Risk prediction score for severe high altitude illness: a cohort study.

BACKGROUND: Risk prediction of acute mountain sickness, high altitude (HA) pulmonary or cerebral edema is currently based on clinical assessment. Our objective was to develop a risk prediction score of Severe High Altitude Illness (SHAI) combining clinical and physiological factors. Study population was 1017 sea-level subjects who performed a hypoxia exercise test before a stay at HA. The outcome was the occurrence of SHAI during HA exposure. Two scores were built, according to the presence (PRE, n = 537) or absence (ABS, n = 480) of previous experience at HA, using multivariate logistic regression. Calibration was evaluated by Hosmer-Lemeshow chisquare test and discrimination by Area Under ROC Curve (AUC) and Net Reclassification Index (NRI). RESULTS: The score was a linear combination of history of SHAI, ventilatory and cardiac response to hypoxia at exercise, speed of ascent, desaturation during hypoxic exercise, history of migraine, geographical location, female sex, age under 46 and regular physical activity. In the PRE/ABS groups, the score ranged from 0 to 12/10, a cut-off of 5/5.5 gave a sensitivity of 87%/87% and a specificity of 82%/73%. Adding physiological variables via the hypoxic exercise test improved the discrimination ability of the models: AUC increased by 7% to 0.91 (95%CI: 0.87-0.93) and 17% to 0.89 (95%CI: 0.85-0.91), NRI was 30% and 54% in the PRE and ABS groups respectively. A score computed with ten clinical, environmental and physiological factors accurately predicted the risk of SHAI in a large cohort of sea-level residents visiting HA regions.

Physiological risk factors for severe high-altitude illness: a prospective cohort study.

RATIONALE: An increasing number of persons, exposed to high altitude for leisure, sport, or work, may suffer from severe high-altitude illness. OBJECTIVES: To assess, in a large cohort of subjects, the association between physiological parameters and the risk of altitude illness and their discrimination ability in a risk prediction model. METHODS: A total of 1,326 persons went through a hypoxic exercise test before a sojourn above 4,000 m. They were then monitored up at high altitude and classified as suffering from severe high-altitude illness (SHAI) or not. Analysis was stratified according to acetazolamide use. MEASUREMENTS AND MAIN RESULTS: Severe acute mountain sickness occurred in 314 (23.7%), high-altitude pulmonary edema in 22 (1.7%), and high-altitude cerebral edema in 13 (0.98%) patients. Among nonacetazolamide users (n = 917), main factors independently associated with SHAI were previous history of SHAI (adjusted odds ratios [aOR], 12.82; 95% confidence interval [CI], 6.95-23.66; P < 0.001), ascent greater than 400 m/day (aOR, 5.89; 95% CI, 3.78-9.16; P < 0.001), history of migraine (aOR, 2.28; 95% CI, 1.28-4.07; P = 0.005), ventilatory response to hypoxia at exercise less than 0.78 L/minute/kg (aOR, 6.68; 95% CI, 3.83-11.63; P < 0.001), and desaturation at exercise in hypoxia equal to or greater than 22% (aOR, 2.50; 95% CI, 1.52-4.11; P < 0.001). The last two parameters improved substantially the discrimination ability of the multivariate prediction model (C-statistic rose from 0.81 to 0.88; P < 0.001). Preventive use of acetazolamide reduced the relative risk of SHAI by 44%. CONCLUSIONS: In a large population of altitude visitors, chemosensitivity parameters (high desaturation and low ventilatory response to hypoxia at exercise) were independent predictors of severe high-altitude illness. They improved the discrimination ability of a risk prediction model.

Holmes-Adie syndrome associated with high altitude pulmonary edema and low chemo-responsiveness to hypoxia.

A 63-year-old patient with Holmes-Adie syndrome presented an altered peripheral chemoreflex and suffered from high altitude pulmonary edema, suggesting an alteration of sensitive afferent fibers from the peripheral chemoreceptors. Chemo-responsiveness to hypoxia should be explored before any exposure to moderate altitude in Holmes-Adie patients.

Effects of high-altitude hypoxia on the hormonal response to hypothalamic factors.

Acute and chronic exposure to high altitude induces various physiological changes, including activation or inhibition of various hormonal systems. In response to activation processes, a desensitization of several pathways has been described, especially in the adrenergic system. In the present study, we aimed to assess whether the hypophyseal hormones are also subjected to a hypoxia-induced decrease in their response to hypothalamic factors. Basal levels of hormones and the responses of TSH, thyroid hormones, prolactin, sex hormones, and growth hormone to the injection of TRH, gonadotropin-releasing hormone, and growth hormone-releasing hormone (GHRH) were studied in eight men in normoxia and on prolonged exposure (3-4 days) to an altitude of 4,350 m. Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, and follicle-stimulating hormone and prolactin decreased, while leutinizing hormone was unchanged. Norepinephrine and cortisol levels were elevated, while no change was observed in levels of epinephrine, dopamine, growth hormone (GH), IGF-1, and IGFBP-3. The mean response to hypothalamic factors was similar in both altitudes for all studied hormones, although total T4 was lower in hypoxia during 45 to 60 min after injection. The effect of hypoxia on the hypophyseal response to hypothalamic factors was similar among subjects, except for the GH response to GHRH administration. We conclude that prolonged exposure to high-altitude hypoxia induces contrasted changes in hormonal levels, but the hypophyseal response to hypothalamic factors does not appear to be blunted.

Interaction between hypoxia and training on NIRS signal during exercise: contribution of a mathematical model.

Acute exposure to hypoxia provokes a decrease in peak oxygen consumption ( V(O)(2peak)). At and above 4000 m, the decrease in V(O)(2peak) is greater than expected from the decrease in arterial oxygen content (C(a)O(2)) suggesting the participation of other factors. We hypothesized that O(2) transfer within the active muscle may play a role. Therefore we used Near Infra Red Spectroscopy (NIRS) to assess oxy (O2Hb) and deoxyhemoglobin (HHb) concentration in the vastus lateralis of trained athletes (TA) and untrained subjects (US) exercising at various inspired oxygen pressure (PI(O)(2), 131.4, 107.3 and 87.0 mmHg). A mathematical model has been developed to compute: (i) the pulmonary (K(p)) and muscular (K(tm)) O(2) diffusion coefficients and (ii) the proportion of arteriolar:capillary:venous blood participating in the NIRS signal at every exercise intensity from rest to peak exercise in the normoxic and various hypoxic conditions. In TA, O2Hb decreased near maximal exercise at 2500 and 4000 m, while in US, altitude had no effect. In normoxia O2Hb was higher in TA than in US, the difference disappearing in hypoxia. K(tm) increased linearly with workload and altitude and was higher in TA than US while K(p) plateaued near maximal exercise, which was consistent with athletes' greater decrease in C(a)O(2). The greater participation of arterial blood in the NIRS signal in TA at altitudes account for their higher O2Hb values as well as the greater decrease they underwent in hypoxia. At 4000m, athletes loose their advantages of adaptation to training due to a reduced arterial content, and both from NIRS variables and model output, characteristics of O(2) transfer of TA converge toward those of US.

Non-invasive evaluation of the capillary recruitment in the human muscle during exercise in hypoxia.

This study proposes a non-invasive evaluation of capillary recruitment in human muscle from resting state to maximal exercise while under hypoxic conditions. Our work is based on the analysis of oxygen transport variables measured during incremental exercise in endurance-trained men (n=8) and in their sedentary counterparts (n=8). Maximal exercise tests were performed on a cycloergometer in normoxia and at three simulated normobaric levels of hypoxia (altitude equivalent to 1000, 2500 and 4500 m). We made the assumption that the relationship between the oxygen diffusion coefficient (Kt) and cardiac output (Qc) was: Kt=kQcNc where Nc is the capillary recruitment coefficient during exercise. Our results demonstrate that Nc increases with altitude and that the increase is greater in trained compared with untrained subjects at high altitude (4500 m). Moreover, the venous PO2 threshold beyond which capillary recruitment increases is lower in trained men. Despite their greater increase in capillary recruitment, trained men are not able to compensate for their drastic drop in arterial oxygen content during exercise in acute hypoxia, which results in a greater drop in maximal oxygen consumption than in sedentary men.