Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Global REACH 2018: The influence of acute and chronic hypoxia on cerebral haemodynamics and related functional outcomes during cold and heat stress.

KEY POINTS: Thermal and hypoxic stress commonly coexist in environmental, occupational and clinical settings, yet how the brain tolerates these multi-stressor environments is unknown Core cooling by 1.0°C reduced cerebral blood flow (CBF) by 20-30% and cerebral oxygen delivery (CDO2 ) by 12-19% at sea level and high altitude, whereas core heating by 1.5°C did not reliably reduce CBF or CDO2 Oxygen content in arterial blood was fully restored with acclimatisation to 4330 m, but concurrent cold stress reduced CBF and CDO2 Gross indices of cognition were not impaired by any combination of thermal and hypoxic stress despite large reductions in CDO2 Chronic hypoxia renders the brain susceptible to large reductions in oxygen delivery with concurrent cold stress, which might make monitoring core temperature more important in this context ABSTRACT: Real-world settings are composed of multiple environmental stressors, yet the majority of research in environmental physiology investigates these stressors in isolation. The brain is central in both behavioural and physiological responses to threatening stimuli and, given its tight metabolic and haemodynamic requirements, is particularly susceptible to environmental stress. We measured cerebral blood flow (CBF, duplex ultrasound), cerebral oxygen delivery (CDO2 ), oesophageal temperature, and arterial blood gases during exposure to three commonly experienced environmental stressors - heat, cold and hypoxia - in isolation, and in combination. Twelve healthy male subjects (27 ± 11 years) underwent core cooling by 1.0°C and core heating by 1.5°C in randomised order at sea level; acute hypoxia ( PET,O2  = 50 mm Hg) was imposed at baseline and at each thermal extreme. Core cooling and heating protocols were repeated after 16 ± 4 days residing at 4330 m to investigate any interactions with high altitude acclimatisation. Cold stress decreased CBF by 20-30% and CDO2 by 12-19% (both P < 0.01) irrespective of altitude, whereas heating did not reliably change either CBF or CDO2 (both P > 0.08). The increases in CBF with acute hypoxia during thermal stress were appropriate to maintain CDO2 at normothermic, normoxic values. Reaction time was faster and slower by 6-9% with heating and cooling, respectively (both P < 0.01), but central (brain) processes were not impaired by any combination of environmental stressors. These findings highlight the powerful influence of core cooling in reducing CDO2 . Despite these large reductions in CDO2 with cold stress, gross indices of cognition remained stable.

Independent and interactive effects of incremental heat strain, orthostatic stress, and mild hypohydration on cerebral perfusion.

The purpose of this study was to identify the dose-dependent effects of heat strain and orthostasis [via lower body negative pressure (LBNP)], with and without mild hypohydration, on systemic function and cerebral perfusion. Eleven men (means ± SD: 27 ± 7 y; body mass 77 ± 6 kg), resting supine in a water-perfused suit, underwent progressive passive heating [0.5°C increments in core temperature (Tc; esophageal to +2.0°C)] while euhydrated (EUH) or hypohydrated (HYPO; 1.5-2% body mass deficit). At each thermal state, mean cerebral artery blood velocity (MCAvmean; transcranial Doppler), partial pressure of end-tidal carbon dioxide ([Formula: see text]), heart rate (HR) and mean arterial blood pressure (MAP; photoplethysmography) were measured continuously during LBNP (0, -15, -30, and -45 mmHg). Four subjects became intolerant before +2.0°C Tc, unrelated to hydration status. Without LBNP, decreases in [Formula: see text] accounted fully for reductions in MCAvmean across all Tc. With LBNP at heat tolerance (+1.5 or +2.0°C), [Formula: see text] accounted for 69 ± 25% of the change in MCAvmean. The HYPO condition did not affect MCAvmean or any cardiovascular variables during combined LBNP and passive heat stress (all P > 0.13). These findings indicate that hypocapnia accounted fully for the reduction in MCAvmean when passively heat stressed in the absence of LBNP and for two- thirds of the reduction when at heat tolerance combined with LBNP. Furthermore, when elevations in Tc are matched, mild hypohydration does not influence cerebrovascular or cardiovascular responses to LBNP, even when stressed by a combination of hyperthermia and LBNP.

Acute hypoxaemia and vascular function in healthy humans.

NEW FINDINGS: What is the central question of this study? Endothelium-dependent flow-mediated dilatation (FMD) is impaired during acute (60 min) exposure to moderate hypoxia. We examined whether FMD is impaired to the same degree during exposure to milder hypoxia. Additionally, we assessed whether smooth muscle vasodilatory capacity [glyceryl trinitrate (GTN)-induced dilatation] is impaired during acute hypoxic exposure. What is the main finding and its importance? A graded impairment in FMD and GTN-induced dilatation was evident during acute (≤60 min) exposure to mild and moderate hypoxia. This study is the first to document these graded impairments, and provides rationale to examine the relationship between graded increases in sympathetic nerve activity with hypoxia on FMD and GTN-induced dilatation. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent dilatation [induced with glyceryl trinitrate (GTN)] are impaired at high altitude (5050 m), and FMD is impaired after acute exposure (<60 min) to normobaric hypoxia equivalent to ∼5050 m (inspired oxygen fraction âˆ¼0.11). Whether GTN-induced dilatation is impaired acutely and whether FMD is impaired during milder hypoxia are unknown. Therefore, we assessed brachial FMD at baseline and after 30 min of mild (end-tidal PO2 74 ± 2 mmHg) and moderate (end-tidal PO2 50 ± 3 mmHg) normobaric hypoxia (n = 12) or normoxia (time-control trial; n = 10). We also assessed GTN-induced dilatation after the hypoxic FMD tests and in normoxia on a separate control day (n = 8). Compared with the normoxic baseline, reductions during mild and moderate hypoxic exposure were evident in FMD (mild versus moderate, -1.2 ± 1.1 versus -3.1 ± 1.7%; P = 0.01) and GTN-induced dilatation (-2.1 ± 1.0 versus -4.2 ± 2.0%; P = 0.01); the declines in FMD and GTN-induced dilatation were greater during moderate hypoxia (P < 0.01). When allometrically corrected for baseline diameter and FMD shear rate under the curve, FMD was attenuated in both conditions (mild versus moderate, 0.6 ± 0.9 versus 0.8 ± 0.7%; P ≤ 0.01). After 30 min of normoxic time control, FMD was reduced (-0.6 ± 0.3%; P = 0.02). In summary, there was a graded impairment in FMD during mild and moderate hypoxic exposure, which appears to be influenced by shear patterns and incremental decline in smooth muscle vasodilator capacity (impaired GTN-induced dilatation). Our findings from the normoxic control study suggest the decline in FMD in acute hypoxia also appears to be influenced by 30 min of supine rest/inactivity.

Elevations in Intra-cranial blood flow velocities following a SCUBA Dive and the Influence of Post-dive Exercise.

The effect that a SCUBA dive has on cerebral blood flow (CBF) at rest and during exercise is poorly understood. We examined the hypothesis that the altered hemodynamic parameters following a SCUBA dive will lead to differential changes in CBF at rest and during exercise. 16 divers completed a field-based study with a single dive at a depth of 18 m sea water with a 47-min bottom time. A follow-up laboratory based study was conducted - 1 week later. Intra-cranial velocities were measured with transcranial Doppler ultrasound (TCD) pre-dive, post-dive at rest and throughout incremental exercise until exhaustion. Following the dive at rest, middle cerebral artery velocity (MCAv) was elevated 15 and 30 min after surfacing (by 3.3±5.8 and 4.0±6.9 cm/s, respectively; p<0.05); posterior cerebral artery velocity (PCAv) was increased at 30 min after surfacing (by 3.0±4.5 cm/s; p<0.05). During exercise following the dive, both MCAv and PCAv increased up to 150W followed by a decrease towards baseline at 180W (p<0.05). We found no difference in CBV during exercise between field and laboratory studies (p<0.05). The novel finding of this study is the transient elevation in resting intra-cranial velocities within 30 min following a SCUBA dive.

Role of CO2 in the cerebral hyperemic response to incremental normoxic and hyperoxic exercise.

Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end-tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (V̇e) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While V̇ewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, V̇ewas increased to prevent PetCO2 from rising above resting values (∼40 mmHg). Although PetCO2 differed by 2 ± 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (∼12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (∼17-29%) were greater compared with poikilocapnic normoxia (∼8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2.

Influence of nocturnal and daytime sleep on initial orthostatic hypotension.

PURPOSE: The incidence of vasovagal syncope is more common in the morning. Previous researchers have reported negligible diurnal variation in the physiological responses associated with initial orthostatic hypotension (IOH). Nevertheless, physical activity and sleep prior to morning and afternoon test times have not been controlled and may influence the findings. We designed a semi-constant routine protocol to examine diurnal variation in cardiorespiratory and cerebrovascular responses to active standing. METHODS: At 06:00 and 16:00 hours, nine males (27 ± 9 years) completed an upright-stand protocol. Altimetry-measured sleep durations were 3.3 ± 0.4 and 3.2 ± 0.6 h immediately prior to the morning and afternoon test times. Continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial blood pressure (MAP), heart rate (HR), and end-tidal carbon dioxide were obtained. Intestinal body temperature and salivary melatonin concentrations were also measured. RESULTS: Compared with the afternoon, resting HR and body temperature were 4 ± 2 beats min(-1) and 0.45 ± 0.2 °C lower, respectively, whereas melatonin concentration was 28.7 ± 3.2 pg ml(-1) higher in the morning (P ≤ 0.02). Although all individuals experienced IOH at both times of the day, the initial decline in MAP during standing was 13 ± 4 mmHg greater in the afternoon (P = 0.01). Nevertheless, the decline in MCAv was comparable at both times of day (mean difference: 2 ± 3 cm s(-1); P = 0.5). CONCLUSION: These findings indicate that a bout of sleep in the afternoon in healthy young individuals results in greater IOH that is compensated for by effective cerebral blood flow regulation.

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

We examined the hypotheses that: (1) during incremental exercise and recovery following 4-6 days at high altitude (HA) global cerebral blood flow (gCBF) increases to preserve cerebral oxygen delivery (CDO2) in excess of that required by an increasing cerebral metabolic rate of oxygen ( CM RO2); (2) the trans-cerebral exchange of oxygen vs. carbohydrates (OCI; carbohydrates = glucose + ½lactate) would be similar during exercise and recovery at HA and sea level (SL). Global CBF, intra-cranial arterial blood velocities, extra-cranial blood flows, and arterial-jugular venous substrate differences were measured during progressive steady-state exercise (20, 40, 60, 80, 100% maximum workload (Wmax)) and through 30 min of recovery. Measurements (n = 8) were made at SL and following partial acclimatization to 5050 m. At HA, absolute Wmax was reduced by ∼50%. During submaximal exercise workloads (20-60% Wmax), despite an elevated absolute gCBF (∼20%, P < 0.05) the relative increases in gCBF were not different at HA and SL. In contrast, gCBF was elevated at HA compared with SL during 80 and 100% Wmax and recovery. Notwithstanding a maintained CDO2 and elevated absolute CM RO2 at HA compared with SL, the relative increase in CM RO2 was similar during 20-80% Wmax but half that of the SL response (i.e. 17 vs. 27%; P < 0.05 vs. SL) at 100% Wmax. The OCI was reduced at HA compared with SL during 20, 40, and 60% Wmax but comparable at 80 and 100% Wmax. At HA, OCI returned almost immediately to baseline values during recovery, whereas at SL it remained below baseline. In conclusion, the elevations in gCBF during exercise and recovery at HA serve to maintain CDO2. Despite adequate CDO2 at HA the brain appears to increase non-oxidative metabolism during exercise and recovery.

Fundamental relationships between blood pressure and cerebral blood flow in humans.

Cerebral blood flow responses to transient blood pressure challenges are frequently attributed to cerebral autoregulation (CA), yet accumulating evidence indicates vascular properties like compliance are also influential. We hypothesized that middle cerebral blood velocity (MCAv) dynamics during or following a transient blood pressure perturbation can be accurately explained by the windkessel mechanism. Eighteen volunteers underwent blood pressure manipulations, including bilateral thigh-cuff deflation and sit-to-stand maneuvers under normocapnic and hypercapnic (5% CO2) conditions. Pressure-flow recordings were analyzed using a windkessel analysis approach that partitions the frequency-dependent resistance and compliance contributions to MCAv dynamics. The windkessel was typically able to explain more than 50% of the MCAv variance, as indicated by R(2) values for both the flow recovery and postrecovery phase. The most consistent predictors of MCAv dynamics under the control condition were the windkessel capacitive gain and high-frequency resistive gain. However, there were significant interindividual variations in the composition of windkessel predictors. Hypercapnia consistently reduced the capacitive gain and enhanced the low-frequency (0.04-0.20 Hz) resistive gain for both thigh-cuff deflation and sit-to-stand trials. These findings indicate that 1) MCAv dynamics during acute transient hypotension challenges are dominated by cerebrovascular windkessel properties independent of CA; 2) there is significant heterogeneity in windkessel properties between individuals; and 3) hemodynamic effects of hypercapnia during transient blood pressure challenges primarily reflect changes in windkessel properties rather than pure CA impairment.

Influence of cerebrovascular resistance on the dynamic relationship between blood pressure and cerebral blood flow in humans.

We examined the hypothesis that changes in the cerebrovascular resistance index (CVRi), independent of blood pressure (BP), will influence the dynamic relationship between BP and cerebral blood flow in humans. We altered CVRi with (via controlled hyperventilation) and without [via indomethacin (INDO, 1.2 mg/kg)] changes in PaCO2. Sixteen subjects (12 men, 27 ± 7 yr) were tested on two occasions (INDO and hypocapnia) separated by >48 h. Each test incorporated seated rest (5 min), followed by squat-stand maneuvers to increase BP variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis (TFA). Beat-to-beat BP, middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv), and end-tidal Pco2 were monitored. Dynamic pressure-flow relations were quantified using TFA between BP and MCAv/PCAv in the very low and low frequencies through the driven squat-stand maneuvers at 0.05 and 0.10 Hz. MCAv and PCAv reductions by INDO and hypocapnia were well matched, and CVRi was comparably elevated (P < 0.001). During the squat-stand maneuvers (0.05 and 0.10 Hz), the point estimates of absolute gain were universally reduced, and phase was increased under both conditions. In addition to an absence of regional differences, our findings indicate that alterations in CVRi independent of PaCO2 can alter cerebral pressure-flow dynamics. These findings are consistent with the concept of CVRi being a key factor that should be considered in the correct interpretation of cerebral pressure-flow dynamics as indexed using TFA metrics.

Assessment of human baroreflex function using carotid ultrasonography: what have we learnt?

The arterial baroreflex is critical to both short- and long-term regulation of blood pressure. However, human baroreflex research has been largely limited to the association between blood pressure and cardiac period (or heart rate) or indices of vascular sympathetic function. Over the past decade, emerging techniques based on carotid ultrasound imaging have allowed new means of understanding and measuring the baroreflex. In this review, we describe the assessment of the mechanical and neural components of the baroreflex through the use of carotid ultrasound imaging. The mechanical component refers to the change in carotid artery diameter in response to changes in arterial pressure, and the neural component refers to the change in R-R interval (cardiac baroreflex) or muscle sympathetic nerve activity (sympathetic baroreflex) in response to this barosensory vessel stretch. The key analytical concepts and techniques are discussed, with a focus on the assessment of baroreflex sensitivity via the modified Oxford method. We illustrate how the application of carotid ultrasound imaging has contributed to a greater understanding of baroreflex physiology in humans, covering topics such as ageing and diurnal variation, and physiological challenges including exercise, postural changes and mental stress.

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.

Compression garments do not alter cerebrovascular responses to orthostatic stress after mild passive heating.

Whole-body heating increases the likelihood of syncope, whereas utilizing lower-body compression garments may reduce syncope risk. We hypothesized that graded compression garments would reduce the typically observed large postural reductions in arterial blood pressure and middle cerebral artery velocity, in normothermia and especially once passively heat stressed. Fifteen men (age: 27 ± 4 years, aerobic fitness range: 30-75 mL/kg(/) min) completed a supine-to-stand orthostatic challenge for 3 min at normothermia and after passive heating (esophageal temperature, +0.5 °C from baseline) on two occasions (> 7 days): once wearing commercially available compression trousers and once wearing low-compression placebo trousers (randomized order). Blood flow velocity in the middle cerebral artery (transcranial Doppler), mean arterial blood pressure (mean BP: Finometer) and end-tidal carbon dioxide pressure were measured continuously. During normothermia, compression, garments did not alter the magnitude of the postural changes in mean BP or middle cerebral artery velocity. After passive heating, although the magnitudes of these changes were exaggerated, they were not significantly affected by compression garments. Compression garments did not attenuate the initial or sustained orthostatic hypotension associated with posture change, either during normothermia or following passive heat stress.

Regional cerebral blood flow distribution during exercise: influence of oxygen.

We investigated regional changes in cerebral artery velocity during incremental exercise while breathing normoxia (21% O2), hyperoxia (100% O2) or hypoxia (16% O2) [n=10; randomized cross over design]. Middle cerebral and posterior cerebral arterial velocities (MCAv and PCAv) were measured continuously using transcranial Doppler ultrasound. At rest, only PCAv was reduced (-7%; P=0.016) with hyperoxia. During low-intensity exercise (40% workload maximum [Wmax]) MCAv (+17 cms(-1); +14cms(-1)) and PCAv (+9cms(-1); +14 cms(-1)) were increased above baseline with normoxia and hypoxia, respectively (P<0.05). The absolute increase from rest in MCAv was greater than the increase in PCAv between 40 and 80% Wmax with normoxia; this greater increase in MCAv was also evident at 60% Wmax with hypoxia and hyperoxia. Hyperoxic exercise resulted in larger absolute (+19 cms(-1)) and relative (+40%) increases in PCAv compared with normoxia. Our findings highlight the selective changes in PCAv during hyperoxic incremental exercise.

Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans.

We sought to determine the influence of sympathoexcitation on dynamic cerebral autoregulation (CA), cerebrovascular reactivity, and ventilatory control in humans at high altitude (HA). At sea level (SL) and following 3-10 days at HA (5,050 m), we measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined α- and ß-adrenergic blockade. Dynamic CA was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Ventilatory control was assessed from the hypercapnia and during isocapnic hypoxia. Arterial Pco(2) and ventilation and its control were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated (P < 0.01 vs. SL), but MCAv remained unchanged. Blockade reduced MAP more at HA than at SL (26 vs. 15%, P = 0.048). At HA, gain and coherence in the very-low-frequency (VLF) range (0.02-0.07 Hz) increased, and phase lead was reduced (all P < 0.05 vs. SL). Following blockade at SL, coherence was unchanged, whereas VLF phase lead was reduced (-40 ± 23%; P < 0.01). In contrast, blockade at HA reduced low-frequency coherence (-26 ± 20%; P = 0.01 vs. baseline) and elevated VLF phase lead (by 177 ± 238%; P < 0.01 vs. baseline), fully restoring these parameters back to SL values. Irrespective of this elevation in VLF gain at HA (P < 0.01), blockade increased it comparably at SL and HA (∼43-68%; P < 0.01). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced (P < 0.05) it comparably at SL and HA, effects we attributed to the hypotension and/or abolition of the hypercapnic-induced increase in MAP. With the exception of dynamic CA, we provide evidence of a redundant role of sympathetic nerve activity as a direct mechanism underlying changes in cerebrovascular reactivity and ventilatory control following partial acclimatization to HA. These findings have implications for our understanding of CBF function in the context of pathologies associated with sympathoexcitation and hypoxemia.

Assessment of cerebral autoregulation: the quandary of quantification.

We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n = 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n = 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n = 16) who underwent step changes in end-tidal P(CO2) (P(ET)(CO2) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in P(ET)(CO2) were positively related to coherence [LF: ß = 0.0065 arbitrary units (AU)/mmHg and VLF: ß = 0.011 AU/mmHg, both P < 0.01] and inversely related to phase (LF: ß = -0.026 rad/mmHg and VLF: ß = -0.018 rad/mmHg, both P < 0.01) and normalized gain (LF: ß = -0.042%/mmHg(2) and VLF: ß = -0.013%/mmHg(2), both P < 0.01). However, Pet(CO(2)) was positively associated with gain (LF: ß = 0.0070 cm·s(-1)·mmHg(-2), P < 0.05; and VLF: ß = 0.014 cm·s(-1)·mmHg(-2), P < 0.01). Thus, during changes in P(ET)(CO2), LF phase was inversely related to LF gain (ß = -0.29 cm·s(-1)·mmHg(-1)·rad(-1), P < 0.01) but positively related to LF normalized gain (ß = 1.3% mmHg(-1)/rad, P < 0.01). These findings collectively suggest that only select CA metrics can be used interchangeably and that interpretation of these measures should be done cautiously.

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

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.

Aging blunts hyperventilation-induced hypocapnia and reduction in cerebral blood flow velocity during maximal exercise.

Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO(2peak)) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO(2peak). In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO(2peak). Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA V (mean); transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO(2) (P(ET)CO(2)) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO(2peak), despite greater elevations in BP in OA, the change in MCA V(mean) was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO(2peak), the hyperventilation-induced declines in both P(ET)CO(2) (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA V(mean) (-21% (YA) vs. -7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO(2peak)), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.