Steady-state chemoreflex drive captures ventilatory acclimatization during incremental ascent to high altitude: Effect of acetazolamide.

Ventilatory acclimatization (VA) is important to maintain adequate oxygenation with ascent to high altitude (HA). Transient hypoxic ventilatory response tests lack feasibility and fail to capture the integrated steady-state responses to chronic hypoxic exposure in HA fieldwork. We recently characterized a novel index of steady-state respiratory chemoreflex drive (SSCD), accounting for integrated contributions from central and peripheral respiratory chemoreceptors during steady-state breathing at prevailing chemostimuli. Acetazolamide is often utilized during ascent for prevention or treatment of altitude-related illnesses, eliciting metabolic acidosis and stimulating respiratory chemoreceptors. To determine if SSCD reflects VA during ascent to HA, we characterized SSCD in 25 lowlanders during incremental ascent to 4240 m over 7 days. We subsequently compared two separate subgroups: no acetazolamide (NAz; n = 14) and those taking an oral prophylactic dose of acetazolamide (Az; 125 mg BID; n = 11). At 1130/1400 m (day zero) and 4240 m (day seven), steady-state measurements of resting ventilation (V̇I ; L/min), pressure of end-tidal (PET )CO2 (Torr), and peripheral oxygen saturation (SpO2 ; %) were measured. A stimulus index (SI; PET CO2 /SpO2 ) was calculated, and SSCD was calculated by indexing V̇I against SI. We found that (a) both V̇I and SSCD increased with ascent to 4240 m (day seven; V̇I : +39%, p < 0.0001, Hedges' g = 1.52; SSCD: +56.%, p < 0.0001, Hedges' g = 1.65), (b) and these responses were larger in the Az versus NAz subgroup (V̇I : p = 0.02, Hedges' g = 1.04; SSCD: p = 0.02, Hedges' g = 1.05). The SSCD metric may have utility in assessing VA during prolonged stays at altitude, providing a feasible alternative to transient chemoreflex tests.

Variation within the visually evoked neurovascular coupling response of the posterior cerebral artery is not influenced by age or sex.

Neurovascular coupling (NVC) is the temporal and spatial coordination between local neuronal activity and regional cerebral blood flow. The literature is unsettled on whether age and/or sex affect NVC, which may relate to differences in methodology and the quantification of NVC in small sample-sized studies. The aim of this study was to 1) determine the relative and combined contribution of age and sex to the variation observed across several distinct NVC metrics (n = 125, 21-66 yr; 41 males) and 2) present an approach for the comprehensive systematic assessment of the NVC response using transcranial Doppler ultrasound. NVC was measured as the relative change from baseline (absolute and percent change) assessing peak, mean, and total area under the curve (tAUC) of cerebral blood velocity through the posterior cerebral artery (PCAv) during intermittent photic stimulation. In addition, the NVC waveform was compartmentalized into distinct regions, acute (0-9 s), mid (10-19 s), and late (20-30 s), following the onset of photic stimulation. Hierarchical multiple regression modeling was used to determine the extent of variation within each NVC metric attributable to demographic differences in age and sex. After controlling for differences in baseline PCAv, the R2 data suggest that 1.6%, 6.1%, 1.1%, 3.4%, 2.5%, and 4.2% of the variance observed within mean, peak, tAUC, acute, mid, and late response magnitude is attributable to the combination of age and sex. Our study reveals that variability in NVC response magnitude is independent of age and sex in healthy human participants, aged 21-66 yr.NEW & NOTEWORTHY We assessed the variability within the neurovascular coupling response attributable to age and sex (n = 125, 21-66 yr; 41 male). Based on the assessment of posterior cerebral artery responses to visual stimulation, 0%-6% of the variance observed within several metrics of NVC response magnitude are attributable to the combination of age and sex. Therefore, observed differences between age groups and/or sexes are likely a result of other physiological factors.

Severity of central sleep apnea does not affect sleeping oxygen saturation during ascent to high altitude.

Central sleep apnea (CSA) is characterized by periodic breathing (PB) during sleep, defined as intermittent periods of apnea/hypopnea and hyperventilation, with associated acute fluctuations in oxyhemoglobin saturation (SO2). CSA has an incidence of ∼50% in heart failure patients but is universal at high altitude (HA; ≥2,500 m), increasing in severity with further ascent and/or time at altitude. However, whether PB is adaptive, maladaptive, or neutral with respect to sleeping SO2 at altitude is unclear. We hypothesized that PB severity would improve mean sleeping SO2 during acclimatization to HA due to relative, intermittent hyperventilation subsequent to each apnea. We utilized portable sleep monitors to assess the incidence and severity of CSA via apnea-hypopnea index (AHI) and oxygen desaturation index (ODI), and peripheral oxygen saturation ([Formula: see text]) during sleep during two ascent profiles to HA in native lowlanders: 1) rapid ascent to and residence at 3,800 m for 9 days/nights (n = 21) and 2) incremental ascent to 5,160 m over 10 days/nights (n = 21). In both ascent models, severity of AHI and ODI increased and mean sleeping [Formula: see text] decreased, as expected. However, during sleep on the last night/highest altitude of both ascent profiles, neither AHI nor ODI were correlated with mean sleeping [Formula: see text]. In addition, mean sleeping [Formula: see text] was not significantly different between high and low CSA. These data suggest that CSA is neither adaptive nor maladaptive with regard to mean oxygen saturation during sleep, owing to the relative hyperventilation between apneas, likely correcting transient apnea-mediated oxygen desaturation and maintaining mean oxygenation.NEW & NOTEWORTHY Central sleep apnea (CSA) is universal during ascent to high altitude, with intermittent and transient fluctuations in oxygen saturation, but the consequences on mean sleeping blood oxygenation are unclear. We assessed indices of CSA and mean sleeping peripheral oxygen saturation ([Formula: see text]) during ascent to high altitude using two ascent profiles: rapid ascent and residence at 3,800 m and incremental ascent to 5,160 m. The severity of CSA was not correlated with mean sleeping [Formula: see text] with ascent.

Swallow-breathing coordination during incremental ascent to altitude.

Swallow and breathing are highly coordinated behaviors reliant on shared anatomical space and neural pathways. Incremental ascent to high altitudes results in hypoxia/hypocapnic conditions altering respiratory drive, however it is not known whether these changes also alter swallow. We examined the effect of incremental ascent (1045 m, 3440 m and 4371 m) on swallow motor pattern and swallow-breathing coordination in seven healthy adults. Submental surface electromyograms (sEMG) and spirometry were used to evaluate swallow triggered by saliva and water infusion. Swallow-breathing phase preference was different between swallows initiated by saliva versus water. With ascent, saliva swallows changed to a dominate pattern of occurrence during the transition from inspiration to expiration. Additionally, water swallows demonstrated a significant decrease in submental sEMG duration and a shift in submental activity to earlier in the apnea period, especially at 4371 m. Our results suggest that there are changes in swallow-breathing coordination and swallow production that likely increase airway protection with incremental ascent to high altitude. The adaptive changes in swallow were likely due to the exposure to hypoxia and hypocapnia, along with airway irritation.

Peripheral chemoreceptor deactivation attenuates the sympathetic response to glucose ingestion.

Acute increases in blood glucose are associated with heightened muscle sympathetic nerve activity (MSNA). Animal studies have implicated a role for peripheral chemoreceptors in this response, but this has not been examined in humans. Heart rate, cardiac output (CO), mean arterial pressure, total peripheral conductance, and blood glucose concentrations were collected in 11 participants. MSNA was recorded in a subset of 5 participants via microneurography. Participants came to the lab on 2 separate days (i.e., 1 control and 1 experimental day). On both days, participants ingested 75 g of glucose following baseline measurements. On the experimental day, participants breathed 100% oxygen for 3 min at baseline and again at 20, 40, and 60 min after glucose ingestion to deactivate peripheral chemoreceptors. Supplemental oxygen was not given to participants on the control day. There was a main effect of time on blood glucose (P < 0.001), heart rate (P < 0.001), CO (P < 0.001), sympathetic burst frequency (P < 0.001), burst incidence (P = 0.01), and total MSNA (P = 0.001) for both days. Blood glucose concentrations and burst frequency were positively correlated on the control day (r = 0.42; P = 0.03) and experimental day (r = 0.62; P = 0.003). There was a time × condition interaction (i.e., normoxia vs. hyperoxia) on burst frequency, in which hyperoxia significantly blunted burst frequency at 20 and 60 min after glucose ingestion only. Given that hyperoxia blunted burst frequency only during hyperglycemia, our results suggest that the peripheral chemoreceptors are involved in activating MSNA after glucose ingestion.