Nicolas Bourdillon

AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.

An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14) or 21 (n = 7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 9±4 mmHg to 45±4 while PaCO2 dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.

AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery

What is the central question of this study? Hypoxia associated with ascent to high altitude may threaten cerebral oxygen delivery. We sought to determine whether there are regional changes in the distribution of cerebral blood flow that might favour oxygen delivery to areas associated with basic homeostatic functions to promote survival in this extreme environment. What is the main finding and its importance? We show evidence of a ‘brain‐sparing’ effect during acute exposure to high altitude, in which there is a slight increase in relative oxygen delivery to the posterior cerebral circulation. This may serve to support basic regulatory functions associated with the brainstem and hypothalamus.

AltitudeOmics: cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness

Cerebral autoregulation (CA) acts to maintain brain blood flow despite fluctuations in perfusion pressure. Acute hypoxia is thought to impair CA, but it is unclear if CA is affected by acclimatization or related to the development of acute mountain sickness (AMS). We assessed changes in CA using transfer function analysis of spontaneous fluctuations in radial artery blood pressure (indwelling catheter) and resulting changes in middle cerebral artery blood flow velocity (transcranial Doppler) in 21 active individuals at sea level upon arrival at 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon re-exposure to 5,260 m after 7 days at 1,525 m (POST7). The Lake Louise Questionnaire was used to evaluate AMS symptom severity. CA was impaired upon arrival at ALT1 (P < 0.001) and did not change with acclimatization at ALT16 or upon re-exposure at POST7. CA was not associated with AMS symptoms (all R < 0.50, P > 0.05). These findings suggest that alterations in CA are an intrinsic consequence of hypoxia and are not directly related to the occurrence or severity of AMS.

AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure

The present study is the first to examine the effect of high-altitude acclimatization and reexposure on the responses of cerebral blood flow and ventilation to CO2. We also compared the steady-state estimates of these parameters during acclimatization with the modified rebreathing method. We assessed changes in steady-state responses of middle cerebral artery velocity (MCAv), cerebrovascular conductance index (CVCi), and ventilation (V(E)) to varied levels of CO2 in 21 lowlanders (9 women; 21 ± 1 years of age) at sea level (SL), during initial exposure to 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon reexposure to altitude following either 7 (POST7) or 21 days (POST21) at low altitude (1,525 m). In the nonacclimatized state (ALT1), MCAv and V(E) responses to CO2 were elevated compared with those at SL (by 79 ± 75% and 14.8 ± 12.3 l/min, respectively; P = 0.004 and P = 0.011). Acclimatization at ALT16 further elevated both MCAv and Ve responses to CO2 compared with ALT1 (by 89 ± 70% and 48.3 ± 32.0 l/min, respectively; P < 0.001). The acclimatization gained for V(E) responses to CO2 at ALT16 was retained by 38% upon reexposure to altitude at POST7 (P = 0.004 vs. ALT1), whereas no retention was observed for the MCAv responses (P > 0.05). We found good agreement between steady-state and modified rebreathing estimates of MCAv and V(E) responses to CO2 across all three time points (P < 0.001, pooled data). Regardless of the method of assessment, altitude acclimatization elevates both the cerebrovascular and ventilatory responsiveness to CO2. Our data further demonstrate that this enhanced ventilatory CO2 response is partly retained after 7 days at low altitude.

Effect of oral nitrate supplementation on pulmonary hemodynamics during exercise and time trial performance in normoxia and hypoxia: a randomized controlled trial

Background: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. Methods: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. Results: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). Conclusion: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.

Cycling Time Trial Is More Altered in Hypobaric than Normobaric Hypoxia.

PURPOSE Slight physiological differences between acute exposure in normobaric hypoxia (NH) and hypobaric hypoxia (HH) have been reported. Taken together, these differences suggest different physiological responses to hypoxic exposure to a simulated altitude (NH) versus a terrestrial altitude (HH). For this purpose, in the present study, we aimed to directly compare the time-trial performance after acute hypoxia exposure (26 h, 3450 min) by the same subjects under three different conditions: NH, HH, and normobaric normoxia (NN). Based on all of the preceding studies examining the differences among these hypoxic conditions, we hypothesized greater performance impairment in HH than in NH. METHODS The experimental design consisted of three sessions: NN (Sion: FiO2, 20.93), NH (Sion, hypoxic room: FiO2, 13.6%; barometric pressure, 716 mm Hg), and HH (Jungfraujoch: FiO2, 20.93; barometric pressure, 481 mm Hg). The performance was evaluated at the end of each session with a cycle time trial of 250 kJ. RESULTS The mean time trial duration in NN was significantly shorter than under the two hypoxic conditions (P < 0.001). In addition, the mean duration in NH was significantly shorter than that in HH (P < 0.01). The mean pulse oxygen saturation during the time trial was significantly lower for HH than for NH (P < 0.05), and it was significantly higher in NN than for the two other sessions (P < 0.001). CONCLUSION As previously suggested, HH seems to be a more stressful stimulus, and NH and HH should not be used interchangeability when endurance performance is the main objective. The principal factor in this performance difference between hypoxic conditions seemed to be the lower peripheral oxygen saturation in HH at rest, as well as during exercise.

Effect of end-tidal CO2 clamping on cerebrovascular function, oxygenation, and performance during 15-km time trial cycling in severe normobaric hypoxia: the role of cerebral O2 delivery

During heavy exercise, hyperventilation‐induced hypocapnia leads to cerebral vasoconstriction, resulting in a reduction in cerebral blood flow (CBF). A reduction in CBF would impair cerebral O2 delivery and potentially account for reduced exercise performance in hypoxia. We tested the hypothesis that end‐tidal Pco2 (PETCO2) clamping in hypoxic exercise would prevent the hypocapnia‐induced reduction in CBF during heavy exercise, thus improving exercise performance. We measured PETCO2, middle cerebral artery velocity (MCAv; index of CBF), prefrontal cerebral cortex oxygenation (cerebral O2Hb; index of cerebral oxygenation), cerebral O2 delivery (DO2), and leg muscle oxygenation (muscle O2Hb) in 10 healthy men (age 27 ± 7 years; VO2max 63.3 ± 6.6 mL/kg/min; mean ± SD) during simulated 15‐km time trial cycling (TT) in normoxia and hypoxia (FIO2 = 0.10) with and without CO2 clamping. During exercise, hypoxia elevated MCAv and lowered cerebral O2Hb, cerebral DO2, and muscle O2Hb (P < 0.001). CO2 clamping elevated PETCO2 and MCAv during exercise in both normoxic and hypoxic conditions (P < 0.001 and P = 0.024), but had no effect on either cerebral and muscle O2Hb (P = 0.118 and P = 0.124). Nevertheless, CO2 clamping elevated cerebral DO2 during TT in both normoxic and hypoxic conditions (P < 0.001). CO2 clamping restored cerebral DO2 to normoxic values during TT in hypoxia and tended to have a greater effect on TT performance in hypoxia compared to normoxia (P = 0.097). However, post hoc analysis revealed no effect of CO2 clamping on TT performance either in normoxia (P = 0.588) or in hypoxia (P = 0.108). Our findings confirm that the hyperventilation‐induced hypocapnia and the subsequent drop in cerebral oxygenation are unlikely to be the cause of the reduced endurance exercise performance in hypoxia.

Muscle Fatigue Affects the Interpolated Twitch Technique When Assessed Using Electrically-Induced Contractions in Human and Rat Muscles

The interpolated twitch technique (ITT) is the gold standard to assess voluntary activation and central fatigue. Yet, its validity has been questioned. Here we studied how peripheral fatigue can affect the ITT. Repeated contractions at submaximal frequencies were produced by supramaximal electrical stimulations of the human adductor pollicis muscle in vivo and of isolated rat soleus fiber bundles; an extra stimulation pulse was given during contractions to induce a superimposed twitch. Human muscles fatigued by repeated 30-Hz stimulation trains (3 s on–1 s off) showed an ~80% reduction in the superimposed twitch force accompanied by a severely reduced EMG response (M-wave amplitude), which implies action potential failure. Subsequent experiments combined a less intense stimulation protocol (1.5 s on–3 s off) with ischemia to cause muscle fatigue, but which preserved M-wave amplitude. However, the superimposed twitch force still decreased markedly more than the potentiated twitch force; with ITT this would reflect increased “voluntary activation.” In contrast, the superimposed twitch force was relatively spared when a similar protocol was performed in rat soleus bundles. Force relaxation was slowed by >150% in fatigued human muscles, whereas it was unchanged in rat soleus bundles. Accordingly, results similar to those in the human muscle were obtained when relaxation was slowed by cooling the rat soleus muscles. In conclusion, our data demonstrate that muscle fatigue can confound the quantification of central fatigue using the ITT.

Comparison of Sleep Disorders between Real and Simulated 3,450-m Altitude.

STUDY OBJECTIVES Hypoxia is known to generate sleep-disordered breathing but there is a debate about the pathophysiological responses to two different types of hypoxic exposure: normobaric hypoxia (NH) and hypobaric hypoxia (HH), which have never been directly compared. Our aim was to compare sleep disorders induced by these two types of altitude. METHODS Subjects were exposed to 26 h of simulated (NH) or real altitude (HH) corresponding to 3,450 m and a control condition (NN) in a randomized order. The sleep assessments were performed with nocturnal polysomnography (PSG) and questionnaires. Thirteen healthy trained males subjects volunteered for this study (mean ± SD; age 34 ± 9 y, body weight 76.2 ± 6.8 kg, height 179.7 ± 4.2 cm). RESULTS Mean nocturnal oxygen saturation was further decreased during HH than in NH (81.2 ± 3.1 versus 83.6 ± 1.9%; P < 0.01) when compared to NN (95.5 ± 0.9%; P < 0.001). Heart rate was higher in HH than in NH (61 ± 10 versus 55 ± 6 bpm; P < 0.05) and NN (48 ± 5 bpm; P < 0.001). Total sleep time was longer in HH than in NH (351 ± 63 versus 317 ± 65 min, P < 0.05), and both were shorter compared to NN (388 ± 50 min, P < 0.05). Breathing frequency did not differ between conditions. Apnea-hypopnea index was higher in HH than in NH (20.5 [15.8-57.4] versus 11.4 [5.0-65.4]; P < 0.01) and NN (8.2 [3.9-8.8]; P < 0.001). Subjective sleep quality was similar between hypoxic conditions but lower than in NN. CONCLUSIONS Our results suggest that HH has a greater effect on nocturnal breathing and sleep structure than NH. In HH, we observed more periodic breathing, which might arise from the lower saturation due to hypobaria, but needs to be confirmed.

Minimal Window Duration for Accurate HRV Recording in Athletes

Heart rate variability (HRV) is non-invasive and commonly used for monitoring responses to training loads, fitness, or overreaching in athletes. Yet, the recording duration for a series of RR-intervals varies from 1 to 15 min in the literature. The aim of the present work was to assess the minimum record duration to obtain reliable HRV results. RR-intervals from 159 orthostatic tests (7 min supine, SU, followed by 6 min standing, ST) were analyzed. Reference windows were 4 min in SU (min 3–7) and 4 min in ST (min 9–13). Those windows were subsequently divided and the analyses were repeated on eight different fractioned windows: the first min (0–1), the second min (1–2), the third min (2–3), the fourth min (3–4), the first 2 min (0–2), the last 2 min (2–4), the first 3 min (0–3), and the last 3 min (1–4). Correlation and Bland & Altman statistical analyses were systematically performed. The analysis window could be shortened to 0–2 instead of 0–4 for RMSSD only, whereas the 4-min window was necessary for LF and total power. Since there is a need for 1 min of baseline to obtain a steady signal prior the analysis window, we conclude that studies relying on RMSSD may shorten the windows to 3 min (= 1+2) in SU or seated position only and to 6 min (= 1+2 min SU plus 1+2 min ST) if there is an orthostatic test. Studies relying on time- and frequency-domain parameters need a minimum of 5 min (= 1+4) min SU or seated position only but require 10 min (= 1+4 min SU plus 1+4 min ST) for the orthostatic test.