Cerebral uptake of microvesicles occurs in normocapnic but not hypocapnic passive hyperthermia in young healthy male adults.

Passive hyperthermia causes cerebral hypoperfusion primarily from heat-induced respiratory alkalosis. However, despite the cerebral hypoperfusion, it is possible that the mild alkalosis might help to attenuate cerebral inflammation. In this study, the cerebral exchange of extracellular vesicles (microvesicles), which are known to elicit pro-inflammatory responses when released in conditions of stress, were examined in hyperthermia with and without respiratory alkalosis. Ten healthy male adults were heated passively, using a warm water-perfused suit, up to core temperature + 2°C. Blood samples were taken from the radial artery and internal jugular bulb. Microvesicle concentrations were determined in platelet-poor plasma via cells expressing CD62E (activated endothelial cells), CD31+ /CD42b- (apoptotic endothelial cells), CD14 (monocytes) and CD45 (pan-leucocytes). Cerebral blood flow was measured via duplex ultrasound of the internal carotid and vertebral arteries to determine cerebral exchange kinetics. From baseline to poikilocapnic (alkalotic) hyperthermia, there was no change in microvesicle concentration from any cell origin measured (P-values all >0.05). However, when blood CO2 tension was normalized to baseline levels in hyperthermia, there was a marked increase in cerebral uptake of microvesicles expressing CD62E (P = 0.028), CD31+ /CD42b- (P = 0.003) and CD14 (P = 0.031) compared with baseline, corresponding to large increases in arterial but not jugular venous concentrations. In a subset of seven participants who underwent hypercapnia and hypocapnia in the absence of heating, there was no change in microvesicle concentrations or cerebral exchange, suggesting that hyperthermia potentiated the CO2 /pH-mediated cerebral uptake of microvesicles. These data provide insight into a potential beneficial role of respiratory alkalosis in heat stress. KEY POINTS: The hyperthermia-induced hyperventilatory response is observed in most humans, despite causing potentially harmful reductions in cerebral blood flow. We tested the hypothesis that the respiratory-induced alkalosis is associated with lower circulating microvesicle concentrations, specifically in the brain, despite the reductions in blood flow. At core temperature + 2°C with respiratory alkalosis, microvesicles derived from endothelial cells, monocytes and leucocytes were at concentrations similar to baseline in the arterial and cerebral venous circulation, with no changes in cross-brain microvesicle kinetics. However, when core temperature was increased by 2°C with CO2 /pH normalized to resting levels, there was a marked cerebral uptake of microvesicles derived from endothelial cells and monocytes. The CO2 /pH-mediated alteration in cerebral microvesicle uptake occurred only in hyperthermia. These new findings suggest that the heat-induced hyperventilatory response might serve a beneficial role by preventing potentially inflammatory microvesicle uptake in the brain.

Negligible influence of moderate to severe hyperthermia on blood-brain barrier permeability and neuronal parenchymal integrity in healthy men.

With growing use for hyperthermia as a cardiovascular therapeutic, there is surprisingly little information regarding the acute effects it may have on the integrity of the neurovascular unit (NVU). Indeed, relying on animal data would suggest hyperthermia comparable to levels attained in thermal therapy will disrupt the blood-brain barrier (BBB) and damage the cerebral parenchymal cells. We sought to address the hypothesis that controlled passive hyperthermia is not sufficient to damage the NVU in healthy humans. Young men (n = 11) underwent acute passive heating until +2°C or absolute esophageal temperature of 39.5°C. The presence of BBB opening was determined by trans-cerebral exchange kinetics (radial-arterial and jugular venous cannulation) of S100B. Neuronal parenchymal damage was determined by the trans-cerebral exchange of tau protein, neuron-specific enolase (NSE), and neurofilament-light protein (NF-L). Cerebral blood flow to calculate exchange kinetics was measured by duplex ultrasound of the right internal carotid and left vertebral artery. Passive heating was performed via a warm-water perfused suit. In hyperthermia, there was no increase in the cerebral exchange of S100B (P = 0.327), tau protein (P = 0.626), NF-L (P = 0.447), or NSE (P = 0.908) suggesting the +2°C core temperature is not sufficient to acutely stress the NVU in healthy men. However, there was a significant condition effect (P = 0.028) of NSE, corresponding to a significant increase in arterial (P = 0.023) but not venous (P = 0.173) concentrations in hyperthermia, potentially indicating extra-cerebral release of NSE. Collectively, results from the present study support the notion that in young men there is little concern for NVU damage with acute hyperthermia of +2 °C.NEW & NOTEWORTHY The acute effects of passive whole-body hyperthermia on the integrity of the neurovascular unit (NVU) in humans have remained unclear. We demonstrate that passive heating for ∼1 h until an increase of +2°C esophageal temperature in healthy men does not increase the cerebral release of neuronal parenchymal stress biomarkers, suggesting the NVU integrity is maintained. This preliminary study indicates passive heating is safe for the brain, at least in young healthy men.