Anthony R. Bain

Large differences in peak oxygen uptake do not independently alter changes in core temperature and sweating during exercise.

The independent influence of peak oxygen uptake (Vo(₂ peak)) on changes in thermoregulatory responses during exercise in a neutral climate has not been previously isolated because of complex interactions between Vo(₂ peak), metabolic heat production (H(prod)), body mass, and body surface area (BSA). It was hypothesized that Vo(₂ peak) does not independently alter changes in core temperature and sweating during exercise. Fourteen males, 7 high (HI) Vo(₂ peak): 60.1 ± 4.5 ml·kg⁻¹·min⁻¹; 7 low (LO) Vo(₂ peak): 40.3 ± 2.9 ml·kg⁻¹·min⁻¹ matched for body mass (HI: 78.2 ± 6.1 kg; LO: 78.7 ± 7.1 kg) and BSA (HI: 1.97 ± 0.08 m²; LO: 1.94 ± 0.08 m²), cycled for 60-min at 1) a fixed heat production (FHP trial) and 2) a relative exercise intensity of 60% Vo(₂ peak) (REL trial) at 24.8 ± 0.6°C, 26 ± 10% RH. In the FHP trial, H(prod) was similar between the HI (542 ± 38 W, 7.0 ± 0.6 W/kg or 275 ± 25 W/m²) and LO (535 ± 39 W, 6.9 ± 0.9 W/kg or 277 ± 29 W/m²) groups, while changes in rectal (T(re): HI: 0.87 ± 0.15°C, LO: 0.87 ± 0.18°C, P = 1.00) and aural canal (T(au): HI: 0.70 ± 0.12°C, LO: 0.74 ± 0.21°C, P = 0.65) temperature, whole-body sweat loss (WBSL) (HI: 434 ± 80 ml, LO: 440 ± 41 ml; P = 0.86), and steady-state local sweating (LSR(back)) (P = 0.40) were all similar despite relative exercise intensity being different (HI: 39.7 ± 4.2%, LO: 57.6 ± 8.0% Vo(2 peak); P = 0.001). At 60% Vo(2 peak), H(prod) was greater in the HI (834 ± 77 W, 10.7 ± 1.3 W/kg or 423 ± 44 W/m²) compared with LO (600 ± 90 W, 7.7 ± 1.4 W/kg or 310 ± 50 W/m²) group (all P < 0.001), as were changes in T(re) (HI: 1.43 ± 0.28°C, LO: 0.89 ± 0.19°C; P = 0.001) and T(au) (HI: 1.11 ± 0.21°C, LO: 0.66 ± 0.14°C; P < 0.001), and WBSL between 0 and 15, 15 and 30, 30 and 45, and 45 and 60 min (all P < 0.01), and LSR(back) (P = 0.02). The absolute esophageal temperature (T(es)) onset for sudomotor activity was ∼0.3°C lower (P < 0.05) in the HI group, but the change in T(es) from preexercise values before sweating onset was similar between groups. Sudomotor thermosensitivity during exercise were similar in both FHP (P = 0.22) and REL (P = 0.77) trials. In conclusion, changes in core temperature and sweating during exercise in a neutral climate are determined by H(prod), mass, and BSA, not Vo(₂ peak).

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.

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.

Regulation of brain blood flow and oxygen delivery in elite breath-hold divers

The roles of involuntary breathing movements (IBMs) and cerebral oxygen delivery in the tolerance to extreme hypoxemia displayed by elite breath-hold divers are unknown. Cerebral blood flow (CBF), arterial blood gases (ABGs), and cardiorespiratory metrics were measured during maximum dry apneas in elite breath-hold divers (n=17). To isolate the effects of apnea and IBM from the concurrent changes on ABG, end-tidal forcing (‘clamp’) was then used to replicate an identical temporal pattern of decreasing arterial PO2 (PaO2) and increasing arterial PCO2 (PaCO2) while breathing. End-apnea PaO2 ranged from 23  to 37 mm Hg (30±7 mm Hg). Elevation in mean arterial pressure was greater during apnea than during clamp reaching +54±24% versus 34±26%, respectively; however, CBF increased similarly between apnea and clamp (93.6±28% and 83.4±38%, respectively). This latter observation indicates that during the overall apnea period IBM per se do not augment CBF and that the brain remains sufficiently protected against hypertension. Termination of apnea was not determined by reduced cerebral oxygen delivery; despite 40% to 50% reductions in arterial oxygen content, oxygen delivery was maintained by commensurately increased CBF.

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.

Cerebral Vascular Control and Metabolism in Heat Stress

This review provides an in-depth update on the impact of heat stress on cerebrovascular functioning. The regulation of cerebral temperature, blood flow, and metabolism are discussed. We further provide an overview of vascular permeability, the neurocognitive changes, and the key clinical implications and pathologies known to confound cerebral functioning during hyperthermia. A reduction in cerebral blood flow (CBF), derived primarily from a respiratory-induced alkalosis, underscores the cerebrovascular changes to hyperthermia. Arterial pressures may also become compromised because of reduced peripheral resistance secondary to skin vasodilatation. Therefore, when hyperthermia is combined with conditions that increase cardiovascular strain, for example, orthostasis or dehydration, the inability to preserve cerebral perfusion pressure further reduces CBF. A reduced cerebral perfusion pressure is in turn the primary mechanism for impaired tolerance to orthostatic challenges. Any reduction in CBF attenuates the brains convective heat loss, while the hyperthermic-induced increase in metabolic rate increases the cerebral heat gain. This paradoxical uncoupling of CBF to metabolism increases brain temperature, and potentiates a condition whereby cerebral oxygenation may be compromised. With levels of experimentally viable passive hyperthermia (up to 39.5-40.0 °C core temperature), the associated reduction in CBF (∼ 30%) and increase in cerebral metabolic demand (∼ 10%) is likely compensated by increases in cerebral oxygen extraction. However, severe increases in whole-body and brain temperature may increase blood-brain barrier permeability, potentially leading to cerebral vasogenic edema. The cerebrovascular challenges associated with hyperthermia are of paramount importance for populations with compromised thermoregulatory control--for example, spinal cord injury, elderly, and those with preexisting cardiovascular diseases.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance

Vasovagal syncope (a common form of fainting) is frequently associated with excessive breathing and leads to reductions in carbon dioxide (hypocapnia) and cerebral hypoperfusion. The prevention of hypocapnia during orthostatic stress has been shown to improve orthostatic tolerance, but it still remains to be quantified in a larger population, with a more sustained orthostatic stress. Resting brain blood flow has been shown to impact orthostatic tolerance; however, the importance of resting brain blood flow per se in the pathophysiology of vasovagal syncope has not been clearly explicated. Our findings show that cerebral hypoperfusion either at rest or induced by hypocapnia at pre‐syncope do not impact on orthostatic tolerance, probably due to a compensatory increase in oxygen extraction of the brain.

Cerebral oxygenation and hyperthermia.

Hyperthermia is associated with marked reductions in cerebral blood flow (CBF). Increased distribution of cardiac output to the periphery, increases in alveolar ventilation and resultant hypocapnia each contribute to the fall in CBF during passive hyperthermia; however, their relative contribution remains a point of contention, and probably depends on the experimental condition (e.g., posture and degree of hyperthermia). The hyperthermia-induced hyperventilatory response reduces arterial CO2 pressure (PaCO2) causing cerebral vasoconstriction and subsequent reductions in flow. During supine passive hyperthermia, the majority of recent data indicate that reductions in PaCO2 may be the primary, if not sole, culprit for reduced CBF. On the other hand, during more dynamic conditions (e.g., hemorrhage or orthostatic challenges), an inability to appropriately decrease peripheral vascular conductance presents a condition whereby adequate cerebral perfusion pressure may be compromised secondary to reductions in systemic blood pressure. Although studies have reported maintenance of pre-frontal cortex oxygenation (assessed by near-infrared spectroscopy) during exercise and severe heat stress, the influence of cutaneous blood flow is known to contaminate this measure. This review discusses the governing mechanisms associated with changes in CBF and oxygenation during moderate to severe (i.e., 1.0°C to 2.0°C increase in body core temperature) levels of hyperthermia. Future research directions are provided.

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.