741
Exp Physiol 99.5 (2014) pp 741–742
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On the nature of research at high altitude: packing it all in! Philip N. Ainslie School of Health and Exercise Sciences, University of British Columbia, British Columbia, Canada
ExperimentalPhysiology
Email: [email protected]
The unique stress that high-altitude poses to physiological function and adaptation has drawn researchers and clinicians to hard-to-reach places for over a century. Despite the profound logistical and financial challenge, personal risk and time inherent to such science, there have been many large-scale expeditions in the last 100 years that have conducted intensive research at high altitude. Seminal studies include the following: the Anglo-American high-altitude expedition to Pikes Peak in 1911 led by J. S. Haldane (Oxford, UK), Y. Henderson and E. Schneider (USA); The Silver Hut expedition in 1960–1961 led by G. Pugh; the American Research Expedition to Everest in 1981 led by J. B. West; a number of French Medical Expeditions lead by J. Richalet in the 1980s; the Danish High-Altitude Expedition to the Andes led by B. Saltin in 1998; and the Caudwell Xtreme Everest Expedition in 2007 led by M. Grocott and colleagues. The majority of these field studies followed the typical regimen of physiological measurements at sea level, at various time points at high altitude, and sometimes following descent to sea level. Anyone who has been involved in a co-ordinated large-scale expedition to high-altitude appreciates the degree of planning, organization and management that typically begins 2–5 years prior. Expeditions are expensive and require substantial funding (often from unusual sources). They demand a co-ordinated approach by a compatible research team, typically spearheaded by a number of lead investigators along with their respective students and/or fellows. This makes gaining ethical approval for the resultantly broad range of experiments an arduous prospect. The logistical and financial nightmare
of personnel and equipment transport must finally be tackled. The transportation of expensive and fragile equipment to high-altitude regions where conventional carriage is impossible and difficulties with importation tax and customs make this final hurdle not trivial. It is for these reasons that high-altitude field studies have normally included multiple experimental questions and their corollary publications, often yielding >10–20 papers from a single expedition. Such a research design is sometimes criticized for duplication or overlap of data, but is defensible providing that that any duplication of data is acknowledged and that publications are not intentionally partitioned, but rather best packaged to address their respective a priori hypothesis. Moreover, because of unknown complications and related risks of conducting research at altitude, many of the planned experiments are unsuccessful; hence, they are never published. Thus, packing it all in from a research perspective – as long as there is little or no contamination of experiments – makes good sense. The most recent addition to the detailed physiological study of humans at high altitude, called ‘AltitudeOmics’, was conducted at 5260 m in Bolivia in 2012 and is an excellent example of this perspective. AltitudeOmics is a multifaceted research programme on acclimatization to high altitude. Lowland volunteers were taken rapidly to 5260 m, where they acclimatized for 16 days. They then descended to 1525 m for 7 or 21 days, after which they returned quickly to 5260 m and were retested. Numerous physiological metrics and features of acclimatization were measured, as follows: arterial blood oxygenation, acute mountain sickness scores, cognitive function tests and submaximal exercise performance; cerebral blood flow and autoregulation; chemical control of breathing; total haemoglobin mass and blood volume compartments; central and peripheral fatigue; blood flow through intracardiac shunt (patent foramen ovale) and intrapulmonary arteriovenous anastomoses; and a broad array of ‘omics’ responses (transcriptomics, epigenomics, metabolomics and proteomics) were
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
monitored. The AltitudeOmics expedition is an archetype of the expedition discussed above, and such a comprehensive range questions and their attendant metrics do not belong in single publication, despite all being assessed in the same group of subjects. The AltitudeOmics expedition deviated from typical altitude field study modus operandi with the following two major experimental additions: (i) a subset of subjects were rapidly transported to high altitude whilst breathing supplemental oxygen in order to elicit an abrupt change in arterial P O2 ; and (ii) following partial acclimatization, subjects re-ascended to altitude. In many ways, this approach is similar to that which can be achieved in laboratory studies with hypoxic gas or hypobaric chambers (e.g. the Operation Everest II and III chamber studies). Nevertheless, the AltitudeOmics project should be commended for their elegantly unique study design, but their findings should be interpreted in this context and are likely to be different from other field studies that have followed more traditional progressive ascents. The design reduced the typical confounders of slow ascent (e.g. variable ventilatory acclimatization, dehydration, sleep disturbances and gastrointestinal distress); hence, it improved the separation of the acute physiological adjustments from the variable duress of prolonged exposure to high altitude. Consequently, these data might be more applicable to rapid military deployment to high altitude and the related prediction for susceptibility to altitude illness. In this issue of Experimental Physiology, the authors assessed volumetric regional brain blood flow and intracranial blood velocity at sea level and 2–4 h after arrival at 5260 m following cessation of supplemental oxygen (Subudhi et al. 2014b). Subjects then acclimatized over the next 15 days, with a majority of the time spent at 5260 m. Measurements were repeated on days 15–16. Unlike other experiments from this project (e.g. Fan et al. 2014; Subudhi et al. 2014a), the adjustments or ‘memory’ to re-exposure to 5260 m were not assessed. Their findings (Subudhi et al. 2014b) confirm that global cerebral oxygen delivery
DOI: 10.1113/expphysiol.2013.077362
Viewpoint
742 is preserved, despite reductions in arterial O2 content with ascent, by commensurately increased cerebral blood flow (Willie et al. 2014). The novel finding was that there was slight increase (9%) in relative oxygen delivery to the posterior cerebral circulation when compared with the anterior region during acute exposure to 5260 m. Although consistent with findings at sea level in conditions of severe isocapnic hypoxia (Willie et al. 2012), the mechanism and physiological relevance of a small increase in posture posterior cerebral perfusion are unknown. Finally, the findings by Subudhi et al. (2014b) of a large discrepancy between velocity in the middle cerebral artery (MCA) and internal carotid artery flow are also consistent with dilatation of the MCA at 5050 m (Willie et al. 2013), but also raise doubt about assertions made in other studies from this project that MCA velocities reflect changes in flow at this altitude (e.g. Fan et al. 2014.) The ‘threshold’ at which dilatation of the MCA might occur during conditions of poikilocapnic hypoxia is currently unknown.
In summary, the AltitudeOmics project demonstrates the feasibility of a multifarious design, and the current and forthcoming publications will provide a diversely rich addition to our understanding of the biological adaptation – and, potentially, maladaptation – to high altitude.
Call for comments Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/ expphysiol;99/5/741.
References Fan J-L, Subudhi AW, Evero O, Bourdillon N, Kayser B, Lovering AT & Roach RC (2014). AltitudeOmics: Enhanced cerebrovascular reactivity and ventilatory response to CO2 with high altitude acclimatisation and re-exposure. J Appl Physiol, In Press.
Exp Physiol 99.5 (2014) pp 741–742
Subudhi AW, Fan J-L, Evero O, Bourdillon N, Kayser B, Julian CG, Lovering AT, Panerai RB & Roach RC (2014a). AltitudeOmics: Cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness. J Appl Physiol, In Press. Subudhi AW, Fan J-L, Evero O, Bourdillon N, Kayser B, Julian CG, Lovering AT & Roach RC (2014b). AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery. Exp Physiol, 99, 772–781. Willie CK, Macleod DB, Shaw AD, Smith KJ, Tzeng YC, Eves ND, Ikeda K, Graham J, Lewis NC, Day TA & Ainslie PN (2012). Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 590, 3261–3275. Willie CK, Smith KJ, Day TA, Ray LA, Lewis NC, Bakker A, Macleod DB & Ainslie PN (2014). Regional cerebral blood flow in humans at high altitude: gradual ascent and two weeks at 5050m. J Appl Physiol. In Press.
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
Exp Physiol 99.5 (2014) pp 741–742
Viewpoint Viewpoint
On the nature of research at high altitude: packing it all in! Philip N. Ainslie School of Health and Exercise Sciences, University of British Columbia, British Columbia, Canada
ExperimentalPhysiology
Email: [email protected]
The unique stress that high-altitude poses to physiological function and adaptation has drawn researchers and clinicians to hard-to-reach places for over a century. Despite the profound logistical and financial challenge, personal risk and time inherent to such science, there have been many large-scale expeditions in the last 100 years that have conducted intensive research at high altitude. Seminal studies include the following: the Anglo-American high-altitude expedition to Pikes Peak in 1911 led by J. S. Haldane (Oxford, UK), Y. Henderson and E. Schneider (USA); The Silver Hut expedition in 1960–1961 led by G. Pugh; the American Research Expedition to Everest in 1981 led by J. B. West; a number of French Medical Expeditions lead by J. Richalet in the 1980s; the Danish High-Altitude Expedition to the Andes led by B. Saltin in 1998; and the Caudwell Xtreme Everest Expedition in 2007 led by M. Grocott and colleagues. The majority of these field studies followed the typical regimen of physiological measurements at sea level, at various time points at high altitude, and sometimes following descent to sea level. Anyone who has been involved in a co-ordinated large-scale expedition to high-altitude appreciates the degree of planning, organization and management that typically begins 2–5 years prior. Expeditions are expensive and require substantial funding (often from unusual sources). They demand a co-ordinated approach by a compatible research team, typically spearheaded by a number of lead investigators along with their respective students and/or fellows. This makes gaining ethical approval for the resultantly broad range of experiments an arduous prospect. The logistical and financial nightmare
of personnel and equipment transport must finally be tackled. The transportation of expensive and fragile equipment to high-altitude regions where conventional carriage is impossible and difficulties with importation tax and customs make this final hurdle not trivial. It is for these reasons that high-altitude field studies have normally included multiple experimental questions and their corollary publications, often yielding >10–20 papers from a single expedition. Such a research design is sometimes criticized for duplication or overlap of data, but is defensible providing that that any duplication of data is acknowledged and that publications are not intentionally partitioned, but rather best packaged to address their respective a priori hypothesis. Moreover, because of unknown complications and related risks of conducting research at altitude, many of the planned experiments are unsuccessful; hence, they are never published. Thus, packing it all in from a research perspective – as long as there is little or no contamination of experiments – makes good sense. The most recent addition to the detailed physiological study of humans at high altitude, called ‘AltitudeOmics’, was conducted at 5260 m in Bolivia in 2012 and is an excellent example of this perspective. AltitudeOmics is a multifaceted research programme on acclimatization to high altitude. Lowland volunteers were taken rapidly to 5260 m, where they acclimatized for 16 days. They then descended to 1525 m for 7 or 21 days, after which they returned quickly to 5260 m and were retested. Numerous physiological metrics and features of acclimatization were measured, as follows: arterial blood oxygenation, acute mountain sickness scores, cognitive function tests and submaximal exercise performance; cerebral blood flow and autoregulation; chemical control of breathing; total haemoglobin mass and blood volume compartments; central and peripheral fatigue; blood flow through intracardiac shunt (patent foramen ovale) and intrapulmonary arteriovenous anastomoses; and a broad array of ‘omics’ responses (transcriptomics, epigenomics, metabolomics and proteomics) were
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
monitored. The AltitudeOmics expedition is an archetype of the expedition discussed above, and such a comprehensive range questions and their attendant metrics do not belong in single publication, despite all being assessed in the same group of subjects. The AltitudeOmics expedition deviated from typical altitude field study modus operandi with the following two major experimental additions: (i) a subset of subjects were rapidly transported to high altitude whilst breathing supplemental oxygen in order to elicit an abrupt change in arterial P O2 ; and (ii) following partial acclimatization, subjects re-ascended to altitude. In many ways, this approach is similar to that which can be achieved in laboratory studies with hypoxic gas or hypobaric chambers (e.g. the Operation Everest II and III chamber studies). Nevertheless, the AltitudeOmics project should be commended for their elegantly unique study design, but their findings should be interpreted in this context and are likely to be different from other field studies that have followed more traditional progressive ascents. The design reduced the typical confounders of slow ascent (e.g. variable ventilatory acclimatization, dehydration, sleep disturbances and gastrointestinal distress); hence, it improved the separation of the acute physiological adjustments from the variable duress of prolonged exposure to high altitude. Consequently, these data might be more applicable to rapid military deployment to high altitude and the related prediction for susceptibility to altitude illness. In this issue of Experimental Physiology, the authors assessed volumetric regional brain blood flow and intracranial blood velocity at sea level and 2–4 h after arrival at 5260 m following cessation of supplemental oxygen (Subudhi et al. 2014b). Subjects then acclimatized over the next 15 days, with a majority of the time spent at 5260 m. Measurements were repeated on days 15–16. Unlike other experiments from this project (e.g. Fan et al. 2014; Subudhi et al. 2014a), the adjustments or ‘memory’ to re-exposure to 5260 m were not assessed. Their findings (Subudhi et al. 2014b) confirm that global cerebral oxygen delivery
DOI: 10.1113/expphysiol.2013.077362
Viewpoint
742 is preserved, despite reductions in arterial O2 content with ascent, by commensurately increased cerebral blood flow (Willie et al. 2014). The novel finding was that there was slight increase (9%) in relative oxygen delivery to the posterior cerebral circulation when compared with the anterior region during acute exposure to 5260 m. Although consistent with findings at sea level in conditions of severe isocapnic hypoxia (Willie et al. 2012), the mechanism and physiological relevance of a small increase in posture posterior cerebral perfusion are unknown. Finally, the findings by Subudhi et al. (2014b) of a large discrepancy between velocity in the middle cerebral artery (MCA) and internal carotid artery flow are also consistent with dilatation of the MCA at 5050 m (Willie et al. 2013), but also raise doubt about assertions made in other studies from this project that MCA velocities reflect changes in flow at this altitude (e.g. Fan et al. 2014.) The ‘threshold’ at which dilatation of the MCA might occur during conditions of poikilocapnic hypoxia is currently unknown.
In summary, the AltitudeOmics project demonstrates the feasibility of a multifarious design, and the current and forthcoming publications will provide a diversely rich addition to our understanding of the biological adaptation – and, potentially, maladaptation – to high altitude.
Call for comments Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/ expphysiol;99/5/741.
References Fan J-L, Subudhi AW, Evero O, Bourdillon N, Kayser B, Lovering AT & Roach RC (2014). AltitudeOmics: Enhanced cerebrovascular reactivity and ventilatory response to CO2 with high altitude acclimatisation and re-exposure. J Appl Physiol, In Press.
Exp Physiol 99.5 (2014) pp 741–742
Subudhi AW, Fan J-L, Evero O, Bourdillon N, Kayser B, Julian CG, Lovering AT, Panerai RB & Roach RC (2014a). AltitudeOmics: Cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness. J Appl Physiol, In Press. Subudhi AW, Fan J-L, Evero O, Bourdillon N, Kayser B, Julian CG, Lovering AT & Roach RC (2014b). AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery. Exp Physiol, 99, 772–781. Willie CK, Macleod DB, Shaw AD, Smith KJ, Tzeng YC, Eves ND, Ikeda K, Graham J, Lewis NC, Day TA & Ainslie PN (2012). Regional brain blood flow in man during acute changes in arterial blood gases. J Physiol 590, 3261–3275. Willie CK, Smith KJ, Day TA, Ray LA, Lewis NC, Bakker A, Macleod DB & Ainslie PN (2014). Regional cerebral blood flow in humans at high altitude: gradual ascent and two weeks at 5050m. J Appl Physiol. In Press.
C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society
