Pro: Hypoxic Cardiopulmonary Exercise Testing Identifies Subjects at Risk for Severe High Altitude Illnesses

An increased number of sea-level residents visit areas above 4000 m of altitude for leisure, sport or work. They may suffer from severe acute mountain sickness, high altitude pulmonary or cerebral edema, especially when they are not yet acclimatized to the hypoxic environment (Hackett et al., 1976; Bärtsch and Swenson, 2013). The above clinical outcomes have been regrouped in a clinical entity called severe high altitude illness (SHAI). Severe acute mountain sickness is defined by a Hackett's score of at least 6, with incapacitating symptoms leading to a stop or a significant reduction of planned activity. (Richalet et al., 2012a). Until recently, current literature about the risk factors of SHAI mainly mentioned clinical features as predisposing factors (Hackett et al., 1976; Bärtsch and Swenson, 2013). Unfortunately, the clinical conditions recognized as risk factors for altitude problems are scarce and unspecific, such as migraine or obesity. The main risk factors identified were history of previous problems at high altitude and excessive speed of ascent during the acclimatization period (Schneider et al., 2002). However, the first factor is, in many cases, unavailable since people come to the consultation with no previous experience of prolonged stay at high altitude. The second factor is retrospective or can just be considered as a hypothesis for the planned trip at high altitude. Resting ventilatory response to hypoxia has been related to the risk of altitude illness but with a very limited sensitivity and specificity (Bärtsch and Swenson, 2013). Therefore, our aim was to develop a useful, objective, and quantified tool based on the pathophysiological knowledge of altitude related illnesses in order to ameliorate the risk prediction for candidates to high altitude.

Considering that severe health problems at high altitude (SHAI) are clearly due to hypoxia, and more precisely to hypoxemia and that the prevalence of these problems increases with altitude and therefore with the level of hypoxemia, it is reasonable to think that physiological mechanisms acting on the level of hypoxemia will be determinant factors for SHAI. The sensitivity of the peripheral chemoreceptors to hypoxia is one of the most powerful determinants of the level of hypoxemia. Moreover, hypoxemia is aggravated by exercise in altitude conditions, due to diffusion limitation, especially in highly endurance-trained subjects (Mollard et al., 2007; Woorons et al., 2007), suggesting that it would be more appropriate to study the response to hypoxia during exercise rather than at rest. Therefore, we developed a hypoxia exercise test in order to evaluate the ventilatory and cardiac responses to hypoxia at exercise, which mainly depends on the sensitivity of peripheral chemoreceptors (Richalet et al., 1988; Richalet et al., 2012a; Lhuissier et al., 2012a; Lhuissier et al., 2012b).

Recently, we assessed several clinical, environmental and physiological independent risk factors of SHAI in a unique cohort of 1326 sea-level residents who came to an outpatient mountain medicine consultation and underwent the hypoxic exercise test before a stay at altitude above 4000 m (Richalet et al., 2012a). The occurrence of SHAI was evaluated through a self-assessment questionnaire. The main risk factors evidenced were previous history of SHAI, low ventilatory and cardiac response to hypoxia at exercise, speed of ascent above 400 m per day in the acclimatization period, high desaturation during exercise in hypoxia, history of migraine, geographical location (Aconcagua, Mont-Blanc, Ladakh), female gender, regular endurance training and age under 46 years old. This study was the first to demonstrate that adding physiological measurements to clinical evaluation greatly improved the discrimination between susceptible and non-susceptible subjects (Richalet et al., 2013). As 45% of the subjects coming to the outpatient consultation had no previous experience of sojourn at high altitude, one of the main risk factor (history of SHAI) could not be taken into account in the risk prediction. Moreover, our study allowed quantifying (−44%) the reduction of SHAI risk in the population taking spontaneously acetazolamide as a preventive medication (Richalet et al., 2012a).

Then, we developed and validated a risk prediction score for SHAI occurrence including clinical and physiological factors (Canoui-Poitrine et al., 2014). The objective was to assess and quantify the benefit of performing a hypoxia exercise test to predict the risk of SHAI, especially in subjects without previous experience at high altitude. This score may be useful to detect highly susceptible subjects and improve the prevention of SHAI for newcomers at high altitude. To better take into account the personal history of each participant, two scores could be built, according to the presence (PRE; n=537) or absence (ABS; n=480) of previous experience at high altitude, using multivariate logistic regression. Calibration was evaluated by Hosmer-Lemeshow chisquare test and discrimination by Area Under ROC Curve (AUC). The scores are linear combinations of history of SHAI, ventilatory response to hypoxia at exercise (<0.68 L/min/kg), cardiac response to hypoxia at exercise, (<0.72 b/min/%), speed of ascent, desaturation during hypoxic exercise (≥24%), history of migraine, geographical location, female sex, age under 46 and regular physical activity. Adding physiological variables via the hypoxic exercise test improved the discrimination ability of the models: AUC increased by 7.4 % in the PRE group and 17.2 % in the ABS group (Table 1). Therefore, our 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.

Some limitations can be mentioned. Due to the selection of our population (mostly trekkers, rather physically fit, very few obese persons), obesity was not found here as a risk factor, although this condition was found at risk in more sedentary groups (Ri-Li et al., 2003). All subjects coming to the consultation were unacclimatized (no recent stay at high altitude), but it is clear that previous acclimatization is clearly a protecting factor against SHAI (Schneider et al., 2002). Finally, our score will be open for validation in other centers involved in mountain medicine.

In conclusion, our hypoxic exercise test allowed the development of a quantitative, objective clinical and physiological score that significantly improves the detection of subjects at high risk for SHAI and rationalizes the advice given to the patients in terms of ascent profile and use of acetazolamide, especially for “altitude naïve” subjects. The use of this score, as a decisional help for the physician, is in line with a common approach in modern medicine for a therapeutic management in cardiovascular, intensive care or cancer diseases.