Validation of Polar ElixirTM Pulse Oximeter against Arterial Blood Gases during Stepwise Steady State Inspired Hypoxia.

PURPOSE: The purpose of this study was to evaluate the accuracy of peripheral oxygen saturation (SpO2) measurements from Polar ElixirTM pulse oximetry technology compared to arterial oxygen saturation (SaO2) measurements during acute stepwise steady state inspired hypoxia at rest. A post hoc objective was to determine if SpO2 measurements could be improved by recalibrating the Polar ElixirTM algorithm with SaO2 values from a random subset of participants. METHODS: The International Organization for Standardization (ISO) protocol (ISO 80601-2-61:2017) for evaluating the SpO2 accuracy of pulse oximeter equipment was followed whereby five plateaus of SaO2 between 70-100% were achieved using stepwise reductions in inspired O2 during supine rest. Blood samples drawn through a radial arterial catheter from 25 participants were first used to compare SaO2 to SpO2 measurements from Polar ElixirTM. Then the Polar ElixirTM algorithm was recalibrated using SaO2 data from 13 random participants and SpO2 estimates were recalculated for the other 12 participants. For SaO2 values between 70-100%, root mean square error (RMSE), intraclass correlations (ICC), Pearson correlations, and Bland-Altman plots were used to assess the accuracy, agreement, and strength of relationship between SaO2 values and SpO2 values from Polar ElixirTM. RESULTS: The initial RMSE for Polar ElixirTM was 4.13%. After recalibrating the algorithm, the RMSE was improved to 2.67%. The ICC revealed excellent levels of agreement between SaO2 and Polar ElixirTM SpO2 values both before (ICC(3,1) = 0.837, df = 574, p < 0.001) and after (ICC(3,1) = 0.942, df = 287, p < 0.001) recalibration. CONCLUSIONS: Relative to ISO standards, Polar ElixirTM yielded accurate SpO2 measurements during stepwise inspired hypoxia at rest when compared to SaO2 values, which were improved by recalibrating the algorithm using a subset of the SaO2 data.

The effects of acute normobaric hypoxia on standing balance while dual-tasking with and without visual input.

PURPOSE: To investigate the influence of acute normobaric hypoxia on standing balance under single and dual-task conditions, both with and without visual input. METHODS: 20 participants (7 female, 20-31 years old) stood on a force plate for 16, 90-s trials across four balance conditions: single-task (quiet stance) or dual-task (auditory Stroop test), with eyes open or closed. Trials were divided into four oxygen conditions where the fraction of inspired oxygen (FIO2) was manipulated (normoxia: 0.21 and normobaric hypoxia: 0.16, 0.145 and 0.13 FIO2) to simulate altitudes of 1100, 3,400, 4300, and 5200 m. Participants breathed each FIO2 for ~ 3 min before testing, which lasted an additional 7-8 min per oxygen condition. Cardiorespiratory measures included heart rate, peripheral blood oxygen saturation, and pressure of end tidal (PET) CO2 and O2. Center of pressure measures included total path length, 95% ellipse area, and anteroposterior and mediolateral velocity. Auditory Stroop test performance was measured as response accuracy and latency. RESULTS: Significant decreases in oxygen saturation and PETO2, and increased heart rate were observed between normoxia and normobaric hypoxia (P < 0.0001). Total path length was higher at 0.13 compared to 0.21 FIO2 for the eyes closed no Stoop test condition (P = 0.0197). No other significant differences were observed. CONCLUSION: These findings suggest that acute normobaric hypoxia has a minimal impact on standing balance and does not influence auditory Stroop test or dual-task performance. Further investigation with longer exposure is required to understand the impact and time course of normobaric hypoxia on standing balance.

Hemorrhage at high altitude: impact of sustained hypobaric hypoxia on cerebral blood flow, tissue oxygenation, and tolerance to simulated hemorrhage in humans.

With ascent to high altitude (HA), compensatory increases in cerebral blood flow and oxygen delivery must occur to preserve cerebral metabolism and consciousness. We hypothesized that this compensation in cerebral blood flow and oxygen delivery preserves tolerance to simulated hemorrhage (via lower body negative pressure, LBNP), such that tolerance is similar during sustained exposure to HA vs. low altitude (LA). Healthy humans (4F/4 M) participated in LBNP protocols to presyncope at LA (1130 m) and 5-7 days following ascent to HA (3800 m). Internal carotid artery (ICA) blood flow, cerebral delivery of oxygen (CDO2) through the ICA, and cerebral tissue oxygen saturation (ScO2) were determined. LBNP tolerance was similar between conditions (LA: 1276 ± 304 s vs. HA: 1208 ± 306 s; P = 0.58). Overall, ICA blood flow and CDO2 were elevated at HA vs. LA (P ≤ 0.01) and decreased with LBNP under both conditions (P < 0.0001), but there was no effect of altitude on ScO2 responses (P = 0.59). Thus, sustained exposure to hypobaric hypoxia did not negatively impact tolerance to simulated hemorrhage. These data demonstrate the robustness of compensatory physiological mechanisms that preserve human cerebral blood flow and oxygen delivery during sustained hypoxia, ensuring cerebral tissue metabolism and neuronal function is maintained.

Differential splenic responses to hyperoxic breathing at high altitude in Sherpa and lowlanders.

The human spleen contracts in response to stress-induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non-Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = âˆ¼430 torr; P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$  = âˆ¼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation ( S p O 2 ${S_{{\mathrm{p}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non-Sherpa (165 ± 34 mL; P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3-1.6). In response to hyperoxia, non-Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7-48.9; P < 0.001; ES = 1.8, 95% CI: 0.93-2.66), while spleen size remained unchanged in Sherpa (-2 ± 13 mL, 95% CI: -2.4 to 7.3; P = 0.640; ES = 0.18, 95% CI: -0.10 to 0.47). Our findings suggest that Sherpa and non-Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude-related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non-Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb].

The jugular venous-to-arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during rebreathing and end-tidal forcing: Relationship with cerebral perfusion.

We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv-a CO2 )] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv-a CO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end-tidal forcing (ETF) protocols (termed: ETF-1 and ETF-2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF-1 (n = 11) and ETF-2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv-a CO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF-1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF-2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv-a CO2 difference did not change during the rebreathing protocol (-0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF-1 (-3.9 ± 1.1 mmHg; P < 0.001) and ETF-2 (-3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv-a CO2 difference during ETF (-0.095 ± 0.089 mmHg cm-1  s-1 ; P = 0.001) but not during rebreathing (-0.028 ± 0.045 mmHg · cm-1  · s-1 ; P = 0.067). These findings suggest that, although the Pjv-a CO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2 . KEY POINTS: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow. We assessed these assumptions by measuring arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end-tidal forcing. The difference between arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end-tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end-tidal forcing but not rebreathing. These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings.

Comparison of mild physiological effects of surgical masks and N95 respirators over 60 min at rest.

Dead-space-associated rebreathing of expired air and heat trapping with use of surgical masks and N95 respirators may underlie anecdotal reports of adverse symptoms associated with medical face barriers. Limited data exist directly comparing the physiological effects of masks and respirators at rest. We assessed the short-term physiological effects of both barrier types over 60 min at rest, including face microclimate temperature, end-tidal gases, and venous blood acid-base variables. We recruited 34 participants into two trials: surgical masks (n = 17) and N95 respirators (n = 17). In a seated position, participants underwent a 10-min baseline without a barrier and then wore a standardized surgical mask or dome-shaped N95 respirator for 60 min, followed by a 10-min washout. We instrumented healthy human participants with a peripheral pulse oximeter ([Formula: see text]) and a nasal cannula connected to a dual gas analyzer for measurement of the pressure of end-tidal [Formula: see text] and [Formula: see text], with an associated temperature probe for face microclimate temperature. Venous (v) blood samples were obtained at baseline and following 60-min mask/respirator wearing to assess [Formula: see text], [HCO3-]v and pHv. Compared with baseline during/following 60 min, temperature, [Formula: see text], [Formula: see text], and [HCO3-]v were mildly but significantly higher, and [Formula: see text] and [Formula: see text] were significantly lower, but [Formula: see text] was unaffected. The magnitude of effects was similar between barrier types. Temperature and [Formula: see text] returned to baseline levels within 1-2 min following removal of the barrier. These mild physiological effects may underlie reports of qualitative symptoms while wearing masks or respirators. However, the magnitudes were mild, not physiologically relevant and reversed immediately with the removal of the barrier.NEW & NOTEWORTHY Anecdotal reports suggest mild physiological effects of wearing surgical masks and/or N95 respirators, including heat trapping and rebreathing of expired air. There are limited data directly comparing the physiological effects of wearing medical barriers at rest. We found that the time course and magnitude of changes to face microclimate temperature, end-tidal gases, and venous blood gases and acid-base variables were mild in magnitude, not physiologically relevant, equivalent between barrier types, and immediately reversible on removal.

Sex-related Differences in Loop Gain during High-Altitude Sleep-disordered Breathing.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

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.

On the use and misuse of cerebral hemodynamics terminology using transcranial Doppler ultrasound: a call for standardization.

Cerebral hemodynamics, e.g., cerebral blood flow, can be measured and quantified using many different methods, with transcranial Doppler ultrasound (TCD) being one of the most commonly used approaches. In human physiology, the terminology used to describe metrics of cerebral hemodynamics are inconsistent and in some instances technically inaccurate; this is especially true when evaluating, reporting, and interpreting measures from TCD. Therefore, this perspective article presents recommended terminology when reporting cerebral hemodynamic data. We discuss the current use and misuse of the terminology in the context of using TCD to measure and quantify cerebral hemodynamics and present our rationale and consensus on the terminology that we recommend moving forward. For example, one recommendation is to discontinue the use of the term "cerebral blood flow velocity" in favor of "cerebral blood velocity" with precise indication of the vessel of interest. We also recommend clarity when differentiating between discrete cerebrovascular regulatory mechanisms, namely, cerebral autoregulation, neurovascular coupling, and cerebrovascular reactivity. This will be a useful guide for investigators in the field of cerebral hemodynamics research.

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.

Functional optical coherence tomography at altitude: retinal microvascular perfusion and retinal thickness at 3,800 meters.

Cerebral hypoxia is a serious consequence of several cardiorespiratory illnesses. Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into cerebral hypoxia in critical illness. In addition, although sex-specific differences in cardiovascular diseases are strongly supported, few have focused on differences in ocular blood flow. We evaluated the retinal microvasculature in males (n = 11) and females (n = 7) using functional optical coherence tomography at baseline (1,130 m) (day 0), following rapid ascent (day 2), and prolonged exposure (day 9) to high altitude (3,800 m). Retinal vascular perfusion density (rVPD; an index of total blood supply), retinal thickness (RT; reflecting vascular and neural tissue volume), and arterial blood were acquired. As a group, rVPD increased on day 2 versus day 0 (P < 0.001) and was inversely related to [Formula: see text] (R2 = 0.45; P = 0.006). By day 9, rVPD recovered to baseline but was significantly lower in males than in females (P = 0.007). RT was not different on day 2 versus day 0 (P > 0.99) but was reduced by day 9 relative to day 0 and day 2 (P < 0.001). RT changes relative to day 0 were inversely related to changes in [Formula: see text] on day 2 (R2 = 0.6; P = 0.001) and day 9 (R2 = 0.4; P = 0.02). RT did not differ between sexes. These data suggest differential time course and regulation of the retina during rapid ascent and prolonged exposure to high altitude and are the first to demonstrate sex-specific differences in rVPD at high altitude. The ability to assess intact microvasculature contiguous with the brain has widespread research and clinical applications.NEW & NOTEWORTHY Measuring the retinal microvasculature at high altitude provides a surrogate for cerebral microvasculature, offering potential insight into consequence of cerebral hypoxia in critical illness. This study demonstrates dynamic regulation of the retina during rapid ascent and prolonged exposure to high altitude and is the first to demonstrate sex-specific differences in retinal microvasculature at high altitude. The ability to dynamically assess intact microvasculature contiguous with the brain has widespread research and clinical applications.

Assessing central and peripheral respiratory chemoreceptor interaction in humans.

NEW FINDINGS: What is the central question of this study? We investigated the interaction between central and peripheral respiratory chemoreceptors in healthy, awake human participants by using a background of step increases in steady-state normoxic fraction of inspired carbon dioxide to alter central chemoreceptor activation and by using the transient hypoxia test to target the peripheral chemoreceptors. What is the main finding and its importance? Our data suggest that the interaction between central and peripheral respiratory chemoreceptors is additive in minute ventilation and respiratory rate, but hypo-additive in tidal volume. Our study adds important new data in reconciling chemoreceptor interaction in awake healthy humans and is consistent with previous reports of simple addition in intact rodents and humans. ABSTRACT: Arterial blood gas levels are maintained through respiratory chemoreflexes, mediated by central chemoreceptors in the CNS and peripheral chemoreceptors located in the carotid bodies. The interaction between central and peripheral chemoreceptors is controversial, and few studies have investigated this interaction in awake, healthy humans, owing, in part, to methodological challenges. We investigated the interaction between the central and peripheral chemoreceptors in healthy humans using a transient hypoxia test (three consecutive breaths of 100% N2 ; TT-HVR), which targets the temporal domain and stimulus specificity of the peripheral chemoreceptors. The TT-HVRs were superimposed upon three randomized background levels of steady-state inspired fraction of normoxic CO2 ( F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ ; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation ( S cO 2 ${S}_{{\rm{cO}}_{\rm{2}}}$ )] and respiratory variable responses [respiratory rate (RR ), inspired tidal volume (VTI ) and ventilation ( V ̇ I ${{{\dot{V}}}_{\rm{I}}}$ )] were averaged from all three TT-HVR trials at each F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ level. Responses were assessed as: (1) a change (∆) from baseline; and (2) indexed against Δ S cO 2 $\Delta {S}_{{\rm{cO}}_{\rm{2}}}$ . Aside from a significantly lower ∆VTI response in 0.04 F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ (P = 0.01), the hypoxic rate responses (∆RR or ∆RR / Δ S cO 2 $\Delta {S}_{{\rm{cO}}_{\rm{2}}}$ ; P = 0.46 and P = 0.81), hypoxic tidal volume response ( Δ V TI / Δ V TI Δ S cO 2 Δ S cO 2 ${{\Delta {V}_{{\rm{TI}}}} \mathord{/ {\vphantom {{\Delta {V}_{{\rm{TI}}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$ ; P = 0.08) and the hypoxic ventilatory responses ( Δ V ̇ I ${{\Delta {{\dot{V}}}_{\rm{I}}}}$ and Δ V ̇ I / Δ V ̇ I Δ S cO 2 Δ S cO 2 ${{\Delta {{\dot{V}}}_{\rm{I}}} \mathord{/ {\vphantom {{\Delta {{\dot{V}}}_{\rm{I}}} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}} \kern-\nulldelimiterspace} {\Delta {S}_{{\rm{cO}}_{\rm{2}}}}}$ ; P = 0.09 and P = 0.31) were not significantly different across F I , C O 2 ${F}_{{\rm{I,C}}{{\rm{O}}}_{\rm{2}}}$ trials. Our data suggest simple addition between central and peripheral chemoreceptors in V ̇ I ${{{\dot{V}}}_{\rm{I}}}$ , which is mediated through simple addition in RR responses, but hypo-addition in VTI responses. Our study adds important new data in reconciling chemoreceptor interaction in awake, healthy humans and is consistent with previous reports of simple addition in intact rodents and humans.

The coronary vascular response to the metaboreflex at low altitude and during acute and prolonged high altitude in males.

Myocardial oxygen delivery is primarily regulated through changes in vascular tone to match increased metabolic demands. In males, activation of the muscle metaboreflex during acute isocapnic hypoxia results in paradoxical coronary vasoconstriction. Whether coronary blood velocity is reduced by metaboreflex activation following travel and/or adaptation to high altitude is unknown. This study determined if the response of the coronary vasculature to muscle metaboreflex activation at low altitude differs from acute (1/2 days) and prolonged (8/9 days) high altitude. Healthy males (n = 16) were recruited and performed isometric handgrip exercise (30% max) followed by postexercise circulatory occlusion (PECO) to isolate the muscle metaboreflex at low altitude and following acute and prolonged high altitude (3,800 m). Mean left anterior descending coronary artery blood velocity (LADvmean, transthoracic Doppler echocardiography), heart rate, mean arterial pressure (MAP), ventilation, and respired gases were assessed during baseline and PECO at all time points. Coronary vascular conductance index (CVCi) was calculated as LADVmean/MAP. The change in LADvmean (acute altitude: -1.7 ± 3.9 cm/s, low altitude: 2.6 ± 3.4 cm/s, P = 0.01) and CVCi (acute altitude: -0.05 ± 0.04 cm/s/mmHg, low altitude: -0.01 ± 0.03 cm/s/mmHg, P = 0.005) induced by PECO differed significantly between acute high altitude and low altitude. The change in LADVmean and CVCi induced by PECO following prolonged high altitude was not different from low altitude. Our results suggest that coronary vasoconstriction with metaboreflex activation in males is greatest following acute ascent to high-altitude and restored to low-altitude levels following 8-9 days of acclimatization.NEW & NOTEWORTHY Coronary blood flow is regulated by both local metabolic signaling pathways and adrenergic activity in healthy humans. The integrated effects of these systems on coronary vascular physiology are not well understood. Using Doppler echocardiography, this study demonstrates that adrenergic stimulation caused by metaboreflex activation leads to greater reductions in coronary vascular conductance following acute high-altitude but not after prolonged high-altitude exposure.

Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years.

Twenty-five years ago, a new physiological preparation called the working heart-brainstem preparation (WHBP) was introduced with the claim it would provide a new platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of the progress made with the WHBP, some advantages and disadvantages along with potential future applications, and provide photographs and technical drawings of all the customised equipment used for the preparation. Using mice or rats, the WHBP is an in situ experimental model that is perfused via an extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability of the brain for whole cell recording and an uncompromised use of pharmacological agents akin to in vitro approaches. The preparation has revealed novel mechanistic insights into, for example, the generation of distinct respiratory rhythms, the neurogenesis of sympathetic activity, coupling between respiration and the heart and circulation, hypothalamic and spinal control mechanisms, and peripheral and central chemoreceptor mechanisms. Insights have been gleaned into diseases such as hypertension, heart failure and sleep apnoea. Findings from the in situ preparation have been ratified in conscious in vivo animals and when tested have translated to humans. We conclude by discussing potential future applications of the WHBP including two-photon imaging of peripheral and central nervous systems and adoption of pharmacogenetic tools that will improve our understanding of physiological mechanisms and reveal novel mechanisms that may guide new treatment strategies for cardiorespiratory diseases.

Cerebrovascular and blood pressure responses during voluntary apneas are larger than rebreathing.

Both voluntary rebreathing (RB) of expired air and voluntary apneas (VA) elicit changes in arterial carbon dioxide and oxygen (CO2 and O2) chemostimuli. These chemostimuli elicit synergistic increases in cerebral blood flow (CBF) and sympathetic nervous system activation, with the latter increasing systemic blood pressure. The extent that simultaneous and inverse changes in arterial CO2 and O2 and associated increases in blood pressure affect the CBF responses during RB versus VAs are unclear. We instrumented 21 healthy participants with a finometer (beat-by-beat mean arterial blood pressure; MAP), transcranial Doppler ultrasound (middle and posterior cerebral artery velocity; MCAv, PCAv) and a mouthpiece with sample line attached to a dual gas analyzer to assess pressure of end-tidal (PET)CO2 and PETO2. Participants performed two protocols: RB and a maximal end-inspiratory VA. A second-by-second stimulus index (SI) was calculated as PETCO2/PETO2 during RB. For VA, where PETCO2 and PETO2 could not be measured throughout, SI values were calculated using interpolated end-tidal gas values before and at the end of the apneas. MAP reactivity (MAPR) was calculated as the slope of the MAP/SI, and cerebrovascular reactivity (CVR) was calculated as the slope of MCAv or PCAv/SI. We found that compared to RB, VA elicited ~ fourfold increases in MAPR slope (P < 0.001), translating to larger anterior and posterior CVR (P ≤ 0.01). However, cerebrovascular conductance (MCAv or PCAv/MAP) was unchanged between interventions (P ≥ 0.2). MAP responses during VAs are larger than those during RB across similar chemostimuli, and differential CVR may be driven by increases in perfusion pressure.

Acid-base balance at high altitude in lowlanders and indigenous highlanders.

High-altitude exposure results in a hyperventilatory-induced respiratory alkalosis followed by renal compensation (bicarbonaturia) to return arterial blood pH (pHa) toward sea-level values. However, acid-base balance has not been comprehensively examined in both lowlanders and indigenous populations-where the latter are thought to be fully adapted to high altitude. The purpose of this investigation was to compare acid-base balance between acclimatizing lowlanders and Andean and Sherpa highlanders at various altitudes (∼3,800, ∼4,300, and ∼5,000 m). We compiled data collected across five independent high-altitude expeditions and report the following novel findings: 1) at 3,800 m, Andeans (n = 7) had elevated pHa compared with Sherpas (n = 12; P < 0.01), but not to lowlanders (n = 16; 9 days acclimatized; P = 0.09); 2) at 4,300 m, lowlanders (n = 16; 21 days acclimatized) had elevated pHa compared with Andeans (n = 32) and Sherpas (n = 11; both P < 0.01), and Andeans had elevated pHa compared with Sherpas (P = 0.01); and 3) at 5,000 m, lowlanders (n = 16; 14 days acclimatized) had higher pHa compared with both Andeans (n = 66) and Sherpas (n = 18; P < 0.01, and P = 0.03, respectively), and Andean and Sherpa highlanders had similar blood pHa (P = 0.65). These novel data characterize acid-base balance acclimatization and adaptation to various altitudes in lowlanders and indigenous highlanders.NEW & NOTEWORTHY Lowlander, Andean, and Sherpa arterial blood data were combined across five independent high-altitude expeditions in the United States, Nepal, and Peru to assess acid-base status at ∼3,800, ∼4,300, and ∼5,000 m. The main finding was that Andean and Sherpa highlander populations have more acidic arterial blood, due to elevated arterial carbon dioxide and similar arterial bicarbonate compared with acclimatizing lowlanders at altitudes ≥4,300 m.

Acute hyperglycemia does not affect central respiratory chemoreflex responsiveness to CO2 in healthy humans.

The central respiratory chemoreceptor complex (CCRC) is comprised of brainstem neurons and surrounding interoceptors, which collectively increase ventilation in response to elevated brainstem tissue CO2/[H+] (i.e., central chemoreflex; CCR). The extent that the CCRC detects/responds to other metabolically related chemostimuli is unknown. We aimed to test the effects of acute oral glucose ingestion on CCR reactivity in heathy human participants (n = 38). We instrumented participants with a pneumotachometer (minute ventilation) and a gas sample line connected to a dual gas analyzer (pressure of end-tidal CO2). Following a baseline (BL) period and capillary blood [glucose] (BG) sample, fasted (F) participants underwent a modified hyperoxic rebreathing test to assess CCR reactivity. Participants then consumed a 75 g standard glucose beverage (glucose loaded; GL). Following 30-min, they underwent a second BL, BG sample and hyperoxic rebreathing test. BG and metabolic rate were higher in GL, confirming the metabolic stimulus. However, the ventilatory recruitment threshold and the CCR responses were unchanged between F and GL states.

Sex differences in the coronary vascular response to combined chemoreflex and metaboreflex stimulation in healthy humans.

NEW FINDINGS: What is the central question of this study? Coronary blood flow in healthy humans is controlled by both local metabolic signalling and adrenergic activity: does the integration of these signals during acute hypoxia and adrenergic activation differ between sexes? What are the main findings and its importance? Both males and females exhibit an increase in coronary blood velocity in response to acute hypoxia, a response that is constrained by adrenergic stimulation in males but not females. These findings suggest that coronary blood flow control differs between males and females. ABSTRACT: Coronary hyperaemia is mediated through multiple signalling pathways, including local metabolic messengers and adrenergic stimulation. This study aimed to determine whether the coronary vascular response to adrenergic stressors is different between sexes in normoxia and hypoxia. Young, healthy participants (n = 32; 16F) underwent three randomized trials of isometric handgrip exercise followed by post-exercise circulatory occlusion (PECO) to activate the muscle metaboreflex. End-tidal PO2 was controlled at (1) normoxic levels throughout the trial, (2) 50 mmHg for the duration of the trial (hypoxia trial), or (3) 50 mmHg only during PECO (mixed trial). Mean left anterior descending coronary artery velocity (LADVmean ; transthoracic Doppler echocardiography), heart rate and blood pressure were assessed at baseline and during PECO. In normoxia, there was no change in LADVmean or cardiac workload induced by PECO in males and females. Acute hypoxia increased baseline LADVmean to a greater extent in males compared with females (P < 0.05), despite a similar increase in cardiac workload. The change in LADVmean induced by PECO was similar between sexes in normoxia (P = 0.31), greater in males during the mixed trial (male: 12.8 (7.7) cm/s vs. female: 8.1 (6.3) cm/s; P = 0.02) and reduced in males but not females in acute hypoxia (male: -4.8 (4.5) cm/s vs. female: 0.8 (6.2) cm/s; P = 0.006). In summary, sex differences in the coronary vasodilatory response to hypoxia were observed, and metaboreflex activation during hypoxia caused a paradoxical reduction in coronary blood velocity in males but not females.