilatory dynamics. Our data indicate that steady‐state end‐tidal forcing techniques reduce the arterial–venous gradients, attenuating the effect of brain blood flow on ventilatory responses. Our study confirms the importance of measuring posterior cerebrovasculature when investigating the link between cerebral blood flow and the chemical control of breathing.

Measuring the human ventilatory and cerebral blood flow response to CO2: a technical consideration for the end-tidal-to-arterial gas gradient.

Our aim was to quantify the end-tidal-to-arterial gas gradients for O2 (PET-PaO2) and CO2 (Pa-PETCO2) during a CO2 reactivity test to determine their influence on the cerebrovascular (CVR) and ventilatory (HCVR) response in subjects with (PFO+, n = 8) and without (PFO-, n = 7) a patent foramen ovale (PFO). We hypothesized that 1) the Pa-PETCO2 would be greater in hypoxia compared with normoxia, 2) the Pa-PETCO2 would be similar, whereas the PET-PaO2 gradient would be greater in those with a PFO, 3) the HCVR and CVR would be underestimated when plotted against PETCO2 compared with PaCO2, and 4) previously derived prediction algorithms will accurately target PaCO2. PETCO2 was controlled by dynamic end-tidal forcing in steady-state steps of -8, -4, 0, +4, and +8 mmHg from baseline in normoxia and hypoxia. Minute ventilation (V̇E), internal carotid artery blood flow (Q̇ICA), middle cerebral artery blood velocity (MCAv), and temperature corrected end-tidal and arterial blood gases were measured throughout experimentation. HCVR and CVR were calculated using linear regression analysis by indexing V̇E and relative changes in Q̇ICA, and MCAv against PETCO2, predicted PaCO2, and measured PaCO2. The Pa-PETCO2 was similar between hypoxia and normoxia and PFO+ and PFO-. The PET-PaO2 was greater in PFO+ by 2.1 mmHg during normoxia (P = 0.003). HCVR and CVR plotted against PETCO2 underestimated HCVR and CVR indexed against PaCO2 in normoxia and hypoxia. Our PaCO2 prediction equation modestly improved estimates of HCVR and CVR. In summary, care must be taken when indexing reactivity measures to PETCO2 compared with PaCO2.

The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude.

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial–jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H+ relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.

Evidence for Shear Stress–Mediated Dilation of the Internal Carotid Artery in Humans

Increases in arterial carbon dioxide tension (hypercapnia) elicit potent vasodilation of cerebral arterioles. Recent studies have also reported vasodilation of the internal carotid artery during hypercapnia, but the mechanism(s) mediating this extracranial vasoreactivity are unknown. Hypercapnia increases carotid shear stress, a known stimulus to vasodilation in other conduit arteries. To explore the hypothesis that shear stress contributes to hypercapnic internal carotid dilation in humans, temporal changes in internal and common carotid shear rate and diameter, along with changes in middle cerebral artery velocity, were simultaneously assessed in 18 subjects at rest and during hypercapnia (6% carbon dioxide). Middle cerebral artery velocity increased significantly (69±10–103±17 cm/s; P<0.01) along with shear in both the internal (316±52–518±105 1/s; P<0.01) and common (188±40–275±61 1/s; P<0.01) carotids. Diameter also increased (P<0.01) in both carotid arteries (internal: +6.3±2.9%; common: +5.8±3.0%). Following hypercapnia onset, there was a significant delay between the onset of internal carotid shear (22±12 seconds) and diameter change (85±51 seconds). This time course is associated with shear-mediated dilation of larger conduit arteries in humans. There was a strong association between change in shear and diameter of the internal carotid (r=0.68; P<0.01). These data indicate, for the first time in humans, that shear stress is an important stimulus for hypercapnic vasodilation of the internal carotid artery. The combination of a hypercapnic stimulus and continuous noninvasive, high-resolution assessment of internal carotid shear and dilation may provide novel insights into the function and health of the clinically important extracranial arteries in humans.

Cerebral oxidative metabolism is decreased with extreme apnoea in humans; impact of hypercapnia

The present study describes the cerebral oxidative and non‐oxidative metabolism in man during a prolonged apnoea (ranging from 3 min 36 s to 7 min 26 s) that generates extremely low levels of blood oxygen and high levels of carbon dioxide. The cerebral oxidative metabolism, measured from the product of cerebral blood flow and the radial artery‐jugular venous oxygen content difference, was reduced by ∼29% at the termination of apnoea, although there was no change in the non‐oxidative metabolism. A subset study with mild and severe hypercapnic breathing at the same level of hypoxia suggests that hypercapnia can partly explain the cerebral metabolic reduction near the apnoea breakpoint. A hypercapnia‐induced oxygen‐conserving response may protect the brain against severe oxygen deprivation associated with prolonged apnoea.