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Our objective in this exploratory study was to identify novel biomarkers of importance for acute mountain sickness (AMS) using discovery-based proteomic methods. Peripheral blood samples were collected and AMS symptoms were assessed in 20 healthy volunteers prior to [-15 h (baseline) and 0 h; 1,609 m; barometric pressure = 625 mmHg] and after a 9-h exposure to hypobaric hypoxia (9 h; 4,875 m; barometric pressure = 425 mmHg). AMS status was assessed using the Lake Louise Questionnaire. Plasma samples were pooled according to AMS status at each time point. Protein composition of the samples was determined by a GeLC-MS/MS approach using two analytical platforms (LTQ-XL linear ion trap mass spectrometer and a LTQ-FT ultra hybrid mass spectrometer) for technical replication. Spectral counting was used to make semiquantitative comparisons of protein abundance between AMS-susceptible (AMS) and AMS-resistant (AMS·R) subjects with exposure to hypobaric hypoxia. After 9 h of hypoxia, the abundance of proteins with antioxidant properties (i.e., peroxiredoxin 6, glutathione peroxidase, and sulfhydryl oxidase 1) rose in AMS but not AMS·R. Our exploratory analyses suggest that exposure to hypobaric hypoxia enhances enzymatic antioxidant systems in AMS vs. AMS·R, which, we propose, may be an overcompensation for hypoxia-induced oxidant production. On the basis of our findings we 1) speculate that quenching oxidant activity may have adverse downstream effects that are of pathophysiological importance for AMS such as interrupting oxidant-sensitive cell signaling and gene transcription and 2) question the existing assumption that increased oxidant production in AMS is pathological.

Carbon dioxide regulates ventilation and cerebral blood flow during exercise. There are significant limitations in breathing systems designed to control end-tidal gas concentrations when used during high-intensity exercise. We designed a simple, inexpensive breathing system which controls end-tidal carbon dioxide (PET CO2) during exercise from rest to peak work capacity (W(max)). The system is operated by an investigator who, in response to breath-by-breath PET CO2, titrates flow of a 10 % CO(2), 21 % O(2) mixture into an open-ended 5-L inspiratory reservoir. To demonstrate system efficacy, nine fit male subjects performed two maximal, incremental exercise tests (25 W min(-1) ramp) on a cycle ergometer: a poikilocapnic control trial in which PET CO2 varied with work intensity, and an experimental trial, in which we planned to clamp PET CO2 at 50 mmHg. With our breathing system, we maintained PET CO2 at 51 ± 2 mmHg throughout exercise (rest, 50 ± 2; W(max), 52 ± 5 mmHg; mean ± SD) despite large changes in ventilation (range 27-65 at rest, 134-185 L min(-1) BTPS at W (max)) and carbon dioxide production (range 0.3-0.7 at rest, 4.5-5.5 L min(-1) at W (max)). This simple, inexpensive system achieves PET CO2 control at rest and throughout exercise.

Previous studies have suggested that a reduction in cerebral oxygen delivery may limit motor drive, particularly in hypoxic conditions, where oxygen transport is impaired. We hypothesized that raising end-tidal Pco(2) (Pet(CO(2))) during incremental exercise would increase cerebral blood flow (CBF) and oxygen delivery, thereby improving peak power output (W(peak)). Amateur cyclists performed two ramped exercise tests (25 W/min) in a counterbalanced order to compare the normal, poikilocapnic response against a clamped condition, in which Pet(CO(2)) was held at 50 Torr throughout exercise. Tests were performed in normoxia (barometric pressure = 630 mmHg, 1,650 m) and hypoxia (barometric pressure = 425 mmHg, 4,875 m) in a hypobaric chamber. An additional trial in hypoxia investigated effects of clamping at a lower Pet(CO(2)) (40 Torr) from ∼75 to 100% W(peak) to reduce potential influences of respiratory acidosis and muscle fatigue imposed by clamping Pet(CO(2)) at 50 Torr. Metabolic gases, ventilation, middle cerebral artery CBF velocity (transcranial Doppler), forehead pulse oximetry, and cerebral (prefrontal) and muscle (vastus lateralis) hemoglobin oxygenation (near infrared spectroscopy) were monitored across trials. Clamping Pet(CO(2)) at 50 Torr in both normoxia (n = 9) and hypoxia (n = 11) elevated CBF velocity (∼40%) and improved cerebral hemoglobin oxygenation (∼15%), but decreased W(peak) (6%) and peak oxygen consumption (11%). Clamping at 40 Torr near maximal effort in hypoxia (n = 6) also improved cerebral oxygenation (∼15%), but again limited W(peak) (5%). These findings demonstrate that increasing mass cerebral oxygen delivery via CO(2)-mediated vasodilation does not improve incremental exercise performance, at least when accompanied by respiratory acidosis.

The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1β, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1β, VEGF, TNF-α, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1β was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.

Previous attempts to detect global cerebral hemodynamic differences between those who develop headache, nausea, and fatigue following rapid exposure to hypoxia [acute mountain sickness (AMS)] and those who remain healthy have been inconclusive. In this study, we investigated the effects of two drugs known to reduce symptoms of AMS to determine if a common cerebral hemodynamic mechanism could explain the prophylactic effect within individuals. With the use of randomized, placebo-controlled, double-blind, crossover design, 20 healthy volunteers were given oral acetazolamide (250 mg), dexamethasone (4 mg), or placebo every 8 h for 24 h prior to and during a 10-h exposure to a simulated altitude of 4,875 m in a hypobaric chamber, which included 2 h of exercise at 50% of altitude-specific VO(2max). Cerebral hemodynamic parameters derived from ultrasound assessments of dynamic cerebral autoregulation and vasomotor reactivity were recorded 15 h prior to and after 9 h of hypoxia. AMS symptoms were scored using the Lake Louise Questionnaire (LLQ). It was found that both drugs prevented AMS in those who became ill on placebo (~70% decrease in LLQ), yet a common cerebral hemodynamic mechanism was not identified. Compared with placebo, acetazolamide reduced middle cerebral artery blood flow velocity (11%) and improved dynamic cerebral autoregulation after 9 h of hypoxia, but these effects appeared independent of AMS. Dexamethasone had no measureable cerebral hemodynamic effects in hypoxia. In conclusion, global cerebral hemodynamic changes resulting from hypoxia may not explain the development of AMS.

During exercise, as end-tidal carbon dioxide (P(ET)(CO₂)) drops after the respiratory compensation point (RCP), so does cerebral blood flow velocity (CBFv) and cerebral oxygenation. This low-flow, low-oxygenation state may limit work capacity. We hypothesized that by preventing the fall in P(ET)(CO₂) at peak work capacity (W(max)) with a newly designed high-flow, low-resistance rebreathing circuit, we would improve CBFv, cerebral oxygenation, and W(max). Ten cyclists performed two incremental exercise tests, one as control and one with P(ET)(CO₂) constant (clamped) after the RCP. We analyzed , middle cerebral artery CBFv, cerebral oxygenation, and cardiopulmonary measures. At W(max), when we clamped P(ET)(CO₂) (39.7 ± 5.2 mmHg vs. 29.6 ± 4.7 mmHg, P < 0.001), CBFv increased (92.6 ± 15.9 cm/s vs. 73.6 ± 12.5 cm/s, P < 0.001). However, cerebral oxygenation was unchanged (ΔTSI -21.3 ± 13.1% vs. -24.3 ± 8.1%, P = 0.33), and W(max) decreased (380.9 ± 20.4W vs. 405.7 ± 26.8 W, P < 0.001). At W(max), clamping P(ET)(CO₂) increases CBFv, but this does not appear to improve W(max)., (Copyright © 2010 Elsevier B.V. All rights reserved.)

To determine if fatigue at maximal aerobic power output was associated with a critical decrease in cerebral oxygenation, 13 male cyclists performed incremental maximal exercise tests (25 W/min ramp) under normoxic (Norm: 21% Fi(O2)) and acute hypoxic (Hypox: 12% Fi(O2)) conditions. Near-infrared spectroscopy (NIRS) was used to monitor concentration (microM) changes of oxy- and deoxyhemoglobin (Delta[O2Hb], Delta[HHb]) in the left vastus lateralis muscle and frontal cerebral cortex. Changes in total Hb were calculated (Delta[THb] = Delta[O2Hb] + Delta[HHb]) and used as an index of change in regional blood volume. Repeated-measures ANOVA were performed across treatments and work rates (alpha = 0.05). During Norm, cerebral oxygenation rose between 25 and 75% peak power output {Power(peak); increased (inc) Delta[O2Hb], inc. Delta[HHb], inc. Delta[THb]}, but fell from 75 to 100% Power(peak) {decreased (dec) Delta[O2Hb], inc. Delta[HHb], no change Delta[THb]}. In contrast, during Hypox, cerebral oxygenation dropped progressively across all work rates (dec. Delta[O2Hb], inc. Delta[HHb]), whereas Delta[THb] again rose up to 75% Power(peak) and remained constant thereafter. Changes in cerebral oxygenation during Hypox were larger than Norm. In muscle, oxygenation decreased progressively throughout exercise in both Norm and Hypox (dec. Delta[O2Hb], inc. Delta [HHb], inc. Delta[THb]), although Delta[O2Hb] was unchanged between 75 and 100% Power peak. Changes in muscle oxygenation were also greater in Hypox compared with Norm. On the basis of these findings, it is unlikely that changes in cerebral oxygenation limit incremental exercise performance in normoxia, yet it is possible that such changes play a more pivotal role in hypoxia.