Nia C. S. Lewis

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

•  The partial pressures of arterial carbon dioxide () and oxygen () has a marked influence on brain blood flow. •  It is unclear if the larger brain arteries are also sensitive to changing and and if different areas of the brain possess different sensitivities. •  We separately altered and and measured the diameter and blood flow in the main arteries delivering blood to the cortex and brainstem. •  During alterations in and , the large arteries changed diameter and blood flow to the brainstem changed more than that to the cortex. •  These findings change the basis of our understanding of brain blood flow control in humans.

Post-exercise blood pressure reduction is greater following intermittent than continuous exercise and is influenced less by diurnal variation

Recently, we reported that circadian variation exists in the response of blood pressure (BP) following a bout of uninterrupted exercise. The usual phenomenon of post‐exercise hypotension was absent or reversed when such exercise was performed between 04:00–08:00 h. Nevertheless, research examining BP changes following bouts of intermittent exercise at different times of the day is scarce, even though this type of activity is probably more popular. Therefore, we aimed to compare post‐exercise BP reductions of continuous (CONT) and intermittent (INT) exercise protocols performed at 08:00 h and 16:00 h. At both of these times of day, eight normotensive males completed 30 min of continuous cycling in the CONT and three 10 min bouts of cycling separated by 10 min of rest in the INT protocol. The exercise intensity was set at 70% V˙O2peak during both protocols. Heart rate, systolic (S) and diastolic (D) BP, and mean arterial pressure (MAP) were measured 5 min before and 20 min after exercise. Changes from pre‐exercise baseline were analyzed using linear mixed modeling. MAP was 8±1 mm Hg lower following INT compared with CONT exercise (p<0.05). SBP and DBP were also significantly lower following INT compared with CONT exercise (p<0.05). Diurnal variation in MAP was evident, with attenuated hypotension being observed after morning exercise (p<0.05), although this diurnal variation was less marked following INT compared with CONT exercise (p<0.05). We conclude that intermittent exercise mediates greater post‐exercise hypotension compared with a single continuous bout of equivalent work and that this protocol‐dependent difference is greatest in the afternoon. Therefore, a bout of afternoon exercise that is occasionally interrupted with short rest periods is recommended for lowering BP acutely.

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.

Technical recommendations for the use of carotid duplex ultrasound for the assessment of extracranial blood flow.

Duplex ultrasound is an evolving technology that allows the assessment of volumetric blood flow in the carotid and vertebral arteries during a range of interventions along the spectrum of health and chronic disease. Duplex ultrasound can provide high-resolution diameter and velocity information in real-time and is noninvasive with minimal risks or contraindications. However, this ultrasound approach is a specialized technique requiring intensive training and stringent control of multiple complex settings; results are highly operator-dependent, and analysis approaches are inconsistent. Importantly, therefore, methodological differences can invalidate comparisons between different imaging modalities and studies; such methodological errors have potential to discredit study findings completely. The task of this review is to provide the first comprehensive, user-friendly technical guideline for the application of duplex ultrasound in measuring extracranial blood flow in human research. An update on recent developments in the use of edge-detection software for offline analysis is highlighted, and suggestions for future directions in this field are provided. These recommendations are presented in an attempt to standardize measurements across research groups and, hence, ultimately to improve the accuracy and reproducibility of measuring extracranial blood flow both within subjects and between groups.

Conduit artery structure and function in lowlanders and native highlanders: relationships with oxidative stress and role of sympathoexcitation

Information describing alterations in vascular function during either acute or prolonged normobaric or hypobaric hypoxia is sparse and often confounded by pathology and methodological limitations. We show that high altitude exposure in lowlanders is associated with impairments in both endothelial and smooth muscle function, and with increased central arterial stiffness; furthermore, in all of these respects, lowlanders’ vasculature becomes comparable to that of natives born and raised at altitude. Changes in endothelial function occur very rapidly in normobaric hypoxia, and partly under the influence of sympathetic nerve activity. Thus, a lifetime of high‐altitude exposure neither attenuates nor intensifies the impairments in vascular function observed with short‐term exposure in lowlanders; such impairment and altered structure likely translate into an elevated cardiovascular risk.

Regional cerebral blood flow in humans at high altitude: gradual ascent and 2 wk at 5,050 m

The interindividual variation in ventilatory acclimatization to high altitude is likely reflected in variability in the cerebrovascular responses to high altitude, particularly between brain regions displaying disparate hypoxic sensitivity. We assessed regional differences in cerebral blood flow (CBF) measured with Duplex ultrasound of the left internal carotid and vertebral arteries. End-tidal Pco2, oxyhemoglobin saturation (SpO2), blood pressure, and heart rate were measured during a trekking ascent to, and during the first 2 wk at, 5,050 m. Transcranial color-coded Duplex ultrasound (TCCD) was employed to measure flow and diameter of the middle cerebral artery (MCA). Measures were collected at 344 m (TCCD-baseline), 1,338 m (CBF-baseline), 3,440 m, and 4,371 m. Following arrival to 5,050 m, regional CBF was measured every 12 h during the first 3 days, once at 5-9 days, and once at 12-16 days. Total CBF was calculated as twice the sum of internal carotid and vertebral flow and increased steadily with ascent, reaching a maximum of 842 ± 110 ml/min (+53 ± 7.6% vs. 1,338 m; mean ± SE) at ∼ 60 h after arrival at 5,050 m. These changes returned to +15 ± 12% after 12-16 days at 5,050 m and were related to changes in SpO2 (R(2) = 0.36; P < 0.0001). TCCD-measured MCA flow paralleled the temporal changes in total CBF. Dilation of the MCA was sustained on days 2 (+12.6 ± 4.6%) and 8 (+12.9 ± 2.9%) after arrival at 5,050 m. We observed no significant differences in regional CBF at any time point. In conclusion, the variability in CBF during ascent and acclimatization is related to ventilatory acclimatization, as reflected in changes in SpO2.

Impact of transient hypotension on regional cerebral blood flow in humans.

We examined the impact of progressive hypotension with and without hypocapnia on regional extracranial cerebral blood flow (CBF) and intracranial velocities. Participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope to inflict hypotension. End-tidal carbon dioxide was clamped at baseline levels (isocapnic trial) or uncontrolled (poikilocapnic trial). Middle cerebral artery (MCA) and posterior cerebral artery (PCA) blood velocities (transcranial Doppler; TCD), heart rate, blood pressure and end-tidal carbon dioxide were obtained continuously. Measurements of internal carotid artery (ICA) and vertebral artery (VA) blood flow (ICABF and VABF respectively) were also obtained. Overall, blood pressure was reduced by ~20% from baseline in both trials (P<0.001). In the isocapnic trial, end-tidal carbon dioxide was successfully clamped at baseline with hypotension, whereas in the poikilocapnic trial it was reduced by 11.1 mmHg (P<0.001) with hypotension. The decline in the ICABF with hypotension was comparable between trials (-139 ± 82 ml; ~30%; P<0.0001); however, the decline in the VABF was -28 ± 22 ml/min (~21%) greater in the poikilocapnic trial compared with the isocapnic trial (P=0.002). Regardless of trial, the blood flow reductions in ICA (-26 ± 14%) and VA (-27 ± 14%) were greater than the decline in MCA (-21 ± 15%) and PCA (-19 ± 10%) velocities respectively (P ≤ 0.01). Significant reductions in the diameter of both the ICA (~5%) and the VA (~7%) contributed to the decline in cerebral perfusion with systemic hypotension, independent of hypocapnia. In summary, our findings indicate that blood flow in the VA, unlike the ICA, is sensitive to changes hypotension and hypocapnia. We show for the first time that the decline in global CBF with hypotension is influenced by arterial constriction in the ICA and VA. Additionally, our findings suggest TCD measures of blood flow velocity may modestly underestimate changes in CBF during hypotension with and without hypocapnia, particularly in the posterior circulation.

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.

Effect of acute hypoxia on regional cerebral blood flow: effect of sympathetic nerve activity.

We examined 1) whether global cerebral blood flow (CBF) would increase across a 6-h bout of normobaric poikilocapnic hypoxia and be mediated by a larger increase in blood flow in the vertebral artery (VA) than in the internal carotid artery (ICA); and 2) whether additional increases in global CBF would be evident following an α1-adrenergic blockade via further dilation of the ICA and VA. In 11 young normotensive individuals, ultrasound measures of ICA and VA flow were obtained in normoxia (baseline) and following 60, 210, and 330 min of hypoxia (FiO2 = 0.11). Ninety minutes prior to final assessment, participants received an α1-adrenoreceptor blocker (prazosin, 1 mg/20 kg body mass) or placebo. Compared with baseline, following 60, 220, and 330 min of hypoxia, global CBF [(ICAFlow + VAFlow) ∗ 2] increased by 160 ± 52 ml/min (+28%; P = 0.05), 134 ± 23 ml/min (+23%; P = 0.02), and 113 ± 51 (+19%; P = 0.27), respectively. Compared with baseline, ICAFlow increased by 23% following 60 min of hypoxia (P = 0.06), after which it progressively declined. The percentage increase in VA flow was consistently larger than ICA flow during hypoxia by ∼20% (P = 0.002). Compared with baseline, ICA and VA diameters increased during hypoxia by ∼9% and ∼12%, respectively (P ≤ 0.05), and were correlated with reductions in SaO2. Flow and diameters were unaltered following α1 blockade (P ≥ 0.10). In conclusion, elevations in global CBF during acute hypoxia are partly mediated via greater increases in VA flow compared with ICA flow; this regional difference was unaltered following α1 blockade, indicating that a heightened sympathetic nerve activity with hypoxia does not constrain further dilation of larger extracranial blood vessels.

Resting pulmonary haemodynamics and shunting: a comparison of sea‐level inhabitants to high altitude Sherpas

Evolutionary pressure to improve gas exchange and/or resting pulmonary haemodynamics in hypoxic environments may have led to differences in the amount of blood that flows through right‐to‐left shunt pathways between Sherpas and sea‐level inhabitants. We studied sea‐level inhabitants during rest at sea level and acute isocapnic hypoxia and during rest at high altitude following 3 weeks of acclimatization and compared their responses to those of Sherpas during rest at high altitude. Contrary to some previous literature, we found similar resting pulmonary pressure and total pulmonary resistance between acclimatized sea‐level inhabitants and Sherpas at high altitude. We also found a similar number of subjects from each group with intracardiac shunt and intrapulmonary shunt at high altitude. These results help us better understand resting cardiopulmonary adaptations to high altitude by comparing life‐long high altitude residents with sea‐level inhabitants acclimatized to high altitude.