UBC-Nepal Expedition: An experimental overview of the 2016 University of British Columbia Scientific Expedition to Nepal Himalaya

The University of British Columbia Nepal Expedition took place over several months in the fall of 2016 and was comprised of an international team of 37 researchers. This paper describes the objectives, study characteristics, organization and management of this expedition, and presents novel blood gas data during acclimatization in both lowlanders and Sherpa. An overview and framework for the forthcoming publications is provided. The expedition conducted 17 major studies with two principal goals—to identify physiological differences in: 1) acclimatization; and 2) responses to sustained high-altitude exposure between lowland natives and people of Tibetan descent. We performed observational cohort studies of human responses to progressive hypobaric hypoxia (during ascent), and to sustained exposure to 5050 m over 3 weeks comparing lowlander adults (n = 30) with Sherpa adults (n = 24). Sherpa were tested both with (n = 12) and without (n = 12) descent to Kathmandu. Data collected from lowlander children (n = 30) in Canada were compared with those collected from Sherpa children (n = 57; 3400–3900m). Studies were conducted in Canada (344m) and the following locations in Nepal: Kathmandu (1400m), Namche Bazaar (3440m), Kunde Hospital (3480m), Pheriche (4371m) and the Ev-K2-CNR Research Pyramid Laboratory (5050m). The core studies focused on the mechanisms of cerebral blood flow regulation, the role of iron in cardiopulmonary regulation, pulmonary pressures, intra-ocular pressures, cardiac function, neuromuscular fatigue and function, blood volume regulation, autonomic control, and micro and macro vascular function. A total of 335 study sessions were conducted over three weeks at 5050m. In addition to an overview of this expedition and arterial blood gas data from Sherpa, suggestions for scientists aiming to perform field-based altitude research are also presented. Together, these findings will contribute to our understanding of human acclimatization and adaptation to the stress of residence at high-altitude

Hemoglobin and cerebral hypoxic vasodilation in humans: evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ((Formula presented.)) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and (Formula presented.). Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not (Formula presented.), while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</p

Hemoglobin and cerebral hypoxic vasodilation in humans:Evidence for nitric oxide-dependent and S-nitrosothiol mediated signal transduction

Cerebral hypoxic vasodilation is poorly understood in humans, which undermines the development of therapeutics to optimize cerebral oxygen delivery. Across four investigations (total n = 195) we investigated the role of nitric oxide (NO) and hemoglobin-based S-nitrosothiol (RSNO) and nitrite ((Formula presented.)) signaling in the regulation of cerebral hypoxic vasodilation. We conducted hemodilution (n = 10) and NO synthase inhibition experiments (n = 11) as well as hemoglobin oxygen desaturation protocols, wherein we measured cerebral blood flow (CBF), intra-arterial blood pressure, and in subsets of participants trans-cerebral release/uptake of RSNO and (Formula presented.). Higher CBF during hypoxia was associated with greater trans-cerebral RSNO release but not (Formula presented.), while NO synthase inhibition reduced cerebral hypoxic vasodilation. Hemodilution increased the magnitude of cerebral hypoxic vasodilation following acute hemodilution, while in 134 participants tested under normal conditions, hypoxic cerebral vasodilation was inversely correlated to arterial hemoglobin concentration. These studies were replicated in a sample of polycythemic high-altitude native Andeans suffering from excessive erythrocytosis (n = 40), where cerebral hypoxic vasodilation was inversely correlated to hemoglobin concentration, and improved with hemodilution (n = 6). Collectively, our data indicate that cerebral hypoxic vasodilation is partially NO-dependent, associated with trans-cerebral RSNO release, and place hemoglobin-based NO signaling as a central mechanism of cerebral hypoxic vasodilation in humans.</p

Acute reductions in hematocrit increase flow-mediated dilation independent ofresting nitric oxide bioavailability in humans

Hemoglobin (Hb) may impact the transduction of endothelium‐dependent and nitric oxide (NO) mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and hematocrit (Hct) would increase brachial artery flow‐mediated dilation (FMD). In eleven healthy males (28 ± 7 years; 23 ± 2 kg m−2), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone‐based chemiluminescence) were measured before and after isovolumic hemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Hemodilution reduced Hct by 18 ± 2% (P < 0.001) and whole blood viscosity by 22 ± 5% (P < 0.001). Plasma nitrite (P = 0.01), S‐nitrosothiols (P = 0.03), and total red blood cell NO (P = 0.001) were collectively reduced by ∼15–40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that hemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium‐dependent NO‐mediated vasodilation in healthy humans

Global REACH 2018: The influence of acute and chronic hypoxia on cerebral haemodynamics and related functional outcomes during cold and heat stress

Real-world settings are composed of multiple environmental stressors, yet the majority of research in environmental physiology investigates these stressors in isolation. The brain is central in both behavioural and physiological responses to threatening stimuli and, given its tight metabolic and haemodynamic requirements, is particularly susceptible to environmental stress. We measured cerebral blood flow (CBF, duplex ultrasound), cerebral oxygen delivery (CDO2), oesophageal temperature, and arterial blood gases during exposure to three commonly experienced environmental stressors –heat, cold and hypoxia –in isolation, and in combination. Twelve healthy male subjects (27±11 years) underwent core cooling by 1.0ºC and core heating by 1.5ºC in randomized order at sea-level; acute hypoxia (PetO2= 50mmHg) was imposed at baseline and at each thermal extreme. Core cooling and heating protocols were repeated after 16±4 days residing at 4330m to investigate any interactions with high altitude acclimatization. Cold stress decreased CBF by 20–30% and CDO2 by 12–19%(both p0.08). The increases in CBF with acute hypoxia during thermal stress were appropriate to maintain CDO2 at normothermic, normoxic values. Reaction time was faster and slower by 6-9%with heating and cooling, respectively(both p<0.01), but central (brain) processes were not impaired by any combination of environmental stressors. These findings highlight the powerful influence of core cooling in reducing CDO2. Despite these large reductions in CDO2 with cold stress, gross indices of cognition remained stable

The 2018 Global Research Expedition on Altitude-related Chronic Health (REACH) to Cerro de Pasco, Peru: An Experimental Overview

In 2016, the international research team - Global Research Expedition onAltitude-related Chronic Health (REACH) - was established and executed a high altituderesearch expedition to Nepal. The team consists of ~45 students, principal investigatorsand physicians with the common objective of conducting experiments focused on highaltitude adaptation in lowlanders, and highlanders with lifelong exposure to high altitude.In 2018, Global REACH traveled to Peru where we performed a series of experiments inthe Andean highlanders. The experimental objectives, organization and characteristics,and key cohort data from Global REACH's latest research expedition are outlined herein.Herein, fifteen major studies are described that aimed to elucidate the physiologicaldifferences in high altitude acclimatization between lowlanders (n=30) and Andean bornhighlanders with (n=22) and without (n=45) Excessive Erythrocytosis (EE). Afterbaseline testing in Kelowna, BC, Canada (344m), Global REACH travelled to Lima, Peru(~80 m), and then ascended by automobile to Cerro de Pasco, Peru (~4300m) whereexperiments were conducted over 25 days. The core studies focused on elucidating themechanism(s) governing cerebral and peripheral vascular function, cardiopulmonaryregulation, exercise performance, and autonomic control. Despite encountering seriouslogistical challenges, each of the proposed studies were completed at both sea level andhigh altitude amounting to ~780 study sessions and >3000 hrs of experimental testing.Participant demographics and data related to acid-base balance and exercise capacityare presented. The collective findings will contribute to our understanding of howlowlanders and Andean highlanders have adapted under high altitude stress

Physiological aspects of iron status and manipulation in lowlander and adapted highlanders at high altitude

With ascent to high altitude, the reduction in the partial pressure of oxygen (PO₂) drives the stabilization of the hypoxia-inducible factor (HIF) family. As the key cellular oxygen sensor, HIF up-regulates the expression of numerous genes designed to increase and preserve O₂ tissue delivery. Since iron plays an inverse and constituent role in HIF stabilization, the overall objectives of the current thesis were: 1) determine the role of iron status manipulation on pulmonary, peripheral and cerebral responses to high-altitude; 2) and examine if indigenous high-altitude populations (i.e. Sherpa and Andeans), with ancestral adaptation to their hypoxic environment, exhibit iron-regulatory advantages. Study 1 investigated the effects of ascent and prolonged stay at 5050 m on iron status and hypoxic pulmonary vasoconstriction. The primary findings were that 1) during ascent, reductions in iron bioavailability were more prevalent in lowlanders, compared to Sherpa; 2) following partial acclimatization to 5050 m, iron infusion (HIF-down regulation) attenuated pulmonary artery systolic pressure (PASP) in both lowlanders and Sherpa while deferoxamine infusion (HIF-up regulation) had little influence. Study 2, in a block-randomized and placebo-controlled design, examined whether the pulmonary vasculature of lowlanders and adapted Andeans at 4300 m are responsive to iron infusion. The findings revealed that, unlike the placebo condition, iron infusion reduced PASP in both lowlanders and Andeans. Study 3 then evaluated the role of iron infusion on peripheral vascular function in the same volunteers at 4300 m. Here, iron infusion (but not saline) increased brachial blood flow and increased microvascular function across the 4-hours, in both lowlanders and Andeans. Upon pooling data (n=83), across both lowlanders and highlanders, Study 4 explored whether the same iron manipulations can modulate hypoxic cerebral vasodilation. It was found that baseline iron levels were related to the variability in magnitude of the hypoxic cerebral vasodilation at high-altitude. In summary, new evidence is provided that support iron status may influence blood flow regulation in the pulmonary, peripheral and cerebral circulations during exposure to high-altitude. Future studies are needed to explore the mechanisms and implications of these observations in high-altitude physiology and pathology.Health and Social Development, Faculty of (Okanagan)Health and Exercise Sciences, School of (Okanagan)Graduat

Association Between Arterial Oxygen Saturation and Lung Ultrasound B-Lines After Competitive Deep Breath-Hold Diving

Breath-hold diving (freediving) is an underwater sport that is associated with elevated hydrostatic pressure, which has a compressive effect on the lungs that can lead to the development of pulmonary edema. Pulmonary edema reduces oxygen uptake and thereby the recovery from the hypoxia developed during freediving, and increases the risk of hypoxic syncope. We aimed to examine the efficacy of SpO2, via pulse-oximetry, as a tool to detect pulmonary edema by comparing it to lung ultrasound B-line measurements after deep diving. SpO2 and B-lines were collected in 40 freedivers participating in an international deep freediving competition. SpO2 was measured within 17 ± 6 min and lung B-lines using ultrasound within 44 ± 15 min after surfacing. A specific symptoms questionnaire was used during SpO2 measurements. We found a negative correlation between B-line score and minimum SpO2 (rs = −0.491; p = 0.002) and mean SpO2 (rs = −0.335; p = 0.046). B-line scores were positively correlated with depth (rs = 0.408; p = 0.013), confirming that extra-vascular lung water is increased with deeper dives. Compared to dives that were asymptomatic, symptomatic dives had a 27% greater B-line score, and both a lower mean and minimum SpO2 (all p &amp;lt; 0.05). Indeed, a minimum SpO2 ≤ 95% after a deep dive has a positive predictive value of 29% and a negative predictive value of 100% regarding symptoms. We concluded that elevated B-line scores are associated with reduced SpO2 after dives, suggesting that SpO2 via pulse oximetry could be a useful screening tool to detect increased extra-vascular lung water. The practical application is not to diagnose pulmonary edema based on SpO2 – as pulse oximetry is inexact – rather, to utilize it as a tool to determine which divers require further evaluation before returning to deep freediving