Rationale: Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. Objectives: To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR. Methods: After two normoxic control days (Day −4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1–4) of intermittent hypoxia for 6 hours per day. Measurements and Main Results: AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring α-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and α-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002). Conclusions: Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Pun, Matiram, Rachel Turner, Giacomo Strapazzon, Hermann Brugger, and Erik R. Swenson. Lower incidence of COVID-19 at high altitude: Facts and confounders. High Alt Med Biol . 21:217–222, 2020.—The rapid transmission, increased morbidity, and mortality of coronavirus disease 2019 (COVID-19) has exhausted many health care systems and the global economy. Large variations in COVID-19 prevalence and incidence have been reported across and within many countries worldwide; however, this remains poorly understood. The variability and susceptibility across the world have been mainly attributed to differing socioeconomic status, burden of chronic diseases, access to health care, strength of health care systems, and early or late adoption of control measures. Environmental factors such as pollution, ambient temperature, humidity, and seasonal weather patterns at different latitudes may influence how severe the pandemic is and the incidence of infection in any part of the world. In addition, recent epidemiological data have been used to propose that altitude of residence may not only influence those environmental features considered key to lesser viral transmission, but also susceptibility to more severe forms of COVID-19 through hypoxic-hypobaria driven genomic or nongenomic adaptations specific to high-altitude populations. In this review, we critically examine these factors and attempt to determine based upon available scientific and epidemiological data whether living in high-altitude regions might be protective against COVID-19 as recent publications have claimed.

Objective: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). Methods: Double-blind, randomized, placebo-controlled trial. Results: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P = .01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P = .01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P = .035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P = .129 for AMS incidence, 9.6% vs 8.2%; P = .74 for AMS severity, 54.8% vs 42.7%; P = .11 for HAH incidence, and 8.2% vs 3.6%; P = .18 for HAH severity). Conclusions: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS.

Objective: Neurocognitive functions are affected by high altitude, however the altitude effects of acclimatization and repeated exposures are unclear. We investigated the effects of acute, subacute and repeated exposure to 5,050 m on cognition among altitude-naïve participants compared to control subjects tested at low altitude. Methods: Twenty-one altitude-naïve individuals (25.3 ± 3.8 years, 13 females) were exposed to 5,050 m for 1 week (Cycle 1) and re-exposed after a week of rest at sea-level (Cycle 2). Baseline (BL, 520 m), acute (Day 1, HA1) and acclimatization (Day 6, HA6, 5,050 m) measurements were taken in both cycles. Seventeen control subjects (24.9 ± 2.6 years, 12 females) were tested over a similar period in Calgary, Canada (1,103 m). The Reaction Time (RTI), Attention Switching Task (AST), Rapid Visual Processing (RVP) and One Touch Stockings of Cambridge (OTS) tasks were administered and outcomes were expressed in milliseconds/frequencies. Lake Louise Score (LLS) and blood oxygen saturation (SpO₂) were recorded. Results: In both cycles, no significant changes were found with acute exposure on the AST total score, mean latency and SD. Significant changes were found upon acclimatization solely in the altitude group, with improved AST Mean Latency [HA1 (588 ± 92) vs. HA6 (526 ± 91), p < 0.001] and Latency SD [HA1 (189 ± 86) vs. HA6 (135 ± 65), p < 0.001] compared to acute exposure, in Cycle 1. No significant differences were present in the control group. When entering Acute SpO₂ (HA1-BL), Acclimatization SpO₂ (HA6-BL) and LLS score as covariates for both cycles, the effects of acclimatization on AST outcomes disappeared indicating that the changes were partially explained by SpO₂ and LLS. The changes in AST Mean Latency [ΔBL (−61.2 ± 70.2) vs. ΔHA6 (−28.0 ± 58), p = 0.005] and the changes in Latency SD [ΔBL (−28.4 ± 41.2) vs. ΔHA6 (−0.2235 ± 34.8), p = 0.007] across the two cycles were smaller with acclimatization. However, the percent changes did not differ between cycles. These results indicate independent effects of altitude across repeated exposures. Conclusions: Selective and sustained attention are impaired at altitude and improves with acclimatization.The observed changes are associated, in part, with AMS score and SpO₂. The gains in cognition with acclimatization during a first exposure are not carried over to repeated exposures.

Background: Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)‐induced inflammation. Cyclooxygenase (COX)‐formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure andCBFresponses toIHis unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses toIH.Methods and Results: Twelve healthy, male participants underwent three, 6‐hourIHexposures. For 4 days before eachIHexposure, participants ingested a placebo, indomethacin (nonselectiveCOXinhibitor), or Celebrex^®(selectiveCOX‐2 inhibitor) in a double‐blind, randomized, crossover study design. Pre‐ and post‐IHblood pressure,CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreatedOSApatients (n=33). NonselectiveCOXinhibition increased pre‐IHblood pressure (P≤0.04) and decreased pre‐IH CBF(P=0.04) while neither physiological variable was affected byCOX‐2 inhibition (P≥0.90). Post‐IH,MAPwas elevated (P≤0.05) andCBFwas unchanged with placebo and nonselectiveCOXinhibition. SelectiveCOX‐2 inhibition abrogated theIH‐inducedMAPincrease (P=0.19), but resulted in lower post‐IH CBF(P=0.01). Prostanoids were unaffected byIH, except prostaglandin E₂was elevated with the placebo (P=0.02). Finally,OSApatients had elevated blood pressure (P≤0.4) andCOX‐1 formed thromboxane A₂concentrations (P=0.02).Conclusions: COX‐2 andCOX‐1 have divergent roles in modulating vascular responses to acute and chronicIH. Moreover,COX‐1 inhibition may mitigate cardiovascular and cerebrovascular morbidity inOSA.Clinical Trial Registration: URL:www.clinicaltrials.gov. Unique identifier: NCT01280006