Internal medicine

Endocrinology

Perfusion

Organic chemistry

Chemistry

Vasoconstriction

Hypoxic pulmonary vasoconstriction

Potassium

Sodium

Oxygen

Oxygenation

Medicine

Biology

The Journal of Physiology

Nevertheless, some physiological responses such as the erythropoietic (Hauser et al. 2016) and the cerebral oxygenation/perfusion (DiPasquale et al. 2016) do seem unaffected by the differential PB. Overall, there are currently (November 2019) >50 peer reviewed scientific publications reporting different responses between HH vs. NH and most support the conclusion that ‘NH is not a surrogate of HH’ and ‘cannot be used interchangeably’ (Fulco et al. 2011), with HH representing a more severe physiological stimulus than NH at the same . Whilst the exact mechanisms by which the lower PB in HH independently modulates the observed NH vs. HH differences remain elusive, some potential underlying factors have been identified previously. In particular, hypobaria per se has been suggested to provoke higher hypoxic pulmonary vasoconstriction that could result in changes of alveolar dead space and altered ventilation–perfusion ratio (Loeppky et al. 1997). Increased physiological dead space has also been suggested as one of the potential -independent mechanisms of hypobaria (Savourey et al. 2003) which could underlie the reported differences in the ventilatory and blood gas parameters. Different regulation of fluid and acid–base balance as a consequence of hypobaria has also been suggested (Loeppky et al. 2005). In particular, the hypobaria-related augmentation of aldosterone and altered cell-membrane permeability might importantly modulate changes in sodium and potassium concentrations and subsequently fluid balance (Loeppky et al. 2005). Finally, hypobaria-provoked changes in nitric oxide back-diffusion from alveoli to pulmonary circulation, potentially caused by the reduced gas density, have also been suggested to underlie the reported NH and HH differences (Hemmingsson & Linnarsson, 2009). In order to advance our understanding of the involved mechanisms and subsequent physiological differences, further studies should employ comprehensive methodological approaches which consider the potential independent and combined effects of hypoxia, hypobaria as well as gas density. Prospective studies should thus, besides normobaric and hypobaric hypoxic exposures, aim to also incorporate hyperbaric normoxic and normobaric hyperoxic exposures. In addition, proper control and standardization of other environmental factors (temperature, humidity and/or hypercapnia in chamber studies) is of paramount importance. From a methodological point of view, an often neglected, but important aspect of altitude research relates to the temporal PB variations. This issue has already been highlighted almost four decades ago by West et al. (1983). In line with their work and in order to get contemporary insight into PB variations, we collected (www.meteoswiss.ch) the mean hourly values of PB over one year (2018) at 20 meteorological stations across Switzerland and calculated the averages of five stations at four different altitudes: near sea-level, 1000, 2000 and 3000 m, respectively. By using the obtained PB values, we calculated the corresponding as well as the corresponding ‘simulated altitude’ (Gallagher & Hackett, 2004). Finally, we calculated the means and maximal ranges of changes over 24 h, 1 week and 1 year. The obtained data, presented in Table 1, show that changes in ‘calculated’ altitudes at the same terrestrial locations can reach ≥250 m over 24 h and ≥500 m over 1 year. The noted temporal PB changes (daily or seasonal) during the course of high-altitude sojourns and/or altitude/hypoxia studies remain poorly characterized and seem to be, for the most part, neglected. The present data along with other methodological issues thus have important clinical applications. First, the general recommendation for preventing high altitude illness, to not ascend more than 300–500 m per day (Bartsch & Swenson, 2013), might be insufficient since the actual change in ‘altitude’ at the same terrestrial point can reach ∼270 m over 24 h (Table 1). While we agree that the current ascent recommendation remains relevant from a public health perspective (on most days the change in PB is negligible), it might nevertheless be prudent to update these recommendations for mountain professionals (guides, athletes, first responders), by take daily PB variation into account, and also complement it with enhanced educational strategies (Pasquier et al. 2019). Second, the commonly reported rather large interindividual variability in susceptibility to high altitude illness (Luks et al. 2017) may also, at least in part, be related to the variation in hypoxia severity due to differential PB conditions. This point is particularly important for valid comparisons of different studies investigating incidence of high altitude-related ailments at the same terrestrial locations but with different PB conditions. Indeed, most long-term high altitude studies (e.g. weeks or years; Schneider et al. 2002) only report terrestrial altitudes and only rarely provide mean values of PB or (Saugy et al. 2016b). It thus seems crucial that future studies not only report the terrestrial altitudes and but also average values and variability of PB and . Finally, the ventilatory acclimatization of individuals exposed to NH was shown to be effective only when measured in NH but not in HH and did not provoke any subsequent performance benefit (Fulco et al. 2013). While we agree that a hypoxic exercise test performed in NH is of value to predict high altitude illness at-risk individuals (Richalet et al. 2012), one may argue that, given the above-described potential independent influence of PB, a similar test performed in HH would result in greater predictive power. Notable future focus should also be dedicated to discerning the potential independent effect of PB on health and wellbeing of clinical populations, especially since PB changes have previously been suggested to importantly influence the medical status of patient with myocardial infarction (Danet et al. 1999), pulmonary embolism (Meral et al. 2005) and/or osteoarthritis (McAlindon et al. 2007). As emphasized previously, these scientific questions should be addressed using robust and properly designed experimental studies conducted under laboratory and field-based frameworks. Overall, the currently available data suggests that (1) the barometric pressure may independently exert an important influence on many physiological responses; (2) this independent barometric pressure effect may result in significant differences in physiological responses between normobaric and hypobaric hypoxia; and (3) the potential variation in barometric pressure has to be taken into account when interpreting the results of the altitude/hypoxia studies and also, even more importantly, within the applied framework of high-altitude medicine. We thus maintain that the barometric pressure remains the forgotten parameter in altitude physiology and mountain medicine, as if, similarly to the Himalayan Yeti, there are certain things we first ought to see before we consider them seriously. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘LastWord’. Please email your comment, including a title and a declaration of interest, to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. Grégoire Millet is Professor of Exercise Physiology at ISSUL (Institute of Sport Sciences) in Lausanne, the “Olympic Capital”. His main research topic is on the ergogenic and therapeutic effects of hypoxia/altitude in athletes and patient. He has been a professional triathlete and elite coach attending many Word Championships and several Olympic Games. Tadej Debevec is an Assistant Professor at Faculty of Sport, University of Ljubljana and Research Associate at “Jozef Stefan” Institute, Ljubljana, Slovenia. His research work is predominantly oriented on the effects of hypoxia and/or altitude on cardiorespiratory, metabolic and oxidative stress responses in various population from athletes to patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None.

CrossTalk proposal: Barometric pressure, independent of , is the forgotten parameter in altitude physiology and mountain medicine