Jui-Lin Fan

Human cardiorespiratory and cerebrovascular function during severe passive hyperthermia: effects of mild hypohydration

The influence of severe passive heat stress and hypohydration (Hypo) on cardiorespiratory and cerebrovascular function is not known. We hypothesized that 1) heating-induced hypocapnia and peripheral redistribution of cardiac output (Q) would compromise blood flow velocity in the middle cerebral artery (MCAv) and cerebral oxygenation; 2) Hypo would exacerbate the hyperthermic-induced hypocapnia, further decreasing MCAv; and 3) heating would reduce MCAv-CO2 reactivity, thereby altering ventilation. Ten men, resting supine in a water-perfused suit, underwent progressive hyperthermia [0.5 degrees C increments in core (esophageal) temperature (TC) to +2 degrees C] while euhydrated (Euh) or Hypo by 1.5% body mass (attained previous evening). Time-control (i.e., non-heat stressed) data were obtained on six of these subjects. Cerebral oxygenation (near-infrared spectroscopy), MCAv, end-tidal carbon dioxide (PetCO2) and arterial blood pressure, Q (flow model), and brachial and carotid blood flows (CCA) were measured continuously each 0.5 degrees C change in TC. At each level, hypercapnia was achieved through 3-min administrations of 5% CO2, and hypocapnia was achieved with controlled hyperventilation. At baseline in Hypo, heart rate, MCAv and CCA were elevated (P<0.05 vs. Euh). MCAv-CO2 reactivity was unchanged in both groups at all TC levels. Independent of hydration, hyperthermic-induced hyperventilation caused a severe drop in PetCO2 (-8+/-1 mmHg/ degrees C), which was related to lower MCAv (-15+/-3%/ degrees C; R2=0.98; P<0.001). Elevations in Q were related to increases in brachial blood flow (R2=0.65; P<0.01) and reductions in MCAv (R2=0.70; P<0.01), reflecting peripheral distribution of Q. Cerebral oxygenation was maintained, presumably via enhanced O2-extraction or regional differences in cerebral perfusion.

Alterations in cerebral blood flow and cerebrovascular reactivity during 14 days at 5050 m

Brain blood flow increases during the first week of living at high altitude. We do not understand completely what causes the increase or how the factors that regulate brain blood flow are affected by the high‐altitude environment. Our results show that the balance of oxygen (O2) and carbon dioxide (CO2) pressures in arterial blood explains 40% of the change in brain blood flow upon arrival at high altitude (5050 m). We also show that blood vessels in the brain respond to increases and decreases in CO2 differently at high altitude compared to sea level, and that this can affect breathing responses as well. These results help us to better understand the regulation of brain blood flow at high altitude and are also relevant to diseases that are accompanied by reductions in the pressure of oxygen in the blood.

Cerebrovascular and corticomotor function during progressive passive hyperthermia in humans

The present study examined the integrative effects of passive heating on cerebral perfusion and alterations in central motor drive. Eight participants underwent passive hyperthermia [0.5°C increments in core temperature (Tc) from normothermia (37 ± 0.3°C) to their limit of thermal tolerance (T-LIM; 39.0 ± 0.4°C)]. Blood flow velocity in the middle cerebral artery (CBFv) and respiratory responses were measured continuously. Arterial blood gases and blood pressure were obtained intermittently. At baseline and each Tc level, supramaximal femoral nerve stimulation and transcranial magnetic stimulation (TMS) were performed to assess neuromuscular and cortical function, respectively. At T-LIM, measures were (in a randomized order) also made during a period of breathing 5% CO(2) gas to restore eucapnia (+5% CO(2)). Mean heating time was 179 ± 51 min, with each 0.5°C increment in Tc taking 40 ± 10 min. CBFv was reduced by ∼20% below baseline from +0.5°C until T-LIM. Maximal voluntary contraction (MVC) of the knee extensors was decreased at T-LIM (-9 ± 10%; P < 0.05), and cortical voluntary activation (VA), assessed by TMS, was decreased at +1.5°C and T-LIM by 11 ± 8 and 22 ± 23%, respectively (P < 0.05). Corticospinal excitability (measured as the EMG response produced by TMS) was unaltered. Reductions in cortical VA were related to changes in ventilation (Ve; R(2) = 0.76; P < 0.05) and partial pressure of end-tidal CO(2) (Pet(CO(2)); R(2) = 0.63; P < 0.05) and to changes in CBFv (R(2) = 0.61; P = 0.067). Interestingly, although CBFv was not fully restored, MVC and cortical VA were restored towards baseline values during inhalation of 5% CO(2). These results indicate that descending voluntary drive becomes progressively impaired as Tc is increased, presumably due, in part, to reductions in CBFv and to hyperthermia-induced hyperventilation and subsequent hypocapnia.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery

What is the central question of this study? Hypoxia associated with ascent to high altitude may threaten cerebral oxygen delivery. We sought to determine whether there are regional changes in the distribution of cerebral blood flow that might favour oxygen delivery to areas associated with basic homeostatic functions to promote survival in this extreme environment. What is the main finding and its importance? We show evidence of a ‘brain‐sparing’ effect during acute exposure to high altitude, in which there is a slight increase in relative oxygen delivery to the posterior cerebral circulation. This may serve to support basic regulatory functions associated with the brainstem and hypothalamus.

Effects of acetazolamide on cerebrovascular function and breathing stability at 5050 m

•  Acetazolamide improves breathing stability during sleep in newcomers to high altitude, but the mechanism remains unclear. •  We examined the effects of a single i.v. dose of acetazolamide on brain vascular function and breathing at sea level and following 7 days at high altitude (5050 m). •  We demonstrated that acute i.v. acetazolamide at high altitude enhances the brain blood flow response to changes in CO2 and improves breathing stability. •  We speculate that the enhanced brain blood flow responses following acetazolamide ingestion may account for the well‐documented acetazolamide‐induced improvement in abnormal breathing at high altitude.

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 β-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.

AltitudeOmics: cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness

Cerebral autoregulation (CA) acts to maintain brain blood flow despite fluctuations in perfusion pressure. Acute hypoxia is thought to impair CA, but it is unclear if CA is affected by acclimatization or related to the development of acute mountain sickness (AMS). We assessed changes in CA using transfer function analysis of spontaneous fluctuations in radial artery blood pressure (indwelling catheter) and resulting changes in middle cerebral artery blood flow velocity (transcranial Doppler) in 21 active individuals at sea level upon arrival at 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon re-exposure to 5,260 m after 7 days at 1,525 m (POST7). The Lake Louise Questionnaire was used to evaluate AMS symptom severity. CA was impaired upon arrival at ALT1 (P < 0.001) and did not change with acclimatization at ALT16 or upon re-exposure at POST7. CA was not associated with AMS symptoms (all R < 0.50, P > 0.05). These findings suggest that alterations in CA are an intrinsic consequence of hypoxia and are not directly related to the occurrence or severity of AMS.

Cerebrovascular reactivity and dynamic autoregulation in tetraplegia

Humans with spinal cord injury have impaired cardiovascular function proportional to the level and completeness of the lesion. The effect on cerebrovascular function is unclear, especially for high-level lesions. The purpose of this study was to evaluate the integrity of dynamic cerebral autoregulation (CA) and the cerebrovascular reactivity in chronic tetraplegia (Tetra). After baseline, steady-state hypercapnia (5% CO(2)) and hypocapnia (controlled hyperventilation) were used to assess cerebrovascular reactivity in 6 men with Tetra (C5-C7 lesion) and 14 men without [able-bodied (AB)]. Middle cerebral artery blood flow velocity (MCAv), cerebral oxygenation, arterial blood pressure (BP), heart rate (HR), cardiac output (Q; model flow), partial pressure of end-tidal CO(2) (Pet(CO(2))), and plasma catecholamines were measured. Dynamic CA was assessed by transfer function analysis of spontaneous fluctuations in BP and MCAv. MCAv pulsatility index (MCAv PI) was calculated as (MCAv(systolic) - MCAv(diastolic))/MCAv(mean) and standardized by dividing by mean arterial pressure (MAP). Resting BP, total peripheral resistance, and catecholamines were lower in Tetra (P < 0.05), and standardized MCAv PI was approximately 36% higher in Tetra (P = 0.003). Resting MCAv, cerebral oxygenation, HR, and Pet(CO(2)) were similar between groups (P > 0.05). Although phase and transfer function gain relationships in dynamic CA were maintained with Tetra (P > 0.05), coherence in the very low-frequency range (0.02-0.07 Hz) was approximately 21% lower in Tetra (P = 0.006). Full (hypo- and hypercapnic) cerebrovascular reactivity to CO(2) was unchanged with Tetra (P > 0.05). During hypercapnia, standardized MCAv PI reactivity was enhanced by approximately 78% in Tetra (P = 0.016). Despite impaired cardiovascular function, chronic Tetra involves subtle changes in dynamic CA and cerebrovascular reactivity to CO(2). Changes are evident in coherence at baseline and MCAv PI during baseline and hypercapnic states in chronic Tetra, which may be indicative of cerebrovascular adaptation.

AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure

The present study is the first to examine the effect of high-altitude acclimatization and reexposure on the responses of cerebral blood flow and ventilation to CO2. We also compared the steady-state estimates of these parameters during acclimatization with the modified rebreathing method. We assessed changes in steady-state responses of middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), and ventilation (V(E)) to varied levels of CO2 in 21 lowlanders (9 women; 21 ± 1 years of age) at sea level (SL), during initial exposure to 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon reexposure to altitude following either 7 (POST7) or 21 days (POST21) at low altitude (1,525 m). In the nonacclimatized state (ALT1), MCAv and V(E) responses to CO2 were elevated compared with those at SL (by 79 ± 75% and 14.8 ± 12.3 l/min, respectively; P = 0.004 and P = 0.011). Acclimatization at ALT16 further elevated both MCAv and Ve responses to CO2 compared with ALT1 (by 89 ± 70% and 48.3 ± 32.0 l/min, respectively; P < 0.001). The acclimatization gained for V(E) responses to CO2 at ALT16 was retained by 38% upon reexposure to altitude at POST7 (P = 0.004 vs. ALT1), whereas no retention was observed for the MCAv responses (P > 0.05). We found good agreement between steady-state and modified rebreathing estimates of MCAv and V(E) responses to CO2 across all three time points (P < 0.001, pooled data). Regardless of the method of assessment, altitude acclimatization elevates both the cerebrovascular and ventilatory responsiveness to CO2. Our data further demonstrate that this enhanced ventilatory CO2 response is partly retained after 7 days at low altitude.

The effect of adding CO2 to hypoxic inspired gas on cerebral blood flow velocity and breathing during incremental exercise.

Hypoxia increases the ventilatory response to exercise, which leads to hyperventilation-induced hypocapnia and subsequent reduction in cerebral blood flow (CBF). We studied the effects of adding CO2 to a hypoxic inspired gas on CBF during heavy exercise in an altitude naïve population. We hypothesized that augmented inspired CO2 and hypoxia would exert synergistic effects on increasing CBF during exercise, which would improve exercise capacity compared to hypocapnic hypoxia. We also examined the responsiveness of CO2 and O2 chemoreception on the regulation ventilation (E) during incremental exercise. We measured middle cerebral artery velocity (MCAv; index of CBF), E, end-tidal PCO2, respiratory compensation threshold (RC) and ventilatory response to exercise (E slope) in ten healthy men during incremental cycling to exhaustion in normoxia and hypoxia (FIO2 = 0.10) with and without augmenting the fraction of inspired CO2 (FICO2). During exercise in normoxia, augmenting FICO2 elevated MCAv throughout exercise and lowered both RC onset andE slope below RC (P<0.05). In hypoxia, MCAv and E slope below RC during exercise were elevated, while the onset of RC occurred at lower exercise intensity (P<0.05). Augmenting FICO2 in hypoxia increased E at RC (P<0.05) but no difference was observed in RC onset, MCAv, or E slope below RC (P>0.05). The E slope above RC was unchanged with either hypoxia or augmented FICO2 (P>0.05). We found augmenting FICO2 increased CBF during sub-maximal exercise in normoxia, but not in hypoxia, indicating that the ‘normal’ cerebrovascular response to hypercapnia is blunted during exercise in hypoxia, possibly due to an exhaustion of cerebral vasodilatory reserve. This finding may explain the lack of improvement of exercise capacity in hypoxia with augmented CO2. Our data further indicate that, during exercise below RC, chemoreception is responsive, while above RC the ventilatory response to CO2 is blunted.